Translocation and neurotoxicity of CdTe quantum dots in RMEs motor neurons in nematode Caenorhabditis elegans

Energy Technology Data Exchange (ETDEWEB)

Zhao, Yunli; Wang, Xiong; Wu, Qiuli; Li, Yiping; Wang, Dayong, E-mail: dayongw@seu.edu.cn

2015-02-11

Graphical abstract: - Highlights: • We investigated in vivo neurotoxicity of CdTe QDs on RMEs motor neurons in C. elegans. • CdTe QDs in the range of μg/L caused neurotoxicity on RMEs motor neurons. • Bioavailability of CdTe QDs may be the primary inducer for CdTe QDs neurotoxicity. • Both oxidative stress and cell identity regulate the CdTe QDs neurotoxicity. • CdTe QDs were translocated and deposited into RMEs motor neurons. - Abstract: We employed Caenorhabditis elegans assay system to investigate in vivo neurotoxicity of CdTe quantum dots (QDs) on RMEs motor neurons, which are involved in controlling foraging behavior, and the underlying mechanism of such neurotoxicity. After prolonged exposure to 0.1–1 μg/L of CdTe QDs, abnormal foraging behavior and deficits in development of RMEs motor neurons were observed. The observed neurotoxicity from CdTe QDs on RMEs motor neurons might be not due to released Cd{sup 2+}. Overexpression of genes encoding Mn-SODs or unc-30 gene controlling cell identity of RMEs neurons prevented neurotoxic effects of CdTe QDs on RMEs motor neurons, suggesting the crucial roles of oxidative stress and cell identity in regulating CdTe QDs neurotoxicity. In nematodes, CdTe QDs could be translocated through intestinal barrier and be deposited in RMEs motor neurons. In contrast, CdTe@ZnS QDs could not be translocated into RMEs motor neurons and therefore, could only moderately accumulated in intestinal cells, suggesting that ZnS coating might reduce neurotoxicity of CdTe QDs on RMEs motor neurons. Therefore, the combinational effects of oxidative stress, cell identity, and bioavailability may contribute greatly to the mechanism of CdTe QDs neurotoxicity on RMEs motor neurons. Our results provide insights into understanding the potential risks of CdTe QDs on the development and function of nervous systems in animals.

Paralytic Toxins Accumulation and Tissue Expression of α-Amylase and Lipase Genes in the Pacific Oyster Crassostrea gigas Fed with the Neurotoxic Dinoflagellate Alexandrium catenella

Directory of Open Access Journals (Sweden)

Mohamed Laabir

2012-11-01

Full Text Available The pacific oyster Crassostrea gigas was experimentally exposed to the neurotoxic Alexandrium catenella and a non-producer of PSTs, Alexandrium tamarense (control algae, at concentrations corresponding to those observed during the blooming period. At fixed time intervals, from 0 to 48 h, we determined the clearance rate, the total filtered cells, the composition of the fecal ribbons, the profile of the PSP toxins and the variation of the expression of two α-amylase and triacylglecerol lipase precursor (TLP genes through semi-quantitative RT-PCR. The results showed a significant decrease of the clearance rate of C. gigas fed with both Alexandrium species. However, from 29 to 48 h, the clearance rate and cell filtration activity increased only in oysters fed with A. tamarense. The toxin concentrations in the digestive gland rose above the sanitary threshold in less than 48 h of exposure and GTX6, a compound absent in A. catenella cells, accumulated. The α-amylase B gene expression level increased significantly in the time interval from 6 to 48 h in the digestive gland of oysters fed with A. tamarense, whereas the TLP gene transcript was significantly up-regulated in the digestive gland of oysters fed with the neurotoxic A. catenella. All together, these results suggest that the digestion capacity could be affected by PSP toxins.

Thallium Toxicity: General Issues, Neurological Symptoms, and Neurotoxic Mechanisms.

Science.gov (United States)

Osorio-Rico, Laura; Santamaria, Abel; Galván-Arzate, Sonia

2017-01-01

Thallium (Tl + ) is a ubiquitous natural trace metal considered as the most toxic among heavy metals. The ionic ratio of Tl + is similar to that of potassium (K + ), therefore accounting for the replacement of the latter during enzymatic reactions. The principal organelle damaged after Tl + exposure is mitochondria. Studies on the mechanisms of Tl + include intrinsic pathways altered and changes in antiapoptotic and proapoptotic proteins, cytochrome c, and caspases. Oxidative damage pathways increase after Tl + exposure to produce reactive oxygen species (ROS), changes in physical properties of the cell membrane caused by lipid peroxidation, and concomitant activation of antioxidant mechanisms. These processes are likely to account for the neurotoxic effects of the metal. In humans, Tl + is absorbed through the skin and mucous membranes and then is widely distributed throughout the body to be accumulated in bones, renal medulla, liver, and the Central Nervous System. Given the growing relevance of Tl + intoxication, in recent years there is a notorious increase in the number of reports attending Tl + pollution in different countries. In this sense, the neurological symptoms produced by Tl + and its neurotoxic effects are gaining attention as they represent a serious health problem all over the world. Through this review, we present an update to general information about Tl + toxicity, making emphasis on some recent data about Tl + neurotoxicity, as a field requiring attention at the clinical and preclinical levels.

Biomarkers of adult and developmental neurotoxicity

International Nuclear Information System (INIS)

Slikker, William; Bowyer, John F.

2005-01-01

Neurotoxicity may be defined as any adverse effect on the structure or function of the central and/or peripheral nervous system by a biological, chemical, or physical agent. A multidisciplinary approach is necessary to assess adult and developmental neurotoxicity due to the complex and diverse functions of the nervous system. The overall strategy for understanding developmental neurotoxicity is based on two assumptions: (1) significant differences in the adult versus the developing nervous system susceptibility to neurotoxicity exist and they are often developmental stage dependent; (2) a multidisciplinary approach using neurobiological, including gene expression assays, neurophysiological, neuropathological, and behavioral function is necessary for a precise assessment of neurotoxicity. Application of genomic approaches to developmental studies must use the same criteria for evaluating microarray studies as those in adults including consideration of reproducibility, statistical analysis, homogenous cell populations, and confirmation with non-array methods. A study using amphetamine to induce neurotoxicity supports the following: (1) gene expression data can help define neurotoxic mechanism(s) (2) gene expression changes can be useful biomarkers of effect, and (3) the site-selective nature of gene expression in the nervous system may mandate assessment of selective cell populations

Effects of primary dicarboxylic acids on microstructure and mechanical properties of sub-microcrystalline Ni-Co alloys

International Nuclear Information System (INIS)

Vijayakumar, J.; Mohan, S.; Yadav, S. Sunil

2011-01-01

Highlights: → The electrodeposited Ni-Co alloys are mostly used in magnetic sensors and it has good mechanical and corrosion resistance properties. → The effect of dicarboxylic acid leads to preferred (2 0 0) crystalline orientation, this may improve magnetic properties dicarboxylic acid can alter the elemental composition of Ni-Co alloy. → Dicarboxylic acid acts as a good brightner. - Abstract: Nickel-cobalt alloys were deposited from sulfate electrolyte with oxalic, malonic and succinic acids as additives and their microstructure and mechanical properties were studied. The crystal structure, surface morphologies, and chemical composition of coatings were investigated using X-ray diffraction, scanning electron microscope, and energy dispersive spectroscopy. The crystal structure and surface morphology analysis showed that the addition of dicarboxylic acid leads to (2 0 0) crystal face and the surface were more compact and uniform due to the grain refining. Ni 60 -Co 40 alloy was achieved when succinic acid is used as additive.

Reversible Lithium Neurotoxicity: Review of the Literature

Science.gov (United States)

Netto, Ivan

2012-01-01

Objective: Lithium neurotoxicity may be reversible or irreversible. Reversible lithium neurotoxicity has been defined as cases of lithium neurotoxicity in which patients recovered without any permanent neurologic sequelae, even after 2 months of an episode of lithium toxicity. Cases of reversible lithium neurotoxicity differ in clinical presentation from those of irreversible lithium neurotoxicity and have important implications in clinical practice. This review aims to study the clinical presentation of cases of reversible lithium neurotoxicity. Data Sources: A comprehensive electronic search was conducted in the following databases: MEDLINE (PubMed), 1950 to November 2010; PsycINFO, 1967 to November 2010; and SCOPUS (EMBASE), 1950 to November 2010. MEDLINE and PsycINFO were searched by using the OvidSP interface. Study Selection: A combination of the following search terms was used: lithium AND adverse effects AND central nervous system OR neurologic manifestation. Publications cited include articles concerned with reversible lithium neurotoxicity. Data Extraction: The age, sex, clinical features, diagnostic categories, lithium doses, serum lithium levels, precipitating factors, and preventive measures of 52 cases of reversible lithium neurotoxicity were extracted. Data Synthesis: Among the 52 cases of reversible lithium neurotoxicity, patients ranged in age from 10 to 80 years and a greater number were female (P = .008). Most patients had affective disorders, schizoaffective disorders, and/or depression (P lithium levels were less than or equal to 1.5 mEq/L (P lithium, underlying brain pathology, abnormal tissue levels, specific diagnostic categories, and elderly populations were some of the precipitating factors reported for reversible lithium neurotoxicity. The preventive measures were also described. Conclusions: Reversible lithium neurotoxicity presents with a certain clinical profile and precipitating factors for which there are appropriate

Reversible lithium neurotoxicity: review of the literatur.

Science.gov (United States)

Netto, Ivan; Phutane, Vivek H

2012-01-01

Lithium neurotoxicity may be reversible or irreversible. Reversible lithium neurotoxicity has been defined as cases of lithium neurotoxicity in which patients recovered without any permanent neurologic sequelae, even after 2 months of an episode of lithium toxicity. Cases of reversible lithium neurotoxicity differ in clinical presentation from those of irreversible lithium neurotoxicity and have important implications in clinical practice. This review aims to study the clinical presentation of cases of reversible lithium neurotoxicity. A comprehensive electronic search was conducted in the following databases: MEDLINE (PubMed), 1950 to November 2010; PsycINFO, 1967 to November 2010; and SCOPUS (EMBASE), 1950 to November 2010. MEDLINE and PsycINFO were searched by using the OvidSP interface. A combination of the following search terms was used: lithium AND adverse effects AND central nervous system OR neurologic manifestation. Publications cited include articles concerned with reversible lithium neurotoxicity. The age, sex, clinical features, diagnostic categories, lithium doses, serum lithium levels, precipitating factors, and preventive measures of 52 cases of reversible lithium neurotoxicity were extracted. Among the 52 cases of reversible lithium neurotoxicity, patients ranged in age from 10 to 80 years and a greater number were female (P = .008). Most patients had affective disorders, schizoaffective disorders, and/or depression (P lithium levels were less than or equal to 1.5 mEq/L (P lithium, underlying brain pathology, abnormal tissue levels, specific diagnostic categories, and elderly populations were some of the precipitating factors reported for reversible lithium neurotoxicity. The preventive measures were also described. Reversible lithium neurotoxicity presents with a certain clinical profile and precipitating factors for which there are appropriate preventive measures. This recognition will help in early diagnosis and prompt treatment of

Neurotoxicity of "ecstasy" and its metabolites in human dopaminergic differentiated SH-SY5Y cells.

Science.gov (United States)

Ferreira, Patrícia Silva; Nogueira, Tiago Bernandes; Costa, Vera Marisa; Branco, Paula Sério; Ferreira, Luísa Maria; Fernandes, Eduarda; Bastos, Maria Lourdes; Meisel, Andreas; Carvalho, Félix; Capela, João Paulo

2013-02-04

"Ecstasy" (3,4-methylenedioxymethamphetamine or MDMA) is a widely abused recreational drug, reported to produce neurotoxic effects, both in laboratory animals and in humans. MDMA metabolites can be major contributors for MDMA neurotoxicity. This work studied the neurotoxicity of MDMA and its catechol metabolites, α-methyldopamine (α-MeDA) and N-methyl-α-methyldopamine (N-Me-α-MeDA) in human dopaminergic SH-SY5Y cells differentiated with retinoic acid and 12-O-tetradecanoyl-phorbol-13-acetate. Differentiation led to SH-SY5Y neurons with higher ability to accumulate dopamine and higher resistance towards dopamine neurotoxicity. MDMA catechol metabolites were neurotoxic to SH-SY5Y neurons, leading to caspase 3-independent cell death in a concentration- and time-dependent manner. MDMA did not show a concentration- and time-dependent death. Pre-treatment with the antioxidant and glutathione precursor, N-acetylcysteine (NAC), resulted in strong protection against the MDMA metabolites' neurotoxicity. Neither the superoxide radical scavenger, tiron, nor the inhibitor of the dopamine (DA) transporter, GBR 12909, prevented the metabolites' toxicity. Cells exposed to α-MeDA showed an increase in intracellular glutathione (GSH) levels, which, at the 48 h time-point, was not dependent in the activity increase of γ-glutamylcysteine synthetase (γ-GCS), revealing a possible transient effect. Importantly, pre-treatment with buthionine sulfoximine (BSO), an inhibitor of γ-GCS, prevented α-MeDA induced increase in GSH levels, but did not augment this metabolite cytotoxicity. Even so, BSO pre-treatment abolished NAC protective effects against α-MeDA neurotoxicity, which were, at least partially, due to GSH de novo synthesis. Inversely, pre-treatment of cells with BSO augmented N-Me-α-MeDA-induced neurotoxicity, but only slightly affected NAC neuroprotection. In conclusion, MDMA catechol metabolites promote differential toxic effects to differentiated dopaminergic human SH

Production of Odd-Carbon Dicarboxylic Acids in Escherichia coli Using an Engineered Biotin–Fatty Acid Biosynthetic Pathway

Energy Technology Data Exchange (ETDEWEB)

Haushalter, Robert W. [Joint BioEnergy Inst. (JBEI), Emeryville, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Physical Bioscience Division; Phelan, Ryan M. [Joint BioEnergy Inst. (JBEI), Emeryville, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Physical Bioscience Division; Hoh, Kristina M. [Joint BioEnergy Inst. (JBEI), Emeryville, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Physical Bioscience Division; Su, Cindy [Joint BioEnergy Inst. (JBEI), Emeryville, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Physical Bioscience Division; Wang, George [Joint BioEnergy Inst. (JBEI), Emeryville, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Physical Bioscience Division; Baidoo, Edward E. K. [Joint BioEnergy Inst. (JBEI), Emeryville, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Physical Bioscience Division; Keasling, Jay D. [Joint BioEnergy Inst. (JBEI), Emeryville, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Physical Bioscience Division

2017-03-14

Dicarboxylic acids are commodity chemicals used in the production of plastics, polyesters, nylons, fragrances, and medications. Bio-based routes to dicarboxylic acids are gaining attention due to environmental concerns about petroleum-based production of these compounds. Some industrial applications require dicarboxylic acids with specific carbon chain lengths, including odd-carbon species. Biosynthetic pathways involving cytochrome P450-catalyzed oxidation of fatty acids in yeast and bacteria have been reported, but these systems produce almost exclusively even-carbon species. Here in this paper we report a novel pathway to odd-carbon dicarboxylic acids directly from glucose in Escherichia coli by employing an engineered pathway combining enzymes from biotin and fatty acid synthesis. Optimization of the pathway will lead to industrial strains for the production of valuable odd-carbon diacids.

Involvement of Programmed Cell Death in Neurotoxicity of Metallic Nanoparticles: Recent Advances and Future Perspectives

Science.gov (United States)

Song, Bin; Zhou, Ting; Liu, Jia; Shao, LongQuan

2016-11-01

The widespread application of metallic nanoparticles (NPs) or NP-based products has increased the risk of exposure to NPs in humans. The brain is an important organ that is more susceptible to exogenous stimuli. Moreover, any impairment to the brain is irreversible. Recently, several in vivo studies have found that metallic NPs can be absorbed into the animal body and then translocated into the brain, mainly through the blood-brain barrier and olfactory pathway after systemic administration. Furthermore, metallic NPs can cross the placental barrier to accumulate in the fetal brain, causing developmental neurotoxicity on exposure during pregnancy. Therefore, metallic NPs become a big threat to the brain. However, the mechanisms underlying the neurotoxicity of metallic NPs remain unclear. Programmed cell death (PCD), which is different from necrosis, is defined as active cell death and is regulated by certain genes. PCD can be mainly classified into apoptosis, autophagy, necroptosis, and pyroptosis. It is involved in brain development, neurodegenerative disorders, psychiatric disorders, and brain injury. Given the pivotal role of PCD in neurological functions, we reviewed relevant articles and tried to summarize the recent advances and future perspectives of PCD involvement in the neurotoxicity of metallic NPs, with the purpose of comprehensively understanding the neurotoxic mechanisms of NPs.

Mechanisms underlying the neurotoxicity induced by glyphosate-based herbicide in immature rat hippocampus: Involvement of glutamate excitotoxicity

International Nuclear Information System (INIS)

Cattani, Daiane; Oliveira Cavalli, Liz Vera Lúcia de; Heinz Rieg, Carla Elise; Domingues, Juliana Tonietto; Dal-Cim, Tharine; Tasca, Carla Inês; Mena Barreto Silva, Fátima Regina; Zamoner, Ariane

2014-01-01

Graphical abstract: - Highlights: • Roundup ® induces Ca 2+ influx through L-VDCC and NMDA receptor activation. • The mechanisms underlying Roundup ® neurotoxicity involve glutamatergic excitotoxicity. • Kinase pathways participate in Roundup ® -induced neural toxicity. • Roundup ® alters glutamate uptake, release and metabolism in hippocampal cells. - Abstract: Previous studies demonstrate that glyphosate exposure is associated with oxidative damage and neurotoxicity. Therefore, the mechanism of glyphosate-induced neurotoxic effects needs to be determined. The aim of this study was to investigate whether Roundup ® (a glyphosate-based herbicide) leads to neurotoxicity in hippocampus of immature rats following acute (30 min) and chronic (pregnancy and lactation) pesticide exposure. Maternal exposure to pesticide was undertaken by treating dams orally with 1% Roundup ® (0.38% glyphosate) during pregnancy and lactation (till 15-day-old). Hippocampal slices from 15 day old rats were acutely exposed to Roundup ® (0.00005–0.1%) during 30 min and experiments were carried out to determine whether glyphosate affects 45 Ca 2+ influx and cell viability. Moreover, we investigated the pesticide effects on oxidative stress parameters, 14 C-α-methyl-amino-isobutyric acid ( 14 C-MeAIB) accumulation, as well as glutamate uptake, release and metabolism. Results showed that acute exposure to Roundup ® (30 min) increases 45 Ca 2+ influx by activating NMDA receptors and voltage-dependent Ca 2+ channels, leading to oxidative stress and neural cell death. The mechanisms underlying Roundup ® -induced neurotoxicity also involve the activation of CaMKII and ERK. Moreover, acute exposure to Roundup ® increased 3 H-glutamate released into the synaptic cleft, decreased GSH content and increased the lipoperoxidation, characterizing excitotoxicity and oxidative damage. We also observed that both acute and chronic exposure to Roundup ® decreased 3 H-glutamate uptake and

Cyclohexane-1,2-dicarboxylic acid diisononyl ester and metabolite effects on rat epididymal stromal vascular fraction differentiation of adipose tissue

Energy Technology Data Exchange (ETDEWEB)

Campioli, Enrico [Research Institute of the McGill University Health Centre (Canada); Department of Medicine, McGill University, Montréal, Québec (Canada); Duong, Tam B. [Research Institute of the McGill University Health Centre (Canada); Deschamps, François [Synthèse AptoChem Inc., Montréal, Québec (Canada); Papadopoulos, Vassilios, E-mail: vassilios.papadopoulos@mcgill.ca [Research Institute of the McGill University Health Centre (Canada); Department of Medicine, McGill University, Montréal, Québec (Canada); Department of Biochemistry, McGill University, Montréal, Québec (Canada); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec (Canada)

2015-07-15

Plastics are generally mixed with additives like plasticizers to enhance their flexibility, pliability, and elasticity proprieties. Plasticizers are easily released into the environment and are absorbed mainly through ingestion, dermal contact, and inhalation. One of the main classes of plasticizers, phthalates, has been associated with endocrine and reproductive diseases. In 2002, 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) was introduced in the market for use in plastic materials and articles intended to come into contact with food, and it received final approval from the European Food Safety Authority in 2006. At present, there is limited knowledge about the safety and potential metabolic and endocrine-disrupting properties of DINCH and its metabolites. The purpose of this study was to evaluate the biological effects of DINCH and its active metabolites, cyclohexane-1,2-dicarboxylic acid (CHDA) and cyclohexane-1,2-dicarboxylic acid mono isononyl ester (MINCH), on rat primary stromal vascular fraction (SVF) of adipose tissue. DINCH and its metabolite, CHDA, were not able to directly affect SVF differentiation. However, exposure of SVF to 50 μM and 100 μM concentrations of MINCH affected the expression of Cebpa and Fabp4, thus inducing SVF preadipocytes to accumulate lipids and fully differentiate into mature adipocytes. The effect of MINCH was blocked by the specific peroxisome proliferator-activated receptor (PPAR)-α antagonist, GW6471. Taken together, these results suggest that MINCH is a potent PPAR-α agonist and a metabolic disruptor, capable of inducing SVF preadipocyte differentiation, that may interfere with the endocrine system in mammals. - Highlights: • DINCH and CHDA did not affect the adipogenesis of the SVF. • MINCH affected the adipogenesis of the SVF. • MINCH effect was blocked by the specific PPAR-α antagonist GW6471. • MINCH exerted a similar effect as MEHP on SVF adipogenesis. • DINCH/MINCH are potential metabolic

Isoquercitrin Esters with Mono- or Dicarboxylic Acids: Enzymatic Preparation and Properties.

Science.gov (United States)

Vavříková, Eva; Langschwager, Fanny; Jezova-Kalachova, Lubica; Křenková, Alena; Mikulová, Barbora; Kuzma, Marek; Křen, Vladimír; Valentová, Kateřina

2016-06-07

A series of isoquercitrin (quercetin-3-O-β-d-glucopyranoside) esters with mono- or dicarboxylic acids was designed to modulate hydro- and lipophilicity and biological properties. Esterification of isoquercitrin was accomplished by direct chemoenzymatic reaction using Novozym 435 (lipase from Candida antarctica), which accepted C₅- to C12-dicarboxylic acids; the shorter ones, such as oxalic (C₂), malonic (C₃), succinic (C₄) and maleic (C₄) acids were not substrates of the lipase. Lipophilicity of monocarboxylic acid derivatives, measured as log P, increased with the chain length. Esters with glutaric and adipic acids exhibited hydrophilicity, and the dodecanedioic acid hemiester was more lipophilic. All derivatives were less able to reduce Folin-Ciocalteau reagent (FCR) and scavenge DPPH (1,1-diphenyl-2-picrylhydrazyl) than isoquercitrin; ABTS (2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)) radical-scavenging activity was comparable. Dodecanoate and palmitate were the least active in FCR and ABTS scavenging; dodecanoate and hemiglutarate were the strongest DPPH scavengers. In contrast, most derivatives were much better inhibitors of microsomal lipoperoxidation than isoquercitrin; butyrate and hexanoate were the most efficient. Anti-lipoperoxidant activity of monocarboxylic derivatives, except acetates, decreased with increasing aliphatic chain. The opposite trend was noted for dicarboxylic acid hemiesters, isoquercitrin hemidodecanedioate being the most active. Overall, IQ butyrate, hexanoate and hemidodecanedioate are the most promising candidates for further studies.

Impaired pH homeostasis in Arabidopsis lacking the vacuolar dicarboxylate transporter and analysis of carboxylic acid transport across the tonoplast.

Science.gov (United States)

Hurth, Marco Alois; Suh, Su Jeoung; Kretzschmar, Tobias; Geis, Tina; Bregante, Monica; Gambale, Franco; Martinoia, Enrico; Neuhaus, H Ekkehard

2005-03-01

Arabidopsis (Arabidopsis thaliana) mutants lacking the tonoplastic malate transporter AttDT (A. thaliana tonoplast dicarboxylate transporter) and wild-type plants showed no phenotypic differences when grown under standard conditions. To identify putative metabolic changes in AttDT knock-out plants, we provoked a metabolic scenario connected to an increased consumption of dicarboxylates. Acidification of leaf discs stimulated dicarboxylate consumption and led to extremely low levels of dicarboxylates in mutants. To investigate whether reduced dicarboxylate concentrations in mutant leaf cells and, hence, reduced capacity to produce OH(-) to overcome acidification might affect metabolism, we measured photosynthetic oxygen evolution under conditions where the cytosol is acidified. AttDT::tDNA protoplasts showed a much stronger inhibition of oxygen evolution at low pH values when compared to wild-type protoplasts. Apparently citrate, which is present in higher amounts in knock-out plants, is not able to replace dicarboxylates to overcome acidification. To raise more information on the cellular level, we performed localization studies of carboxylates. Although the total pool of carboxylates in mutant vacuoles was nearly unaltered, these organelles contained a lower proportion of malate and fumarate and a higher proportion of citrate when compared to wild-type vacuoles. These alterations concur with the observation that radioactively labeled malate and citrate are transported into Arabidopsis vacuoles by different carriers. In addition, wild-type vacuoles and corresponding organelles from AttDT::tDNA mutants exhibited similar malate channel activities. In conclusion, these results show that Arabidopsis vacuoles contain at least two transporters and a channel for dicarboxylates and citrate and that the activity of AttDT is critical for regulation of pH homeostasis.

Elevated environmental temperature and methamphetamine neurotoxicity

International Nuclear Information System (INIS)

Miller, Diane B.; O'Callaghan, James P.

2003-01-01

Amphetamines have been of considerable research interest for the last several decades. More recent work has renewed interest in the role of ambient temperature in both the toxicity and neurotoxicity of these drugs. We have determined that the striatal dopaminergic neurotoxicity observed in the mouse is linked in some fashion to both body and environmental temperature. Most studies of d-methamphetamine (d-METH) neurotoxicity are conducted at standard laboratory ambient temperatures (e.g., ∼21-22 deg. C) and utilizing a repeated dosage regimen (e.g., three to four injections spaced 2 h apart). A lowering of the ambient temperature provides neuro protection, while an elevation increases neurotoxicity. d-METH causes long-term depletions of triatal dopamine (DA) that are accompanied by other changes that are indicative of nerve terminal degeneration. These include argyrophilia, as detected by silver degeneration stains, and an elevation in glial fibrillary acidic protein (GFAP), a marker of reactive gliosis in response to injury, as well as a long-term decrease in tyrosine hydroxylase (TH) protein levels. here we show that increasing the ambient temperature during and for some time following dosing increases the neurotoxicity of d-METH. Mice (female 57BL6/J) given a single dosage of d-METH (20 mg/kg s.c.) and maintained at the usual laboratory ambient temperature show minimal striatal damage (an ∼15% depletion of DA and an ∼ 86% increase in GFAP). substantial striatal damage (e.g., an ∼70% depletion of DA and an ∼200% elevation in GFAP) was induced by this regimen if mice were maintained at 27 deg. C for 24 or 72 h following dosing. An increase in neurotoxicity was also apparent in mice kept at an elevated temperature for only 5 or 9 h, but keeping animals at 27 deg. C for 24 or 72 h was the most effective in increasing the neurotoxicity of d-METH. Our data show how a relatively minor change in ambient temperature can have a major impact on the degree of

An odd–even effect on solubility of dicarboxylic acids in organic solvents

International Nuclear Information System (INIS)

Zhang, Hui; Yin, Qiuxiang; Liu, Zengkun; Gong, Junbo; Bao, Ying; Zhang, Meijing; Hao, Hongxun; Hou, Baohong; Xie, Chuang

2014-01-01

Highlights: • The solubilities of the homologous series of C2–C10 dicarboxylic acids were determined in four selected solvents. • The experimental data were well correlated with the modified Apelblat equation. • The odd–even effect of solubility was found and explained. • The enthalpy, entropy and the molar Gibbs free energy of solution were predicted. - Abstract: The solubility of the homologous series of dicarboxylic acids, HOOC-(CH 2 ) n−2 -COOH (n = 2 to 10), in ethanol, acetic acid, acetone and ethyl acetate was measured at temperatures ranging from (278.15 to 323.15) K by a static analytic method at atmospheric pressure. Dicarboxylic acids with even number of carbon atoms exhibit lower values of solubility than adjacent homologues with odd carbon numbers. This odd–even effect of solubility is attributed to the twist of molecules and interlayer packing in solid state as explained in our previous work. The alternation varies in different solvents, which is believed to be associated with the properties of solvents. Finally, the dissolution enthalpy, dissolution entropy and the molar Gibbs free energy were calculated using the fitting parameters of the modified Apelblat equation. The molar Gibbs free energy also showed apparent odd–even alternation in keeping with the alternation of solubility

A Neurotoxic Glycerophosphocholine Impacts PtdIns-4, 5-Bisphosphate and TORC2 Signaling by Altering Ceramide Biosynthesis in Yeast

OpenAIRE

Kennedy, Michael A.; Gable, Kenneth; Niewola-Staszkowska, Karolina; Abreu, Susana; Johnston, Anne; Harris, Linda J.; Reggiori, Fulvio; Loewith, Robbie; Dunn, Teresa; Bennett, Steffany A. L.; Baetz, Kristin

2014-01-01

Unbiased lipidomic approaches have identified impairments in glycerophosphocholine second messenger metabolism in patients with Alzheimer's disease. Specifically, we have shown that amyloid-β42 signals the intraneuronal accumulation of PC(O-16:0/2:0) which is associated with neurotoxicity. Similar to neuronal cells, intracellular accumulation of PC(O-16:0/2:0) is also toxic to Saccharomyces cerevisiae, making yeast an excellent model to decipher the pathological effects of this lipid. We prev...

Immunosuppressant-Associated Neurotoxicity Responding to Olanzapine

Directory of Open Access Journals (Sweden)

James A. Bourgeois

2014-01-01

Full Text Available Immunosuppressants, particularly tacrolimus, can induce neurotoxicity in solid organ transplantation cases. A lower clinical threshold to switch from tacrolimus to another immunosuppressant agent has been a common approach to reverse this neurotoxicity. However, immunosuppressant switch may place the graft at risk, and, in some cases, continuation of the same treatment protocol may be necessary. We report a case of immunosuppressant-associated neurotoxicity with prominent neuropsychiatric manifestation and describe psychiatric intervention with olanzapine that led to clinical improvement while continuing tacrolimus maintenance.

Impaired pH Homeostasis in Arabidopsis Lacking the Vacuolar Dicarboxylate Transporter and Analysis of Carboxylic Acid Transport across the Tonoplast1

Science.gov (United States)

Hurth, Marco Alois; Suh, Su Jeoung; Kretzschmar, Tobias; Geis, Tina; Bregante, Monica; Gambale, Franco; Martinoia, Enrico; Neuhaus, H. Ekkehard

2005-01-01

Arabidopsis (Arabidopsis thaliana) mutants lacking the tonoplastic malate transporter AttDT (A. thaliana tonoplast dicarboxylate transporter) and wild-type plants showed no phenotypic differences when grown under standard conditions. To identify putative metabolic changes in AttDT knock-out plants, we provoked a metabolic scenario connected to an increased consumption of dicarboxylates. Acidification of leaf discs stimulated dicarboxylate consumption and led to extremely low levels of dicarboxylates in mutants. To investigate whether reduced dicarboxylate concentrations in mutant leaf cells and, hence, reduced capacity to produce OH− to overcome acidification might affect metabolism, we measured photosynthetic oxygen evolution under conditions where the cytosol is acidified. AttDT::tDNA protoplasts showed a much stronger inhibition of oxygen evolution at low pH values when compared to wild-type protoplasts. Apparently citrate, which is present in higher amounts in knock-out plants, is not able to replace dicarboxylates to overcome acidification. To raise more information on the cellular level, we performed localization studies of carboxylates. Although the total pool of carboxylates in mutant vacuoles was nearly unaltered, these organelles contained a lower proportion of malate and fumarate and a higher proportion of citrate when compared to wild-type vacuoles. These alterations concur with the observation that radioactively labeled malate and citrate are transported into Arabidopsis vacuoles by different carriers. In addition, wild-type vacuoles and corresponding organelles from AttDT::tDNA mutants exhibited similar malate channel activities. In conclusion, these results show that Arabidopsis vacuoles contain at least two transporters and a channel for dicarboxylates and citrate and that the activity of AttDT is critical for regulation of pH homeostasis. PMID:15728336

Adiponectin is protective against oxidative stress induced cytotoxicity in amyloid-beta neurotoxicity.

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Koon-Ho Chan

Full Text Available Beta-amyloid (Aβ neurotoxicity is important in Alzheimer's disease (AD pathogenesis. Aβ neurotoxicity causes oxidative stress, inflammation and mitochondrial damage resulting in neuronal degeneration and death. Oxidative stress, inflammation and mitochondrial failure are also pathophysiological mechanisms of type 2 diabetes (T(2DM which is characterized by insulin resistance. Interestingly, T(2DM increases risk to develop AD which is associated with reduced neuronal insulin sensitivity (central insulin resistance. We studied the potential protective effect of adiponectin (an adipokine with insulin-sensitizing, anti-inflammatory and anti-oxidant properties against Aβ neurotoxicity in human neuroblastoma cells (SH-SY5Y transfected with the Swedish amyloid precursor protein (Sw-APP mutant, which overproduced Aβ with abnormal intracellular Aβ accumulation. Cytotoxicity was measured by assay for lactate dehydrogenase (LDH released upon cell death and lysis. Our results revealed that Sw-APP transfected SH-SY5Y cells expressed both adiponectin receptor 1 and 2, and had increased AMP-activated protein kinase (AMPK activation and enhanced nuclear factor-kappa B (NF-κB activation compared to control empty-vector transfected SH-SY5Y cells. Importantly, adiponectin at physiological concentration of 10 µg/ml protected Sw-APP transfected SH-SY5Y cells against cytotoxicity under oxidative stress induced by hydrogen peroxide. This neuroprotective action of adiponectin against Aβ neurotoxicity-induced cytotoxicity under oxidative stress involved 1 AMPK activation mediated via the endosomal adaptor protein APPL1 (adaptor protein with phosphotyrosine binding, pleckstrin homology domains and leucine zipper motif and possibly 2 suppression of NF-κB activation. This raises the possibility of novel therapies for AD such as adiponectin receptor agonists.

2-Phenylimidazolium hemi(benzene-1,3-dicarboxylate monohydrate

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Wen-Yu Zhang

2011-08-01

Full Text Available The asymmetric unit of the title compound, C9H9N2+·0.5C8H4O4−·H2O, contains one 2-phenylimidazolium cation, half a benzene-1,3-dicarboxylate anion and one water molecule. In the crystal, components are connected by N—H...O and O—H...O hydrogen-bonding interactions into a three-dimensional network.

Minocycline attenuates colistin-induced neurotoxicity via suppression of apoptosis, mitochondrial dysfunction and oxidative stress.

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Dai, Chongshan; Ciccotosto, Giuseppe D; Cappai, Roberto; Wang, Yang; Tang, Shusheng; Xiao, Xilong; Velkov, Tony

2017-06-01

Neurotoxicity is an adverse effect patients experience during colistin therapy. The development of effective neuroprotective agents that can be co-administered during polymyxin therapy remains a priority area in antimicrobial chemotherapy. The present study investigates the neuroprotective effect of the synergistic tetracycline antibiotic minocycline against colistin-induced neurotoxicity. The impact of minocycline pretreatment on colistin-induced apoptosis, caspase activation, oxidative stress and mitochondrial dysfunction were investigated using cultured mouse neuroblastoma-2a (N2a) and primary cortical neuronal cells. Colistin-induced neurotoxicity in mouse N2a and primary cortical cells gives rise to the generation of reactive oxygen species (ROS) and subsequent cell death via apoptosis. Pretreatment of the neuronal cells with minocycline at 5, 10 and 20 μM for 2 h prior to colistin (200 μM) exposure (24 h), had an neuroprotective effect by significantly decreasing intracellular ROS production and by upregulating the activities of the anti-ROS enzymes superoxide dismutase and catalase. Minocycline pretreatment also protected the cells from colistin-induced mitochondrial dysfunction, caspase activation and subsequent apoptosis. Immunohistochemical imaging studies revealed colistin accumulates within the dendrite projections and cell body of primary cortical neuronal cells. To our knowledge, this is first study demonstrating the protective effect of minocycline on colistin-induced neurotoxicity by scavenging of ROS and suppression of apoptosis. Our study highlights that co-administration of minocycline kills two birds with one stone: in addition to its synergistic antimicrobial activity, minocycline could potentially ameliorate unwanted neurotoxicity in patients undergoing polymyxin therapy. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions

General anesthetics in children: neurotoxic or neuroprotective?

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Jéssica Farias Rebouças

2017-02-01

Full Text Available Introduction: general anesthetics are involved in neuroprotection in adults after ischemic events and cognitive impairment, thus, they also may be associated with learning disorders in children exposed to them before three years of age. Objective: Describe about the neurotoxic effects of general anesthetics in experimental animals and children. Method: This is a systematic review, performed from search in databases and on PubMed using the keywords "neurotoxicity" and "general anesthetics," and "general anesthetics," "neurotoxicity", "children", "young child "and" pediatric ". Results: The search resulted in 185 articles. Out of these, 78 met our inclusion criteria. We found that there was a significant evidence of neurotoxicity induced by general anesthetics in experimental animals that were just born, resulting in late and permanent cognitive deficits. This effect was associated with multiple exposures, exposure length of time and combination of drugs. However, some studies found cognitive impairment after a single exposure to anesthetic. Conclusion: There is insufficient evidence to state that general anesthetics are neurotoxic and have the potential to trigger learning and behavior disabilities in children. However, we suggest caution in indicating surgery in children under three years old, analyzing risk-benefit and inserting the family in the decision process.   Keywords: Neurotoxicity; Neuroprotection; Cognitive Impairment; Children; General Anesthesics

Central neurotoxicity of immunomodulatory drugs in multiple myeloma

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Urmeel H. Patel

2015-03-01

Full Text Available Immunomodulatory drugs (IMiDs currently used in the treatment of multiple myeloma, are thalidomide, lenalidomide and pomalidomide. One of the most common side effects of thalidomide is neurotoxicity, predominantly in the form of peripheral neuropathy. We report 6 cases of significant central neurotoxicity associated with IMiD therapy. Treatment with thalidomide (1 patient, lenalidomide (4 patients, and pomalidomide (1 patient was associated with various clinical manifestations of central neurotoxicity, including reversible coma, amnesia, expressive aphasia, and dysarthria. Central neurotoxicity should be recognized as an important side effect of IMiD therapy.

Central neurotoxicity of immunomodulatory drugs in multiple myeloma.

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Patel, Urmeel H; Mir, Muhammad A; Sivik, Jeffrey K; Raheja, Divisha; Pandey, Manoj K; Talamo, Giampaolo

2015-02-24

Immunomodulatory drugs (IMiDs) currently used in the treatment of multiple myeloma, are thalidomide, lenalidomide and pomalidomide. One of the most common side effects of thalidomide is neurotoxicity, predominantly in the form of peripheral neuropathy. We report 6 cases of significant central neurotoxicity associated with IMiD therapy. Treatment with thalidomide (1 patient), lenalidomide (4 patients), and pomalidomide (1 patient) was associated with various clinical manifestations of central neurotoxicity, including reversible coma, amnesia, expressive aphasia, and dysarthria. Central neurotoxicity should be recognized as an important side effect of IMiD therapy.

Investigation of the atmospheric behavior of dicarboxylic acids and other polar organic aerosol constituents

International Nuclear Information System (INIS)

Limbeck, A.

2001-05-01

The objective of the present work was to improve the present knowledge about the atmospheric behavior of polar organic aerosol constituents with special respect to dicarboxylic acids. To enable the simultaneous determination of polar organic compounds in atmospheric samples like aerosol or precipitation samples (atmospheric hydrometeors) a new GCMS method was developed. Almost all classes of oxygenated organic compounds like mono- and dicarboxylic acids, aldehydes, alcohols or polar aromatic compounds like phthalates could be determined with only one sample preparation scheme. The separation into two classes of organic compounds with different polarity was performed using solid phase extraction. After a sample pre-treatment of the derived fractions, including esterification of the acids and extraction with cyclohexane, the samples were analyzed with a GCMS system. The new method was applied for the analysis of simultaneously collected interstitial aerosol and cloud water samples from a continental background site in Central Europe (Sonnblick Observatory, located at 3106-m elevation in the Austrian Alps). In all samples a large variety of mono- and dicarboxylic acids were identified and quantified, together with some aldehydes, alcohols and aromatic compounds. Using the obtained data set, for the first time in-cloud scavenging efficiencies for dicarboxylic acids, monocarboxylic acids, and other polar organic compounds were calculated. The results were compared to sulfate, which exhibited an average scavenging efficiency of 0.94. In the last part of the present work the results from laboratory and field investigations conducted with the intention to yield an improved sampling technique for the correction of the positive sampling artifact (adsorption of gas phase organics onto the filter substrate) were presented. (author)

Potential Health Risks Posed by Plant-Derived Cumulative Neurotoxic Bufadienolides in South Africa

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Christo Botha

2016-03-01

Full Text Available Bufadienolide-type cardiac glycosides have a worldwide distribution and are mainly synthesized by plants, but there are also animal sources. In South Africa, members of three genera of the Crassulaceae (Cotyledon, Tylecodon and Kalanchoe cause a unique chronic form of cardiac glycoside poisoning, predominantly in small stock. This paretic/paralytic condition is referred to as “krimpsiekte”, cotyledonosis or “nenta”. “Krimpsiekte” is a plant poisoning only reported from South Africa and is regarded as the most important plant poisoning of small stock in the semi-arid Little Karoo and southern fringes of the Great Karoo. The toxicosis is caused by cumulative bufadienolides which have neurotoxic properties. Four types of cumulative neurotoxic bufadienolides, namely cotyledoside, and the tyledosides, orbicusides and lanceotoxins, have been isolated. Based on the structure activity relationships and certain toxicokinetic parameters possible reasons for their accumulation are presented. Consumption of edible tissues from animals that have ingested these plants poses a potential risk to humans.

Corneal Neurotoxicity Due to Topical Benzalkonium Chloride

OpenAIRE

Sarkar, Joy; Chaudhary, Shweta; Namavari, Abed; Ozturk, Okan; Chang, Jin-Hong; Yco, Lisette; Sonawane, Snehal; Khanolkar, Vishakha; Hallak, Joelle; Jain, Sandeep

2012-01-01

Topical application of benzalkonium chloride (BAK) to the eye causes dose-related corneal neurotoxicity. Corneal inflammation and reduction in aqueous tear production accompany neurotoxicity. Cessation of BAK treatment leads to recovery of corneal nerve density.

A review on potential neurotoxicity of titanium dioxide nanoparticles

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Song, Bin; Liu, Jia; Feng, Xiaoli; Wei, Limin; Shao, Longquan

2015-08-01

As the rapid development of nanotechnology in the past three decades, titanium dioxide nanoparticles (TiO2 NPs), for their peculiar physicochemical properties, are widely applied in consumer products, food additives, cosmetics, drug carriers, and so on. However, little is known about their potential exposure and neurotoxic effects. Once NPs are unintentionally exposed to human beings, they could be absorbed, and then accumulated in the brain regions by passing through the blood-brain barrier (BBB) or through the nose-to-brain pathway, potentially leading to dysfunctions of central nerve system (CNS). Besides, NPs may affect the brain development of embryo by crossing the placental barrier. A few in vivo and in vitro researches have demonstrated that the morphology and function of neuronal or glial cells could be impaired by TiO2 NPs which might induce cell necrosis. Cellular components, such as mitochondrial, lysosome, and cytoskeleton, could also be influenced as well. The recognition ability, spatial memory, and learning ability of TiO2 NPs-treated rodents were significantly impaired, which meant that accumulation of TiO2 NPs in the brain could lead to neurodegeneration. However, conclusions obtained from those studies were not consistent with each other as researchers may choose different experimental parameters, including administration ways, dosage, size, and crystal structure of TiO2 NPs. Therefore, in order to fully understand the potential risks of TiO2 NPs to brain health, figure out research areas where further studies are required, and improve its bio-safety for applications in the near future, how TiO2 NPs interact with the brain is investigated in this review by summarizing the current researches on neurotoxicity induced by TiO2 NPs.

Pathophysiology of Manganese-Associated Neurotoxicity

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Racette, Brad A.; Aschner, Michael; Guilarte, Tomas R.; Dydak, Ulrike; Criswell, Susan R.; Zheng, Wei

2012-01-01

Conference Summary Manganese (Mn) is a well established neurotoxin associated with specific damage to the basal ganglia in humans. The phenotype associated with Mn neurotoxicity was first described in two workers with occupational exposure to Mn oxide.(Couper, 1837) Although the description did not use modern clinical terminology, a parkinsonian illness characterized by slowness of movement (bradykinesia), masked facies, and gait impairment (postural instability) appears to have predominated. Nearly 100 years later an outbreak of an atypical parkinsonian illness in a Chilean Mn mine provided a phenotypic description of a fulminant neurologic disorder with parkinsonism, dystonia, and neuropsychiatric symptoms.(Rodier J, 1955) Exposures associated with this syndrome were massive and an order of magnitude greater than modern exposures.(Rodier J, 1955; Hobson et al., 2011) The clinical syndrome associated with Mn neurotoxicity has been called manganism. Modern exposures to Mn occur primarily through occupations in the steel industry and welding. These exposures are often chronic and varied, occurring over decades in the healthy workforce. Although the severe neurologic disorder described by Rodier and Couper are no longer seen, several reports have suggested a possible increased risk of neurotoxicity in these workers.(Racette et al., 2005b; Bowler et al., 2007; Harris et al., 2011) Based upon limited prior imaging and pathologic investigations into the pathophysiology of neurotoxicity in Mn exposed workers,(Huang et al., 2003) many investigators have concluded that the syndrome spares the dopamine system distinguishing manganism from Parkinson disease (PD), the most common cause of parkinsonism in the general population, and a disease with characteristic degenerative changes in the dopaminergic system.(Jankovic, 2005) The purpose of this symposium was to highlight recent advances in the understanding of the pathophysiology of Mn associated neurotoxicity from C. elegans

Manganese accumulation in hair and teeth as a biomarker of manganese exposure and neurotoxicity in rats.

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Liang, Guiqiang; Zhang, Li'e; Ma, Shuyan; Lv, Yingnan; Qin, Huiyan; Huang, Xiaowei; Qing, Li; Li, Qin; Chen, Kangcheng; Xiong, Feng; Ma, Yifei; Nong, Jie; Yang, Xiaobo; Zou, Yunfeng

2016-06-01

Manganese (Mn) is an essential trace element to humans. However, excessive Mn causes cognitive impairment resulting from injury to the central nervous system within the hippocampus. No ideal biomarker is currently available for evaluating Mn exposure and associated neurotoxicity in the body. Hence, this study used Mn levels in the serum (MnS), teeth (MnT), and hair (MnH) as biomarkers for evaluating the association between Mn exposure and cognitive impairment in Mn-treated rats. A total of 32 male Sprague-Dawley rats were randomly divided into four groups, received 0, 5, 10, and 20 mg/(kg day) of MnCl2·4H2O for 5 days a week for 18 weeks, respectively. Lifetime Mn cumulative dose (LMCD) was used to evaluate external Mn exposure. Hippocampus, serum, teeth, and hair specimens were collected from the rats for Mn determination by graphite furnace atomic absorption spectrometry. Learning and memory functions were assessed using the Morris water maze test. Results showed that chronic Mn exposure increased the hippocampus (MnHip), MnS, MnT, and MnH levels, as well as impaired learning and memory function in rats. MnHip, MnT, and MnH levels were positively correlated with LMCD (r = 0.759, r = 0.925, and r = 0.908, respectively; p  0.05). Thus, MnT and MnH detected long-term low-dose Mn exposure. These parameters can be reliable biomarkers for Mn exposure and associated neurotoxicity in Mn-treated rats.

Neurotoxic effects of ecstasy on the thalamus

NARCIS (Netherlands)

de Win, Maartje M. L.; Jager, Gerry; Booij, Jan; Reneman, Liesbeth; Schilt, Thelma; Lavini, Cristina; Olabarriaga, Sílvia D.; Ramsey, Nick F.; den Heeten, Gerard J.; van den Brink, Wim

2008-01-01

Background Neurotoxic effects of ecstasy have been reported, although it remains unclear whether effects can be attributed to ecstasy, other recreational drugs or a combination of these. Aims To assess specific/independent neurotoxic effects of heavy ecstasy use and contributions of amphetamine,

Management of paclitaxel-induced neurotoxicity

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Manisha Bhutani

2011-12-01

Full Text Available Paclitaxel exerts its antitumor activity by promoting microtubule assembly and stabilizing microtubules. Microtubules are important for the development and maintenance of neurons. As a consequence, neurotoxicity is one of the drug’s major side effects. The risk of neurotoxicity depends on dose, duration and schedule of paclitaxel. Risk increases for patients with pre-existing conditions that may cause neuropathy (such as alcohol consumption, diabetes, or renal disease or with simultaneous or prior exposure to other neurotoxic chemotherapy such as platinum-based drugs, vinca alkaloids, immunomodulators, proteasome inhibitors, and epothilones. Patients with paclitaxel-induced neurotoxicity (PINT experience a constellation of symptoms over the course of treatment and beyond, ranging from mild to severe. Typically, the clinical presentation reflects an axonal peripheral neuropathy with glove-and-stocking distribution sensory loss, combined with features suggestive of nerve hyperexcitability including paresthesia, dysesthesia, and pain. Proprioceptive and motor effects become apparent as neuropathy becomes more advanced. These symptoms may be prolonged, severe, disabling, relatively resistant to intervention and adversely affect activities of daily living and thereby quality of life. Management is mainly symptomatic and supportive. Despite attempts to minimize PINT with changes in dose, vehicle, delivery systems, infusion schedule and premedication or co-treatment with neuroprotective agents, PINT remains dose-limiting in many instances and is a barrier to achieving the desired clinical response.

Cetuximab-induced hypomagnesaemia aggravates peripheral sensory neurotoxicity caused by oxaliplatin

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Satomi, Machiko; Asama, Toshiyuki; Ebisawa, Yoshiaki; Chisato, Naoyuki; Suno, Manabu; Karasaki, Hidenori; Furukawa, Hiroyuki; Matsubara, Kazuo

2010-01-01

Calcium and magnesium replacement is effective in reducing oxaliplatin-induced neurotoxicity. However, cetuximab treatment has been associated with severe hypomagnesaemia. Therefore, we retrospectively investigated whether cetuximab-induced hypomagnesaemia exacerbated oxaliplatin-induced neurotoxicity. Six patients with metastatic colorectal cancer who were previously treated with oxaliplatin-fluorouracil combination therapy were administered cetuximab in combination with irinotecan alone or irinotecan and fluorouracil as a second-line treatment. All patients had normal magnesium levels before receiving cetuximab. The Common Terminology Criteria for Adverse Events version 3.0 was used to evaluate the grade of neurotoxicity, hypomagnesaemia, hypocalcaemia, and hypokalemia every week. All six patients had grade 1 or higher hypomagnesaemia after starting cetuximab therapy. The serum calcium and potassium levels were within the normal range at the onset of hypomagnesaemia. Oxaliplatin-induced neurotoxicity occurred in all patients at the beginning of cetuximab therapy, with grade 1 neurotoxicity in five patients and grade 2 in one patient. After cetuximab administration, the neurotoxicity worsened in all six patients, and three progressed to grade 3. Among the three patients with grade 3 neurotoxicity, two required a dose reduction and one had to discontinue cetuximab therapy. A discontinuation or dose reduction in cetuximab therapy was associated with exacerbated oxaliplatin-induced neurotoxicity due to cetuximab-induced hypomagnesaemia in half of patients who had previously received oxaliplatin. Therefore, when administering cetuximab after oxaliplatin therapy, we suggest serially evaluating serum magnesium levels and neurotoxicity. PMID:22811813

Determination of low-molecular-weight dicarboxylic acids in atmospheric aerosols by injection-port derivatization and gas chromatography-mass spectrometry.

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Hsu, Ching-Lin; Ding, Wang-Hsien

2009-12-15

A rapid and environmental-friendly injection-port derivatization with gas chromatography-mass spectrometry (GC-MS) method was developed to determine selected low-molecular weight (LMW) dicarboxylic acids (from C2 to C10) in atmospheric aerosol samples. The parameters related to the derivatization process (i.e., type of ion-pair reagent, injection-port temperature and concentration of ion-pair reagent) were optimized. Tetrabutylammonium hydroxide (TBA-OH) 20 mM in methanol gave excellent yield for di-butyl ester dicarboxylate derivatives at injection-port temperature at 300 degrees C. Solid-phase extraction (SPE) method instead of rotary evaporation was used to concentrate analytes from filter extracts. The recovery from filter extracts ranged from 78 to 95% with relative standard deviation (RSD) less than 12%. Limits of quantitation (LOQs) ranged from 25 to 250 pg/m(3). The concentrations of di-carboxylated C2-C5 and total C6-C10 in particles of atmospheric aerosols ranged from 91.9 to 240, 11.3 to 56.7, 9.2 to 49.2, 8.7 to 35.3 and n.d. to 37.8 ng/m(3), respectively. Oxalic acid (C2) was the dominant LMW-dicarboxylic acids detected in aerosol samples. The quantitative results were comparable to the results obtained by the off-line derivatization.

Single-Step Access to Long-Chain α,ω-Dicarboxylic Acids by Isomerizing Hydroxycarbonylation of Unsaturated Fatty Acids

KAUST Repository

Goldbach, Verena

2016-11-09

Dicarboxylic acids are compounds of high value, but to date long-chain alpha,omega-dicarboxylic acids have been difficult to access in a direct way. Unsaturated fatty acids are ideal starting materials with their molecular structure of long methylene sequences and a carboxylate functionality, in addition to a double bond that offers itself for functionalization. Within this paper, we established a direct access to alpha,omega-dicarboxylic acids by combining isomerization and selective terminal carbonylation of the internal double bond with water as a nucleophile on unsaturated fatty acids. We identified the key elements of this reaction: a homogeneous reaction mixture ensuring sufficient contact between all reactants and a catalyst system allowing for activation of the Pd precursor under aqueous conditions. Experiments under pressure reactor conditions with [(dtbpx)Pd(OTf)(2)] as catalyst precursor revealed the importance of nucleophile and reactant concentrations and the addition of the diprotonated diphosphine ligand (dtbpxH(2))(OTf)(2) to achieve turnover numbers >120. A variety of unsaturated fatty acids, including a triglyceride, were converted to valuable long-chain dicarboxylic acids with high turnover numbers and selectivities for the linear product of >90%. We unraveled the activation pathway of the Pd-II precursor, which proceeds via a reductive elimination step forming a Pd species and oxidative addition of the diprotonated diphosphine ligand, resulting in the formation of the catalytically active Pd hydride species. Theoretical calculations identified the hydrolysis as the rate-determining step. A low nucleophile concentration in the reaction mixture in combination with this high energetic barrier limits the potential of this reaction. In conclusion, water can be utilized as a nucleophile in isomerizing functionalization reactions and gives access to long-chain dicarboxylic acids from a variety of unsaturated substrates. The activity of the catalytic

Taxane-Induced Peripheral Neurotoxicity

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Roser Velasco

2015-04-01

Full Text Available Taxane-derived agents are chemotherapy drugs widely employed in cancer treatment. Among them, paclitaxel and docetaxel are most commonly administered, but newer formulations are being investigated. Taxane antineoplastic activity is mainly based on the ability of the drugs to promote microtubule assembly, leading to mitotic arrest and apoptosis in cancer cells. Peripheral neurotoxicity is the major non-hematological adverse effect of taxane, often manifested as painful neuropathy experienced during treatment, and it is sometimes irreversible. Unfortunately, taxane-induced neurotoxicity is an uncertainty prior to the initiation of treatment. The present review aims to dissect current knowledge on real incidence, underlying pathophysiology, clinical features and predisposing factors related with the development of taxane-induced neuropathy.

Prevention of dopaminergic neurotoxicity by targeting nitric oxide and peroxynitrite: implications for the prevention of methamphetamine-induced neurotoxic damage.

Science.gov (United States)

Imam, S Z; Islam, F; Itzhak, Y; Slikker, W; Ali, S F

2000-09-01

Methamphetamine (METH) is a neurotoxic psychostimulant that produces catecholaminergic brain damage by producing oxidative stress and free radical generation. The role of oxygen and nitrogen radicals is well documented as a cause of METH-induced neurotoxic damage. In this study, we have obtained evidence that METH-induced neurotoxicity is the resultant of interaction between oxygen and nitrogen radicals, and it is mediated by the production of peroxynitrite. We have also assessed the effects of inhibitors of neuronal nitric oxide synthase (nNOS) as well as scavenger of nitric oxide and a peroxynitrite decomposition catalyst. Significant protective effects were observed with the inhibitor of nNOS, 7-nitroindazole (7-NI), as well as by the selective peroxynitrite scavenger or decomposition catalyst, 5,10,15,20-tetrakis(2,4,6-trimethyl-3,5-sulfonatophenyl)porphyrinato iron III (FeTPPS). However, the use of a nitric oxide scavenger, 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO), did not provide any significant protection against METH-induced hyperthermia or peroxynitrite generation and the resulting dopaminergic neurotoxicity. In particular, treatment with FeTPPS completely prevented METH-induced hyperthermia, peroxynitrite production, and METH-induced dopaminergic depletion. Together, these data demonstrate that METH-induced dopaminergic neurotoxicity is mediated by the generation of peroxynitrite, which can be selectively protected by nNOS inhibitors or peroxynitrite scavenger or decomposition catalysts.

Acrylamide neurotoxicity on the cerebrum of weaning rats

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Su-min Tian

2015-01-01

Full Text Available The mechanism underlying acrylamide-induced neurotoxicity remains controversial. Previous studies have focused on acrylamide-induced toxicity in adult rodents, but neurotoxicity in weaning rats has not been investigated. To explore the neurotoxic effect of acrylamide on the developing brain, weaning rats were gavaged with 0, 5, 15, and 30 mg/kg acrylamide for 4 consecutive weeks. No obvious neurotoxicity was observed in weaning rats in the low-dose acrylamide group (5 mg/kg. However, rats from the moderate- and high-dose acrylamide groups (15 and 30 mg/kg had an abnormal gait. Furthermore, biochemical tests in these rats demonstrated that glutamate concentration was significantly reduced, and γ-aminobutyric acid content was significantly increased and was dependent on acrylamide dose. Immunohistochemical staining showed that in the cerebral cortex, γ-aminobutyric acid, glutamic acid decarboxylase and glial fibrillary acidic protein expression increased remarkably in the moderate- and high-dose acrylamide groups. These results indicate that in weaning rats, acrylamide is positively associated with neurotoxicity in a dose-dependent manner, which may correlate with upregulation of γ-aminobutyric acid and subsequent neuronal degeneration after the initial acrylamide exposure.

Serotonergic neurotoxic metabolites of ecstasy identified in rat brain.

Science.gov (United States)

Jones, Douglas C; Duvauchelle, Christine; Ikegami, Aiko; Olsen, Christopher M; Lau, Serrine S; de la Torre, Rafael; Monks, Terrence J

2005-04-01

The selective serotonergic neurotoxicity of 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) depends on their systemic metabolism. We have recently shown that inhibition of brain endothelial cell gamma-glutamyl transpeptidase (gamma-GT) potentiates the neurotoxicity of both MDMA and MDA, indicating that metabolites that are substrates for this enzyme contribute to the neurotoxicity. Consistent with this view, glutathione (GSH) and N-acetylcysteine conjugates of alpha-methyl dopamine (alpha-MeDA) are selective neurotoxicants. However, neurotoxic metabolites of MDMA or MDA have yet to be identified in brain. Using in vivo microdialysis coupled to liquid chromatography-tandem mass spectroscopy and a high-performance liquid chromatography-coulometric electrode array system, we now show that GSH and N-acetylcysteine conjugates of N-methyl-alpha-MeDA are present in the striatum of rats administered MDMA by subcutaneous injection. Moreover, inhibition of gamma-GT with acivicin increases the concentration of GSH and N-acetylcysteine conjugates of N-methyl-alpha-MeDA in brain dialysate, and there is a direct correlation between the concentrations of metabolites in dialysate and the extent of neurotoxicity, measured by decreases in serotonin (5-HT) and 5-hydroxyindole acetic (5-HIAA) levels. Importantly, the effects of acivicin are independent of MDMA-induced hyperthermia, since acivicin-mediated potentiation of MDMA neurotoxicity occurs in the context of acivicin-mediated decreases in body temperature. Finally, we have synthesized 5-(N-acetylcystein-S-yl)-N-methyl-alpha-MeDA and established that it is a relatively potent serotonergic neurotoxicant. Together, the data support the contention that MDMA-mediated serotonergic neurotoxicity is mediated by the systemic formation of GSH and N-acetylcysteine conjugates of N-methyl-alpha-MeDA (and alpha-MeDA). The mechanisms by which such metabolites access the brain and produce selective

pH-metric studies on the mixed ligand-chelates of oxovanadium(IV) with 2,2'-bipyridyl and dicarboxylic or hydroxy acids

International Nuclear Information System (INIS)

Jain, A.K.; Kumari, V.; Chaturvedi, G.K.

1978-01-01

The interaction of vanadyl ion with 2,2'-bipyridyl and some dicarboxylic or hydroxy acids (where dicarboxylic acid = oxalic (OX), malonic (MALN), phthalic (PHA), maleic (MAL) acids; hydroxy acids salicylic (SA), 5-sulfosalicylic (5-SSA), mandelic (MAND) and glycollic (HG) acids was studied potentiometrically. pH-titrations of the reaction mixtures containing vanadyl sulphate, 2,2'-bipyridyl and one of the dicarboxylic or hydroxy acids (OX, MALN, PHA, MAL, SA, 5-SSA, MAND and HG acids) in equimolar ratio exhibited the formation of 1:1:1 mixed ligand chelates. The formation constants of the resulting biligand chelates were calculated, at 35 + -1 0 and 45 + -1 0 and also the thermodynamic functions viz. ΔF, ΔH and ΔS (μ=0.1M KNO 3 ) (auth.)

Determination of low-molecular-weight dicarboxylic acids in atmospheric aerosols by injection-port derivatization and gas chromatography-mass spectrometry

Science.gov (United States)

Ding, W.; Hsu, C.

2008-12-01

Currently, the investigations on aerosol water-soluble organic compounds (WSOCs) formed by burning biomass have become increasingly concerned with the role of these compounds in atmospheric chemistry and their effect on climate, because they have great potential to influence cloud formation, precipitation, and climate on both global and regional scales. Of these compounds, low-molecular weight (LMW) dicarboxylic acids (from C2 to C10) have attracted the most interest because of their properties as specific tracers for the burning of biomass. In this study, a modified injection-port derivatization and gas chromatography - mass spectrometry method was developed and evaluated for rapid determination of LMW dicarboxylic acids in atmospheric aerosol samples. The parameters related to the derivatization process (i.e., type of ion-pair reagent, injection-port temperature and concentration of ion-pair reagent) were optimized. Tetrabutylammonium hydroxide (TBA-OH) dissolved in methanol used as the ion-pair solution gave excellent yield for di-butyl ester low-molecular weight derivatives. Solid-phase extraction method instead of rotary evaporation was used to concentrate analytes from filter extracts. The recovery from filter extracts ranged from 67 to 86% with relative standard deviation (RSD) less than 13%. The concentrations of dicarboxylated C2, C3, C4, C5 and C6-C10 in atmospheric aerosols ranged from 91-240 ng/m3, 11-56 ng/m3, 12-49 ng/m3, 8-35 ng/m3 and n.d. to 17 ng/m3, respectively. Oxalic (C2) acid was the dominant dicarboxylic acids detected in aerosol samples. The total concentrations of the LMW dicarboxylic acids (from C2 to C10) correspond to 2.2 to 2.6% of the total aerosol mass.

Synthesis, properties and applications of biodegradable polymers derived from diols and dicarboxylic acids: from polyesters to poly(ester amide)s.

Science.gov (United States)

Díaz, Angélica; Katsarava, Ramaz; Puiggalí, Jordi

2014-04-25

Poly(alkylene dicarboxylate)s constitute a family of biodegradable polymers with increasing interest for both commodity and speciality applications. Most of these polymers can be prepared from biobased diols and dicarboxylic acids such as 1,4-butanediol, succinic acid and carbohydrates. This review provides a current status report concerning synthesis, biodegradation and applications of a series of polymers that cover a wide range of properties, namely, materials from elastomeric to rigid characteristics that are suitable for applications such as hydrogels, soft tissue engineering, drug delivery systems and liquid crystals. Finally, the incorporation of aromatic units and α-amino acids is considered since stiffness of molecular chains and intermolecular interactions can be drastically changed. In fact, poly(ester amide)s derived from naturally occurring amino acids offer great possibilities as biodegradable materials for biomedical applications which are also extensively discussed.

Task-specific enhancement of short-term, but not long-term, memory by class I metabotropic glutamate receptor antagonist 1-aminoindan-1,5-dicarboxylic acid in rats

DEFF Research Database (Denmark)

Christoffersen, G.R.J.; Christensen, Lone H.; Harrington, Nicholas R.

1999-01-01

Metabotropic glutamate receptors; Class I antagonist; 1-aminoindan-1,5-dicarboxylic acid; spatial learning; contextual conditioning; rats......Metabotropic glutamate receptors; Class I antagonist; 1-aminoindan-1,5-dicarboxylic acid; spatial learning; contextual conditioning; rats...

Protective effect of quercetin on bupivacaine-induced neurotoxicity ...

African Journals Online (AJOL)

certain side effects, especially neurotoxicity. It has been shown that neurotoxicity caused by local anesthetics such as lidocaine and bupivacaine are related to changes in calcium homeostasis, resulting in intracellular calcium overload [1]. Calcium homeostasis is regulated by many different kinds of calcium channels such.

pH-metric studies on the mixed ligand-chelates of oxovanadium(IV) with 2,2'-bipyridyl and dicarboxylic or hydroxy acids

Energy Technology Data Exchange (ETDEWEB)

Jain, A K; Kumari, V; Chaturvedi, G K [Agra Coll. (India)

1978-12-01

The interaction of vanadyl ion with 2,2'-bipyridyl and some dicarboxylic or hydroxy acids (where dicarboxylic acid = oxalic (OX), malonic (MALN), phthalic (PHA), maleic (MAL) acids; hydroxy acids salicylic (SA), 5-sulfosalicylic (5-SSA), mandelic (MAND) and glycollic (HG) acids was studied potentiometrically. pH-titrations of the reaction mixtures containing vanadyl sulphate, 2,2'-bipyridyl and one of the dicarboxylic or hydroxy acids (OX, MALN, PHA, MAL, SA, 5-SSA, MAND and HG acids) in equimolar ratio exhibited the formation of 1:1:1 mixed ligand chelates. The formation constants of the resulting biligand chelates were calculated, at 35/sup +/-1/sup 0/ and 45/sup +/-1/sup 0/ and also the thermodynamic functions viz. ..delta..F, ..delta..H and ..delta..S (..mu..=0.1M KNO/sub 3/) (auth.).

THC Prevents MDMA Neurotoxicity in Mice.

Directory of Open Access Journals (Sweden)

Clara Touriño

2010-02-01

Full Text Available The majority of MDMA (ecstasy recreational users also consume cannabis. Despite the rewarding effects that both drugs have, they induce several opposite pharmacological responses. MDMA causes hyperthermia, oxidative stress and neuronal damage, especially at warm ambient temperature. However, THC, the main psychoactive compound of cannabis, produces hypothermic, anti-inflammatory and antioxidant effects. Therefore, THC may have a neuroprotective effect against MDMA-induced neurotoxicity. Mice receiving a neurotoxic regimen of MDMA (20 mg/kg x 4 were pretreated with THC (3 mg/kg x 4 at room (21 degrees C and at warm (26 degrees C temperature, and body temperature, striatal glial activation and DA terminal loss were assessed. To find out the mechanisms by which THC may prevent MDMA hyperthermia and neurotoxicity, the same procedure was carried out in animals pretreated with the CB(1 receptor antagonist AM251 and the CB(2 receptor antagonist AM630, as well as in CB(1, CB(2 and CB(1/CB(2 deficient mice. THC prevented MDMA-induced-hyperthermia and glial activation in animals housed at both room and warm temperature. Surprisingly, MDMA-induced DA terminal loss was only observed in animals housed at warm but not at room temperature, and this neurotoxic effect was reversed by THC administration. However, THC did not prevent MDMA-induced hyperthermia, glial activation, and DA terminal loss in animals treated with the CB(1 receptor antagonist AM251, neither in CB(1 and CB(1/CB(2 knockout mice. On the other hand, THC prevented MDMA-induced hyperthermia and DA terminal loss, but only partially suppressed glial activation in animals treated with the CB(2 cannabinoid antagonist and in CB(2 knockout animals. Our results indicate that THC protects against MDMA neurotoxicity, and suggest that these neuroprotective actions are primarily mediated by the reduction of hyperthermia through the activation of CB(1 receptor, although CB(2 receptors may also contribute to

3,6-Dithiaoctane-1,8-dicarboxylic acid and its metal complexes

NARCIS (Netherlands)

Bellaart, A.C.; Verbeek, J.L.

1969-01-01

A soln. contg. 1.5 g 3,6-dithiaoctane-1,8-dicarboxylic acid (HL) in 20 ml H2O was treated with 1.8 g Ag2O for 20 min on a boiling water bath to give H[AgL2], m.p. 115-16 Deg (uncor.). A structure is proposed on the basis of ir spectral studies and elec. cond. measurements. H[CuL2] was similarly

Current status of developmental neurotoxicity: regulatory view

DEFF Research Database (Denmark)

Hass, Ulla

2003-01-01

in the testing strategy for new and existing substances, and biocides. Hopefully, this will lead to an improved database for risk assessment of potential developmental neurotoxicants. However, the regulatory authorities and toxicologists will also be faced with the challenge that decisions have to be made......The need for developmental neurotoxicity testing has been recognized for decades and guidelines are available, as the USEPA guideline and the OECD draft TG 426. Regulatory testing of industrial chemicals for developmental neurotoxicity is required to some extent, especially for pesticides in the US....... Until recently, however, developmental neurotoxicity testing of industrial chemicals has not been a clear regulatory requirement in EU, probably due to the lack of an accepted OECD TG. The revised EU Technical Guidance Document for Risk Assessment (EU-TGD) has now included the OECD draft TG 426...

Local Anesthetic-Induced Neurotoxicity

NARCIS (Netherlands)

Verlinde, Mark; Hollmann, Markus W.; Stevens, Markus F.; Hermanns, Henning; Werdehausen, Robert; Lirk, Philipp

2016-01-01

This review summarizes current knowledge concerning incidence, risk factors, and mechanisms of perioperative nerve injury, with focus on local anesthetic-induced neurotoxicity. Perioperative nerve injury is a complex phenomenon and can be caused by a number of clinical factors. Anesthetic risk

Cyanobacterial Xenobiotics as Evaluated by a Caenorhabditis elegans Neurotoxicity Screening Test

Science.gov (United States)

Ju, Jingjuan; Saul, Nadine; Kochan, Cindy; Putschew, Anke; Pu, Yuepu; Yin, Lihong; Steinberg, Christian E. W.

2014-01-01

In fresh waters cyanobacterial blooms can produce a variety of toxins, such as microcystin variants (MCs) and anatoxin-a (ANA). ANA is a well-known neurotoxin, whereas MCs are hepatotoxic and, to a lesser degree, also neurotoxic. Neurotoxicity applies especially to invertebrates lacking livers. Current standardized neurotoxicity screening methods use rats or mice. However, in order to minimize vertebrate animal experiments as well as experimental time and effort, many investigators have proposed the nematode Caenorhabditis elegans as an appropriate invertebrate model. Therefore, four known neurotoxic compounds (positive compounds: chlorpyrifos, abamectin, atropine, and acrylamide) were chosen to verify the expected impacts on autonomic (locomotion, feeding, defecation) and sensory (thermal, chemical, and mechanical sensory perception) functions in C. elegans. This study is another step towards successfully establishing C. elegans as an alternative neurotoxicity model. By using this protocol, anatoxin-a adversely affected locomotive behavior and pharyngeal pumping frequency and, most strongly, chemotactic and thermotactic behavior, whereas MC-LR impacted locomotion, pumping, and mechanical behavior, but not chemical sensory behavior. Environmental samples can also be screened in this simple and fast way for neurotoxic characteristics. The filtrate of a Microcystis aeruginosa culture, known for its hepatotoxicity, also displayed mild neurotoxicity (modulated short-term thermotaxis). These results show the suitability of this assay for environmental cyanotoxin-containing samples. PMID:24776722

Synthesis and characterization of Mg-Al-layered double hydroxides intercalated with cubane-1,4-dicarboxylate anions.

Science.gov (United States)

Rezvani, Zolfaghar; Arjomandi Rad, Farzad; Khodam, Fatemeh

2015-01-21

In the present work, Mg2Al-layered double hydroxide (LDH) intercalated with cubane-1,4-dicarboxylate anions was prepared from the reaction of solutions of Mg(ii) and Al(iii) nitrate salts with an alkaline solution of cubane-1,4-dicarboxylic acid by using the coprecipitation method. The successful preparation of a nanohybrid of cubane-1,4-dicarboxylate(cubane-dc) anions with LDH was confirmed by powder X-ray diffraction, FTIR spectroscopy and thermal gravimetric analysis (TGA). The increase in the basal spacing of LDHs from 8.67 Å to 13.40 Å shows that cubane-dc anions were successfully incorporated into the interlayer space. Thermogravimetric analyses confirm that the thermal stability of the intercalated cubane-dc anions is greater than that of the pure form before intercalation because of host-guest interactions involving hydrogen bonds. The interlayer structure, hydrogen bonding, and subsequent distension of LDH compounds containing cubane-dc anions were shown by molecular simulation. The RDF (radial distribution function), mean square displacement (MSD), and self-diffusion coefficient were calculated using the trajectory files on the basis of molecular dynamics (MD) simulations, and the results indicated that the cubane-dc anions were more stable when intercalated into the LDH layers. A good agreement was obtained between calculated and measured X-ray diffraction patterns and between experimental and calculated basal spacings.

Pyridine 2,4-Dicarboxylic Acid Suppresses Tomato Seedling Growth

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Sotirios Fragkostefanakis

2018-01-01

Full Text Available Pyridine 2,4-dicarboxylic acid is a structural analog of 2-oxoglutarate and is known to inhibit 2-oxoglutare-dependent dioxygenases. The effect of this inhibitor in tomato seedlings grown in MS media supplied with various concentrations of PDCA was investigated, resulting in shorter roots and hypocotyls in a dose-dependent manner. The partial inhibition of growth in roots was more drastic compared to hypocotyls and was attributed to a decrease in the elongation of root and hypocotyl cells. Concentrations of 100 and 250 μM of PDCA decreased hydroxyproline content in roots while only the 250 μM treatment reduced the hydroxyproline content in shoots. Seedlings treated with 100 μM PDCA exhibited enhanced growth of hypocotyl and cotyledon cells and higher hydroxyproline content resulting in cotyledons with greater surface area. However, no alterations in hypocotyl length were observed. Prolyl 4 hydroxylases (P4Hs are involved in the O-glycosylation of AGPs and were also highly expressed during seedling growth. Moreover PDCA induced a decrease in the accumulation of HRGPs and particularly in AGPs-bound epitopes in a dose dependent-manner while more drastic reduction were observed in roots compared to shoots. In addition, bulged root epidermal cells were observed at the high concentration of 250 μM which is characteristic of root tissues with glycosylation defects. These results indicate that PDCA induced pleiotropic effects during seedling growth while further studies are required to better investigate the physiological significance of this 2-oxoglutarate analog. This pharmacological approach might be used as a tool to better understand the physiological significance of HRGPs and probably P4Hs in various growth and developmental programs in plants.

Pyridine 2,4-dicarboxylic acid suppresses tomato seedling growth

Science.gov (United States)

Fragkostefanakis, Sotirios; Kaloudas, Dimitrios; Kalaitzis, Panagiotis

2018-01-01

Pyridine 2,4-dicarboxylic acid is a structural analogue of 2-oxoglutarate and is known to inhibit 2-oxoglutare-dependent dioxygenases. The effect of this inhibitor in tomato seedlings grown in MS media supplied with various concentrations of PDCA was investigated, resulting in shorter roots and hypocotyls in a dose-dependent manner. The partial inhibition of growth in roots was more drastic compared to hypocotyls and was attributed to a decrease in the elongation of root and hypocotyl cells. Concentrations of 100 and 250 μΜ of PDCA decreased hydroxyproline content in roots while only the 250 μΜ treatment reduced the hydroxyproline content in shoots. Seedlings treated with 100 μΜ PDCA exhibited enhanced growth of hypocotyl and cotyledon cells and higher hydroxyproline content resulting in cotyledons with greater surface area. However, no alterations in hypocotyl length were observed. Prolyl 4 hydroxylases (P4Hs) are involved in the O-glycosylation of AGPs and were also highly expressed during seedling growth. Moreover PDCA induced a decrease in the accumulation of HRGPs and particularly in AGPs-bound epitopes in a dose dependent-manner while more drastic reduction were observed in roots compared to shoots. In addition, bulged root epidermal cells were observed at the high concentration of 250 μΜ which is characteristic of root tissues with glycosylation defects. These results indicate that PDCA induced pleiotropic effects during seedling growth while further studies are required to better investigate the physiological significance of this 2-oxoglutarate analogue. This pharmacological approach might be used as a tool to better understand the physiological significance of HRGPs and probably P4Hs in various growth and developmental programs in plants.

Changes in gene expression linked to methamphetamine-induced dopaminergic neurotoxicity.

Science.gov (United States)

Xie, Tao; Tong, Liqiong; Barrett, Tanya; Yuan, Jie; Hatzidimitriou, George; McCann, Una D; Becker, Kevin G; Donovan, David M; Ricaurte, George A

2002-01-01

The purpose of these studies was to examine the role of gene expression in methamphetamine (METH)-induced dopamine (DA) neurotoxicity. First, the effects of the mRNA synthesis inhibitor, actinomycin-D, and the protein synthesis inhibitor, cycloheximide, were examined. Both agents afforded complete protection against METH-induced DA neurotoxicity and did so independently of effects on core temperature, DA transporter function, or METH brain levels, suggesting that gene transcription and mRNA translation play a role in METH neurotoxicity. Next, microarray technology, in combination with an experimental approach designed to facilitate recognition of relevant gene expression patterns, was used to identify gene products linked to METH-induced DA neurotoxicity. This led to the identification of several genes in the ventral midbrain associated with the neurotoxic process, including genes for energy metabolism [cytochrome c oxidase subunit 1 (COX1), reduced nicotinamide adenine dinucleotide ubiquinone oxidoreductase chain 2, and phosphoglycerate mutase B], ion regulation (members of sodium/hydrogen exchanger and sodium/bile acid cotransporter family), signal transduction (adenylyl cyclase III), and cell differentiation and degeneration (N-myc downstream-regulated gene 3 and tau protein). Of these differentially expressed genes, we elected to further examine the increase in COX1 expression, because of data implicating energy utilization in METH neurotoxicity and the known role of COX1 in energy metabolism. On the basis of time course studies, Northern blot analyses, in situ hybridization results, and temperature studies, we now report that increased COX1 expression in the ventral midbrain is linked to METH-induced DA neuronal injury. The precise role of COX1 and other genes in METH neurotoxicity remains to be elucidated.

Developmental neurotoxicity of pyrethroid insecticides in zebrafish embryos.

Science.gov (United States)

DeMicco, Amy; Cooper, Keith R; Richardson, Jason R; White, Lori A

2010-01-01

Pyrethroid insecticides are one of the most commonly used residential and agricultural insecticides. Based on the increased use of pyrethroids and recent studies showing that pregnant women and children are exposed to pyrethroids, there are concerns over the potential for developmental neurotoxicity. However, there have been relatively few studies on the developmental neurotoxicity of pyrethroids. In this study, we sought to investigate the developmental toxicity of six common pyrethroids, three type I compounds (permethrin, resmethrin, and bifenthrin) and three type II compounds (deltamethrin, cypermethrin, and lambda-cyhalothrin), and to determine whether zebrafish embryos may be an appropriate model for studying the developmental neurotoxicity of pyrethroids. Exposure of zebrafish embryos to pyrethroids caused a dose-dependent increase in mortality and pericardial edema, with type II compounds being the most potent. At doses approaching the LC(50), permethrin and deltamethrin caused craniofacial abnormalities. These findings are consistent with mammalian studies demonstrating that pyrethroids are mildly teratogenic at very high doses. However, at lower doses, body axis curvature and spasms were observed, which were reminiscent of the classic syndromes observed with pyrethroid toxicity. Treatment with diazepam ameliorated the spasms, while treatment with the sodium channel antagonist MS-222 ameliorated both spasms and body curvature, suggesting that pyrethroid-induced neurotoxicity is similar in zebrafish and mammals. Taken in concert, these data suggest that zebrafish may be an appropriate alternative model to study the mechanism(s) responsible for the developmental neurotoxicity of pyrethroid insecticides and aid in identification of compounds that should be further tested in mammalian systems.

Inhibitors of Microglial Neurotoxicity: Focus on Natural Products

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Kyoungho Suk

2011-01-01

Full Text Available Microglial cells play a dual role in the central nervous system as they have both neurotoxic and neuroprotective effects. Uncontrolled and excessive activation of microglia often contributes to inflammation-mediated neurodegeneration. Recently, much attention has been paid to therapeutic strategies aimed at inhibiting neurotoxic microglial activation. Pharmacological inhibitors of microglial activation are emerging as a result of such endeavors. In this review, natural products-based inhibitors of microglial activation will be reviewed. Potential neuroprotective activity of these compounds will also be discussed. Future works should focus on the discovery of novel drug targets that specifically mediate microglial neurotoxicity rather than neuroprotection. Development of new drugs based on these targets may require a better understanding of microglial biology and neuroinflammation at the molecular, cellular, and systems levels.

Multiple neurotoxic effects of haloperidol resulting in neuronal death.

Science.gov (United States)

Nasrallah, Henry A; Chen, Alexander T

2017-08-01

Several published studies have reported an association between antipsychotic medications, especially first-generation agents, and a decline in gray matter volume. This prompted us to review the possible neurotoxic mechanisms of first-generation antipsychotics (FGAs), especially haloperidol, which has been widely used over the past several decades. A PubMed search was conducted using the keywords haloperidol, antipsychotic, neurotoxicity, apoptosis, oxidative stress, and neuroplasticity. No restrictions were placed on the date of the articles or language. Studies with a clearly described methodology were included. Animal, cell culture, and human tissue studies were identified. Thirty reports met the criteria for the search. All studies included haloperidol; a few also included other FGAs (fluphenazine and perphenazine) and/or second-generation agents (SGAs) (aripiprazole, paliperidone, and risperidone). A neurotoxic effect of haloperidol and other FGAs was a common theme across all studies. Minimal (mainly at high doses) or no neurotoxic effects were noted in SGAs. A review of the literature suggests that haloperidol exerts measurable neurotoxic effects at all doses via many molecular mechanisms that lead to neuronal death. A similar effect was observed in 2 other FGAs, but the effect in SGAs was much smaller and occurred mainly at high doses. A stronger binding to serotonin 5HT-2A receptors than to dopamine D2 receptors may have a neuroprotective effect among SGAs. Further studies are warranted to confirm these findings.

Assessing the Developmental Neurotoxicity of 27 ...

Science.gov (United States)

Assessing the Developmental Neurotoxicity of 27 Organophosphorus Pesticides Using a Zebrafish Behavioral Assay, Waalkes, M., Hunter, D.L., Jarema, K., Mundy, W., and S. Padilla. The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize organophosphorus pesticides for developmental neurotoxicity. As such, we are exploring a behavioral testing paradigm that can assess the effects of sublethal and subteratogenic concentrations of developmental neurotoxicants on zebrafish (Danio rerio). This in vivo assay quantifies the locomotor response to light stimuli under tandem light and dark conditions in a 96-well plate using a video tracking system on 6 day post fertilization zebrafish larvae. Each of twenty-seven organophosphorus pesticides was tested for their developmental neurotoxic potential by exposing zebrafish embryos/larvae to the pesticide at several concentrations (≤ 100 μM nominal concentration) during the first five days of development, followed by 24 hours of depuration and then behavioral testing. Approximately 22% of the chemicals (Acephate, Dichlorvos, Diazoxon, Bensulide,Tribufos, Tebupirimfos) did not produce any behavioral changes after developmental exposure, while many (Malaoxon Fosthiazate, Dimethoate, Dicrotophos, Ethoprop, Malathion, Naled, Diazinon, Methamidophos, Terbufos, Trichlorfon, Phorate, Pirimiphos-methyl, Profenofos, Z-Tetrachlorvinphos, Chlorpyrifos, Coumaphos, Phosmet, Omethoate) produced changes in swi

Neurotoxicity of fragrance compounds: A review.

Science.gov (United States)

Pinkas, Adi; Gonçalves, Cinara Ludvig; Aschner, Michael

2017-10-01

Fragrance compounds are chemicals belonging to one of several families, which are used frequently and globally in cosmetics, household products, foods and beverages. A complete list of such compounds is rarely found on the ingredients-list of such products, as "fragrance mixtures" are defined as "trade secrets" and thus protected by law. While some information regarding the general toxicity of some of these compounds is available, their neurotoxicity is known to a lesser extent. Here, we discuss the prevalence and neurotoxicity of fragrance compounds belonging to the three most common groups: phthalates, synthetic musks and chemical sensitizers. Copyright © 2017 Elsevier Inc. All rights reserved.

Neurotoxic shellfish poisoning: A review

NARCIS (Netherlands)

Apeldoorn ME van; Egmond HP van; Speijers GJA; CSR; ARO

2001-01-01

Dit literatuuroverzicht bevat informatie betreffende het "neurotoxic shellfish poisoning" (NSP) syndroom en de veroorzakende toxines, nl.de brevetoxines, welke geproduceerd worden door de dinoflagellaat Gymnodinium breve. Chemische structuren en detectie-methodes van de brevetoxines,

Ginger and Propolis Exert Neuroprotective Effects against Monosodium Glutamate-Induced Neurotoxicity in Rats

Directory of Open Access Journals (Sweden)

Usama K. Hussein

2017-11-01

Full Text Available Central nervous system cytotoxicity is linked to neurodegenerative disorders. The objective of the study was to investigate whether monosodium glutamate (MSG neurotoxicity can be reversed by natural products, such as ginger or propolis, in male rats. Four different groups of Wistar rats were utilized in the study. Group A served as a normal control, whereas group B was orally administered with MSG (100 mg/kg body weight, via oral gavage. Two additional groups, C and D, were given MSG as group B along with oral dose (500 mg/kg body weight of either ginger or propolis (600 mg/kg body weight once a day for two months. At the end, the rats were sacrificed, and the brain tissue was excised and levels of neurotransmitters, ß-amyloid, and DNA oxidative marker 8-OHdG were estimated in the brain homogenates. Further, formalin-fixed and paraffin-embedded brain sections were used for histopathological evaluation. The results showed that MSG increased lipid peroxidation, nitric oxide, neurotransmitters, and 8-OHdG as well as registered an accumulation of ß-amyloid peptides compared to normal control rats. Moreover, significant depletions of glutathione, superoxide dismutase, and catalase as well as histopathological alterations in the brain tissue of MSG-treated rats were noticed in comparison with the normal control. In contrast, treatment with ginger greatly attenuated the neurotoxic effects of MSG through suppression of 8-OHdG and β-amyloid accumulation as well as alteration of neurotransmitter levels. Further improvements were also noticed based on histological alterations and reduction of neurodegeneration in the brain tissue. A modest inhibition of the neurodegenerative markers was observed by propolis. The study clearly indicates a neuroprotective effect of ginger and propolis against MSG-induced neurodegenerative disorders and these beneficial effects could be attributed to the polyphenolic compounds present in these natural products.

Ameliorating effects of aged garlic extracts against Aβ-induced neurotoxicity and cognitive impairment

Science.gov (United States)

2013-01-01

Background In vitro antioxidant activities and neuron-like PC12 cell protective effects of solvent fractions from aged garlic extracts were investigated to evaluate their anti-amnesic functions. Ethyl acetate fractions of aged garlic had higher total phenolics than other fractions. Methods Antioxidant activities of ethyl acetate fractions from aged garlic were examined using 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) diammonium salt (ABTS) and malondialdehyde (MDA) inhibitory effect using mouse whole brain homogenates. Levels of cellular oxidative stress as reactive oxygen species (ROS) accumulation were measured using 2',7'-dichlorofluorescein diacetate (DCF-DA). PC12 cell viability was investigated by 3-[4,5-dimethythiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and lactate dehydtrogenase (LDH) assay. The learning and memory impairment in institute of cancer research (ICR) mice was induced by neurotoxic amyloid beta protein (Aβ) to investigate in vivo anti-amnesic effects of aged garlic extracts by using Y-maze and passive avoidance tests. Results We discovered that ethyl acetate fractions showed the highest ABTS radical scavenging activity and MDA inhibitory effect. Intracellular ROS accumulation resulting from Aβ treatment in PC12 cells was significantly reduced when ethyl acetate fractions were presented in the medium compare to PC12 cells which was only treated with Aβ only. Ethyl acetate fractions from aged garlic extracts showed protection against Aβ-induced neurotoxicity. Pre-administration with aged garlic extracts attenuated Aβ-induced learning and memory deficits in both in vivo tests. Conclusions Our findings suggest that aged garlic extracts with antioxidant activities may improve cognitive impairment against Aβ-induced neuronal deficit, and possess a wide range of beneficial activities for neurodegenerative disorders, notably Alzheimer's disease (AD). PMID:24134394

Neurite outgrowth in human induced pluripotent stem cell-derived neurons as a high-throughput screen for developmental neurotoxicity or neurotoxicity.

Science.gov (United States)

Ryan, Kristen R; Sirenko, Oksana; Parham, Fred; Hsieh, Jui-Hua; Cromwell, Evan F; Tice, Raymond R; Behl, Mamta

2016-03-01

Due to the increasing prevalence of neurological disorders and the large number of untested compounds in the environment, there is a need to develop reliable and efficient screening tools to identify environmental chemicals that could potentially affect neurological development. Herein, we report on a library of 80 compounds screened for their ability to inhibit neurite outgrowth, a process by which compounds may elicit developmental neurotoxicity, in a high-throughput, high-content assay using human neurons derived from induced pluripotent stem cells (iPSC). The library contains a diverse set of compounds including those that have been known to be associated with developmental neurotoxicity (DNT) and/or neurotoxicity (NT), environmental compounds with unknown neurotoxic potential (e.g., polycyclic aromatic hydrocarbons (PAHs) and flame retardants (FRs)), as well as compounds with no documented neurotoxic potential. Neurons were treated for 72h across a 6-point concentration range (∼0.3-100μM) in 384-well plates. Effects on neurite outgrowth were assessed by quantifying total outgrowth, branches, and processes. We also assessed the number ofviable cells per well. Concentration-response profiles were evaluated using a Hill model to derive benchmark concentration (BMC) values. Assay performance was evaluated using positive and negative controls and test replicates. Compounds were ranked by activity and selectivity (i.e., specific effects on neurite outgrowth in the absence of concomitant cytotoxicity) and repeat studies were conducted to confirm selectivity. Among the 80 compounds tested, 38 compounds were active, of which 16 selectively inhibited neurite outgrowth. Of these 16 compounds, 12 were known to cause DNT/NT and the remaining 4 compounds included 3 PAHs and 1 FR. In independent repeat studies, 14/16 selective compounds were reproducibly active in the assay, of which only 6 were selective for inhibition of neurite outgrowth. These 6 compounds were

A novel one-dimensional chain built of vanadyl ions and pyrazine-2,5-dicarboxylate

NARCIS (Netherlands)

Lankelma, M.; de Boer, J.; Ferbinteanu, M.; Dantas Ramos, A.L.; Tanasa, R.; Rothenberg, G.; Tanase, S.

2015-01-01

We present a new coordination polymer, {[VO(pzdc)(H2O)(2)] H2O}(n), built from vanadyl and pyrazine-2,5-dicarboxylate (pzdc) ions. It consists of a one-dimensional chain of vanadyl ions linked by pzdc ions. The carboxylate groups show monodentate coordination, while the pyrazine ring is present both

Mutation in HFE gene decreases manganese accumulation and oxidative stress in the brain after olfactory manganese exposure.

Science.gov (United States)

Ye, Qi; Kim, Jonghan

2016-06-01

Increased accumulation of manganese (Mn) in the brain is significantly associated with neurobehavioral deficits and impaired brain function. Airborne Mn has a high systemic bioavailability and can be directly taken up into the brain, making it highly neurotoxic. While Mn transport is in part mediated by several iron transporters, the expression of these transporters is altered by the iron regulatory gene, HFE. Mutations in the HFE gene are the major cause of the iron overload disorder, hereditary hemochromatosis, one of the prevalent genetic diseases in humans. However, whether or not HFE mutation modifies Mn-induced neurotoxicity has not been evaluated. Therefore, our goal was to define the role of HFE mutation in Mn deposition in the brain and the resultant neurotoxic effects after olfactory Mn exposure. Mice carrying the H67D HFE mutation, which is homologous to the H63D mutation in humans, and their control, wild-type mice, were intranasally instilled with MnCl2 with different doses (0, 0.2, 1.0 and 5.0 mg kg(-1)) daily for 3 days. Mn levels in the blood, liver and brain were determined using inductively-coupled plasma mass spectrometry (ICP-MS). H67D mutant mice showed significantly lower Mn levels in the blood, liver, and most brain regions, especially in the striatum, while mice fed an iron-overload diet did not. Moreover, mRNA expression of ferroportin, an essential exporter of iron and Mn, was up-regulated in the striatum. In addition, the levels of isoprostane, a marker of lipid peroxidation, were increased in the striatum after Mn exposure in wild-type mice, but were unchanged in H67D mice. Together, our results suggest that the H67D mutation provides decreased susceptibility to Mn accumulation in the brain and neurotoxicity induced by inhaled Mn.

Elucidating the neurotoxic effects of MDMA and its analogs.

Science.gov (United States)

Karuppagounder, Senthilkumar S; Bhattacharya, Dwipayan; Ahuja, Manuj; Suppiramaniam, Vishnu; Deruiter, Jack; Clark, Randall; Dhanasekaran, Muralikrishnan

2014-04-17

There is a rapid increase in the use of methylenedioxymethamphetamine (MDMA) and its structural congeners/analogs globally. MDMA and MDMA-analogs have been synthesized illegally in furtive dwellings and are abused due to its addictive potential. Furthermore, MDMA and MDMA-analogs have shown to have induced several adverse effects. Hence, understanding the mechanisms mediating this neurotoxic insult of MDMA-analogs is of immense importance for the public health in the world. We synthesized and investigated the neurotoxic effects of MDMA and its analogs [4-methylenedioxyamphetamine (MDA), 2, 6-methylenedioxyamphetamine (MDMA), and N-ethyl-3, 4-methylenedioxyamphetamine (MDEA)]. The stimulatory or the dopaminergic agonist effects of MDMA and MDMA-analogs were elucidated using the established 6-hydroxydopamine lesioned animal model. Additionally, we also investigated the neurotoxic mechanisms of MDMA and MDMA-analogs on mitochondrial complex-I activity and reactive oxygen species generation. MDMA and MDMA-analogs exhibited stimulatory activity as compared to amphetamines and also induced several behavioral changes in the rodents. MDMA and MDMA-analogs enhanced the reactive oxygen generation and inhibited mitochondrial complex-I activity which can lead to neurodegeneration. Hence the mechanism of neurotoxicity, MDMA and MDMA-analogs can enhance the release of monoamines, alter the monoaminergic neurotransmission, and augment oxidative stress and mitochondrial abnormalities leading to neurotoxicity. Thus, our study will help in developing effective pharmacological and therapeutic approaches for the treatment of MDMA and MDMA-analog abuse. Copyright © 2014 Elsevier Inc. All rights reserved.

Neuroprotective effects of statins against amyloid β-induced neurotoxicity

Directory of Open Access Journals (Sweden)

Hsin-Hua Li

2018-01-01

Full Text Available A growing body of evidence suggests that disruption of the homeostasis of lipid metabolism affects the pathogenesis of Alzheimer's disease (AD. In particular, dysregulation of cholesterol homeostasis in the brain has been reported to considerably increase the risk of developing AD. Thus, dysregulation of lipid homeostasis may increase the amyloid β (Aβ levels by affecting amyloid precursor protein (APP cleavage, which is the most important risk factor involved in the pathogenesis of AD. Previous research demonstrated that Aβ can trigger neuronal insulin resistance, which plays an important role in response to Aβ-induced neurotoxicity in AD. Epidemiological studies also suggested that statin use is associated with a decreased incidence of AD. Therefore, statins are believed to be a good candidate for conferring neuroprotective effects against AD. Statins may play a beneficial role in reducing Aβ-induced neurotoxicity. Their effect involves a putative mechanism beyond its cholesterol-lowering effects in preventing Aβ-induced neurotoxicity. However, the underlying molecular mechanisms of the protective effect of statins have not been clearly determined in Aβ-induced neurotoxicity. Given that statins may provide benefits beyond the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase, these drugs may also improve the brain. Thus, statins may have beneficial effects on impaired insulin signaling by activating AMP-activated protein kinase (AMPK in neuronal cells. They play a potential therapeutic role in targeting Aβ-mediated neurotoxicity.

Critical consideration of the multiplicity of experimental and organismic determinants of pyrethroid neurotoxicity: a proof of concept.

Science.gov (United States)

Wolansky, M J; Tornero-Velez, R

2013-01-01

Pyrethroids (PYR) are pesticides with high insecticidal activity that may disrupt neuronal excitability in target and nontarget species. The accumulated evidence consistently showed that this neurophysiologic action is followed by alterations in motor, sensorimotor, neuromuscular, and thermoregulatory responses. Nevertheless, there are some equivocal results regarding the potency of PYR in lab animals. The estimation of potency is an important step in pesticide chemical risk assessment. In order to identify the variables influencing neurobehavioral findings across PYR studies, evidence on experimental and organismic determinants of acute PYR-induced neurotoxicity was reviewed in rodents. A comprehensive analysis of these studies was conducted focusing on test material and dosing conditions, testing conditions, animal models, and other determinants such as testing room temperature. Variations in the severity of the neurotoxicity, under lab-controlled conditions, was explained based upon factors including influence of animal species and age, test material features such as chemical structure and stereochemistry, and dosing conditions such as vehicle, route of exposure, and dose volume. If not controlled, the interplay of these factors may lead to large variance in potency estimation. This review examined the scope of acute toxicological data required to determine the safety of pesticide products, and factors and covariates that need to be controlled in order to ensure that predictivity and precaution are balanced in a risk assessment process within a reasonable time-frame, using acute PYR-induced neurotoxicity in rodents as an exemplar.

Is Neurotoxicity of Metallic Nanoparticles the Cascades of Oxidative Stress?

Science.gov (United States)

Song, Bin; Zhang, YanLi; Liu, Jia; Feng, XiaoLi; Zhou, Ting; Shao, LongQuan

2016-06-01

With the rapid development of nanotechnology, metallic (metal or metal oxide) nanoparticles (NPs) are widely used in many fields such as cosmetics, the food and building industries, and bio-medical instruments. Widespread applications of metallic NP-based products increase the health risk associated with human exposures. Studies revealed that the brain, a critical organ that consumes substantial amounts of oxygen, is a primary target of metallic NPs once they are absorbed into the body. Oxidative stress (OS), apoptosis, and the inflammatory response are believed to be the main mechanisms underlying the neurotoxicity of metallic NPs. Other studies have disclosed that antioxidant pretreatment or co-treatment can reverse the neurotoxicity of metallic NPs by decreasing the level of reactive oxygen species, up-regulating the activities of antioxidant enzymes, decreasing the proportion of apoptotic cells, and suppressing the inflammatory response. These findings suggest that the neurotoxicity of metallic NPs might involve a cascade of events following NP-induced OS. However, additional research is needed to determine whether NP-induced OS plays a central role in the neurotoxicity of metallic NPs, to develop a comprehensive understanding of the correlations among neurotoxic mechanisms and to improve the bio-safety of metallic NP-based products.

Multiple mechanisms of PCB neurotoxicity

Energy Technology Data Exchange (ETDEWEB)

Carpenter, D.O.; Stoner, C.T.; Lawrence, D.A. [Univ. of New York, Albany, NY (United States)] [and others

1996-12-31

Polychlorinated biphenyls (PCBs) have been implicated in cancer, but many of the symptoms in humans exposed to PCBs are related to the nervous system and behavior. We demonstrated three different direct mechanisms whereby PCBs are neurotoxic in rats. By using flow cytometry, we demonstrated that the orthosubstituted PCB congener 2,4,4{prime}, but neither TCDD nor the coplanar PCB congener 3,4,5,3{prime},4{prime}, causes rapid death of cerebellar granule cells. The ortho-substituted congener 2,4,4{prime} reduced long-term potentiation, an indicator of cognitive potential, in hippocampal brain slices, but a similar effect was observed for the coplanar congener 3,4,3{prime},4{prime}, indicating that this effect may be caused by both ortho- and coplanar congeners by mechanisms presumably not mediated via the Ah receptor. It was previously shown that some ortho-substituted PCB congeners cause a reduction in levels of the neurotransmitter dopamine, and we present in vitro and in vivo evidence that this is due to reduction of synthesis of dopamine via inhibition of the enzyme tyrosine hydroxylase. Thus, PCBs have a variety of mechanisms of primary neurotoxicity, and neurotoxicity is a characteristic of ortho-substituted, non-dioxin-like congeners as well as some coplanar congeners. The relative contribution of each of these mechanisms to the loss of cognitive function in humans exposed to PCBs remains to be determined. 42 refs., 3 figs., 1 tab.

Neurotoxic shellfish poisoning: A review

NARCIS (Netherlands)

Apeldoorn ME van; Egmond HP van; Speijers GJA; CSR; ARO

2001-01-01

This review contains information on the neurotoxic shellfish poisoning (NSP) syndrome and the provoking toxins called brevetoxins, produced by the dinoflagellate Gymnodinium breve. Data on chemical structures and detection methods for brevetoxins, sources for brevetoxins, marine organisms associated

A convenient preparation of 9 H -carbazole-3,6-dicarbonitrile and 9 H -carbazole-3,6-dicarboxylic acid

KAUST Repository

Weselinski, Lukasz Jan; Luebke, Ryan; Eddaoudi, Mohamed

2014-01-01

,6-dicarboxylic acid. Both compounds are versatile and fine-tunable organic building blocks and therefore offer potential in material science, medicinal and supramolecular chemistry. © Georg Thieme Verlag Stuttgart New York.

Mechanistic insight into neurotoxicity induced by developmental insults

International Nuclear Information System (INIS)

Tamm, Christoffer; Ceccatelli, Sandra

2017-01-01

Epidemiological and/or experimental studies have shown that unfavorable prenatal environmental factors, such as stress or exposure to certain neurotoxic environmental contaminants, may have adverse consequences for neurodevelopment. Alterations in neurogenesis can have harmful effects not only for the developing nervous system, but also for the adult brain where neurogenesis is believed to play a role in learning, memory, and even in depression. Many recent advances in the understanding of the complex process of nervous system development can be integrated into the field of neurotoxicology. In the past 15 years we have been using cultured neural stem or progenitor cells to investigate the effects of neurotoxic stimuli on cell survival, proliferation and differentiation, with special focus on heritable effects. This is an overview of the work performed by our group in the attempt to elucidate the mechanisms of developmental neurotoxicity and possibly provide relevant information for the understanding of the etiopathogenesis of complex brain disorders. - Highlights: • The developing nervous system is highly sensitive to toxic insults. • Neural stem cells are relevant models for mechanistic studies as well as for identifying heritable effects due to epigenetic changes. • Depending on the dose, the outcome of exposure to neurotoxicants ranges from altered proliferation and differentiation to cell death. • The elucidation of neurotoxicity mechanisms is relevant for understanding the etiopathogenesis of developmental and adult nervous system disorders.

Biomarkers of cytokine release syndrome and neurotoxicity related to CAR-T cell therapy.

Science.gov (United States)

Wang, Zhenguang; Han, Weidong

2018-01-01

Severe cytokine release syndrome (CRS) and neurotoxicity following chimeric antigen receptor T cell (CAR-T) therapy can be life-threatening in some cases, and management of those toxicities is still a great challenge for physicians. Researchers hope to understand the pathophysiology of CRS and neurotoxicity, and identify predictive biomarkers that can forecast those toxicities in advance. Some risk factors for severe CRS and/or neurotoxicity including patient and treatment characteristics have been identified in multiple clinical trials of CAR-T cell therapy. Moreover, several groups have identified some predictive biomarkers that are able to determine beforehand which patients may suffer severe CRS and/or neurotoxicity during CAR-T cell therapy, facilitating testing of early intervention strategies for those toxicities. However, further studies are needed to better understand the biology and related risk factors for CRS and/or neurotoxicity, and determine if those identified predictors can be extrapolated to other series. Herein, we review the pathophysiology of CRS and neurotoxicity, and summarize the progress of predictive biomarkers to improve CAR-T cell therapy in cancer.

Diffusion abnormalities of the globi pallidi in manganese neurotoxicity

Energy Technology Data Exchange (ETDEWEB)

McKinney, Alexander M.; Filice, Ross W.; Teksam, Mehmet; Casey, Sean; Truwit, Charles; Clark, H. Brent; Woon, Carolyn; Liu, Hai Ying [Department of Radiology, Medical School, Box 292, 420 Delaware Street S.E., 55455, Minneapolis, MN (United States)

2004-04-01

Manganese is an essential trace metal required for normal central nervous system function, which is toxic when in excess amounts in serum. Manganese neurotoxicity has been demonstrated in patients with chronic liver/biliary failure where an inability to excrete manganese via the biliary system causes increased serum levels, and in patients on total parenteral nutrition (TPN), occupational/inhalational exposure, or other source of excess exogenous manganese. Manganese has been well described in the literature to deposit selectively in the globi pallidi and to induce focal neurotoxicity. We present a case of a 53-year-old woman who presented for a brain MR 3 weeks after liver transplant due to progressively decreasing level of consciousness. The patient had severe liver failure by liver function tests and bilirubin levels, and had also been receiving TPN since the transplant. The MR demonstrated symmetric hyperintensity on T1-weighted images in the globi pallidi. Apparent diffusion coefficient (ADC) map indicated restricted diffusion in the globi pallidi bilaterally. The patient eventually succumbed to systemic aspergillosis 3 days after the MR. The serum manganese level was 195 mcg/l (micrograms per liter) on postmortem exam (over 20 times the upper limits of normal). The patient was presumed to have suffered from manganese neurotoxicity since elevated serum manganese levels have been shown in the literature to correlate with hyperintensity on T1-weighted images, neurotoxicity symptoms, and focal concentration of manganese in the globi pallidi. Neuropathologic sectioning of the globi pallidi at autopsy was also consistent with manganese neurotoxicity. (orig.)

Fingerprinting of neurotoxic compounds using a mouse embryonic stem cell dual luminescence reporter assay

NARCIS (Netherlands)

Colaianna, M.; Ilmjärv, S.; Peterson, H.; Ilse Kern, I.; Julien, S.; Baquié, M.; allocca, G.; Bosgra, S.; Sachinidis, A.; Hengstler, J.G.; Leist, M.; Krause, K.H.

2017-01-01

Identification of neurotoxic drugs and environmental chemicals is an important challenge. However, only few tools to address this topic are available. The aim of this study was to develop a neurotoxicity/developmental neurotoxicity (DNT) test system, using the pluripotent mouse embryonic stem cell

Hygroscopic Behavior of Multicomponent Aerosols Involving NaCl and Dicarboxylic Acids.

Science.gov (United States)

Peng, Chao; Jing, Bo; Guo, Yu-Cong; Zhang, Yun-Hong; Ge, Mao-Fa

2016-02-25

Atmospheric aerosols are usually complex mixtures of inorganic and organic compounds. The hygroscopicity of mixed particles is closely related to their chemical composition and interactions between components, which is still poorly understood. In this study, the hygroscopic properties of submicron particles composed of NaCl and dicarboxylic acids including oxalic acid (OA), malonic acid (MA), and succinic acid (SA) with various mass ratios are investigated with a hygroscopicity tandem differential mobility analyzer (HTDMA) system. Both the Zdanovskii-Stokes-Robinson (ZSR) method and extended aerosol inorganics model (E-AIM) are applied to predict the water uptake behaviors of sodium chloride/dicarboxylic acid mixtures. For NaCl/OA mixed particles, the measured growth factors were significantly lower than predictions from the model methods, indicating a change in particle composition caused by chloride depletion. The hygroscopic growth of NaCl/MA particles was well described by E-AIM, and that of NaCl/SA particles was dependent upon mixing ratio. Compared with model predictions, it was determined that water uptake of the NaCl/OA mixture could be enhanced and could be closer to the predictions by addition of levoglucosan or malonic acid, which retained water even at low relative humidity (RH), leading to inhibition of HCl evaporation during dehydration. These results demonstrate that the coexisting hygroscopic species have a strong influence on the phase state of particles, thus affecting chemical interactions between inorganic and organic compounds as well as the overall hygroscopicity of mixed particles.

Occupational Neurotoxic Diseases in Taiwan

Directory of Open Access Journals (Sweden)

Chi-Hung Liu

2012-12-01

Full Text Available Occupational neurotoxic diseases have become increasingly common in Taiwan due to industrialization. Over the past 40 years, Taiwan has transformed from an agricultural society to an industrial society. The most common neurotoxic diseases also changed from organophosphate poisoning to heavy metal intoxication, and then to organic solvent and semiconductor agent poisoning. The nervous system is particularly vulnerable to toxic agents because of its high metabolic rate. Neurological manifestations may be transient or permanent, and may range from cognitive dysfunction, cerebellar ataxia, Parkinsonism, sensorimotor neuropathy and autonomic dysfunction to neuromuscular junction disorders. This study attempts to provide a review of the major outbreaks of occupational neurotoxins from 1968 to 2012. A total of 16 occupational neurotoxins, including organophosphates, toxic gases, heavy metals, organic solvents, and other toxic chemicals, were reviewed. Peer-reviewed articles related to the electrophysiology, neuroimaging, treatment and long-term follow up of these neurotoxic diseases were also obtained. The heavy metals involved consisted of lead, manganese, organic tin, mercury, arsenic, and thallium. The organic solvents included n-hexane, toluene, mixed solvents and carbon disulfide. Toxic gases such as carbon monoxide, and hydrogen sulfide were also included, along with toxic chemicals including polychlorinated biphenyls, tetramethylammonium hydroxide, organophosphates, and dimethylamine borane. In addition we attempted to correlate these events to the timeline of industrial development in Taiwan. By researching this topic, the hope is that it may help other developing countries to improve industrial hygiene and promote occupational safety and health care during the process of industrialization.

O-alkylation of disodium salt of diethyl 3,4-dihydroxythiophene-2,5-dicarboxylate with 1,2-dichloroethane catalyzed by ionic type phase transfer catalyst and potassium iodide

Energy Technology Data Exchange (ETDEWEB)

Lu, Huasheng; Yin, Hengbo; Wang, Aili; Shen, Jun; Yan, Xiaobo; Liu, Yumin; Zhang, Changhua [Jiangsu University, Zhenjiang (China)

2014-01-15

Diethyl 3,4-ethylenedioxy thiophene-2,5-dicarboxylate was efficiently synthesized via the O-alkylation of disodium salt of diethyl 3,4-dihydroxy thiophene-2,5-dicarboxylate with 1,2-dichloroethane over ionic type phase transfer catalysts, such as tetrabutyl ammonium bromide and benzyl triethyl ammonium chloride. The ionic type phase transfer catalysts showed higher catalytic activities than the nonionic type phase transfer catalysts, such as triethylamine, pyridine, 18-crown-6, and polyethylene glycol 400/600, in the O-alkylation reaction. The conversion of the disodium salt of more than 97% and the selectivity of diethyl 3,4-ethylenedioxy thiophene-2,5-dicarboxylate of more than 98% were achieved when the O-alkylation reaction was synergistically catalyzed by tetrabutyl ammonium bromide and potassium iodide.

Clinical Neurotoxic Disorders : Past, Present and Future

Directory of Open Access Journals (Sweden)

Nag Devika

2001-01-01

Full Text Available Neurotoxins have existed on the earth from times immemorial. Old neurotoxic disorders were due to ingestion/ exposure of heavy metals and food like lathyrus sativus over a long period of time. The 20th Century with rapid industrialsation and expanding chemical and drug industry has spawned several new, hitherto unknown disorders. Old disorders continue to exist e.g. fluorosis, arsenicosis, lathyrism, manganism and lead neuropathy, along with new diseases like Minamata disease, subacute myelo optic neuropathy (SMON, MPTP-Parkinsonian syndorme, triorthcresyl phosphate (TOCP neuroparalytic disease, pesticide induced seizures, tremor and neuropathy, solvent encephalopthy, antipileptic drug foetal syndrome and excitotoxin induced behavioural disorders. Studies on pesticides Organochlorine and organophosphates, synthetic pyrethrins, solvents, heavy metals and substances abuse in the Indian context confirm the neurotoxic nature of many synthetic substances. Future problems envisaged are of concern to clinical neurologists as many of these neurotoxic disorders mimic syndromes of well known neurological disease. The new millenium poses a challenge to the clinician as newer compounds in industry, food, drugs and chemical war agents are being developed. Molecular genetics has advanced rapidly with release of the human genome map. Animal cloning and genetically modified plant products have entered the food chain. How safe are these new inventions for the central nervous system is a big question? India cannot afford disasters like Union Carbide′s Bhopal gas leak nor be a silent spectator to manipulative biotechnology. Unless it is proven beyond all doubt to be a safe innovation, Chemicals have to be cautiously introduced in our environment. To Study, ascertain and confirm safety or neurotoxicity is an exciting challenge for the neuroscientists of the 21st century.

Berberine Reduces Neurotoxicity Related to Nonalcoholic Steatohepatitis in Rats

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Doaa A. Ghareeb

2015-01-01

Full Text Available Berberine is a plant alkaloid that has several pharmacological effects such as antioxidant, antilipidemic, and anti-inflammatory effects. Nonalcoholic steatohepatitis (NASH triggers different aspects of disorders such as impaired endogenous lipid metabolism, hypercholesterolemia, oxidative stress, and neurotoxicity. In this study, we examined the mechanism by which NASH induces neurotoxicity and the protective effect of berberine against both NASH and its associated neurotoxicity. NASH induced rats showed significant impairments in lipid metabolism with increased serum triglycerides, cholesterol, and low-density lipoprotein (LDL. The NASH induced group also demonstrated a significant oxidative stress which is characterized by increased TBARs level and decreased antioxidant capacity such as GSH and SOD levels. Moreover, the NASH induction was associated with inflammation which was demonstrated by increased TNFα and nitric oxide levels. Hyperglycemia and hyperinsulinemia were observed in the NASH induced group. Also, our results showed a significant increase in the expression of the acetylcholine esterase (AChE and amyloid beta precursor protein (AβPP. These changes were significantly correlated with decreased insulin degrading enzyme (IDE and beta-amyloid40 (Aβ40 and increased beta-amyloid42 (Aβ42 in the hippocampal region. Daily administration of berberine (50 mg/kg for three weeks ameliorated oxidative stress, inflammation, hyperlipidemia, hyperglycemia, hyperinsulinemia, and the observed neurotoxicity.

Current research on methamphetamine-induced neurotoxicity: animal models of monoamine disruption.

Science.gov (United States)

Kita, Taizo; Wagner, George C; Nakashima, Toshikatsu

2003-07-01

Methamphetamine (METH)-induced neurotoxicity is characterized by a long-lasting depletion of striatal dopamine (DA) and serotonin as well as damage to striatal dopaminergic and serotonergic nerve terminals. Several hypotheses regarding the mechanism underlying METH-induced neurotoxicity have been proposed. In particular, it is thought that endogenous DA in the striatum may play an important role in mediating METH-induced neuronal damage. This hypothesis is based on the observation of free radical formation and oxidative stress produced by auto-oxidation of DA consequent to its displacement from synaptic vesicles to cytoplasm. In addition, METH-induced neurotoxicity may be linked to the glutamate and nitric oxide systems within the striatum. Moreover, using knockout mice lacking the DA transporter, the vesicular monoamine transporter 2, c-fos, or nitric oxide synthetase, it was determined that these factors may be connected in some way to METH-induced neurotoxicity. Finally a role for apoptosis in METH-induced neurotoxicity has also been established including evidence of protection of bcl-2, expression of p53 protein, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), activity of caspase-3. The neuronal damage induced by METH may reflect neurological disorders such as autism and Parkinson's disease.

Differentiation of DctA and DcuS function in the DctA/DcuS sensor complex of Escherichia coli: function of DctA as an activity switch and of DcuS as the C4-dicarboxylate sensor.

Science.gov (United States)

Steinmetz, Philipp Aloysius; Wörner, Sebastian; Unden, Gottfried

2014-10-01

The C4-dicarboxylate responsiveness of the sensor kinase DcuS is only provided in concert with C4-dicarboxylate transporters DctA or DcuB. The individual roles of DctA and DcuS for the function of the DctA/DcuS sensor complex were analysed. (i) Variant DctA(S380D) in the C4-dicarboxylate site of DctA conferred C4-dicarboxylate sensitivity to DcuS in the DctA/DcuS complex, but was deficient for transport and for growth on C4-dicarboxylates. Consequently transport activity of DctA is not required for its function in the sensor complex. (ii) Effectors like fumarate induced expression of DctA/DcuS-dependent reporter genes (dcuB-lacZ) and served as substrates of DctA, whereas citrate served only as an inducer of dcuB-lacZ without affecting DctA function. (iii) Induction of dcuB-lacZ by fumarate required 33-fold higher concentrations than for transport by DctA (Km  = 30 μM), demonstrating the existence of different fumarate sites for both processes. (iv) In titration experiments with increasing dctA expression levels, the effect of DctA on the C4-dicarboxylate sensitivity of DcuS was concentration dependent. The data uniformly show that C4-dicarboxylate sensing by DctA/DcuS resides in DcuS, and that DctA serves as an activity switch. Shifting of DcuS from the constitutive ON to the C4-dicarboxylate responsive state, required presence of DctA but not transport by DctA. © 2014 John Wiley & Sons Ltd.

Antioxidant potential properties of mushroom extract (Agaricus bisporus) against aluminum-induced neurotoxicity in rat brain.

Science.gov (United States)

Waly, Mostafa I; Guizani, Nejib

2014-09-01

Aluminum (Al) is an environmental toxin that induces oxidative stress in neuronal cells. Mushroom cultivar extract (MCE) acted as a potent antioxidant agent and protects against cellular oxidative stress in human cultured neuronal cells. This study aimed to investigate the neuroprotective effect of MCE against Al-induced neurotoxicity in rat brain. Forty Sprague-Dawley rats were divided into 4 groups (10 rats per group), control group, MCE-fed group, Al-administered group and MCE/Al-treated group. Animals were continuously fed ad-libitum their specific diets for 4 weeks. At the end of the experiment, all rats were sacrificed and the brain tissues were homogenized and examined for biochemical measurements of neurocellular oxidative stress indices [glutathione (GSH), Total Antioxidant Capacity (TAC), antioxidant enzymes and oxidized dichlorofluorescein (DCF)]. Al-administration caused inhibition of antioxidant enzymes and a significant decrease in GSH and TAC levels, meanwhile it positively increased cellular oxidized DCF level, as well as Al concentration in brain tissues. Feeding animals with MCE had completely offset the Al-induced oxidative stress and significantly restrict the Al accumulation in brain tissues of Al-administered rats. The results obtained suggest that MCE acted as a potent dietary antioxidant and protects against Al-mediated neurotoxicity, by abrogating neuronal oxidative stress.

Developmental neurotoxic effects of two pesticides: Behavior and biomolecular studies on chlorpyrifos and carbaryl

International Nuclear Information System (INIS)

Lee, Iwa; Eriksson, Per; Fredriksson, Anders; Buratovic, Sonja; Viberg, Henrik

2015-01-01

In recent times, an increased occurrence of neurodevelopmental disorders, such as neurodevelopmental delays and cognitive abnormalities has been recognized. Exposure to pesticides has been suspected to be a possible cause of these disorders, as these compounds target the nervous system of pests. Due to the similarities of brain development and composition, these pesticides may also be neurotoxic to humans. We studied two different pesticides, chlorpyrifos and carbaryl, which specifically inhibit acetylcholinesterase (AChE) in the nervous system. The aim of the study was to investigate if the pesticides can induce neurotoxic effects, when exposure occurs during a period of rapid brain growth and maturation. The results from the present study show that both compounds can affect protein levels in the developing brain and induce persistent adult behavior and cognitive impairments, in mice neonatally exposed to a single oral dose of chlorpyrifos (0.1, 1.0 or 5 mg/kg body weight) or carbaryl (0.5, 5.0 or 20.0 mg/kg body weight) on postnatal day 10. The results also indicate that the developmental neurotoxic effects induced are not related to the classical mechanism of acute cholinergic hyperstimulation, as the AChE inhibition level (8–12%) remained below the threshold for causing systemic toxicity. The neurotoxic effects are more likely caused by a disturbed neurodevelopment, as similar behavioral neurotoxic effects have been reported in studies with pesticides such as organochlorines, organophosphates, pyrethroids and POPs, when exposed during a critical window of neonatal brain development. - Highlights: • A single neonatal exposure to chlorpyrifos or carbaryl induced developmental neurotoxic effects. • The neurotoxic effects were not caused by acute AChE inhibition. • The neurotoxic effects manifested as altered levels of neuroproteins in the developing brain. • The neurotoxic effects manifested as adult persistent aberrant behavior and cognitive function. �

Developmental neurotoxic effects of two pesticides: Behavior and biomolecular studies on chlorpyrifos and carbaryl

Energy Technology Data Exchange (ETDEWEB)

Lee, Iwa; Eriksson, Per; Fredriksson, Anders; Buratovic, Sonja; Viberg, Henrik, E-mail: henrik.viberg@ebc.uu.se

2015-11-01

In recent times, an increased occurrence of neurodevelopmental disorders, such as neurodevelopmental delays and cognitive abnormalities has been recognized. Exposure to pesticides has been suspected to be a possible cause of these disorders, as these compounds target the nervous system of pests. Due to the similarities of brain development and composition, these pesticides may also be neurotoxic to humans. We studied two different pesticides, chlorpyrifos and carbaryl, which specifically inhibit acetylcholinesterase (AChE) in the nervous system. The aim of the study was to investigate if the pesticides can induce neurotoxic effects, when exposure occurs during a period of rapid brain growth and maturation. The results from the present study show that both compounds can affect protein levels in the developing brain and induce persistent adult behavior and cognitive impairments, in mice neonatally exposed to a single oral dose of chlorpyrifos (0.1, 1.0 or 5 mg/kg body weight) or carbaryl (0.5, 5.0 or 20.0 mg/kg body weight) on postnatal day 10. The results also indicate that the developmental neurotoxic effects induced are not related to the classical mechanism of acute cholinergic hyperstimulation, as the AChE inhibition level (8–12%) remained below the threshold for causing systemic toxicity. The neurotoxic effects are more likely caused by a disturbed neurodevelopment, as similar behavioral neurotoxic effects have been reported in studies with pesticides such as organochlorines, organophosphates, pyrethroids and POPs, when exposed during a critical window of neonatal brain development. - Highlights: • A single neonatal exposure to chlorpyrifos or carbaryl induced developmental neurotoxic effects. • The neurotoxic effects were not caused by acute AChE inhibition. • The neurotoxic effects manifested as altered levels of neuroproteins in the developing brain. • The neurotoxic effects manifested as adult persistent aberrant behavior and cognitive function. �

The Effects of IGF-1 on Trk Expressing DRG Neurons with HIV-gp120- Induced Neurotoxicity.

Science.gov (United States)

Li, Hao; Liu, Zhen; Chi, Heng; Bi, Yanwen; Song, Lijun; Liu, Huaxiang

2016-01-01

HIV envelope glycoprotein gp120 is the main protein that causes HIVassociated sensory neuropathy. However, the underlying mechanisms of gp120-induced neurotoxicity are still unclear. There are lack effective treatments for relieving HIV-related neuropathic symptoms caused by gp120-induced neurotoxicity. In the present study, tyrosine kinase receptor (Trk)A, TrkB, and TrkC expression in primary cultured dorsal root ganglion (DRG) neurons with gp120-induced neurotoxicity was investigated. The effects of IGF-1 on distinct Trk-positive DRG neurons with gp120-induced neurotoxicity were also determined. The results showed that gp120 not only dose-dependently induced DRG neuronal apoptosis and inhibited neuronal survival and neurite outgrowth, but also decreased distinct Trk expression levels. IGF-1 rescued DRG neurons from apoptosis and improved neuronal survival of gp120 neurotoxic DRG neurons in vitro. IGF-1 also improved TrkA and TrkB, but not TrkC, expression in gp120 neurotoxic conditions. The effects of IGF-1 could be blocked by preincubation with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. These results suggested that gp120 may have a wide range of neurotoxicity on different subpopulations of DRG neurons, while IGF-1 might only relieve some subpopulations of DRG neurons with gp120-induced neurotoxicity. These data provide novel information of mechanisms of gp120 neurotoxicity on primary sensory neurons and the potential therapeutic effects of IGF-1 on gp120-induced neurotoxicity.

Molecular distributions of dicarboxylic acids, ketocarboxylic acids and α-dicarbonyls in biomass burning aerosols: implications for photochemical production and degradation in smoke layers

Directory of Open Access Journals (Sweden)

A. Hoffer

2010-03-01

Full Text Available Aerosols in the size class <2.5 μm (6 daytime and 9 nighttime samples were collected at a pasture site in Rondônia, Brazil, during the intensive biomass burning period of 16–26 September 2002 as part of the Large-Scale Biosphere-Atmosphere Experiment in Amazonia – Smoke, Aerosols, Clouds, Rainfall and Climate (LBA-SMOCC. Homologous series of dicarboxylic acids (C2–C11 and related compounds (ketocarboxylic acids and α-dicarbonyls were identified using gas chromatography (GC and GC/mass spectrometry (GC/MS. Among the species detected, oxalic acid was found to be the most abundant, followed by succinic, malonic and glyoxylic acids. Average concentrations of total dicarboxylic acids, ketocarboxylic acids and α-dicarbonyls in the aerosol samples were 2180, 167 and 56 ng m−3, respectively. These are 2–8, 3–11 and 2–16 times higher, respectively, than those reported in urban aerosols, such as in 14 Chinese megacities. Higher ratios of dicarboxylic acids and related compounds to biomass burning tracers (levoglucosan and K+ were found in the daytime than in the nighttime, suggesting the importance of photochemical production. On the other hand, higher ratios of oxalic acid to other dicarboxylic acids and related compounds normalized to biomass burning tracers (levoglucosan and K+ in the daytime provide evidence for the possible degradation of dicarboxylic acids (≥C3 in this smoke-polluted environment. Assuming that these and related compounds are photo-chemically oxidized to oxalic acid in the daytime, and given their linear relationship, they could account for, on average, 77% of the formation of oxalic acid. The remaining portion of oxalic acid may have been directly emitted from biomass burning as suggested by a good correlation with the biomass burning tracers (K+, CO and ECa and organic carbon (OC. However, photochemical production from other precursors could not be excluded.

Methamphetamine-induced neurotoxicity is attenuated in transgenic mice with a null mutation for interleukin-6.

Science.gov (United States)

Ladenheim, B; Krasnova, I N; Deng, X; Oyler, J M; Polettini, A; Moran, T H; Huestis, M A; Cadet, J L

2000-12-01

Increasing evidence implicates apoptosis as a major mechanism of cell death in methamphetamine (METH) neurotoxicity. The involvement of a neuroimmune component in apoptotic cell death after injury or chemical damage suggests that cytokines may play a role in METH effects. In the present study, we examined if the absence of IL-6 in knockout (IL-6-/-) mice could provide protection against METH-induced neurotoxicity. Administration of METH resulted in a significant reduction of [(125)I]RTI-121-labeled dopamine transporters in the caudate-putamen (CPu) and cortex as well as depletion of dopamine in the CPu and frontal cortex of wild-type mice. However, these METH-induced effects were significantly attenuated in IL-6-/- animals. METH also caused a decrease in serotonin levels in the CPu and hippocampus of wild-type mice, but no reduction was observed in IL-6-/- animals. Moreover, METH induced decreases in [(125)I]RTI-55-labeled serotonin transporters in the hippocampal CA3 region and in the substantia nigra-reticulata but increases in serotonin transporters in the CPu and cingulate cortex in wild-type animals, all of which were attenuated in IL-6-/- mice. Additionally, METH caused increased gliosis in the CPu and cortices of wild-type mice as measured by [(3)H]PK-11195 binding; this gliotic response was almost completely inhibited in IL-6-/- animals. There was also significant protection against METH-induced DNA fragmentation, measured by the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeled (TUNEL) cells in the cortices. The protective effects against METH toxicity observed in the IL-6-/- mice were not caused by differences in temperature elevation or in METH accumulation in wild-type and mutant animals. Therefore, these observations support the proposition that IL-6 may play an important role in the neurotoxicity of METH.

Identification and Functional Characterization of a Tonoplast Dicarboxylate Transporter in Tomato (Solanum lycopersicum)

OpenAIRE

Liu, Ruiling; Li, Boqiang; Qin, Guozheng; Zhang, Zhanquan; Tian, Shiping

2017-01-01

Acidity plays an important role in flavor and overall organoleptic quality of fruit and is mainly due to the presence of organic acids. Understanding the molecular basis of organic acid metabolism is thus of primary importance for fruit quality improvement. Here, we cloned a putative tonoplast dicarboxylate transporter gene (SlTDT) from tomato, and submitted it to the NCBI database (GenBank accession number: KC733165). SlTDT protein contained 13 putative transmembrane domains in silico analys...

Environmental Chemicals and Human Neurotoxicity: Magnitude ...

African Journals Online (AJOL)

Olaleye

altered neurocthemical, electrophysiological or behavioural functions. The adverse effects of neurotoxicity are among the most feared ill health in humans ... chemicals through air, food, or drinking water. The infamous ..... environment can disrupt the neurological control .... that perception and memory gradually fade,.

Reversible metronidazole-induced neurotoxicity after 10 weeks of therapy.

Science.gov (United States)

AlDhaleei, Wafa; AlMarzooqi, Ayesha; Gaber, Nouran

2018-04-20

Metronidazole is a commonly used antimicrobial worldwide. The most common side effects that have been reported are nausea, vomiting and hypersensitivity reactions. However, neurotoxicity has been reported with the use of metronidazole but rather rare. The most common neurological manifestation is peripheral neuropathy involvement in the form of sensory loss. It is worth mentioning that central neurotoxicity is a rare side effect of metronidazole use but reversible. The manifestations vary from a headache, altered mental status to focal neurological deficits. The diagnosis is mainly by neuroimaging in the setting of acute neurological change in the patient status. Here, we report a case of metronidazole-induced neurotoxicity in a 38-year-old male patient who was admitted with a brain abscess and was started on metronidazole for more than 10 weeks. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA (``Ecstasy'')

Science.gov (United States)

Ricaurte, George A.; Yuan, Jie; Hatzidimitriou, George; Cord, Branden J.; McCann, Una D.

2002-09-01

The prevailing view is that the popular recreational drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, or ``ecstasy'') is a selective serotonin neurotoxin in animals and possibly in humans. Nonhuman primates exposed to several sequential doses of MDMA, a regimen modeled after one used by humans, developed severe brain dopaminergic neurotoxicity, in addition to less pronounced serotonergic neurotoxicity. MDMA neurotoxicity was associated with increased vulnerability to motor dysfunction secondary to dopamine depletion. These results have implications for mechanisms of MDMA neurotoxicity and suggest that recreational MDMA users may unwittingly be putting themselves at risk, either as young adults or later in life, for developing neuropsychiatric disorders related to brain dopamine and/or serotonin deficiency.

Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish.

Science.gov (United States)

Lisse, Thomas S; Middleton, Leah J; Pellegrini, Adriana D; Martin, Paige B; Spaulding, Emily L; Lopes, Olivia; Brochu, Elizabeth A; Carter, Erin V; Waldron, Ashley; Rieger, Sandra

2016-04-12

Paclitaxel is a microtubule-stabilizing chemotherapeutic agent that is widely used in cancer treatment and in a number of curative and palliative regimens. Despite its beneficial effects on cancer, paclitaxel also damages healthy tissues, most prominently the peripheral sensory nervous system. The mechanisms leading to paclitaxel-induced peripheral neuropathy remain elusive, and therapies that prevent or alleviate this condition are not available. We established a zebrafish in vivo model to study the underlying mechanisms and to identify pharmacological agents that may be developed into therapeutics. Both adult and larval zebrafish displayed signs of paclitaxel neurotoxicity, including sensory axon degeneration and the loss of touch response in the distal caudal fin. Intriguingly, studies in zebrafish larvae showed that paclitaxel rapidly promotes epithelial damage and decreased mechanical stress resistance of the skin before induction of axon degeneration. Moreover, injured paclitaxel-treated zebrafish skin and scratch-wounded human keratinocytes (HEK001) display reduced healing capacity. Epithelial damage correlated with rapid accumulation of fluorescein-conjugated paclitaxel in epidermal basal keratinocytes, but not axons, and up-regulation of matrix-metalloproteinase 13 (MMP-13, collagenase 3) in the skin. Pharmacological inhibition of MMP-13, in contrast, largely rescued paclitaxel-induced epithelial damage and neurotoxicity, whereas MMP-13 overexpression in zebrafish embryos rendered the skin vulnerable to injury under mechanical stress conditions. Thus, our studies provide evidence that the epidermis plays a critical role in this condition, and we provide a previously unidentified candidate for therapeutic interventions.

Crystal structure and luminescence of complexes of Eu(III) and Tb(III) with furan-2,5-dicarboxylate

NARCIS (Netherlands)

Akerboom, S.; Fu, W.T.; Lutz, M.; Bouwman, E.

2012-01-01

Four new Ln(III) complexes (Ln = Eu, Tb) with furan-2,5-dicarboxylic acid (H2FDA) as a ligand have been synthesized and characterized in the solid state. Luminescence studies indicate that the compounds exhibit line-like luminescence characteristic of the lanthanide centre upon excitation in the

Involvement of glial cells in the neurotoxicity of parathion and chlorpyrifos

International Nuclear Information System (INIS)

Zurich, M.-G.; Honegger, P.; Schilter, B.; Costa, L.G.; Monnet-Tschudi, F.

2004-01-01

An in vitro model, the aggregating brain cell culture of fetal rat telencephalon, has been used to investigate the influence of glial cells on the neurotoxicity of two organophosphorus pesticides (OPs), chlorpyrifos and parathion. Mixed-cell aggregate cultures were treated continuously for 10 days between DIV 5 and 15. Parathion induced astrogliosis at concentration at which MAP-2 immunostaining, found here to be more sensitive than neuron-specific enzyme activities, was not affected. In contrast, chlorpyrifos induced a comparatively weak gliotic reaction, and only at concentrations at which neurons were already affected. After similar treatments, increased neurotoxicity of parathion and chlorpyrifos was found in aggregate cultures deprived of glial cells. These results suggest that glial cells provide neuroprotection against OPs toxicity. To address the question of the difference in toxicity between parathion and chlorpyrifos, the toxic effects of their leaving groups, p-nitrophenol and trichloropyridinol, were studied in mixed-cell aggregates. General cytotoxicity was more pronounced for trichloropyridinol and both compounds had similar toxic effects on neuron-specific enzyme activities. In contrast, trichloropyridinol induced a much stronger decrease in glutamine synthetase activity, the enzymatic marker of astrocytes. Trichloropyridinol may exert a toxic effect on astrocytes, compromising their neuroprotective function, thus exacerbating the neurotoxicity of chlorpyrifos. This is in line with the suggestion that glial cells may contribute to OPs neurotoxicity, and with the view that OPs may exert their neurotoxic effects through different mechanisms

Optical Absorption, Stability and Structure of NpO2+ Complexes with Dicarboxylic Acids

International Nuclear Information System (INIS)

Guoxin Tian; Linfeng Rao

2006-01-01

Complexation of NpO2+ with oxalic acid (OX),2,2'-oxydiacetic acid (ODA), 2,2'-iminodiacetic acid (IDA) and 2,2'-thiodiacetic acid (TDA), has been studied using spectrophotometry in1 M NaClO4. Both the position and the intensity of the absorption band of NpO2+ at 980 nm are affected by the formation of NpO2+/dicarboxylate complexes, providing useful information on the complexation strength, the coordination mode and the structure of the complexes

Crystallographic aspects of hydrated salts of 4,6-diaminopyrimidine with the first five dicarboxylic acids

Czech Academy of Sciences Publication Activity Database

Matulková, I.; Andreoni, R.; Císařová, I.; Němec, I.; Fábry, Jan

2017-01-01

Roč. 232, č. 6 (2017), s. 471-484 ISSN 2194-4946 R&D Projects: GA ČR GA14-05506S Institutional support: RVO:68378271 Keywords : crystal structure analysis * 4,6-diaminopyrimidine * dicarboxylic acids * hydrogen-bonding * vibrational spectroscopy * X-ray diffraction Subject RIV: BM - Solid Matter Physics ; Magnetism OBOR OECD: Condensed matter physics (including formerly solid state physics, supercond.) Impact factor: 3.179, year: 2016

A role for D1 dopamine receptors in striatal methamphetamine-induced neurotoxicity.

Science.gov (United States)

Friend, Danielle M; Keefe, Kristen A

2013-10-25

Methamphetamine (METH) exposure results in long-term damage to the dopamine system in both human METH abusers and animal models. One factor that has been heavily implicated in this METH-induced damage to the dopaminergic system is the activation of D1 dopamine (DA) receptors. However, a significant caveat to the studies investigating the role of the receptor in such toxicity is that genetic and pharmacological manipulations of the D1 DA receptor also mitigate METH-induced hyperthermia. Importantly, METH-induced hyperthermia is tightly associated with the neurotoxicity, such that simply cooling animals during METH exposure protects against the neurotoxicity. Therefore, it is difficult to determine whether D1 DA receptors per se play an important role in METH-induced neurotoxicity or whether the protection observed simply resulted from a mitigation of METH-induced hyperthermia. To answer this important question, the current study infused a D1 DA receptor antagonist into striatum during METH exposure while controlling for METH-induced hyperthermia. Here we found that even when METH-induced hyperthermia is maintained, the coadministration of a D1 DA receptor antagonist protects against METH-induced neurotoxicity, strongly suggesting that D1 DA receptors play an important role in METH-induced neurotoxicity apart from the mitigation of METH-induced hyperthermia. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

DipA, a pore-forming protein in the outer membrane of Lyme disease spirochetes exhibits specificity for the permeation of dicarboxylates.

Directory of Open Access Journals (Sweden)

Marcus Thein

Full Text Available Lyme disease Borreliae are highly dependent on the uptake of nutrients provided by their hosts. Our study describes the identification of a 36 kDa protein that functions as putative dicarboxylate-specific porin in the outer membrane of Lyme disease Borrelia. The protein was purified by hydroxyapatite chromatography from Borrelia burgdorferi B31 and designated as DipA, for dicarboxylate-specific porin A. DipA was partially sequenced, and corresponding genes were identified in the genomes of B. burgdorferi B31, Borrelia garinii PBi and Borrelia afzelii PKo. DipA exhibits high homology to the Oms38 porins of relapsing fever Borreliae. B. burgdorferi DipA was characterized using the black lipid bilayer assay. The protein has a single-channel conductance of 50 pS in 1 M KCl, is slightly selective for anions with a permeability ratio for cations over anions of 0.57 in KCl and is not voltage-dependent. The channel could be partly blocked by different di- and tricarboxylic anions. Particular high stability constants up to about 28,000 l/mol (in 0.1 M KCl were obtained among the 11 tested anions for oxaloacetate, 2-oxoglutarate and citrate. The results imply that DipA forms a porin specific for dicarboxylates which may play an important role for the uptake of specific nutrients in different Borrelia species.

Coligand-regulated assembly, fluorescence, and magnetic properties of Co(II) and Cd(II) complexes with a non-coplanar dicarboxylate

International Nuclear Information System (INIS)

Xin, Ling-Yun; Liu, Guang-Zhen; Ma, Lu-Fang; Wang, Li-Ya

2013-01-01

A non-coplanar dicarboxylate ndca (H 2 ndca=5-norbornene-2,3-dicarboxylic acid), combining with various dipyridyl-typed tectons, constructs six Cd(II)/Co(II) coordination polymers under hydrothermal conditions, namely [Co(ndca)(H 2 O)] n (1), ([Co(ndca)(bpe)(H 2 O)]·H 2 O) n (2), [Co(ndca)(bpa) 0.5 (H 2 O)] n (3), [Cd(ndca)(bpe)(H 2 O)] n (4), ([Cd(ndca)(bpa)(H 2 O)]·0.5H 2 O) n (5), and ([Cd(ndca)(bpp) (H 2 O)]·H 2 O) n (6) (bpe=1,2-di(4-pyridyl)ethylene, bpa=1,2-bi(4-pyridyl)ethane, and bpp=1,3-bis(4-pyridyl)propane). All these compounds contain various metal(II)–carboxylate motifs, including carboxylate binuclear (2, 4, 5), carboxylate chain (1, 6) and carboxylate layer (3), which are further extended by dipyridyl-typed coligands to afford a vast diversity of the structures with 2D pyknotic layers (1, 6), 2D open layer (5), 2D→3D interpenetrated networks (2,4), and 3D pillared-layer framework (3), respectively. In addition, fluorescent spectra of Cd(II) complexes and magnetic properties of Co(II) complexes are also given. - Graphical abstract: Six various cadmium(II)/cobalt(II)–organic frameworks were constructed by 5-norbornene-2,3-dicarboxylic acid and different bis(pyridine) rod-like tectons, and Cd (II) complexes exhibit blue–violet emissions, whereas Co (II) complexes show antiferromagnetic behaviours. Display Omitted

Peripheral Ammonia as a Mediator of Methamphetamine Neurotoxicity

Science.gov (United States)

Halpin, Laura E.; Yamamoto, Bryan K.

2012-01-01

Ammonia is metabolized by the liver and has established neurological effects. The current study examined the possibility that ammonia contributes to the neurotoxic effects of methamphetamine (METH). The results show that a binge dosing regimen of METH to the rat increased plasma and brain ammonia concentrations that were paralleled by evidence of hepatotoxicity. The role of peripheral ammonia in the neurotoxic effects of METH was further substantiated by the demonstration that the enhancement of peripheral ammonia excretion blocked the increases in brain and plasma ammonia and attenuated the long term depletions of dopamine and serotonin typically produced by METH. Conversely, the localized perfusion of ammonia in combination with METH, but not METH alone or ammonia alone, into the striatum recapitulated the neuronal damage produced by the systemic administration of METH. Furthermore, this damage produced by the local administration of ammonia and METH was blocked by the GYKI 52466, an AMPA receptor antagonist. These findings highlight the importance of ammonia derived from the periphery as a small molecule mediator of METH neurotoxicity and more broadly emphasize the importance of peripheral organ damage as a possible mechanism that mediates the neuropathology produced by drugs of abuse and other neuroactive molecules. PMID:22993432

Urinary concentrations of cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester, a metabolite of the non-phthalate plasticizer di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), and markers of ovarian response among women attending a fertility center

Energy Technology Data Exchange (ETDEWEB)

Mínguez-Alarcón, Lidia, E-mail: lminguez@hsph.harvard.edu [Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston (United States); Souter, Irene [Vincent Obstetrics and Gynecology, Massachusetts General Hospital and Harvard Medical School, Boston (United States); Chiu, Yu-Han [Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston (United States); Williams, Paige L. [Department of Epidemiology, and Harvard T.H. Chan School of Public Health, Boston (United States); Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston (United States); Ford, Jennifer B. [Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston (United States); Ye, Xiaoyun; Calafat, Antonia M. [National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta (United States); Hauser, Russ [Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston (United States); Department of Epidemiology, and Harvard T.H. Chan School of Public Health, Boston (United States); Vincent Obstetrics and Gynecology, Massachusetts General Hospital and Harvard Medical School, Boston (United States)

2016-11-15

Di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), a non-phthalate plasticizer, was introduced commercially in 2002 as an alternative to ortho-phthalate esters because of its favorable toxicological profile. However, the potential health effects from DINCH exposure remain largely unknown. We explored the associations between urinary concentrations of metabolites of DINCH on markers of ovarian response among women undergoing in vitro fertilization (IVF) treatments. Between 2011 and 2015, 113 women enrolled a prospective cohort study at the Massachusetts General Hospital Fertility Center and provided up to two urine samples prior to oocyte retrieval. The urinary concentrations of two DINCH metabolites, cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester (MHiNCH) and cyclohexane-1,2-dicarboxylic acid monocarboxyisooctyl ester (MCOCH), were quantified by isotope dilution tandem mass spectrometry. We used generalized linear mixed models to evaluate the association between urinary metabolite concentrations and markers of ovarian response, accounting for multiple IVF cycles per woman via random intercepts. On average, women with detectable urinary MHiNCH concentrations, as compared to those below LOD, had a lower estradiol levels (−325 pmol/l, p=0.09) and number of retrieved oocytes (−1.8, p=0.08), with a stronger association among older women. However, urinary MHiNCH concentrations were unrelated to mature oocyte yield and endometrial wall thickness. In conclusion, we found suggestive negative associations between urinary MHiNCH concentrations and peak estradiol levels and number of total oocyte yields. This is the first study evaluating the effect of DINCH exposure on human reproductive health and raises the need for further experimental and epidemiological studies to better understand the potential effects of this chemical on health. - Highlights: • Women with detectable urinary MHiNCH concentrations had a lower estradiol levels and number of retrieved

Urinary concentrations of cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester, a metabolite of the non-phthalate plasticizer di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), and markers of ovarian response among women attending a fertility center

International Nuclear Information System (INIS)

Mínguez-Alarcón, Lidia; Souter, Irene; Chiu, Yu-Han; Williams, Paige L.; Ford, Jennifer B.; Ye, Xiaoyun; Calafat, Antonia M.; Hauser, Russ

2016-01-01

Di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), a non-phthalate plasticizer, was introduced commercially in 2002 as an alternative to ortho-phthalate esters because of its favorable toxicological profile. However, the potential health effects from DINCH exposure remain largely unknown. We explored the associations between urinary concentrations of metabolites of DINCH on markers of ovarian response among women undergoing in vitro fertilization (IVF) treatments. Between 2011 and 2015, 113 women enrolled a prospective cohort study at the Massachusetts General Hospital Fertility Center and provided up to two urine samples prior to oocyte retrieval. The urinary concentrations of two DINCH metabolites, cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester (MHiNCH) and cyclohexane-1,2-dicarboxylic acid monocarboxyisooctyl ester (MCOCH), were quantified by isotope dilution tandem mass spectrometry. We used generalized linear mixed models to evaluate the association between urinary metabolite concentrations and markers of ovarian response, accounting for multiple IVF cycles per woman via random intercepts. On average, women with detectable urinary MHiNCH concentrations, as compared to those below LOD, had a lower estradiol levels (−325 pmol/l, p=0.09) and number of retrieved oocytes (−1.8, p=0.08), with a stronger association among older women. However, urinary MHiNCH concentrations were unrelated to mature oocyte yield and endometrial wall thickness. In conclusion, we found suggestive negative associations between urinary MHiNCH concentrations and peak estradiol levels and number of total oocyte yields. This is the first study evaluating the effect of DINCH exposure on human reproductive health and raises the need for further experimental and epidemiological studies to better understand the potential effects of this chemical on health. - Highlights: • Women with detectable urinary MHiNCH concentrations had a lower estradiol levels and number of retrieved

Mitochondrial dysfunction associated with nitric oxide pathways in glutamate neurotoxicity.

Science.gov (United States)

Manucha, Walter

Multiple mechanisms underlying glutamate-induced neurotoxicity have recently been discussed. Likewise, a clear deregulation of the mitochondrial respiratory mechanism has been described in patients with neurodegeneration, oxidative stress, and inflammation. This article highlights nitric oxide, an atypical neurotransmitter synthesized and released on demand by the post-synaptic neurons, and has many important implications for nerve cell survival and differentiation. Consequently, synaptogenesis, synapse elimination, and neurotransmitter release, are nitric oxide-modulated. Interesting, an emergent role of nitric oxide pathways has been discussed as regards neurotoxicity from glutamate-induced apoptosis. These findings suggest that nitric oxide pathways modulation could prevent oxidative damage to neurons through apoptosis inhibition. This review aims to highlight the emergent aspects of nitric oxide-mediated signaling in the brain, and how they can be related to neurotoxicity, as well as the development of neurodegenerative diseases development. Copyright © 2016 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.

Determination of submicromolar amounts of uranium(VI) by compleximetric titration with pyridine-2,6-dicarboxylic acid

International Nuclear Information System (INIS)

Marsh, S.F.; Betts, M.R.; Rein, J.E.

1980-01-01

Uranium(VI) is selectively determined by a compleximetric titration with pyridine-2,6-dicarboxylic acid, using arsenazo-I indicator and hexamethylenetetramine buffer at pH 4.9. Cyclohexanediaminetetraacetic acid and diethylenetriaminepentaacetic acid provide masking of interfering metal ions. A probe colorimeter apparatus is recommended for end-point detection. The relative standard deviation is 0.6% for 0.17-0.76 μmol of uranium. (Auth.)

Determination of submicromolar amounts of uranium(VI) by compleximetric titration with pyridine-2,6-dicarboxylic acid

Energy Technology Data Exchange (ETDEWEB)

Marsh, S F; Betts, M R; Rein, J E [Los Alamos Scientific Lab., NM (USA)

1980-10-01

Uranium(VI) is selectively determined by a compleximetric titration with pyridine-2,6-dicarboxylic acid, using arsenazo-I indicator and hexamethylenetetramine buffer at pH 4.9. Cyclohexanediaminetetraacetic acid and diethylenetriaminepentaacetic acid provide masking of interfering metal ions. A probe colorimeter apparatus is recommended for end-point detection. The relative standard deviation is 0.6% for 0.17-0.76 ..mu..mol of uranium.

Scutellarin Mitigates Aβ-Induced Neurotoxicity and Improves Behavior Impairments in AD Mice

Directory of Open Access Journals (Sweden)

Yue-Qin Zeng

2018-04-01

Full Text Available Alzheimer’s disease (AD is pathologically characterized by excessive accumulation of amyloid-beta (Aβ within extracellular spaces of the brain. Aggregation of Aβ has been shown to trigger oxidative stress, inflammation, and neurotoxicity resulting in cognitive dysfunction. In this study, we use models of cerebral Aβ amyloidosis to investigate anti-amyloidogenic effects of scutellarin in vitro and in vivo. Our results show that scutellarin, through binding to Aβ42, efficiently inhibits oligomerization as well as fibril formation and reduces Aβ oligomer-induced neuronal toxicity in cell line SH-SY5Y. After nine months of treatment in APP/PS1 double-transgenic mice, scutellarin significantly improves behavior, reduces soluble and insoluble Aβ levels in the brain and plasma, decreases Aβ plaque associated gliosis and levels of proinflammatory cytokines TNF-α and IL-6, attenuates neuroinflammation, displays anti-amyloidogenic effects, and highlights the beneficial effects of intervention on development or progression of AD-like neuropathology.

Improving in vitro to in vivo extrapolation by incorporating toxicokinetic measurements: A case study of lindane-induced neurotoxicity

Energy Technology Data Exchange (ETDEWEB)

Croom, Edward L.; Shafer, Timothy J.; Evans, Marina V.; Mundy, William R.; Eklund, Chris R.; Johnstone, Andrew F.M.; Mack, Cina M.; Pegram, Rex A., E-mail: pegram.rex@epa.gov

2015-02-15

Approaches for extrapolating in vitro toxicity testing results for prediction of human in vivo outcomes are needed. The purpose of this case study was to employ in vitro toxicokinetics and PBPK modeling to perform in vitro to in vivo extrapolation (IVIVE) of lindane neurotoxicity. Lindane cell and media concentrations in vitro, together with in vitro concentration-response data for lindane effects on neuronal network firing rates, were compared to in vivo data and model simulations as an exercise in extrapolation for chemical-induced neurotoxicity in rodents and humans. Time- and concentration-dependent lindane dosimetry was determined in primary cultures of rat cortical neurons in vitro using “faux” (without electrodes) microelectrode arrays (MEAs). In vivo data were derived from literature values, and physiologically based pharmacokinetic (PBPK) modeling was used to extrapolate from rat to human. The previously determined EC{sub 50} for increased firing rates in primary cultures of cortical neurons was 0.6 μg/ml. Media and cell lindane concentrations at the EC{sub 50} were 0.4 μg/ml and 7.1 μg/ml, respectively, and cellular lindane accumulation was time- and concentration-dependent. Rat blood and brain lindane levels during seizures were 1.7–1.9 μg/ml and 5–11 μg/ml, respectively. Brain lindane levels associated with seizures in rats and those predicted for humans (average = 7 μg/ml) by PBPK modeling were very similar to in vitro concentrations detected in cortical cells at the EC{sub 50} dose. PBPK model predictions matched literature data and timing. These findings indicate that in vitro MEA results are predictive of in vivo responses to lindane and demonstrate a successful modeling approach for IVIVE of rat and human neurotoxicity. - Highlights: • In vitro to in vivo extrapolation for lindane neurotoxicity was performed. • Dosimetry of lindane in a micro-electrode array (MEA) test system was assessed. • Cell concentrations at the MEA EC

Alpha 7 nicotinic acetylcholine receptor-mediated protection against ethanol-induced neurotoxicity.

Science.gov (United States)

de Fiebre, NancyEllen C; de Fiebre, Christopher M

2003-11-01

The alpha(7)-selective nicotinic partial agonist 3-[2,4-dimethoxybenzylidene]anabaseine (DMXB) was examined for its ability to modulate ethanol-induced neurotoxicity in primary cultures of rat neurons. Primary cultures of hippocampal neurons were established from Long-Evans, embryonic day (E)-18 rat fetuses and maintained for 7 days. Ethanol (0-150 mM), DMXB (0-56 microM), or both were subsequently co-applied to cultures. Ethanol was added two additional times to the cultures to compensate for evaporation. After 5 days, neuronal viability was assessed with the MTT cell proliferation assay. Results demonstrated that ethanol reduces neuronal viability in a concentration-dependent fashion and that DMXB protects against this ethanol-induced neurotoxicity, also in a concentration-dependent fashion. These results support the suggestion that nicotinic partial agonists may be useful in treating binge drinking-induced neurotoxicity and may provide clues as to why heavy drinkers are usually smokers.

Coligand-regulated assembly, fluorescence, and magnetic properties of Co(II) and Cd(II) complexes with a non-coplanar dicarboxylate

Energy Technology Data Exchange (ETDEWEB)

Xin, Ling-Yun [College of Chemistry and Chemical Engineering, Luoyang Normal University, Luoyang 471022 (China); Liu, Guang-Zhen, E-mail: gzliuly@126.com [College of Chemistry and Chemical Engineering, Luoyang Normal University, Luoyang 471022 (China); Ma, Lu-Fang [College of Chemistry and Chemical Engineering, Luoyang Normal University, Luoyang 471022 (China); Wang, Li-Ya [College of Chemistry and Chemical Engineering, Luoyang Normal University, Luoyang 471022 (China); College of Chemistry and Pharmacy Engineering, Nanyang Normal University, Nanyang 473061 (China)

2013-10-15

A non-coplanar dicarboxylate ndca (H{sub 2}ndca=5-norbornene-2,3-dicarboxylic acid), combining with various dipyridyl-typed tectons, constructs six Cd(II)/Co(II) coordination polymers under hydrothermal conditions, namely [Co(ndca)(H{sub 2}O)]{sub n} (1), ([Co(ndca)(bpe)(H{sub 2}O)]·H{sub 2}O){sub n} (2), [Co(ndca)(bpa){sub 0.5}(H{sub 2}O)]{sub n} (3), [Cd(ndca)(bpe)(H{sub 2}O)]{sub n} (4), ([Cd(ndca)(bpa)(H{sub 2}O)]·0.5H{sub 2}O){sub n} (5), and ([Cd(ndca)(bpp) (H{sub 2}O)]·H{sub 2}O){sub n} (6) (bpe=1,2-di(4-pyridyl)ethylene, bpa=1,2-bi(4-pyridyl)ethane, and bpp=1,3-bis(4-pyridyl)propane). All these compounds contain various metal(II)–carboxylate motifs, including carboxylate binuclear (2, 4, 5), carboxylate chain (1, 6) and carboxylate layer (3), which are further extended by dipyridyl-typed coligands to afford a vast diversity of the structures with 2D pyknotic layers (1, 6), 2D open layer (5), 2D→3D interpenetrated networks (2,4), and 3D pillared-layer framework (3), respectively. In addition, fluorescent spectra of Cd(II) complexes and magnetic properties of Co(II) complexes are also given. - Graphical abstract: Six various cadmium(II)/cobalt(II)–organic frameworks were constructed by 5-norbornene-2,3-dicarboxylic acid and different bis(pyridine) rod-like tectons, and Cd (II) complexes exhibit blue–violet emissions, whereas Co (II) complexes show antiferromagnetic behaviours. Display Omitted.

Thermodynamics of formation of cadmium dicarboxylate and carboxylate mixed complexes with benzimidazole

Energy Technology Data Exchange (ETDEWEB)

Kharitonov, G V; Bolotov, V M; Kharitonova, R I [Voronezhskij Tekhnologicheskij Inst. (USSR)

1980-01-01

Thermodynamic parameters of the mixed complexing of cadmium propionate, butyrate, valerate, succinate, maleinate and malate with benzimidazole in 20 % aqUeous-ethanol solution of 0.1 M KNO/sub 3/ are studied using polarographic method. It is shown that stability of mixed complexes of cadmium carboxylates with benzimidazole is connected with the process enthalpy and is determined by covalency of the metal-carboxylate bond. Increasing length of hydrocarbon chain of acyl group of monobasic acids hampers amine coordination with central complexing agent (..delta..S<0). The presence of dicarboxylate-ion in the inner coordination sphere decreases the enthalpy and increases the entropy of the process (..delta..S>0).

The role of dopamine receptors in the neurotoxicity of methamphetamine.

Science.gov (United States)

Ares-Santos, S; Granado, N; Moratalla, R

2013-05-01

Methamphetamine is a synthetic drug consumed by millions of users despite its neurotoxic effects in the brain, leading to loss of dopaminergic fibres and cell bodies. Moreover, clinical reports suggest that methamphetamine abusers are predisposed to Parkinson's disease. Therefore, it is important to elucidate the mechanisms involved in methamphetamine-induced neurotoxicity. Dopamine receptors may be a plausible target to prevent this neurotoxicity. Genetic inactivation of dopamine D1 or D2 receptors protects against the loss of dopaminergic fibres in the striatum and loss of dopaminergic neurons in the substantia nigra. Protection by D1 receptor inactivation is due to blockade of hypothermia, reduced dopamine content and turnover and increased stored vesicular dopamine in D1R(-/-) mice. However, the neuroprotective impact of D2 receptor inactivation is partially dependent on an effect on body temperature, as well as on the blockade of dopamine reuptake by decreased dopamine transporter activity, which results in reduced intracytosolic dopamine levels in D2R(-/-) mice. © 2013 The Association for the Publication of the Journal of Internal Medicine.

nNOS inhibitors attenuate methamphetamine-induced dopaminergic neurotoxicity but not hyperthermia in mice.

Science.gov (United States)

Itzhak, Y; Martin, J L; Ail, S F

2000-09-11

Methamphetamine (METH)-induced dopaminergic neurotoxicity is associated with hyperthermia. We investigated the effect of several neuronal nitric oxide synthase (nNOS) inhibitors on METH-induced hyperthermia and striatal dopaminergic neurotoxicity. Administration of METH (5 mg/kg; q. 3 h x 3) to Swiss Webster mice produced marked hyperthermia and 50-60% depletion of striatal dopaminergic markers 72 h after METH administration. Pretreatment with the nNOS inhibitors S-methylthiocitrulline (SMTC; 10 mg/kg) or 3-bromo-7-nitroindazole (3-Br-7-NI; 20 mg/kg) before each METH injection did not affect the persistent hyperthermia produced by METH, but afforded protection against the depletion of dopaminergic markers. A low dose (25 mg/kg) of the nNOS inhibitor 7-nitroindazole (7-NI) did not affect METH-induced hyperthermia, but a high dose (50 mg/kg) produced significant hypothermia. These findings indicate that low dose of selective nNOS inhibitors protect against METH-induced neurotoxicity with no effect on body temperature and support the hypothesis that nitric oxide (NO) and peroxynitrite have a major role in METH-induced dopaminergic neurotoxicity.

Squalestatin alters the intracellular trafficking of a neurotoxic prion peptide

Directory of Open Access Journals (Sweden)

Williams Alun

2007-11-01

Full Text Available Abstract Background Neurotoxic peptides derived from the protease-resistant core of the prion protein are used to model the pathogenesis of prion diseases. The current study characterised the ingestion, internalization and intracellular trafficking of a neurotoxic peptide containing amino acids 105–132 of the murine prion protein (MoPrP105-132 in neuroblastoma cells and primary cortical neurons. Results Fluorescence microscopy and cell fractionation techniques showed that MoPrP105-132 co-localised with lipid raft markers (cholera toxin and caveolin-1 and trafficked intracellularly within lipid rafts. This trafficking followed a non-classical endosomal pathway delivering peptide to the Golgi and ER, avoiding classical endosomal trafficking via early endosomes to lysosomes. Fluorescence resonance energy transfer analysis demonstrated close interactions of MoPrP105-132 with cytoplasmic phospholipase A2 (cPLA2 and cyclo-oxygenase-1 (COX-1, enzymes implicated in the neurotoxicity of prions. Treatment with squalestatin reduced neuronal cholesterol levels and caused the redistribution of MoPrP105-132 out of lipid rafts. In squalestatin-treated cells, MoPrP105-132 was rerouted away from the Golgi/ER into degradative lysosomes. Squalestatin treatment also reduced the association between MoPrP105-132 and cPLA2/COX-1. Conclusion As the observed shift in peptide trafficking was accompanied by increased cell survival these studies suggest that the neurotoxicity of this PrP peptide is dependent on trafficking to specific organelles where it activates specific signal transduction pathways.

Microbial Transformation of Dicarboxylic Acids by Airborne Bacteria

Science.gov (United States)

Cote, V.; Ariya, P.

2004-05-01

Organic aerosols are assumed to be key players in driving climatic changes and can cause health problems for human. Dicarboxylic acids (DCA) include a large fraction of identified important class of organic aerosols. In addition to direct sources, DCA are partly formed as the result of ozonolysis of terpenes and cyclic alkenes. Previous works in our laboratory show that airborne fungi collected from urban and suburban air play an important role in the transformation of severals organic aerosols such as DCA. Our present study focuses on understanding the potential chemical transformation induced by airborne bacteria and on identification of the transformation products. Airborne bacteria have been collected using a biosampler and cultivated on a solid media. Each bacterial colony is being tested by HPLC for their ability to transform DCA in liquid cultures. Also, GC-MS, SPME and NMR are being used to identify the metabolites generated from the transformation. We will present our preliminary results and we will discuss the application of bacterial activities on the chemical transformation of organics in atmosphere.

Indirect coupling to Na+ of p-aminohippuric acid uptake into rat renal basolateral membrane vesicles

International Nuclear Information System (INIS)

Shimada, H.; Moewes, B.; Burckhardt, G.

1987-01-01

Experiments with basolateral membrane vesicles prepared from rat kidney cortex were performed to study the mechanism by which p-aminohippuric acid (PAH) is taken up across the contraluminal membrane and is concentrated in proximal tubule cells. An inward Na + gradient failed to stimulate [ 3 H]PAH uptake compared with K + or Li + and did not cause intravesicular PAH accumulation above equilibrium distribution. In the absence of Na + , the dicarboxylates glutarate and suberate cis-inhibited and trans-stimulated [ 3 H]PAH uptake, indicating a common transport system. In the presence of Na + , 10 μM glutarate in the incubation medium did not cis-inhibit, but rather stimulated [ 3 H]PAH uptake and caused PAH accumulation above equilibrium distribution (over-shoot). Li + diminished this stimulation, but was without effect on [ 3 H]PAH/PAH- and [ 3 H]PAH/glutarate exchange. The data indicate the coexistence of a Na + -sensitive transport system for dicarboxylates and a Li + -insensitive PAH/dicarboxylate exchanger in the basolateral membrane. The authors propose that dicarboxylates are cotransported with Na + into the cell and subsequently exchange for extracellular PAH at the basolateral membrane. PAH uptake is thereby indirectly coupled to Na + via the Na + /dicarboxylate cotransporter

Chemical characteristics of dicarboxylic acids and related organic compounds in PM2.5 during biomass-burning and non-biomass-burning seasons at a rural site of Northeast China.

Science.gov (United States)

Cao, Fang; Zhang, Shi-Chun; Kawamura, Kimitaka; Liu, Xiaoyan; Yang, Chi; Xu, Zufei; Fan, Meiyi; Zhang, Wenqi; Bao, Mengying; Chang, Yunhua; Song, Wenhuai; Liu, Shoudong; Lee, Xuhui; Li, Jun; Zhang, Gan; Zhang, Yan-Lin

2017-12-01

Fine particulate matter (PM2.5) samples were collected using a high-volume air sampler and pre-combusted quartz filters during May 2013 to January 2014 at a background rural site (47 ∘ 35 N, 133 ∘ 31 E) in Sanjiang Plain, Northeast China. A homologous series of dicarboxylic acids (C 2 -C 11 ) and related compounds (oxoacids, α-dicarbonyls and fatty acids) were analyzed by using a gas chromatography (GC) and GC-MS method employing a dibutyl ester derivatization technique. Intensively open biomass-burning (BB) episodes during the harvest season in fall were characterized by high mass concentrations of PM2.5, dicarboxylic acids and levoglucosan. During the BB period, mass concentrations of dicarboxylic acids and related compounds were increased by up to >20 times with different factors for different organic compounds (i.e., succinic (C 4 ) acid > oxalic (C 2 ) acid > malonic (C 3 ) acid). High concentrations were also found for their possible precursors such as glyoxylic acid (ωC 2 ), 4-oxobutanoic acid, pyruvic acid, glyoxal, and methylglyoxal as well as fatty acids. Levoglucosan showed strong correlations with carbonaceous aerosols (OC, EC, WSOC) and dicarboxylic acids although such good correlations were not observed during non-biomass-burning seasons. Our results clearly demonstrate biomass burning emissions are very important contributors to dicarboxylic acids and related compounds. The selected ratios (e.g., C 3 /C 4 , maleic acid/fumaric acid, C 2 /ωC 2 , and C 2 /levoglucosan) were used as tracers for secondary formation of organic aerosols and their aging process. Our results indicate that organic aerosols from biomass burning in this study are fresh without substantial aging or secondary production. The present chemical characteristics of organic compounds in biomass-burning emissions are very important for better understanding the impacts of biomass burning on the atmosphere aerosols. Copyright © 2017 Elsevier Ltd. All rights reserved.

A holistic approach to anesthesia-induced neurotoxicity and its implications for future mechanistic studies.

Science.gov (United States)

Zanghi, Christine N; Jevtovic-Todorovic, Vesna

The year 2016 marked the 15th anniversary since anesthesia-induced developmental neurotoxicity and its resulting cognitive dysfunction were first described. Since that time, multiple scientific studies have supported these original findings and investigated possible mechanisms behind anesthesia-induced neurotoxicity. This paper reviews the existing mechanistic literature on anesthesia-induced neurotoxicity in the context of a holistic approach that emphasizes the importance of both neuronal and non-neuronal cells during early postnatal development. Sections are divided into key stages in early neural development; apoptosis, neurogenesis, migration, differentiation, synaptogenesis, gliogenesis, myelination and blood brain barrier/cerebrovasculature. In addition, the authors combine the established literature in the field of anesthesia-induced neurotoxicity with literature from other related scientific fields to speculate on the potential role of non-neuronal cells and to generate new future hypotheses for understanding anesthetic toxicity and its application to the practice of pediatric anesthesia. Copyright © 2017 Elsevier Inc. All rights reserved.

Photoluminescence properties of lanthanide-organic frameworks (LnOFs) with thiophene-2,5-dicarboxylate and acetate

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Han, Jing; Wei, Qing; Xie, Gang; Chen, Sanping [Key Lab. of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest Univ., Xi' an, Shaanxi (China); Zhang, Sheng [Key Lab. of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest Univ., Xi' an, Shaanxi (China); College of Chemistry and Chemical Engineering, Baoji Univ. of Arts and Science, Baoji, Shaanxi (China)

2017-07-17

S-heterocyclic dicarboxylic acid, thiophene-2,5-dicarboxylic acid (H{sub 2}TDC), was employed to construct a series of lanthanide-organic frameworks (LnOFs) with coligand acetate, formulated as [Ln(TDC)(OAc)(H{sub 2}O)]{sub n} [Ln = Eu (1), Tb (2), Gd (3), Dy (4), Sm (5)] under hydrothermal conditions. Structure analysis reveals that 1-5 have dinuclear 3D metal organic frameworks (MOFs), in which TDC{sup 2-} and OAc{sup -} display (κ{sup 1}-κ{sup 1})-(κ{sup 1}-κ{sup 1})-μ{sub 4} and (κ{sup 2}-κ{sup 1})-μ{sub 2} coordination fashions, respectively. The dehydrated products of all compounds show high thermal stability above 410 C. As for 1, 2, 4, and 5, the photoluminescence analyses exhibit characteristic luminescence emission bands of the corresponding lanthanide ions in the visible region. In particular, compound 2 displays bright green luminescence in the solid state with {sup 5}D{sub 4} lifetime of 0.510 ms and relative high overall quantum yield of 16 %, based on an ideal energy gap between the lowest triplet state energy level of H{sub 2}TDC ligand and the {sup 5}D{sub 4} state energy level of Tb{sup 3+}. The energy transfer mechanisms in compounds 1 and 2 were also discussed. (copyright 2017 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

Death Adder Envenoming Causes Neurotoxicity Not Reversed by Antivenom - Australian Snakebite Project (ASP-16)

Science.gov (United States)

Johnston, Christopher I.; O'Leary, Margaret A.; Brown, Simon G. A.; Currie, Bart J.; Halkidis, Lambros; Whitaker, Richard; Close, Benjamin; Isbister, Geoffrey K.

2012-01-01

Background Death adders (Acanthophis spp) are found in Australia, Papua New Guinea and parts of eastern Indonesia. This study aimed to investigate the clinical syndrome of death adder envenoming and response to antivenom treatment. Methodology/Principal Findings Definite death adder bites were recruited from the Australian Snakebite Project (ASP) as defined by expert identification or detection of death adder venom in blood. Clinical effects and laboratory results were collected prospectively, including the time course of neurotoxicity and response to treatment. Enzyme immunoassay was used to measure venom concentrations. Twenty nine patients had definite death adder bites; median age 45 yr (5–74 yr); 25 were male. Envenoming occurred in 14 patients. Two further patients had allergic reactions without envenoming, both snake handlers with previous death adder bites. Of 14 envenomed patients, 12 developed neurotoxicity characterised by ptosis (12), diplopia (9), bulbar weakness (7), intercostal muscle weakness (2) and limb weakness (2). Intubation and mechanical ventilation were required for two patients for 17 and 83 hours. The median time to onset of neurotoxicity was 4 hours (0.5–15.5 hr). One patient bitten by a northern death adder developed myotoxicity and one patient only developed systemic symptoms without neurotoxicity. No patient developed venom induced consumption coagulopathy. Antivenom was administered to 13 patients, all receiving one vial initially. The median time for resolution of neurotoxicity post-antivenom was 21 hours (5–168). The median peak venom concentration in 13 envenomed patients with blood samples was 22 ng/mL (4.4–245 ng/mL). In eight patients where post-antivenom bloods were available, no venom was detected after one vial of antivenom. Conclusions/Significance Death adder envenoming is characterised by neurotoxicity, which is mild in most cases. One vial of death adder antivenom was sufficient to bind all circulating venom. The

Developmental neurotoxicity of Propylthiouracil in rats

DEFF Research Database (Denmark)

Petersen, Marta Axelstad; Hansen, P.; Christiansen, S.

2007-01-01

early in pregnancy may cause adverse effects on the offspring. This has led to increased concern about thyroid hormone disrupting chemicals (TDCs) in our environment. We have studied how developmental exposure to the known antithyroid agent propylthiouracil (PTU) affects the development of rat pups...... behaviour and hearing function. This supports that exposure to TDC's in general may cause long-lasting developmental neurotoxicity....

alpha7 Nicotinic acetylcholine receptor knockout selectively enhances ethanol-, but not beta-amyloid-induced neurotoxicity.

Science.gov (United States)

de Fiebre, Nancyellen C; de Fiebre, Christopher M

2005-01-03

The alpha7 subtype of nicotinic acetylcholine receptor (nAChR) has been implicated as a potential site of action for two neurotoxins, ethanol and the Alzheimer's disease related peptide, beta-amyloid. Here, we utilized primary neuronal cultures of cerebral cortex from alpha7 nAChR null mutant mice to examine the role of this receptor in modulating the neurotoxic properties of subchronic, "binge" ethanol and beta-amyloid. Knockout of the alpha7 nAChR gene selectively enhanced ethanol-induced neurotoxicity in a gene dosage-related fashion. Susceptibility of cultures to beta-amyloid induced toxicity, however, was unaffected by alpha7 nAChR gene null mutation. Further, beta-amyloid did not inhibit the binding of the highly alpha7-selective radioligand, [(125)I]alpha-bungarotoxin. On the other hand, in studies in Xenopus oocytes ethanol efficaciously inhibited alpha7 nAChR function. These data suggest that alpha7 nAChRs modulate the neurotoxic effects of binge ethanol, but not the neurotoxicity produced by beta-amyloid. It is hypothesized that inhibition of alpha7 nAChRs by ethanol provides partial protection against the neurotoxic properties of subchronic ethanol.

Oxidative damage and neurodegeneration in manganese-induced neurotoxicity

International Nuclear Information System (INIS)

Milatovic, Dejan; Zaja-Milatovic, Snjezana; Gupta, Ramesh C.; Yu, Yingchun; Aschner, Michael

2009-01-01

Exposure to excessive manganese (Mn) levels results in neurotoxicity to the extrapyramidal system and the development of Parkinson's disease (PD)-like movement disorder, referred to as manganism. Although the mechanisms by which Mn induces neuronal damage are not well defined, its neurotoxicity appears to be regulated by a number of factors, including oxidative injury, mitochondrial dysfunction and neuroinflammation. To investigate the mechanisms underlying Mn neurotoxicity, we studied the effects of Mn on reactive oxygen species (ROS) formation, changes in high-energy phosphates (HEP), neuroinflammation mediators and associated neuronal dysfunctions both in vitro and in vivo. Primary cortical neuronal cultures showed concentration-dependent alterations in biomarkers of oxidative damage, F 2 -isoprostanes (F 2 -IsoPs) and mitochondrial dysfunction (ATP), as early as 2 h following Mn exposure. Treatment of neurons with 500 μM Mn also resulted in time-dependent increases in the levels of the inflammatory biomarker, prostaglandin E 2 (PGE 2 ). In vivo analyses corroborated these findings, establishing that either a single or three (100 mg/kg, s.c.) Mn injections (days 1, 4 and 7) induced significant increases in F 2 -IsoPs and PGE 2 in adult mouse brain 24 h following the last injection. Quantitative morphometric analyses of Golgi-impregnated striatal sections from mice exposed to single or three Mn injections revealed progressive spine degeneration and dendritic damage of medium spiny neurons (MSNs). These findings suggest that oxidative stress, mitochondrial dysfunction and neuroinflammation are underlying mechanisms in Mn-induced neurodegeneration.

Microbial and 'de novo' transformation of dicarboxylic acids by three airborne fungi

International Nuclear Information System (INIS)

Cote, Valerie; Kos, Gregor; Mortazavi, Roya; Ariya, Parisa A.

2008-01-01

Micro-organisms and organic compounds of biogenic or anthropogenic origins are important constituents of atmospheric aerosols, which are involved in atmospheric processes and climate change. In order to investigate the role of fungi and their metabolisation activity, we collected airborne fungi using a biosampler in an urban location of Montreal, Quebec, Canada (45 o 28' N, 73 o 45' E). After isolation on Sabouraud dextrose agar, we exposed isolated colonies to dicarboxylic acids (C 2 -C 7 ), a major group of organic aerosols and monitored their growth. Depending on the acid, total fungi numbers varied from 35 (oxalic acid) to 180 CFU/mL (glutaric acid). Transformation kinetics of malonic acid, presumably the most abundant dicarboxylic acid, at concentrations of 0.25 and 1.00 mM for isolated airborne fungi belonging to the genera Aspergillus, Penicillium, Eupenicillium, and Thysanophora with the fastest transformation rate are presented. The initial concentration was halved within 4.5 and 11.4 days. Other collected fungi did not show a significant degradation and the malonic acid concentration remained unchanged (0.25 and 1.00 mM) within 20 days. Degradation of acid with formation of metabolites was followed using high performance liquid chromatography-ultraviolet detection (HPLC/UV) and gas chromatography-mass spectrometry (GC/MS), as well as monitoring of 13 C labelled malonic acid degradation with solid-state nuclear magnetic resonance spectroscopy (NMR). Using GC/MS we identified two processes driving chemical modifications of organic aerosol solutions: (I) formation of metabolites within several days, and (II) rapid release (≤ 2 min) of organic molecules from fungal species upon the insertion of taxa in organic aerosol solutions. Metabolites included aromatic compounds and alcohols (e.g. trimethylbenzene and butanol). Potential atmospheric implications of our results are discussed

Protection against MDMA-induced dopaminergic neurotoxicity in mice by methyllycaconitine: involvement of nicotinic receptors.

Science.gov (United States)

Chipana, C; Camarasa, J; Pubill, D; Escubedo, E

2006-09-01

Methylenedioxymethamphetamine (MDMA) is a relatively selective dopaminergic neurotoxin in mice. Previous studies demonstrated the participation of alpha-7 nicotinic receptors (nAChR) in the neurotoxic effect of methamphetamine. The aim of this paper was to study the role of this receptor type in the acute effects and neurotoxicity of MDMA in mice. In vivo, methyllycaconitine (MLA), a specific alpha-7 nAChR antagonist, significantly prevented MDMA-induced neurotoxicity at dopaminergic but not at serotonergic level, without affecting MDMA-induced hyperthermia. Glial activation was also fully prevented by MLA. In vitro, MDMA induced intrasynaptosomal reactive oxygen species (ROS) generation, which was calcium-, nitric-oxide synthase-, and protein kinase C-dependent. Also, the increase in ROS was prevented by MLA and alpha-bungarotoxin. Experiments with reserpine point to endogenous dopamine (DA) as the main source of MDMA-induced ROS. MLA also brought the MDMA-induced inhibition of [3H]DA uptake down, from 73% to 11%. We demonstrate that a coordinated activation of alpha-7 nAChR, blockade of DA transporter function and displacement of DA from intracellular stores induced by MDMA produces a neurotoxic effect that can be prevented by MLA, suggesting that alpha-7 nAChR have a key role in the MDMA neurotoxicity in mice; however, the involvement of nicotinic receptors containing the beta2 subunit cannot be conclusively ruled out.

Neurotoxicity in long-term survivors of small cell lung cancer

International Nuclear Information System (INIS)

Lee, J.S.; Umsawasdi, T.; Lee, Y.Y.; Barkley, H.T. Jr.; Murphy, W.K.; Welch, S.; Valdivieso, M.

1986-01-01

Chronic central nervous system neurotoxicity was studied in 38 long-term survivors (greater than or equal to 3 years) of small cell lung cancer who were treated at the University of Texas M. D. Anderson Hospital and Tumor Institute at Houston between 1971 and 1980. All but one patient received combination chemotherapy with or without chest irradiation. Twenty-four patients received whole brain irradiation (Group I), 22 for elective and two for therapeutic purposes, while 14 did not (Group II). Abnormalities in computed tomographic (CT) scans of the brain were more frequently observed in Group I than in Group II (70% vs. 0%, p less than 0.01). Clinical central nervous system neurotoxicity developed in three patients in Group I, while none developed in patients in Group II (p less than 0.05). Patients who received methotrexate and procarbazine after whole brain irradiation were at a higher risk for clinical central nervous system neurotoxicity (p less than 0.05), and for development of periventricular white matter changes in CT brain scans (p less than 0.05) than were patients in Group II. Impaired methylation of the myelin sheath is proposed as a possible underlying pathogenic mechanism

Competitive solvent extraction of alkaline-earth cations into chloroform by lipophilic acyclic polyether dicarboxylic acids

International Nuclear Information System (INIS)

Kang, S.I.; Czech, A.; Czech, B.P.; Stewart, L.E.; Bartsch, R.A.

1985-01-01

Competitive solvent extraction of alkaline-earth cations from aqueous solutions into chloroform by a series of lipophilic acyclic polyether dicarboxylic acids is reported. The influence of polyether chain length and of terminal carboxylic acid group variation upon extraction selectivity and efficiency is assessed. In the competitive extraction of concentrated magnesium, calcium, strontium and barium chloride solutions, one complexing agent exhibits pronounced selectivity for barium with Ba 2+ /S 2+ = 50, Ba 2+ /Ca 2+ = 250, and no detectable Mg 2+ extraction. 20 references, 3 figures, 1 table

Multiple sclerosis, brain radiotherapy, and risk of neurotoxicity: The Mayo Clinic experience

International Nuclear Information System (INIS)

Miller, Robert C.; Lachance, Daniel H.; Lucchinetti, Claudia F.; Keegan, B. Mark; Gavrilova, Ralitza H.; Brown, Paul D.; Weinshenker, Brian G.; Rodriguez, Moses

2006-01-01

Purpose: The aim of this study was a retrospective assessment of neurotoxicity in patients with multiple sclerosis (MS) receiving external beam radiotherapy (EBRT) to the brain. Methods and Materials: We studied 15 consecutively treated patients with MS who received brain EBRT. Neurologic toxicity was assessed with the Common Toxicity Criteria v.3.0. Results: Median follow-up for the 5 living patients was 6.0 years (range, 3.3-27.4 years). No exacerbation of MS occurred in any patient during EBRT. Five patients had Grade 4 neurologic toxicity and 1 had possible Grade 5 toxicity. Kaplan-Meier estimated risk of neurotoxicity greater than Grade 4 at 5 years was 57% (95% confidence interval, 27%-82%). Toxicity occurred at 37.5 to 54.0 Gy at a median of 1.0 year (range, 0.2-4.3 years) after EBRT. Univariate analysis showed an association between opposed-field irradiation of the temporal lobes, central white matter, and brainstem and increased risk of neurotoxicity (p < 0.04). Three of 6 cases of toxicity occurred in patients treated before 1986. Conclusions: External beam radiotherapy of the brain in patients with MS may be associated with an increased risk of neurotoxicity compared with patients without demyelinating illnesses. However, this risk is associated with treatment techniques that may not be comparable to modern, conformal radiotherapy

Involvement of ERK in NMDA receptor-independent cortical neurotoxicity of hydrogen sulfide

International Nuclear Information System (INIS)

Kurokawa, Yuko; Sekiguchi, Fumiko; Kubo, Satoko; Yamasaki, Yoshiko; Matsuda, Sachi; Okamoto, Yukari; Sekimoto, Teruki; Fukatsu, Anna; Nishikawa, Hiroyuki; Kume, Toshiaki; Fukushima, Nobuyuki; Akaike, Akinori; Kawabata, Atsufumi

2011-01-01

Highlights: ► Hydrogen sulfide causes NMDA receptor-independent neurotoxicity in mouse fetal cortical neurons. ► Activation of ERK mediates the toxicity of hydrogen sulfide. ► Apoptotic mechanisms are involved in the hydrogen-induced cell death. -- Abstract: Hydrogen sulfide (H 2 S), a gasotransmitter, exerts both neurotoxicity and neuroprotection, and targets multiple molecules including NMDA receptors, T-type calcium channels and NO synthase (NOS) that might affect neuronal viability. Here, we determined and characterized effects of NaHS, an H 2 S donor, on cell viability in the primary cultures of mouse fetal cortical neurons. NaHS caused neuronal death, as assessed by LDH release and trypan blue staining, but did not significantly reduce the glutamate toxicity. The neurotoxicity of NaHS was resistant to inhibitors of NMDA receptors, T-type calcium channels and NOS, and was blocked by inhibitors of MEK, but not JNK, p38 MAP kinase, PKC and Src. NaHS caused prompt phosphorylation of ERK and upregulation of Bad, followed by translocation of Bax to mitochondria and release of mitochondrial cytochrome c, leading to the nuclear condensation/fragmentation. These effects of NaHS were suppressed by the MEK inhibitor. Our data suggest that the NMDA receptor-independent neurotoxicity of H 2 S involves activation of the MEK/ERK pathway and some apoptotic mechanisms.

Genome-scale model-driven strain design for dicarboxylic acid production in Yarrowia lipolytica.

Science.gov (United States)

Mishra, Pranjul; Lee, Na-Rae; Lakshmanan, Meiyappan; Kim, Minsuk; Kim, Byung-Gee; Lee, Dong-Yup

2018-03-19

Recently, there have been several attempts to produce long-chain dicarboxylic acids (DCAs) in various microbial hosts. Of these, Yarrowia lipolytica has great potential due to its oleaginous characteristics and unique ability to utilize hydrophobic substrates. However, Y. lipolytica should be further engineered to make it more competitive: the current approaches are mostly intuitive and cumbersome, thus limiting its industrial application. In this study, we proposed model-guided metabolic engineering strategies for enhanced production of DCAs in Y. lipolytica. At the outset, we reconstructed genome-scale metabolic model (GSMM) of Y. lipolytica (iYLI647) by substantially expanding the previous models. Subsequently, the model was validated using three sets of published culture experiment data. It was finally exploited to identify genetic engineering targets for overexpression, knockout, and cofactor modification by applying several in silico strain design methods, which potentially give rise to high yield production of the industrially relevant long-chain DCAs, e.g., dodecanedioic acid (DDDA). The resultant targets include (1) malate dehydrogenase and malic enzyme genes and (2) glutamate dehydrogenase gene, in silico overexpression of which generated additional NADPH required for fatty acid synthesis, leading to the increased DDDA fluxes by 48% and 22% higher, respectively, compared to wild-type. We further investigated the effect of supplying branched-chain amino acids on the acetyl-CoA turn-over rate which is key metabolite for fatty acid synthesis, suggesting their significance for production of DDDA in Y. lipolytica. In silico model-based strain design strategies allowed us to identify several metabolic engineering targets for overproducing DCAs in lipid accumulating yeast, Y. lipolytica. Thus, the current study can provide a methodological framework that is applicable to other oleaginous yeasts for value-added biochemical production.

Use of imidazole 4,5-dicarboxylic acid in vanadium speciation

International Nuclear Information System (INIS)

Banerjee, D.; Mondal, B.C.; Das, D.; Das, A.K.

2003-01-01

A new resin has been synthesized by fictionalization of polystyrene-divinylbenzene (8 %) with imidazole 4,5-dicarboxylic acid through -N=N- bonding. The resulting resin has been characterized by elemental analysis, thermogravimetric analysis, infrared spectroscopy, hydrogen ion capacity and metal ion capacity. The speciation study of vanadium has been studied by using this resin and the maximum exchange capacity was found to be 0.45 mmol g -1 for V 4+ and that for V 5+ was 1.57 mmol g -1 at pH 3 for both. The eluents malonic acid and sodium hydroxide have been used for the selective separation of vanadium(IV) and vanadium(V) species respectively. The effects of diverse ions on the sorption and recovery of each species have been studied. Finally, the developed method has been applied for the speciation and determination of these two species in natural water samples. (author)

Zn-Al LAYERED DOUBLE HYDROXIDE PILLARED BY DIFFERENT DICARBOXYLATE ANIONS

Directory of Open Access Journals (Sweden)

S. Gago

2004-12-01

Full Text Available Zn-Al layered double hydroxides (LDHs intercalated by terephthalate (TPH and biphenyl-4,4'-dicarboxylate (BPH anions have been synthesized by direct co-precipitation from aqueous solution. The Zn/Al ratio in the final materials was 1.8. The products were characterized by powder X-ray diffraction, thermogravimetric analysis, FTIR and FT Raman spectroscopy, and MAS NMR spectroscopy. The basal spacing for the TPH-LDH intercalate was 14.62 Å, indicating that the guest anions stack to form a monolayer with the aromatic rings perpendicular to the host layers. For the LDH intercalate containing BPH anions, a basal spacing of at least 19.2 Å would be expected if the anions adopted an arrangement similar to that for the TPH anions. The observed spacing was 18.24 Å, suggesting that the anions are tilted slightly with respect to the host layers.

Neurotoxic effects of ecstasy on the thalamus.

Science.gov (United States)

de Win, Maartje M L; Jager, Gerry; Booij, Jan; Reneman, Liesbeth; Schilt, Thelma; Lavini, Cristina; Olabarriaga, Sílvia D; Ramsey, Nick F; Heeten, Gerard J den; van den Brink, Wim

2008-10-01

Neurotoxic effects of ecstasy have been reported, although it remains unclear whether effects can be attributed to ecstasy, other recreational drugs or a combination of these. To assess specific/independent neurotoxic effects of heavy ecstasy use and contributions of amphetamine, cocaine and cannabis as part of The Netherlands XTC Toxicity (NeXT) study. Effects of ecstasy and other substances were assessed with (1)H-magnetic resonance spectroscopy, diffusion tensor imaging, perfusion weighted imaging and [(123)I]2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane ([(123)I]beta-CIT) single photon emission computed tomography (serotonin transporters) in a sample (n=71) with broad variation in drug use, using multiple regression analyses. Ecstasy showed specific effects in the thalamus with decreased [(123)I]beta-CIT binding, suggesting serotonergic axonal damage; decreased fractional anisotropy, suggesting axonal loss; and increased cerebral blood volume probably caused by serotonin depletion. Ecstasy had no effect on brain metabolites and apparent diffusion coefficients. Converging evidence was found for a specific toxic effect of ecstasy on serotonergic axons in the thalamus.

Protective effect of quercetin on bupivacaine-induced neurotoxicity ...

African Journals Online (AJOL)

... bupivacaine, possibly through inhibition of T-type calcium channel. This finding implies a novel mechanism for neuroprotective effect of quercetin, and its potential for treating toxicity arising from the use of local anesthetic agents. Keywords: Quercetin, Bupivacaine, Local anaesthetic, Neuroprotection, Neurotoxicity, T-type ...

Toxicologic evidence of developmental neurotoxicity of environmental chemicals

DEFF Research Database (Denmark)

Andersen, H R; Nielsen, J B; Grandjean, P

2000-01-01

Developmental neurotoxicity constitutes effects occurring in the offspring primarily as a result of exposure of the mother during pregnancy and lactation. To exert their effect, these chemicals or their metabolites must pass the placenta and/or the blood-brain barrier. In experimental animals, ex...

Hyperammonemia following glufosinate-containing herbicide poisoning: a potential marker of severe neurotoxicity.

Science.gov (United States)

Mao, Yan-Chiao; Wang, Jiaan-Der; Hung, Dong-Zong; Deng, Jou-Fang; Yang, Chen-Chang

2011-01-01

Glufosinate-ammonium (GLA) is the active ingredient of certain widely used non-selective contact herbicides ("e.g.," Basta). Although it is thought to be much less toxic to humans than to plants, deliberate ingestion of GLA could still lead to serious effects ("e.g.," neurotoxicity) or even death. Three cases presented with delayed-onset neurotoxicity including stupor, delirium, seizures, coma, and amnesia after ingesting large amount of Basta. Considering that GLA could irreversibly inhibit glutamine synthetase (GS) in plants, we performed serial measurements of serum ammonia in those patients and revealed marked hyperammonemia in all of them. All patients recovered with the sequelae of persistent amnesia after receiving intensive care and hemodialysis. We speculated that the occurrence of hyperammonemia might at least be partially related to GS inhibition in humans. Moreover, hyperammonemia could serve as a potential marker of severe neurotoxicity, especially prolonged amnesia, following massive ingestion of GLA-containing herbicides. The possible dose-response relation between GLA exposure and serum ammonia level, however, needs more investigations.

Tissue accumulation of microplastics in mice and biomarker responses suggest widespread health risks of exposure

Science.gov (United States)

Deng, Yongfeng; Zhang, Yan; Lemos, Bernardo; Ren, Hongqiang

2017-04-01

Microplastics (MPs) are a significant environmental health issue and increasingly greater source of concern. MPs have been detected in oceans, rivers, sediments, sewages, soil and even table salts. MPs exposure on marine organisms and humans has been documented, but information about the toxicity of MPs in mammal is limited. Here we used fluorescent and pristine polystyrene microplastics (PS-MPs) particles with two diameters (5 μm and 20 μm) to investigate the tissue distribution, accumulation, and tissue-specific health risk of MPs in mice. Results indicated that MPs accumulated in liver, kidney and gut, with a tissue-accumulation kinetics and distribution pattern that was strongly depended on the MPs particle size. In addition, analyses of multiple biochemical biomarkers and metabolomic profiles suggested that MPs exposure induced disturbance of energy and lipid metabolism as well as oxidative stress. Interestingly, blood biomarkers of neurotoxicity were also altered. Our results uncovered the distribution and accumulation of MPs across mice tissues and revealed significant alteration in several biomarkers that indicate potential toxicity from MPs exposure. Collectively, our data provided new evidence for the adverse consequences of MPs.

MR findings of cyclosporine neurotoxicity

Energy Technology Data Exchange (ETDEWEB)

Yang, Po Song; Ahn, Kook Jin; Ahn, Bo Young; Jung, Hae An; Kim, Hee Je; Lee, Jae Mun [The Catholic Univ. St Mary' s Hospital, Seoul (Korea, Republic of)

1998-12-01

To analyze the MR findings of cyclosporine-induced neurotoxicity in patients receiving high dose of cyclosporine and to suggest the possible pathogenetic mechanism. The cases of seven patients (2 males, 5 females;18-36 years old) who suffered seizures after receiving high-dose cyclosporine for bone marrow transplantation due to diseases such as aplastic anemia or leukemia were retrospectively reviewed. We evaluated the location and pattern of abnormal signal intensity seen on T2 weighted images, the presence of contrast enhancement, and the changes seen on follow-up MR performed at intervals of 12-30 days after initial MR in five of seven patients. We analyzed levels of blood cyclosporine and magnesium, and investigated the presence of hypertension at the sity of the seizure. Locations of the lesions were bilateral(n=3D5), unilateral(n=3D2), parietal(n=3D6), occipital(n=3D6), temporal(n=3D4), and in the frontal lobe(n=3D3). Frontal lesions showed high signal intensities in the borderline ischemic zone of the frontal lobe between the territory of the anterior and middle cerebral arteries. In six of the seven patients, cortical and subcortical areas including subcortical U-fibers were seen on T2-weighted images to be involved in the parietooccipital lobes. Only one of the seven showed high signal intensity in the left basal ganglia. All lesions showed high signal intensity on T2-weighted images, and iso to low signal intensity on T1-weighted. In five of seven patients there was no definite enhancement, but in the other two, enhancement was slight. In four of seven patients seizures occurred within high therapeutic ranges(250-450ng/ml), while others suffered such attacks at levels below the therapeutic range. After cyclospirine was administered at a reduced dosage or stopped, follow-up MR images showed the complete or near-total disappearance of the abnormal findings previously described. Only two patients had hypertension, and the others normotension. Five of the

MR findings of cyclosporine neurotoxicity

International Nuclear Information System (INIS)

Yang, Po Song; Ahn, Kook Jin; Ahn, Bo Young; Jung, Hae An; Kim, Hee Je; Lee, Jae Mun

1998-01-01

To analyze the MR findings of cyclosporine-induced neurotoxicity in patients receiving high dose of cyclosporine and to suggest the possible pathogenetic mechanism. The cases of seven patients (2 males, 5 females;18-36 years old) who suffered seizures after receiving high-dose cyclosporine for bone marrow transplantation due to diseases such as aplastic anemia or leukemia were retrospectively reviewed. We evaluated the location and pattern of abnormal signal intensity seen on T2 weighted images, the presence of contrast enhancement, and the changes seen on follow-up MR performed at intervals of 12-30 days after initial MR in five of seven patients. We analyzed levels of blood cyclosporine and magnesium, and investigated the presence of hypertension at the sity of the seizure. Locations of the lesions were bilateral(n=3D5), unilateral(n=3D2), parietal(n=3D6), occipital(n=3D6), temporal(n=3D4), and in the frontal lobe(n=3D3). Frontal lesions showed high signal intensities in the borderline ischemic zone of the frontal lobe between the territory of the anterior and middle cerebral arteries. In six of the seven patients, cortical and subcortical areas including subcortical U-fibers were seen on T2-weighted images to be involved in the parietooccipital lobes. Only one of the seven showed high signal intensity in the left basal ganglia. All lesions showed high signal intensity on T2-weighted images, and iso to low signal intensity on T1-weighted. In five of seven patients there was no definite enhancement, but in the other two, enhancement was slight. In four of seven patients seizures occurred within high therapeutic ranges(250-450ng/ml), while others suffered such attacks at levels below the therapeutic range. After cyclospirine was administered at a reduced dosage or stopped, follow-up MR images showed the complete or near-total disappearance of the abnormal findings previously described. Only two patients had hypertension, and the others normotension. Five of the

Neurotoxic Non-proteinogenic Amino Acid β-N-Methylamino-L-alanine and Its Role in Biological Systems.

Science.gov (United States)

Popova, A A; Koksharova, O A

2016-08-01

Secondary metabolites of photoautotrophic organisms have attracted considerable interest in recent years. In particular, molecules of non-proteinogenic amino acids participating in various physiological processes and capable of producing adverse ecological effects have been actively investigated. For example, the non-proteinogenic amino acid β-N-methylamino-L-alanine (BMAA) is neurotoxic to animals including humans. It is known that BMAA accumulation via the food chain can lead to development of neurodegenerative diseases in humans such as Alzheimer's and Parkinson's diseases as well as amyotrophic lateral sclerosis. Moreover, BMAA can be mistakenly incorporated into a protein molecule instead of serine. Natural sources of BMAA and methods for its detection are discussed in this review, as well as the role of BMAA in metabolism of its producers and possible mechanisms of toxicity of this amino acid in different living organisms.

Thermoset coatings from epoxidized sucrose soyate and blocked, bio-based dicarboxylic acids.

Science.gov (United States)

Kovash, Curtiss S; Pavlacky, Erin; Selvakumar, Sermadurai; Sibi, Mukund P; Webster, Dean C

2014-08-01

A new 100% bio-based thermosetting coating system was developed from epoxidized sucrose soyate crosslinked with blocked bio-based dicarboxylic acids. A solvent-free, green method was used to block the carboxylic acid groups and render the acids miscible with the epoxy resin. The thermal reversibility of this blocking allowed for the formulation of epoxy-acid thermoset coatings that are 100% bio-based. This was possible due to the volatility of the vinyl ethers under curing conditions. These systems have good adhesion to metal substrates and perform well under chemical and physical stress. Additionally, the hardness of the coating system is dependent on the chain length of the diacid used, making it tunable. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Lead neurotoxicity: In vitro and in vivo effects

International Nuclear Information System (INIS)

Rowles, T.K.

1989-01-01

Neuroglial cells, in particular astroglia, are thought to play a role in the neurotoxicity of lead. Two hypotheses have been proposed as possible cellular mechanism of this neurotoxicity: (1) lead affects intracellular levels of metals which mediate the toxic effects noted, and (2) lead affects intracellular heme biosynthesis which is then toxic to the cells. Zinc was found to have a profound effect on both intracellular lead levels and on cell numbers in lead-treated rat astroglia. A comparison of bovine and rat astroglia in culture indicated that the bovine cell cultures were not more sensitive to lead, even though calves are more sensitive. Lead was also shown to affect intracellular heme biosynthesis by a decrease in 14 C aminolevulinic acid incorporation into extractable heme in lead-treated rat astroglia. Finally, low levels of lead in immature guinea pigs caused changes in tissue levels of lead, iron, copper, and zinc with no change in weight gain or body:brain weight ratios

Cnidarian Neurotoxic Peptides Affecting Central Nervous System Targets.

Science.gov (United States)

Lazcano-Pérez, Fernando; Hernández-Guzmán, Ulises; Sánchez-Rodríguez, Judith; Arreguín-Espinosa, Roberto

2016-01-01

Natural products from animal venoms have been used widely in the discovery of novel molecules with particular biological activities that enable their use as potential drug candidates. The phylum Cnidaria (jellyfish, sea anemones, corals zoanthids, hydrozoans, etc.) is the most ancient venomous phylum on earth. Its venoms are composed of a complex mixture of peptidic compounds with neurotoxic and cytolitic properties that have shown activity on mammalian systems despite the fact that they are naturally targeted against fish and invertebrate preys, mainly crustaceans. For this reason, cnidarian venoms are an interesting and vast source of molecules with a remarkable activity on central nervous system, targeting mainly voltage-gated ion channels, ASIC channels, and TRPV1 receptors. In this brief review, we list the amino acid sequences of most cnidarian neurotoxic peptides reported to date. Additionally, we propose the inclusion of a new type of voltage-gated sea anemone sodium channel toxins based on the most recent reports.

Neurotoxicity of dental amalgam is mediated by zinc.

Science.gov (United States)

Lobner, D; Asrari, M

2003-03-01

The use of dental amalgam is controversial largely because it contains mercury. We tested whether amalgam caused toxicity in neuronal cultures and whether that toxicity was caused by mercury. In this study, we used cortical cell cultures to show for the first time that amalgam causes nerve cell toxicity in culture. However, the toxicity was not blocked by the mercury chelator, 2,3-dimercaptopropane-1-sulphonate (DMPS), but was blocked by the metal chelator, calcium disodium ethylenediaminetetraacetate (CaEDTA). DMPS was an effective mercury chelator in this system, since it blocked mercury toxicity. Of the components that comprise amalgam (mercury, zinc, tin, copper, and silver), only zinc neurotoxicity was blocked by CaEDTA. These results indicate that amalgam is toxic to nerve cells in culture by releasing zinc. While zinc is known to be neurotoxic, ingestion of zinc is not a major concern because zinc levels in the body are tightly regulated.

What is microglia neurotoxicity (Not)?

DEFF Research Database (Denmark)

Biber, Knut; Owens, Trevor; Boddeke, Erik

2014-01-01

and vulnerable organ like the brain should host numerous potential killers, we here review the concept of microglia neurotoxicity. On one hand it is discussed that most of our understanding about how microglia kill neurons is based on in vitro experiments or correlative staining studies that suffer from...... the difficulty to discriminate microglia and peripheral myeloid cells in the diseased brain. On the other hand it is described that a more functional approach by mutating, inactivating or deleting microglia is seldom associated with a beneficial outcome in an acute injury situation, suggesting that microglia...

Exocytosis: using amperometry to study presynaptic mechanisms of neurotoxicity

NARCIS (Netherlands)

Westerink, R.H.S.

2004-01-01

The development of carbon fiber microelectrode amperometry enabled detailed investigation of the presynaptic response at the single cell level with single vesicle resolution. Consequently, amperometry allowed for detailed studies into the presynaptic mechanisms underlying neurotoxicity. This review

Acute D2/D3 dopaminergic agonism but chronic D2/D3 antagonism prevents NMDA antagonist neurotoxicity.

Science.gov (United States)

Farber, Nuri B; Nemmers, Brian; Noguchi, Kevin K

2006-09-15

Antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor, most likely by producing disinhibtion in complex circuits, acutely produce psychosis and cognitive disturbances in humans, and neurotoxicity in rodents. Studies examining NMDA Receptor Hypofunction (NRHypo) neurotoxicity in animals, therefore, may provide insights into the pathophysiology of psychotic disorders. Dopaminergic D2 and/or D3 agents can modify psychosis over days to weeks, suggesting involvement of these transmitter system(s). We studied the ability of D2/D3 agonists and antagonists to modify NRHypo neurotoxicity both after a one-time acute exposure and after chronic daily exposure. Here we report that D2/D3 dopamine agonists, probably via D3 receptors, prevent NRHypo neurotoxicity when given acutely. The protective effect with D2/D3 agonists is not seen after chronic daily dosing. In contrast, the antipsychotic haloperidol does not affect NRHypo neurotoxicity when given acutely at D2/D3 doses. However, after chronic daily dosing of 1, 3, or 5 weeks, haloperidol does prevent NRHypo neurotoxicity with longer durations producing greater protection. Understanding the changes that occur in the NRHypo circuit after chronic exposure to dopaminergic agents could provide important clues into the pathophysiology of psychotic disorders.

p73 gene in dopaminergic neurons is highly susceptible to manganese neurotoxicity.

Science.gov (United States)

Kim, Dong-Suk; Jin, Huajun; Anantharam, Vellareddy; Gordon, Richard; Kanthasamy, Arthi; Kanthasamy, Anumantha G

2017-03-01

Chronic exposure to elevated levels of manganese (Mn) has been linked to a Parkinsonian-like movement disorder, resulting from dysfunction of the extrapyramidal motor system within the basal ganglia. However, the exact cellular and molecular mechanisms of Mn-induced neurotoxicity remain elusive. In this study, we treated C57BL/6J mice with 30mg/kg Mn via oral gavage for 30 days. Interestingly, in nigral tissues of Mn-exposed mice, we found a significant downregulation of the truncated isoform of p73 protein at the N-terminus (ΔNp73). To further determine the functional role of Mn-induced p73 downregulation in Mn neurotoxicity, we examined the interrelationship between the effect of Mn on p73 gene expression and apoptotic cell death in an N27 dopaminergic neuronal model. Consistent with our animal study, 300μM Mn treatment significantly suppressed p73 mRNA expression in N27 dopaminergic cells. We further determined that protein levels of the ΔNp73 isoform was also reduced in Mn-treated N27 cells and primary striatal cultures. Furthermore, overexpression of ΔNp73 conferred modest cellular protection against Mn-induced neurotoxicity. Taken together, our results demonstrate that Mn exposure downregulates p73 gene expression resulting in enhanced susceptibility to apoptotic cell death. Thus, further characterization of the cellular mechanism underlying p73 gene downregulation will improve our understanding of the molecular underpinnings of Mn neurotoxicity. Copyright © 2016 Elsevier B.V. All rights reserved.

Resistance of neuronal nitric oxide synthase-deficient mice to methamphetamine-induced dopaminergic neurotoxicity.

Science.gov (United States)

Itzhak, Y; Gandia, C; Huang, P L; Ali, S F

1998-03-01

Methamphetamine (METH) is a powerful psychostimulant that produces dopaminergic neurotoxicity manifested by a decrease in the levels of dopamine, tyrosine hydroxylase activity and dopamine transporter (DAT) binding sites in the nigrostriatal system. We have recently reported that blockade of the neuronal nitric oxide synthase (nNOS) isoform by 7-nitroindazole provides protection against METH-induced neurotoxicity in Swiss Webster mice. The present study was undertaken to investigate the effect of a neurotoxic dose of METH on mutant mice lacking the nNOS gene [nNOS(-/-)] and wild-type controls. In addition, we sought to investigate the behavioral outcome of exposure to a neurotoxic dose of METH. Homozygote nNOS(-/-), heterozygote nNOS(+/-) and wild-type animals were administered either saline or METH (5 mg/kg x 3). Dopamine, DOPAC and HVA levels, as well as DAT binding site levels, were determined in striatal tissue derived 72 h after the last METH injection. This regimen of METH given to nNOS(-/-) mice affected neither the tissue content of dopamine and its metabolites nor the number of DAT binding sites. Although a moderate reduction in the levels of dopamine (35%) and DAT binding sites (32%) occurred in striatum of heterozygote nNOS(+/-) mice, a more profound depletion of the dopaminergic markers (up to 68%) was observed in the wild-type animals. METH-induced hyperthermia was observed in all animal strains examined except the nNOS(-/-) mice. Investigation of the animals' spontaneous locomotor activity before and after administration of the neurotoxic dose of METH (5 mg/kg x 3) revealed no differences. A low dose of METH (1.0 mg/kg) administered to naive animals (nNOS(-/-) and wild-type) resulted in a similar intensity of locomotor stimulation. However, 68 to 72 h after exposure to the high-dose METH regimen, a marked sensitized responses to a challenge METH injection was observed in the wild-type mice but not in the nNOS(-/-) mice. Taken together, these results

Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells.

Science.gov (United States)

Gust, Juliane; Hay, Kevin A; Hanafi, Laïla-Aïcha; Li, Daniel; Myerson, David; Gonzalez-Cuyar, Luis F; Yeung, Cecilia; Liles, W Conrad; Wurfel, Mark; Lopez, Jose A; Chen, Junmei; Chung, Dominic; Harju-Baker, Susanna; Özpolat, Tahsin; Fink, Kathleen R; Riddell, Stanley R; Maloney, David G; Turtle, Cameron J

2017-12-01

Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor-modified T (CAR-T) cells can be complicated by neurologic adverse events (AE) in patients with refractory B-cell malignancies. In 133 adults treated with CD19 CAR-T cells, we found that acute lymphoblastic leukemia, high CD19 + cells in bone marrow, high CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier (BBB) permeability. The permeable BBB failed to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFNγ, which induced brain vascular pericyte stress and their secretion of endothelium-activating cytokines. Endothelial activation and multifocal vascular disruption were found in the brain of a patient with fatal neurotoxicity. Biomarkers of endothelial activation were higher before treatment in patients who subsequently developed grade ≥4 neurotoxicity. Significance: We provide a detailed clinical, radiologic, and pathologic characterization of neurotoxicity after CD19 CAR-T cells, and identify risk factors for neurotoxicity. We show endothelial dysfunction and increased BBB permeability in neurotoxicity and find that patients with evidence of endothelial activation before lymphodepletion may be at increased risk of neurotoxicity. Cancer Discov; 7(12); 1404-19. ©2017 AACR. See related commentary by Mackall and Miklos, p. 1371 This article is highlighted in the In This Issue feature, p. 1355 . ©2017 American Association for Cancer Research.

L-Ascorbate attenuates methamphetamine neurotoxicity through enhancing the induction of endogenous heme oxygenase-1

Energy Technology Data Exchange (ETDEWEB)

Huang, Ya-Ni [Department of Nursing, Hsin Sheng College of Medical Care and Management, Taoyuan, Taiwan (China); Wang, Jiz-Yuh [Department of Neurology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan (China); Lee, Ching-Tien [Department of Nursing, Hsin Sheng College of Medical Care and Management, Taoyuan, Taiwan (China); Lin, Chih-Hung [Graduate Institute of Medical Sciences and Department of Physiology, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); Lai, Chien-Cheng [Far Eastern Memorial Hospital, Department of Surgery, Taipei, Taiwan (China); Wang, Jia-Yi, E-mail: jywang2010@tmu.edu.tw [Graduate Institute of Medical Sciences and Department of Physiology, College of Medicine, Taipei Medical University, Taipei, Taiwan (China)

2012-12-01

Methamphetamine (METH) is a drug of abuse which causes neurotoxicity and increased risk of developing neurodegenerative diseases. We previously found that METH induces heme oxygenase (HO)-1 expression in neurons and glial cells, and this offers partial protection against METH toxicity. In this study, we investigated the effects of L-ascorbate (vitamin C, Vit. C) on METH toxicity and HO-1 expression in neuronal/glial cocultures. Cell viability and damage were evaluated by 3-(4,5-dimethylthianol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) reduction and lactate dehydrogenase (LDH) release, respectively. Neuronal and glial localization of HO-1 were identified by double immunofluorescence staining. Reactive oxygen species (ROS) production was measured using the fluorochrome 2′,7′-dichlorofluorescin diacetate. HO-1 mRNA and protein expression were examined by RT-qPCR and Western blotting, respectively. Results show that Vit. C induced HO-1 mRNA and protein expressions in time- and concentration-dependent manners. Inhibition of p38 mitogen-activated protein kinase (MAPK) but not extracellular signal-regulated kinase (ERK) significantly blocked induction of HO-1 by Vit. C. HO-1 mRNA and protein expressions were significantly elevated by a combination of Vit. C and METH, compared to either Vit. C or METH alone. Pretreatment with Vit. C enhanced METH-induced HO-1 expression and attenuated METH-induced ROS production and neurotoxicity. Pharmacological inhibition of HO activity abolished suppressive effects of Vit. C on METH-induced ROS production and attenuated neurotoxicity. We conclude that induction of HO-1 expression contributes to the attenuation of METH-induced ROS production and neurotoxicity by Vit. C. We suggest that HO-1 induction by Vit. C may serve as a strategy to alleviate METH neurotoxicity. -- Highlights: ► Besides the anti-oxidant effect, Vit. C also induces HO-1 expression in brain cells. ► Vit. C reduces METH neurotoxicity and ROS production by

L-Ascorbate attenuates methamphetamine neurotoxicity through enhancing the induction of endogenous heme oxygenase-1

International Nuclear Information System (INIS)

Huang, Ya-Ni; Wang, Jiz-Yuh; Lee, Ching-Tien; Lin, Chih-Hung; Lai, Chien-Cheng; Wang, Jia-Yi

2012-01-01

Methamphetamine (METH) is a drug of abuse which causes neurotoxicity and increased risk of developing neurodegenerative diseases. We previously found that METH induces heme oxygenase (HO)-1 expression in neurons and glial cells, and this offers partial protection against METH toxicity. In this study, we investigated the effects of L-ascorbate (vitamin C, Vit. C) on METH toxicity and HO-1 expression in neuronal/glial cocultures. Cell viability and damage were evaluated by 3-(4,5-dimethylthianol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) reduction and lactate dehydrogenase (LDH) release, respectively. Neuronal and glial localization of HO-1 were identified by double immunofluorescence staining. Reactive oxygen species (ROS) production was measured using the fluorochrome 2′,7′-dichlorofluorescin diacetate. HO-1 mRNA and protein expression were examined by RT-qPCR and Western blotting, respectively. Results show that Vit. C induced HO-1 mRNA and protein expressions in time- and concentration-dependent manners. Inhibition of p38 mitogen-activated protein kinase (MAPK) but not extracellular signal-regulated kinase (ERK) significantly blocked induction of HO-1 by Vit. C. HO-1 mRNA and protein expressions were significantly elevated by a combination of Vit. C and METH, compared to either Vit. C or METH alone. Pretreatment with Vit. C enhanced METH-induced HO-1 expression and attenuated METH-induced ROS production and neurotoxicity. Pharmacological inhibition of HO activity abolished suppressive effects of Vit. C on METH-induced ROS production and attenuated neurotoxicity. We conclude that induction of HO-1 expression contributes to the attenuation of METH-induced ROS production and neurotoxicity by Vit. C. We suggest that HO-1 induction by Vit. C may serve as a strategy to alleviate METH neurotoxicity. -- Highlights: ► Besides the anti-oxidant effect, Vit. C also induces HO-1 expression in brain cells. ► Vit. C reduces METH neurotoxicity and ROS production by

Comparative developmental neurotoxicity of flame-retardants, polybrominated flame-retardants and organophosphorous compounds, in mice

Energy Technology Data Exchange (ETDEWEB)

Eriksson, P.; Johansson, N.; Viberg, H.; Fischer, C.; Fredriksson, A. [Dept. of Environmental Toxicology, Uppsala Univ. (Sweden)

2004-09-15

Recently we have reported that certain PBDEs, such as 2,2',4,4'-tetrabromodiphenyl ether (PBDE 47), 2,2',4,4',5- pentabromodiphenyl ether (PBDE 99), 2,2',4,4',5,5'-hexabromodiphenyl ether (PBDE153) and 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (PBDE 209) can cause developmental neurotoxic effects when given to neonatal mice. The developmental neurotoxic effects after neonatal exposure to PBDE 209 are suggested to be caused by a metabolite (possible de-brominated one). Neonatal exposure HBCDD has also been shown to cause developmental neurotoxic effects. Neonatal exposure to PBDE 99, PBDE 153 and HBCDD was also found to affect learning and memory in the adult animal. The induction of permanent aberration in spontaneous behaviour was induced during limited period of the neonatal brain development. The altered spontaneous behaviour was also seen to worsen with age. In these studies we have also found that the cholinergic system is one target that is affected, observed as changes in the response of the cholinergic system and a decrease in cholinergic receptors, and is one of the mechanisms underlying the observed behavioural changes. BFRs so far studied TBBPA appears not to cause developmental neurotoxic effects when administered at the same dose levels to neonatal mice. In the present studies we have investigated whether neonatal exposure to three highly brominated dipehenyl ethers, 2,2',3,4,4',5',6'-heptabromodiphenyl ether (PBDE183), 2,2',3'4'4',5,5',6- octabromodiphenyl ether (PBDE 203) and 2,2',3,3',4,4',5',6'-nonabromodiphenyl ether (PBDE 206) can induce developmental neurotoxic effects, such as aberrations in spontaneous behaviour and in learning and memory. Furthermore, neonatal developmental neurotoxicity effects were also studied for two OPs used as FR, triphenyl phosphate and tris(2-chloro-ethyl)phosphate.

Neurotoxicity profile of supermethrin, a new pyrethroid insecticide.

Science.gov (United States)

Hornychova, M; Frantik, E; Kubat, J; Formanek, J

1995-11-01

The use of a standard two-tier neurotoxicity screening procedure in the context of risk assessment is exemplified. Testing of a new pyrethroid in rats addressed the following sequence of questions: Does the substance evoke neurotoxic symptoms in sublethal doses? Do these symptoms reflect a primary neurotropic action? What are the dynamic characteristics of injury, the clinical profile of effect, and the relative potency of the tested substance compared to similar compounds? - The testing protocol is an animal analogue of a systematic neurological and psychological examination in man. First tier tests (structured observation, motor activity measurement, simple neurological examination) were applied after the first dose, during repeated dosing phase and in the restitution phase. Facultative tests for the second-tier examination (motor activity pattern, learning/retention test, evoked potentials, dynamic motor performance) were selected on the basis of effects revealed by the first-tier testing. Supermethrin evoked acute neurotoxicity in sublethal doses, ranging from 1/30 to 1/15 of LD50. The clinical pattern was similar to other cyano-substituted pyrethroids. Behavioural inhibition was transient and complete tolerance to it developed after 4-week repeated dosing. No indications of long-lasting changes in neuronal excitability or in learning and memory processes were found. Ataxia and excitomotoric phenomena dominated both the acute and the subchronic picture. Marked and persistent motor disturbances, including symptoms of lower motoneuron injury, were limited to individual animals of the highest, near-lethal dose group (27 mg-kg-1). Compared to lambda-cyhalothrin, the effects of supermethrin were 2 to 3 times weaker, disappeared more rapidly, cumulated less, and had higher tendency to tolerance.

Prion infections and anti-PrP antibodies trigger converging neurotoxic pathways.

Directory of Open Access Journals (Sweden)

Uli S Herrmann

2015-02-01

Full Text Available Prions induce lethal neurodegeneration and consist of PrPSc, an aggregated conformer of the cellular prion protein PrPC. Antibody-derived ligands to the globular domain of PrPC (collectively termed GDL are also neurotoxic. Here we show that GDL and prion infections activate the same pathways. Firstly, both GDL and prion infection of cerebellar organotypic cultured slices (COCS induced the production of reactive oxygen species (ROS. Accordingly, ROS scavenging, which counteracts GDL toxicity in vitro and in vivo, prolonged the lifespan of prion-infected mice and protected prion-infected COCS from neurodegeneration. Instead, neither glutamate receptor antagonists nor inhibitors of endoplasmic reticulum calcium channels abolished neurotoxicity in either model. Secondly, antibodies against the flexible tail (FT of PrPC reduced neurotoxicity in both GDL-exposed and prion-infected COCS, suggesting that the FT executes toxicity in both paradigms. Thirdly, the PERK pathway of the unfolded protein response was activated in both models. Finally, 80% of transcriptionally downregulated genes overlapped between prion-infected and GDL-treated COCS. We conclude that GDL mimic the interaction of PrPSc with PrPC, thereby triggering the downstream events characteristic of prion infection.

[Toxicodynamic properties of liquids used for the cooling of high-power turbines. III. Neurotoxic effects].

Science.gov (United States)

Florek, E; Malendowicz, L; Seńczuk, W

1984-01-01

Results of neurotoxicity studies indicate that preparations IWiOL -3-n, IWiOL -3-e and OMTI administered intragastrically or intraperitoneally induce neurotoxic effects in hens. Those effects are, however, weaker than those of the standard substance, i.e. triorthocresyl . Yet, they get increased in result of IWiOL -3-e, as compared to IWiOL -3-n administration.

3-nitropropionic acid neurotoxicity in hippocampal slice cultures

DEFF Research Database (Denmark)

Noer, Helle; Kristensen, Bjarne W; Noraberg, Jens

2002-01-01

: CA1 > CA3 > fascia dentata. In low glucose much lower concentrations of 3-NP (25 microM) triggered neurotoxicity. One-week-old cultures were less susceptible to 3-NP toxicity than 3-week-old cultures, but the dentate granule cells were relatively more affected in the immature cultures. We found...

Morphology and phase transformations of tin oxide nanostructures synthesized by the hydrothermal method in the presence of dicarboxylic acids

International Nuclear Information System (INIS)

Zima, Tatyana; Bataev, Ivan

2016-01-01

A new approach to the synthesis of non-stoichiometric tin oxide structures with different morphologies and the phase compositions has been evaluated. The nanostructures were synthesized by hydrothermal treatment of the mixtures of dicarboxylic acids ― aminoterephthalic or oxalic ― with nanocrystalline SnO 2 powder, which was obtained via the sol-gel technology. The products were characterized by Raman and IR spectroscopy, SEM, HRTEM, and XRD analysis. It was shown that the controlled addition of a dicarboxylic acid leads not only to a change in the morphology of the nanostructures, but also to SnO 2 –SnO 2 /Sn 3 O 4 –Sn 3 O 4 –SnO phase transformations. A single-phase Sn 3 O 4 in the form of the well-separated hexagonal nanoplates and mixed SnO 2 /Sn 3 O 4 phases in the form of hierarchical flower-like structures were obtained in the presence of organic additives. The effects of concentration, redox activity of the acids and heat treatment on the basic characteristics of the synthesized tin oxide nanostructures and phase transformations in the synthesized materials are discussed. - Graphical abstract: The controlled addition of aminoterephthalic or oxalic acid leads not only to a change in the morphology of the nanostructures, but also to SnO 2 –SnO 2 /Sn 3 O 4 –Sn 3 O 4 –SnO phase transformations. - Highlights: • A new approach to the synthesis of non-stoichiometric tin oxide structures is studied. • Tin oxide structures are synthesized via hydrothermal method with dicarboxylic acids. • Morphology and phase composition are changed with redox activity and dosage of acid. • The redox activity of acid has an effect on ratio of SnO and SnO 2 in crystal structure. • A pure phase Sn 3 O 4 nanoplates and SnO 2 /Sn 3 O 4 hierarchical structures are formed.

Spirulina maxima Extract Prevents Neurotoxicity via Promoting Activation of BDNF/CREB Signaling Pathways in Neuronal Cells and Mice.

Science.gov (United States)

Koh, Eun-Jeong; Seo, Young-Jin; Choi, Jia; Lee, Hyeon Yong; Kang, Do-Hyung; Kim, Kui-Jin; Lee, Boo-Yong

2017-08-17

Spirulina maxima is a microalgae which contains flavonoids and other polyphenols. Although Spirulina maxima 70% ethanol extract (SM70EE) has diverse beneficial effects, its effects on neurotoxicity have not been fully understood. In this study, we investigated the neuroprotective effects of SM70EE against trimethyltin (TMT)-induced neurotoxicity in HT-22 cells. SM70EE inhibited the cleavage of poly-ADP ribose polymerase (PARP). Besides, ROS production was decreased by down-regulating oxidative stress-associated enzymes. SM70EE increased the factors of brain-derived neurotrophic factor (BDNF)/cyclic AMPresponsive elementbinding protein (CREB) signalling pathways. Additionally, acetylcholinesterase (AChE) was suppressed by SM70EE. Furthermore, we investigated whether SM70EE prevents cognitive deficits against scopolamine-induced neurotoxicity in mice by applying behavioral tests. SM70EE increased step-through latency time and decreased the escape latency time. Therefore, our data suggest that SM70EE may prevent TMT neurotoxicity through promoting activation of BDNF/CREB neuroprotective signaling pathways in neuronal cells. In vivo study, SM70EE would prevent cognitive deficits against scopolamine-induced neurotoxicity in mice.

Synthesis, structures and properties of a series of manganese coordination complexes constructed from dicarboxylic fluorene derivatives

Energy Technology Data Exchange (ETDEWEB)

Li Xing, E-mail: lixing@nbu.edu.cn [State Key Laboratory Base of Novel Functional Materials and Preparation Science, Faculty of Materials Science and Chemical Engineering, Ningbo University, Ningbo, Zhejiang, 315211 (China); Zhao Xiuhua; Bing Yue; Zha Meiqin; Xie Hongzhen; Guo Zhiyong [State Key Laboratory Base of Novel Functional Materials and Preparation Science, Faculty of Materials Science and Chemical Engineering, Ningbo University, Ningbo, Zhejiang, 315211 (China)

2013-01-15

Assembly reactions of 9,9-diethylfluorene-2,7-dicarboxylic acid (H{sub 2}DFDC) and Mn(CH{sub 3}COO){sub 2}{center_dot}4H{sub 2}O or MnCl{sub 2}{center_dot}4H{sub 2}O by tuning of various secondary ligands such as 2,2 Prime -bipyridine (2,2 Prime -bpy), 4,4 Prime -bipyridine (4,4 Prime -bpy) or 1,3-bis(4-pyridyl)propane) (bpp), gave rise to four complexes {l_brace} [Mn{sub 2}(DFDC){sub 2}(DMF){sub 2}]{center_dot}H{sub 2}O{r_brace} {sub n} (1), [Mn(DFDC)(2,2 Prime -bpy)]{sub n} (2), {l_brace} [Mn{sub 2}(DFDC){sub 2}(4,4 Prime -bpy){sub 2}]{center_dot}2CH{sub 3}OH{r_brace} {sub n} (3), and {l_brace} [Mn{sub 4}(DFDC){sub 4}(bpp){sub 2}(CH{sub 3}OH){sub 3} (H{sub 2}O){sub 3}]{center_dot}3(CH{sub 3}OH){center_dot}3(H{sub 2}O){r_brace} {sub n} (4). Single crystal X-ray diffraction analysis reveal that complex 1 is three dimensional structure with rhombic channels filled by guest water molecules; 2 presents a close-packed structure with high thermal stability; 3 exhibits a three dimensional framework with micro-porous channels filled by guest methanol molecules and 4 is a two-dimensional structure. The photoluminescent properties of 1-4 have been studied, respectively, showing that the Mn(II) ions, accessorial organic ligands or crystal structures exert important influences on the photoluminescence emissions of H{sub 2}DFDC ligands. Thermogravimetric analysis show that the complexes have remarkably high thermal stability. Magnetic susceptibility measurements have been finished and discussed for the complexes. - Graphical abstract: Assembly of 9,9-diethylfluorene-2,7-dicarboxylic acid and Mn(II) salts by tuning of various accessorial ligands resulted in four manganese complexes with different topological frameworks. Highlights: Black-Right-Pointing-Pointer Four manganese complexes based on 9,9-diethylfluorene-2,7-dicarboxylic acid were obtained. Black-Right-Pointing-Pointer The complexes were structurally characterized by single-crystal X-ray diffraction. Black

The Potential Neurotoxic Effects of Low-Dose Sarin Exposure in a Guinea Pig Model

Science.gov (United States)

2002-01-01

1 THE POTENTIAL NEUROTOXIC EFFECTS OF LOW-DOSE SARIN EXPOSURE IN A GUINEA PIG MODEL Melinda R. Roberson, PhD, Michelle B. Schmidt...Proving Ground, MD 21010 USA ABSTRACT This study is assessing the effects in guinea pigs of repeated low-dose exposure to the nerve...COVERED - 4. TITLE AND SUBTITLE The Potential Neurotoxic Effects Of Low-Dose Sarin Exposure In A Guinea Pig Model 5a. CONTRACT NUMBER 5b

A convenient preparation of 9 H -carbazole-3,6-dicarbonitrile and 9 H -carbazole-3,6-dicarboxylic acid

KAUST Repository

Weselinski, Lukasz Jan

2014-01-23

A catalytic, high yielding and scalable procedure for the synthesis of 9H-carbazole-3,6-dicarbonitrile has been developed. Subsequent hydrolysis of the dinitrile in the presence of a catalytic copper species (i.e., CuI) yields 9H-carbazole-3,6-dicarboxylic acid. Both compounds are versatile and fine-tunable organic building blocks and therefore offer potential in material science, medicinal and supramolecular chemistry. © Georg Thieme Verlag Stuttgart New York.

Synthesis and characterization of Cis-5-Norbornene-2, 3-dicarboxylic anhydride-chitosan

International Nuclear Information System (INIS)

Ku Marshilla Ku Ishak; Zulkifli Ahmad; Hazizan Mohd Akil

2009-01-01

Chitosan was chemically modified with bulky structure, cis-5-norbornene-2, 3-dicarboxylic anhydride and the characteristic of this modified chitosan was studied. The resulting material was analyzed by FTIR, TGA, DSC, XRD and SEM to study the effect of N-acylation to the polysaccharide structure. FTIR results show that the anhydride monomer was successfully bound to amine group of chitosan. Thermal analysis of the modified structure provides the chitosan fibers with thermal stability while XRD and SEM show the lost of crystallinity of modified chitosan. XRD of modified chitosan shows broader peak pattern and a considerable increase in a dimension while SEM of chitosan presented the single particle morphology while norbornene-chitosan shows aggromolarate behaviour due to the hydrophobic nature of norbornene pendant group which induced aggromolaration of the particles in modified structure.(author)

Scoping review: Awareness of neurotoxicity from anesthesia in children in otolaryngology literature.

Science.gov (United States)

Earley, Marisa A; Pham, Liem T; April, Max M

2017-08-01

Review otolaryngology literature for awareness of neurotoxicity from general anesthesia in children. Recently, there has been increasing focus in anesthesia literature on the long-term effects of general anesthesia on neurodevelopment. Multiple animal models have demonstrated evidence of neurotoxicity from both inhalational and intravenous anesthetics. Cohort studies also have revealed modestly increased risk of adverse neurodevelopmental outcomes in children exposed to a single episode of general anesthesia prior to 3 to 4 years of age, with stronger evidence for multiple exposures in this age range. Otolaryngologists may subject children to general anesthesia via procedures or tests, including computed tomography, magnetic resonance imaging, and auditory brainstem response. PubMed, Embase, Scopus, and Web of Science Review. A scoping review using the above databases was performed limited to January 2005 through December 2015. Articles were screened and reviewed based on predefined inclusion and exclusion criteria. Initial search generated 3,909 articles. After 72 full text articles were reviewed, only seven articles mentioned neurotoxicity as a risk of general anesthesia in pediatric patients. Despite the high volume of pediatric otolaryngologic procedures performed annually, there remains limited awareness in our literature discussing neurotoxicity as an outcome. Prospective data from anesthesia literature is still pending; therefore, specific recommendations cannot be made at this time. Otolaryngologists should be aware of the concerns and work toward defining elective procedures, combining surgical procedures with other procedures or imaging, and reassessing the timing and frequency of various interventions under general anesthesia in young children. Laryngoscope, 127:1930-1937, 2017. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

Lithium-mediated protection against ethanol neurotoxicity

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Jia Luo

2010-06-01

Full Text Available Lithium has long been used as a mood stabilizer in the treatment of manic-depressive (bipolar disorder. Recent studies suggest that lithium has neuroprotective properties and may be useful in the treatment of acute brain injuries such as ischemia and chronic neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis. One of the most important neuroprotective properties of lithium is its anti-apoptotic action. Ethanol is a neuroteratogen and fetal alcohol spectrum disorders (FASD are caused by maternal ethanol exposure during pregnancy. FASD is the leading cause of mental retardation. Ethanol exposure causes neuroapoptosis in the developing brain. Ethanol-induced loss of neurons in the central nervous system underlies many of the behavioral deficits observed in FASD. Excessive alcohol consumption is also associated with Wernicke–Korsakoff syndrome and neurodegeneration in the adult brain. Recent in vivo and in vitro studies indicate that lithium is able to ameliorate ethanol-induced neuroapoptosis. Lithium is an inhibitor of glycogen synthase kinase 3 (GSK3 which has recently been identified as a mediator of ethanol neurotoxicity. Lithium’s neuroprotection may be mediated by its inhibition of GSK3. In addition, lithium also affects many other signaling proteins and pathways that regulate neuronal survival and differentiation. This review discusses the recent evidence of lithium-mediated protection against ethanol neurotoxicity and potential underlying mechanisms.

Hirsutine, an indole alkaloid of Uncaria rhynchophylla, inhibits inflammation-mediated neurotoxicity and microglial activation.

Science.gov (United States)

Jung, Hwan Yong; Nam, Kyong Nyon; Woo, Byung-Choel; Kim, Kyoo-Pil; Kim, Sung-Ok; Lee, Eunjoo H

2013-01-01

Chronic microglial activation endangers neuronal survival through the release of various pro-inflammatory and neurotoxic factors. As such, negative regulators of microglial activation have been considered as potential therapeutic candidates to reduce the risk of neurodegeneration associated with inflammation. Uncaria rhynchophylla (U. rhynchophylla) is a traditional oriental herb that has been used for treatment of disorders of the cardiovascular and central nervous systems. Hirsutine (HS), one of the major indole alkaloids of U. rhynchophylla, has demonstrated neuroprotective potential. The aim of the present study was to examine the efficacy of HS in the repression of inflammation-induced neurotoxicity and microglial cell activation. In organotypic hippocampal slice cultures, HS blocked lipopolysaccharide (LPS)-related hippocampal cell death and production of nitric oxide (NO), prostaglandin (PG) E2 and interleukin-1β. HS was demonstrated to effectively inhibit LPS-induced NO release from cultured rat brain microglia. The compound reduced the LPS-stimulated production of PGE2 and intracellular reactive oxygen species. HS significantly decreased LPS-induced phosphorylation of the mitogen-activated protein kinases and Akt signaling proteins. In conclusion, HS reduces the production of various neurotoxic factors in activated microglial cells and possesses neuroprotective activity in a model of inflammation-induced neurotoxicity.

Soybean-derived Bowman-Birk inhibitor inhibits neurotoxicity of LPS-activated macrophages

Directory of Open Access Journals (Sweden)

Persidsky Yuri

2011-02-01

Full Text Available Abstract Background Lipopolysaccharide (LPS, the major component of the outer membrane of gram-negative bacteria, can activate immune cells including macrophages. Activation of macrophages in the central nervous system (CNS contributes to neuronal injury. Bowman-Birk inhibitor (BBI, a soybean-derived protease inhibitor, has anti-inflammatory properties. In this study, we examined whether BBI has the ability to inhibit LPS-mediated macrophage activation, reducing the release of pro-inflammatory cytokines and subsequent neurotoxicity in primary cortical neural cultures. Methods Mixed cortical neural cultures from rat were used as target cells for testing neurotoxicity induced by LPS-treated macrophage supernatant. Neuronal survival was measured using a cell-based ELISA method for expression of the neuronal marker MAP-2. Intracellular reactive oxygen species (ROS production in macrophages was measured via 2', 7'-dichlorofluorescin diacetate (DCFH2DA oxidation. Cytokine expression was determined by quantitative real-time PCR. Results LPS treatment of macrophages induced expression of proinflammatory cytokines (IL-1β, IL-6 and TNF-α and of ROS. In contrast, BBI pretreatment (1-100 μg/ml of macrophages significantly inhibited LPS-mediated induction of these cytokines and ROS. Further, supernatant from BBI-pretreated and LPS-activated macrophage cultures was found to be less cytotoxic to neurons than that from non-BBI-pretreated and LPS-activated macrophage cultures. BBI, when directly added to the neuronal cultures (1-100 μg/ml, had no protective effect on neurons with or without LPS-activated macrophage supernatant treatment. In addition, BBI (100 μg/ml had no effect on N-methyl-D-aspartic acid (NMDA-mediated neurotoxicity. Conclusions These findings demonstrate that BBI, through its anti-inflammatory properties, protects neurons from neurotoxicity mediated by activated macrophages.

Functional, Structural, and Neurotoxicity Biomarkers in Integrative Assessment of Concussions

Directory of Open Access Journals (Sweden)

Svetlana A Dambinova

2016-10-01

Full Text Available Concussion is a complex, heterogenous process affecting the brain. Accurate assessment and diagnosis and appropriate management of concussion are essential to ensure athletes do not prematurely return to play or others to work or active military duty, risking re-injury. To date, clinical diagnosis relies primarily on evaluating subjects for functional impairment using instruments that include neurocognitive testing, subjective symptom report, and neurobehavioral assessments, such as balance and vestibular-ocular reflex testing. Structural biomarkers, defined as advanced neuroimaging techniques and biomarkers assessing neurotoxicity and immunoexcitotoxicity may complement the use of functional biomarkers. We hypothesize that neurotoxicity AMPA, NMDA, and kainite receptor biomarkers might be utilized as a part of comprehensive approach to concussion evaluations, with the goal of increasing diagnostic accuracy and facilitating treatment planning and prognostic assessment.

Endoplasmic reticulum stress responses differ in meninges and associated vasculature, striatum, and parietal cortex after a neurotoxic amphetamine exposure.

Science.gov (United States)

Thomas, Monzy; George, Nysia I; Saini, Upasana T; Patterson, Tucker A; Hanig, Joseph P; Bowyer, John F

2010-08-01

Amphetamine (AMPH) is used to treat attention deficit and hyperactivity disorders, but it can produce neurotoxicity and adverse vascular effects at high doses. The endoplasmic reticulum (ER) stress response (ERSR) entails the unfolded protein response, which helps to avoid or minimize ER dysfunction. ERSR is often associated with toxicities resulting from the accumulation of unfolded or misfolded proteins and has been associated with methamphetamine toxicity in the striatum. The present study evaluates the effect of AMPH on several ERSR elements in meninges and associated vasculature (MAV), parietal cortex, and striatum. Adult, male Sprague-Dawley rats were exposed to saline, environmentally induced hyperthermia (EIH) or four consecutive doses of AMPH that produce hyperthermia. Expression changes (mRNA and protein levels) of key ERSR-related genes in MAV, striatum, and parietal cortex at 3 h or 1 day postdosing were monitored. AMPH increased the expression of some ERSR-related genes in all tissues. Atf4 (activating transcription factor 4, an indicator of Perk pathway activation), Hspa5/Grp78 (Glucose regulated protein 78, master regulator of ERSR), Pdia4 (protein disulfide isomerase, protein-folding enzyme), and Nfkb1 (nuclear factor of kappa b, ERSR sensor) mRNA increased significantly in MAV and parietal cortex 3 h after AMPH. In striatum, Atf4 and Hspa5/Grp78 mRNA significantly increased 3 h after AMPH, but Pdia4 and Nfkb11 did not. Thus, AMPH caused a robust activation of the Perk pathway in all tissues, but significant Ire1 pathway activation occurred only after AMPH treatment in the parietal cortex and striatum. Ddit3/Chop, a downstream effector of the ERSR pathway related to the neurotoxicity, was only increased in striatum and parietal cortex. Conversely, Pdia4, an enzyme protective in the ERSR, was only increased in MAV. The overall ERSR manifestation varied significantly between MAV, striatum, and parietal cortex after a neurotoxic exposure to AMPH.

L-ascorbate attenuates methamphetamine neurotoxicity through enhancing the induction of endogenous heme oxygenase-1.

Science.gov (United States)

Huang, Ya-Ni; Wang, Jiz-Yuh; Lee, Ching-Tien; Lin, Chih-Hung; Lai, Chien-Cheng; Wang, Jia-Yi

2012-12-01

Methamphetamine (METH) is a drug of abuse which causes neurotoxicity and increased risk of developing neurodegenerative diseases. We previously found that METH induces heme oxygenase (HO)-1 expression in neurons and glial cells, and this offers partial protection against METH toxicity. In this study, we investigated the effects of l-ascorbate (vitamin C, Vit. C) on METH toxicity and HO-1 expression in neuronal/glial cocultures. Cell viability and damage were evaluated by 3-(4,5-dimethylthianol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) reduction and lactate dehydrogenase (LDH) release, respectively. Neuronal and glial localization of HO-1 were identified by double immunofluorescence staining. Reactive oxygen species (ROS) production was measured using the fluorochrome 2',7'-dichlorofluorescin diacetate. HO-1 mRNA and protein expression were examined by RT-qPCR and Western blotting, respectively. Results show that Vit. C induced HO-1 mRNA and protein expressions in time- and concentration-dependent manners. Inhibition of p38 mitogen-activated protein kinase (MAPK) but not extracellular signal-regulated kinase (ERK) significantly blocked induction of HO-1 by Vit. C. HO-1 mRNA and protein expressions were significantly elevated by a combination of Vit. C and METH, compared to either Vit. C or METH alone. Pretreatment with Vit. C enhanced METH-induced HO-1 expression and attenuated METH-induced ROS production and neurotoxicity. Pharmacological inhibition of HO activity abolished suppressive effects of Vit. C on METH-induced ROS production and attenuated neurotoxicity. We conclude that induction of HO-1 expression contributes to the attenuation of METH-induced ROS production and neurotoxicity by Vit. C. We suggest that HO-1 induction by Vit. C may serve as a strategy to alleviate METH neurotoxicity. Copyright © 2012 Elsevier Inc. All rights reserved.

Modifying welding process parameters can reduce the neurotoxic potential of manganese-containing welding fumes.

Science.gov (United States)

Sriram, Krishnan; Lin, Gary X; Jefferson, Amy M; Stone, Samuel; Afshari, Aliakbar; Keane, Michael J; McKinney, Walter; Jackson, Mark; Chen, Bean T; Schwegler-Berry, Diane; Cumpston, Amy; Cumpston, Jared L; Roberts, Jenny R; Frazer, David G; Antonini, James M

2015-02-03

Welding fumes (WF) are a complex mixture of toxic metals and gases, inhalation of which can lead to adverse health effects among welders. The presence of manganese (Mn) in welding electrodes is cause for concern about the potential development of Parkinson's disease (PD)-like neurological disorder. Consequently, from an occupational safety perspective, there is a critical need to prevent adverse exposures to WF. As the fume generation rate and physicochemical characteristics of welding aerosols are influenced by welding process parameters like voltage, current or shielding gas, we sought to determine if changing such parameters can alter the fume profile and consequently its neurotoxic potential. Specifically, we evaluated the influence of voltage on fume composition and neurotoxic outcome. Rats were exposed by whole-body inhalation (40 mg/m(3); 3h/day × 5 d/week × 2 weeks) to fumes generated by gas-metal arc welding using stainless steel electrodes (GMA-SS) at standard/regular voltage (25 V; RVSS) or high voltage (30 V; HVSS). Fumes generated under these conditions exhibited similar particulate morphology, appearing as chain-like aggregates; however, HVSS fumes comprised of a larger fraction of ultrafine particulates that are generally considered to be more toxic than their fine counterparts. Paradoxically, exposure to HVSS fumes did not elicit dopaminergic neurotoxicity, as monitored by the expression of dopaminergic and PD-related markers. We show that the lack of neurotoxicity is due to reduced solubility of Mn in HVSS fumes. Our findings show promise for process control procedures in developing prevention strategies for Mn-related neurotoxicity during welding; however, it warrants additional investigations to determine if such modifications can be suitably adapted at the workplace to avert or reduce adverse neurological risks. Published by Elsevier Ireland Ltd.

Modifying welding process parameters can reduce the neurotoxic potential of manganese-containing welding fumes

International Nuclear Information System (INIS)

Sriram, Krishnan; Lin, Gary X.; Jefferson, Amy M.; Stone, Samuel; Afshari, Aliakbar; Keane, Michael J.; McKinney, Walter; Jackson, Mark; Chen, Bean T.; Schwegler-Berry, Diane; Cumpston, Amy; Cumpston, Jared L.; Roberts, Jenny R.; Frazer, David G.; Antonini, James M.

2015-01-01

Welding fumes (WF) are a complex mixture of toxic metals and gases, inhalation of which can lead to adverse health effects among welders. The presence of manganese (Mn) in welding electrodes is cause for concern about the potential development of Parkinson’s disease (PD)-like neurological disorder. Consequently, from an occupational safety perspective, there is a critical need to prevent adverse exposures to WF. As the fume generation rate and physicochemical characteristics of welding aerosols are influenced by welding process parameters like voltage, current or shielding gas, we sought to determine if changing such parameters can alter the fume profile and consequently its neurotoxic potential. Specifically, we evaluated the influence of voltage on fume composition and neurotoxic outcome. Rats were exposed by whole-body inhalation (40 mg/m 3 ; 3 h/day × 5 d/week × 2 weeks) to fumes generated by gas–metal arc welding using stainless steel electrodes (GMA-SS) at standard/regular voltage (25 V; RVSS) or high voltage (30 V; HVSS). Fumes generated under these conditions exhibited similar particulate morphology, appearing as chain-like aggregates; however, HVSS fumes comprised of a larger fraction of ultrafine particulates that are generally considered to be more toxic than their fine counterparts. Paradoxically, exposure to HVSS fumes did not elicit dopaminergic neurotoxicity, as monitored by the expression of dopaminergic and PD-related markers. We show that the lack of neurotoxicity is due to reduced solubility of Mn in HVSS fumes. Our findings show promise for process control procedures in developing prevention strategies for Mn-related neurotoxicity during welding; however, it warrants additional investigations to determine if such modifications can be suitably adapted at the workplace to avert or reduce adverse neurological risks

Chemokines, macrophage inflammatory protein-2 and stromal cell-derived factor-1{alpha}, suppress amyloid {beta}-induced neurotoxicity

Energy Technology Data Exchange (ETDEWEB)

Raman, Dayanidhi; Milatovic, Snjezana-Zaja [Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Milatovic, Dejan [Department of Pediatrics/Pediatric Toxicology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Splittgerber, Ryan [Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Fan, Guo-Huang [Department of Neurobiology and Neurotoxicology, Meharry Medical College, Nashville, TN 37221 (United States); Richmond, Ann, E-mail: ann.richmond@vanderbilt.edu [VA Medical Center, Nashville, TN 37232 (United States); Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States)

2011-11-15

Alzheimer's disease (AD) is characterized by a progressive cognitive decline and accumulation of neurotoxic oligomeric peptides amyloid-{beta} (A{beta}). Although the molecular events are not entirely known, it has become evident that inflammation, environmental and other risk factors may play a causal, disruptive and/or protective role in the development of AD. The present study investigated the ability of the chemokines, macrophage inflammatory protein-2 (MIP-2) and stromal cell-derived factor-1{alpha} (SDF-1{alpha}), the respective ligands for chemokine receptors CXCR2 and CXCR4, to suppress A{beta}-induced neurotoxicity in vitro and in vivo. Pretreatment with MIP-2 or SDF-1{alpha} significantly protected neurons from A{beta}-induced dendritic regression and apoptosis in vitro through activation of Akt, ERK1/2 and maintenance of metalloproteinase ADAM17 especially with SDF-1{alpha}. Intra-cerebroventricular (ICV) injection of A{beta} led to reduction in dendritic length and spine density of pyramidal neurons in the CA1 area of the hippocampus and increased oxidative damage 24 h following the exposure. The A{beta}-induced morphometric changes of neurons and increase in biomarkers of oxidative damage, F{sub 2}-isoprostanes, were significantly inhibited by pretreatment with the chemokines MIP-2 or SDF-1{alpha}. Additionally, MIP-2 or SDF-1{alpha} was able to suppress the aberrant mislocalization of p21-activated kinase (PAK), one of the proteins involved in the maintenance of dendritic spines. Furthermore, MIP-2 also protected neurons against A{beta} neurotoxicity in CXCR2-/- mice, potentially through observed up regulation of CXCR1 mRNA. Understanding the neuroprotective potential of chemokines is crucial in defining the role for their employment during the early stages of neurodegeneration. -- Research highlights: Black-Right-Pointing-Pointer Neuroprotective ability of the chemokines MIP2 and CXCL12 against A{beta} toxicity. Black-Right-Pointing-Pointer MIP

Chemokines, macrophage inflammatory protein-2 and stromal cell-derived factor-1α, suppress amyloid β-induced neurotoxicity

International Nuclear Information System (INIS)

Raman, Dayanidhi; Milatovic, Snjezana-Zaja; Milatovic, Dejan; Splittgerber, Ryan; Fan, Guo-Huang; Richmond, Ann

2011-01-01

Alzheimer's disease (AD) is characterized by a progressive cognitive decline and accumulation of neurotoxic oligomeric peptides amyloid-β (Aβ). Although the molecular events are not entirely known, it has become evident that inflammation, environmental and other risk factors may play a causal, disruptive and/or protective role in the development of AD. The present study investigated the ability of the chemokines, macrophage inflammatory protein-2 (MIP-2) and stromal cell-derived factor-1α (SDF-1α), the respective ligands for chemokine receptors CXCR2 and CXCR4, to suppress Aβ-induced neurotoxicity in vitro and in vivo. Pretreatment with MIP-2 or SDF-1α significantly protected neurons from Aβ-induced dendritic regression and apoptosis in vitro through activation of Akt, ERK1/2 and maintenance of metalloproteinase ADAM17 especially with SDF-1α. Intra-cerebroventricular (ICV) injection of Aβ led to reduction in dendritic length and spine density of pyramidal neurons in the CA1 area of the hippocampus and increased oxidative damage 24 h following the exposure. The Aβ-induced morphometric changes of neurons and increase in biomarkers of oxidative damage, F 2 -isoprostanes, were significantly inhibited by pretreatment with the chemokines MIP-2 or SDF-1α. Additionally, MIP-2 or SDF-1α was able to suppress the aberrant mislocalization of p21-activated kinase (PAK), one of the proteins involved in the maintenance of dendritic spines. Furthermore, MIP-2 also protected neurons against Aβ neurotoxicity in CXCR2−/− mice, potentially through observed up regulation of CXCR1 mRNA. Understanding the neuroprotective potential of chemokines is crucial in defining the role for their employment during the early stages of neurodegeneration. -- Research highlights: ► Neuroprotective ability of the chemokines MIP2 and CXCL12 against Aβ toxicity. ► MIP-2 or CXCL12 prevented dendritic regression and apoptosis in vitro. ► Neuroprotection through activation of Akt, ERK

17β-estradiol and tamoxifen protect mice from manganese-induced dopaminergic neurotoxicity.

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Pajarillo, Edward; Johnson, James; Kim, Judong; Karki, Pratap; Son, Deok-Soo; Aschner, Michael; Lee, Eunsook

2018-03-01

Chronic exposure to manganese (Mn) causes neurotoxicity, referred to as manganism, with common clinical features of parkinsonism. 17β-estradiol (E2) and tamoxifen (TX), a selective estrogen receptor modulator (SERM), afford neuroprotection in several neurological disorders, including Parkinson's disease (PD). In the present study, we tested if E2 and TX attenuate Mn-induced neurotoxicity in mice, assessing motor deficit and dopaminergic neurodegeneration. We implanted E2 and TX pellets in the back of the neck of ovariectomized C57BL/6 mice two weeks prior to a single injection of Mn into the striatum. One week later, we assessed locomotor activity and molecular mechanisms by immunohistochemistry, real-time quantitative PCR, western blot and enzymatic biochemical analyses. The results showed that both E2 and TX attenuated Mn-induced motor deficits and reversed the Mn-induced loss of dopaminergic neurons in the substantia nigra. At the molecular level, E2 and TX reversed the Mn-induced decrease of (1) glutamate aspartate transporter (GLAST) and glutamate transporter 1 (GLT-1) mRNA and protein levels; (2) transforming growth factor-α (TGF-α) and estrogen receptor-α (ER-α) protein levels; and (3) catalase (CAT) activity and glutathione (GSH) levels, and Mn-increased (1) malondialdehyde (MDA) levels and (2) the Bax/Bcl-2 ratio. These results indicate that E2 and TX afford protection against Mn-induced neurotoxicity by reversing Mn-reduced GLT1/GLAST as well as Mn-induced oxidative stress. Our findings may offer estrogenic agents as potential candidates for the development of therapeutics to treat Mn-induced neurotoxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

Neuroprotective effect of curcumin-loaded lactoferrin nano particles against rotenone induced neurotoxicity.

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Bollimpelli, V Satish; Kumar, Prashant; Kumari, Sonali; Kondapi, Anand K

2016-05-01

Curcumin is known to have neuroprotective role and possess antioxidant, anti-inflammatory activities. Rotenone, a flavonoid induced neurotoxicity in dopaminergic cells is being widely studied in Parkinson's Disease (PD) research. In the present study, curcumin loaded lactoferrin nano particles prepared by sol-oil chemistry were used to protect dopaminergic cell line SK-N-SH against rotenone induced neurotoxicity. These curcumin loaded nano particles were of 43-60 nm diameter size and around 100 nm hydrodynamic size as assessed by transmission electron microscopy, atomic force microscopy and dynamic light scattering analysis respectively. The encapsulation efficiency was 61.3% ± 2.4%. Cellular uptake of curcumin through these nano particles was confirmed by confocal imaging and spectrofluorimetric analysis. The curcumin loaded lactoferrin nanoparticles showed greater intracellular drug uptake, sustained retention and greater neuroprotection than soluble counterpart. Neuroprotective activity was characterized through viability assays and by estimating ROS levels. Furthermore rotenone induced PD like features were characterized by decrease in tyrosine hydroxylase expression and increase in α-synuclein expression. Taken together curcumin loaded lactoferrin nanoparticles could be a promising drug delivery strategy against neurotoxicity in dopaminergic neurons. Copyright © 2016 Elsevier Ltd. All rights reserved.

Corneal neurotoxicity due to topical benzalkonium chloride.

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Sarkar, Joy; Chaudhary, Shweta; Namavari, Abed; Ozturk, Okan; Chang, Jin-Hong; Yco, Lisette; Sonawane, Snehal; Khanolkar, Vishakha; Hallak, Joelle; Jain, Sandeep

2012-04-06

The aim of this study was to determine and characterize the effect of topical application of benzalkonium chloride (BAK) on corneal nerves in vivo and in vitro. Thy1-YFP+ neurofluorescent mouse eyes were treated topically with vehicle or BAK (0.01% or 0.1%). Wide-field stereofluorescence microscopy was performed to sequentially image the treated corneas in vivo every week for 4 weeks, and changes in stromal nerve fiber density (NFD) and aqueous tear production were determined. Whole-mount immunofluorescence staining of corneas was performed with antibodies to axonopathy marker SMI-32. Western immunoblot analyses were performed on trigeminal ganglion and corneal lysates to determine abundance of proteins associated with neurotoxicity and regeneration. Compartmental culture of trigeminal ganglion neurons was performed in Campenot devices to determine whether BAK affects neurite outgrowth. BAK-treated corneas exhibited significantly reduced NFD and aqueous tear production, and increased inflammatory cell infiltration and fluorescein staining at 1 week (P reduction in neurites occurred after BAK addition to compartmental cultures of dissociated trigeminal ganglion cells. Although both BAK doses (0.0001% and 0.001%) reduced nerve fiber length, the reduction was significantly more with the higher dose (P < 0.001). Topical application of BAK to the eye causes corneal neurotoxicity, inflammation, and reduced aqueous tear production.

Biochemical Factors Modulating Cellular Neurotoxicity of Methylmercury

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Parvinder Kaur

2011-01-01

Full Text Available Methylmercury (MeHg, an environmental toxicant primarily found in fish and seafood, poses a dilemma to both consumers and regulatory authorities, given the nutritional benefits of fish consumption versus the possible adverse neurological damage. Several studies have shown that MeHg toxicity is influenced by a number of biochemical factors, such as glutathione (GSH, fatty acids, vitamins, and essential elements, but the cellular mechanisms underlying these complex interactions have not yet been fully elucidated. The objective of this paper is to outline the cellular response to dietary nutrients, as well as to describe the neurotoxic exposures to MeHg. In order to determine the cellular mechanism(s of toxicity, the effect of pretreatment with biochemical factors (e.g., N-acetyl cysteine, (NAC; diethyl maleate, (DEM; docosahexaenoic acid, (DHA; selenomethionine, SeM; Trolox and MeHg treatment on intercellular antioxidant status, MeHg content, and other endpoints was evaluated. This paper emphasizes that the protection against oxidative stress offered by these biochemical factors is among one of the major mechanisms responsible for conferring neuroprotection. It is therefore critical to ascertain the cellular mechanisms associated with various dietary nutrients as well as to determine the potential effects of neurotoxic exposures for accurately assessing the risks and benefits associated with fish consumption.

Crystal growth and physical characterization of picolinic acid cocrystallized with dicarboxylic acids

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Somphon, Weenawan; Haller, Kenneth J.

2013-01-01

Pharmaceutical cocrystals are multicomponent materials containing an active pharmaceutical ingredient with another component in well-defined stoichiometry within the same unit cell. Such cocrystals are important in drug design, particularly for improving physicochemical properties such as solubility, bioavailability, or chemical stability. Picolinic acid is an endogenous metabolite of tryptophan and is widely used for neuroprotective, immunological, and anti-proliferative effects within the body. In this paper we present cocrystallization experiments of a series of dicarboxylic acids, oxalic acid, succinic acid, DL-tartaric acid, pimelic acid, and phthalic acid, with picolinic acid. Characterization by FT-IR and Raman spectroscopy, DSC and TG/DTG analysis, and X-ray powder diffraction show that new compounds are formed, including a 1:1 picolinium tartrate monohydrate, a 2:1 monohydrate adduct of picolinic acid and oxalic acid, and a 2:1 picolinic acid-succinic acid monohydrate cocrystal.

Alpha-synuclein oligomers - neurotoxic molecules in Parkinson’s disease and other Lewy body disorders

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Martin Ingelsson

2016-09-01

Full Text Available Adverse intra- and extracellular effects of toxic α-synuclein are believed to be central to the pathogenesis in Parkinson’s disease and other disorders with Lewy body pathology in the nervous system. One of the physiological roles of α-synuclein relates to the regulation of neurotransmitter release at the presynapse, although it is still unclear whether this mechanism depends on the action of monomers or smaller oligomers. As for the pathogenicity, accumulating evidence suggest that prefibrillar species, rather than the deposits per se, are responsible for the toxicity in affected cells. In particular, larger oligomers or protofibrils of α-synuclein have been shown to impair protein degradation as well as the function of several organelles, such as the mitochondria and the endoplasmic reticulum. Accumulating evidence further suggest that oligomers/protofibrils may have a toxic effect on the synapse, which may lead to disrupted electrophysiological properties. In addition, recent data indicate that oligomeric α-synuclein species can spread between cells, either as free-floating proteins or via extracellular vesicles, and thereby act as seeds to propagate disease between interconnected brain regions. Taken together, several lines of evidence suggest that α-synuclein have neurotoxic properties and therefore should be an appropriate molecular target for therapeutic intervention in Parkinson’s disease and other disorders with Lewy pathology. In this context, immunotherapy with monoclonal antibodies against α-synuclein oligomers/protofibrils should be a particularly attractive treatment option.

Mining the Sinorhizobium meliloti transportome to develop FRET biosensors for sugars, dicarboxylates and cyclic polyols.

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Alexandre Bourdès

Full Text Available Förster resonance energy transfer (FRET biosensors are powerful tools to detect biologically important ligands in real time. Currently FRET bisosensors are available for twenty-two compounds distributed in eight classes of chemicals (two pentoses, two hexoses, two disaccharides, four amino acids, one nucleobase, two nucleotides, six ions and three phytoestrogens. To expand the number of available FRET biosensors we used the induction profile of the Sinorhizobium meliloti transportome to systematically screen for new FRET biosensors.Two new vectors were developed for cloning genes for solute-binding proteins (SBPs between those encoding FRET partner fluorescent proteins. In addition to a vector with the widely used cyan and yellow fluorescent protein FRET partners, we developed a vector using orange (mOrange2 and red fluorescent protein (mKate2 FRET partners. From the sixty-nine SBPs tested, seven gave a detectable FRET signal change on binding substrate, resulting in biosensors for D-quinic acid, myo-inositol, L-rhamnose, L-fucose, β-diglucosides (cellobiose and gentiobiose, D-galactose and C4-dicarboxylates (malate, succinate, oxaloacetate and fumarate. To our knowledge, we describe the first two FRET biosensor constructs based on SBPs from Tripartite ATP-independent periplasmic (TRAP transport systems.FRET based on orange (mOrange2 and red fluorescent protein (mKate2 partners allows the use of longer wavelength light, enabling deeper penetration of samples at lower energy and increased resolution with reduced back-ground auto-fluorescence. The FRET biosensors described in this paper for four new classes of compounds; (i cyclic polyols, (ii L-deoxy sugars, (iii β-linked disaccharides and (iv C4-dicarboxylates could be developed to study metabolism in vivo.

TRANSFORMATION OF DEVELOPMENTAL NEUROTOXICITY DATA INTO STRUCTURE-SEARCHABLE TOXML DATABASE IN SUPPORT OF STRUCTURE-ACTIVITY RELATIONSHIP (SAR) WORKFLOW.

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Early hazard identification of new chemicals is often difficult due to lack of data on the novel material for toxicity endpoints, including neurotoxicity. At present, there are no structure searchable neurotoxicity databases. A working group was formed to construct a database to...

Intracystic interferon-α treatment leads to neurotoxicity in craniopharyngioma: case report.

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Sharma, Julia; Bonfield, Christopher M; Singhal, Ash; Hukin, Juliette; Steinbok, Paul

2015-09-01

Craniopharyngioma is a benign, cystic suprasellar tumor that can be treated with intracystic chemotherapy. Interferon-α (IFN-α) has been gaining popularity as an intracystic treatment for craniopharyngioma because of its efficacy and supposed benign neurotoxicity profile. In this case report the authors describe a patient who, while receiving intracystic IFN-α, suffered a neurological event, which was believed to be related to drug leakage outside the cyst. This is the first report of a focal neurological deficit potentially attributable to intracystic IFN-α therapy, highlighting the fact that IFN-α may have neurotoxic effects on the central nervous system. Given this case and the results of a literature review, the authors suggest that a positive leak test is a relative contraindication to intracystic IFN-α treatment.

Insights into Parkinson's disease models and neurotoxicity using non-invasive imaging

International Nuclear Information System (INIS)

Sanchez-Pernaute, Rosario; Brownell, Anna-Liisa; Jenkins, Bruce G.; Isacson, Ole

2005-01-01

Loss of dopamine in the nigrostriatal system causes a severe impairment in motor function in patients with Parkinson's disease and in experimental neurotoxic models of the disease. We have used non-invasive imaging techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (MRI) to investigate in vivo the changes in the dopamine system in neurotoxic models of Parkinson's disease. In addition to classic neurotransmitter studies, in these models, it is also possible to characterize associated and perhaps pathogenic factors, such as the contribution of microglia activation and inflammatory responses to neuronal damage. Functional imaging techniques are instrumental to our understanding and modeling of disease mechanisms, which should in turn lead to development of new therapies for Parkinson's disease and other neurodegenerative disorders

Radiosynthesis of dimethyl-2-[{sup 18}F]-(fluoromethyl)-6-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate for L-type calcium channel imaging

Energy Technology Data Exchange (ETDEWEB)

Sadeghpour, H. [Nuclear Medicine Research Group, Agricultural, Medical and Industrial Research School (AMIRS), Karaj (Iran); Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran Univ. of Medical Sciences, Tehran (Iran); Jalilian, A.R.; Akhlaghi, M.; Mirzaei, M. [Nuclear Medicine Research Group, Agricultural, Medical and Industrial Research School (AMIRS), Karaj (Iran); Shafiee, A. [Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran Univ. of Medical Sciences, Tehran (Iran); Miri, R. [Medicinal and Natural Products Chemistry Research Center, Shiraz Univ. of Medical Sciences, Shiraz (Iran)

2008-07-01

Dimethyl 2-(fluoromethyl)-6-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate 4a, a fluorinated nifedipine analog, has been shown to elicit significant calcium channel blocker activity using a guinea pig ileal longitudinal smooth muscle model. In order to perform biological studies for detection of L-type calcium channel distribution, we decided to prepare the [{sup 18}F]-labeled compound. The latter compound was prepared in no-carrier-added (n.c.a.) form from dimethyl 2-(bromomethyl)-6-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate 2 in one step at 80 C in Kryptofix[222]/K[{sup 18}F]F and acetonitrile as a solvent in 15 min. Column chromatography afforded the radiochemically pure compound in 20 min. Radiochemical purity of the {sup 18}F-nifedipine was determined by RTLC and HPLC (> 98%) and specific activity of 21-48 GBq/{mu}mol (EOB). (orig.)

Curcumin Promotes A-beta Fibrillation and Reduces Neurotoxicity in Transgenic Drosophila

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Caesar, Ina; Jonson, Maria; Nilsson, K. Peter R.; Thor, Stefan; Hammarström, Per

2012-01-01

The pathology of Alzheimer's disease (AD) is characterized by the presence of extracellular deposits of misfolded and aggregated amyloid-β (Aβ) peptide and intraneuronal accumulation of tangles comprised of hyperphosphorylated Tau protein. For several years, the natural compound curcumin has been proposed to be a candidate for enhanced clearance of toxic Aβ amyloid. In this study we have studied the potency of feeding curcumin as a drug candidate to alleviate Aβ toxicity in transgenic Drosophila. The longevity as well as the locomotor activity of five different AD model genotypes, measured relative to a control line, showed up to 75% improved lifespan and activity for curcumin fed flies. In contrast to the majority of studies of curcumin effects on amyloid we did not observe any decrease in the amount of Aβ deposition following curcumin treatment. Conformation-dependent spectra from p-FTAA, a luminescent conjugated oligothiophene bound to Aβ deposits in different Drosophila genotypes over time, indicated accelerated pre-fibrillar to fibril conversion of Aβ1–42 in curcumin treated flies. This finding was supported by in vitro fibrillation assays of recombinant Aβ1–42. Our study shows that curcumin promotes amyloid fibril conversion by reducing the pre-fibrillar/oligomeric species of Aβ, resulting in a reduced neurotoxicity in Drosophila. PMID:22348084

SYNTHESIS AND CHARACTERIZATION OF NEW THERMALLY STABLE POLYAMIDES BASED ON 2,5-PYRIDINE DICARBOXYLIC ACID AND AROMATIC DIAMINES

OpenAIRE

FAGHIHI, KHALIL

2009-01-01

Six new thermally stable polyamides 3a-f were synthesized through the polycondensation reaction of 2,5-pyridine dicarboxylic acid 1 with six different derivatives of aromatic diamines 2a-f in amedium consisting of N-methyl-2-pyrrolidone, triphenyl phosphite, calcium chloride and pyridine. The polycondensation reaction produced a series of novel polyamides containing pyridyl moieties in the main chain in high yield with inherent viscosities between 0.50-0.82 dL/g. The resulting polymers were f...

Temperature dependences of saturated vapor pressure and the enthalpy of vaporization of n-pentyl esters of dicarboxylic acids

Science.gov (United States)

Portnova, S. V.; Krasnykh, E. L.; Levanova, S. V.

2016-05-01

The saturated vapor pressures and enthalpies of vaporization of n-pentyl esters of linear C2-C6 dicarboxylic acids are determined by the transpiration method in the temperature range of 309.2-361.2 K. The dependences of enthalpies of vaporization on the number of carbon atoms in the molecule and on the retention indices have been determined. The predictive capabilities of the existing calculation schemes for estimation of enthalpy of vaporization of the studied compounds have been analyzed.

The NALP3 inflammasome is involved in neurotoxic prion peptide-induced microglial activation

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Shi Fushan

2012-07-01

Full Text Available Abstract Background Prion diseases are neurodegenerative disorders characterized by the accumulation of an abnormal disease-associated prion protein, PrPSc. In prion-infected brains, activated microglia are often present in the vicinity of PrPSc aggregates, and microglial activation is thought to play a key role in the pathogenesis of prion diseases. Although interleukin (IL-1β release by prion-induced microglia has been widely reported, the mechanism by which primed microglia become activated and secrete IL-1β in prion diseases has not yet been elucidated. In this study, we investigated the role of the NACHT, LRR and PYD domains-containing protein (NALP3 inflammasome in IL-1β release from lipopolysaccharide (LPS-primed microglia after exposure to a synthetic neurotoxic prion fragment (PrP106-126. Methods The inflammasome components NALP3 and apoptosis-associated speck-like protein (ASC were knocked down by gene silencing. IL-1β production was assessed using ELISA. The mRNA expression of NALP3, ASC, and pro-inflammatory factors was measured by quantitative PCR. Western blot analysis was used to detect the protein level of NALP3, ASC, caspase-1 and nuclear factor-κB. Results We found that that PrP106-126-induced IL-1β release depends on NALP3 inflammasome activation, that inflammasome activation is required for the synthesis of pro-inflammatory and chemotactic factors by PrP106-126-activated microglia, that inhibition of NF-κB activation abrogated PrP106-126-induced NALP3 upregulation, and that potassium efflux and production of reactive oxygen species were implicated in PrP106-126-induced NALP3 inflammasome activation in microglia. Conclusions We conclude that the NALP3 inflammasome is involved in neurotoxic prion peptide-induced microglial activation. To our knowledge, this is the first time that strong evidence for the involvement of NALP3 inflammasome in prion-associated inflammation has been found.

Δ9-tetrahydrocannabinol prevents methamphetamine-induced neurotoxicity.

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M Paola Castelli

Full Text Available Methamphetamine (METH is a potent psychostimulant with neurotoxic properties. Heavy use increases the activation of neuronal nitric oxide synthase (nNOS, production of peroxynitrites, microglia stimulation, and induces hyperthermia and anorectic effects. Most METH recreational users also consume cannabis. Preclinical studies have shown that natural (Δ9-tetrahydrocannabinol, Δ9-THC and synthetic cannabinoid CB1 and CB2 receptor agonists exert neuroprotective effects on different models of cerebral damage. Here, we investigated the neuroprotective effect of Δ9-THC on METH-induced neurotoxicity by examining its ability to reduce astrocyte activation and nNOS overexpression in selected brain areas. Rats exposed to a METH neurotoxic regimen (4 × 10 mg/kg, 2 hours apart were pre- or post-treated with Δ9-THC (1 or 3 mg/kg and sacrificed 3 days after the last METH administration. Semi-quantitative immunohistochemistry was performed using antibodies against nNOS and Glial Fibrillary Acidic Protein (GFAP. Results showed that, as compared to corresponding controls (i METH-induced nNOS overexpression in the caudate-putamen (CPu was significantly attenuated by pre- and post-treatment with both doses of Δ9-THC (-19% and -28% for 1 mg/kg pre- and post-treated animals; -25% and -21% for 3 mg/kg pre- and post-treated animals; (ii METH-induced GFAP-immunoreactivity (IR was significantly reduced in the CPu by post-treatment with 1 mg/kg Δ9-THC1 (-50% and by pre-treatment with 3 mg/kg Δ9-THC (-53%; (iii METH-induced GFAP-IR was significantly decreased in the prefrontal cortex (PFC by pre- and post-treatment with both doses of Δ9-THC (-34% and -47% for 1 mg/kg pre- and post-treated animals; -37% and -29% for 3 mg/kg pre- and post-treated animals. The cannabinoid CB1 receptor antagonist SR141716A attenuated METH-induced nNOS overexpression in the CPu, but failed to counteract the Δ9-THC-mediated reduction of METH-induced GFAP-IR both in the PFC and CPu. Our

Investigating the potential neurotoxicity of Ecstasy (MDMA): an imaging approach

NARCIS (Netherlands)

Reneman, Liesbeth; Booij, Jan; Majoie, Charles B. L. M.; van den Brink, Wim; den Heeten, Gerard J.

2001-01-01

Human users of 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') users may be at risk of developing MDMA-induced neuronal injury. Previously, no methods were available for directly evaluating the neurotoxic effects of MDMA in the living human brain. However, development of in vivo neuroimaging

Developmental neurotoxicity of different pesticides in PC-12 cells in vitro

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Christen, Verena [University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Gründenstrasse 40, CH-4132, Muttenz (Switzerland); Rusconi, Manuel; Crettaz, Pierre [Federal Office of Public Health, Division Chemical Products, 3003 Bern (Switzerland); Fent, Karl, E-mail: karl.fent@bluewin.ch [University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Gründenstrasse 40, CH-4132, Muttenz (Switzerland); Swiss Federal Institute of Technology Zürich (ETH Zürich), Department of Environmental Systems Sciences, Institute of Biogeochemistry and Pollution Dynamics, CH-8092 Zürich (Switzerland)

2017-06-15

The detection of developmental neurotoxicity (DNT) of chemicals has high relevance for protection of human health. However, DNT of many pesticides is only little known. Furthermore, validated in vitro systems for assessment of DNT are not well established. Here we employed the rat phaeochromocytoma cell line PC-12 to evaluate DNT of 18 frequently used pesticides of different classes, including neonicotinoids, pyrethroids, organophosphates, organochlorines, as well as quaternary ammonium compounds, the organic compound used in pesticides, piperonyl butoxide, as well as the insect repellent diethyltoluamide (DEET). We determined the outgrowth of neurites in PC-12 cells co-treated with nerve growth factor and different concentrations of biocides for 5 days. Furthermore, we determined transcriptional alterations of selected genes that may be associated with DNT, such as camk2α and camk2β, gap-43, neurofilament-h, tubulin-α and tubulin-β. Strong and dose- dependent inhibition of neurite outgrowth was induced by azamethiphos and chlorpyrifos, and dieldrin and heptachlor, which was correlated with up-regulation of gap-43. No or only weak effects on neurite outgrowth and transcriptional alterations occurred for neonicotinoids acetamiprid, clothianidin, imidacloprid and thiamethoxam, the pyrethroids λ-cyhalothrin, cyfluthrin, deltamethrin, and permethrin, the biocidal disinfectants C12-C14-alkyl(ethylbenzyl)dimethylammonium (BAC), benzalkonium chloride and barquat (dimethyl benzyl ammonium chloride), and piperonyl butoxide and DEET. Our study confirms potential developmental neurotoxicity of some pesticides and provides first evidence that azamethiphos has the potential to act as a developmental neurotoxic compound. We also demonstrate that inhibition of neurite outgrowth and transcriptional alterations of gap-43 expression correlate, which suggests the employment of gap-43 expression as a biomarker for detection and initial evaluation of potential DNT of chemicals

Developmental neurotoxicity of different pesticides in PC-12 cells in vitro

International Nuclear Information System (INIS)

Christen, Verena; Rusconi, Manuel; Crettaz, Pierre; Fent, Karl

2017-01-01

The detection of developmental neurotoxicity (DNT) of chemicals has high relevance for protection of human health. However, DNT of many pesticides is only little known. Furthermore, validated in vitro systems for assessment of DNT are not well established. Here we employed the rat phaeochromocytoma cell line PC-12 to evaluate DNT of 18 frequently used pesticides of different classes, including neonicotinoids, pyrethroids, organophosphates, organochlorines, as well as quaternary ammonium compounds, the organic compound used in pesticides, piperonyl butoxide, as well as the insect repellent diethyltoluamide (DEET). We determined the outgrowth of neurites in PC-12 cells co-treated with nerve growth factor and different concentrations of biocides for 5 days. Furthermore, we determined transcriptional alterations of selected genes that may be associated with DNT, such as camk2α and camk2β, gap-43, neurofilament-h, tubulin-α and tubulin-β. Strong and dose- dependent inhibition of neurite outgrowth was induced by azamethiphos and chlorpyrifos, and dieldrin and heptachlor, which was correlated with up-regulation of gap-43. No or only weak effects on neurite outgrowth and transcriptional alterations occurred for neonicotinoids acetamiprid, clothianidin, imidacloprid and thiamethoxam, the pyrethroids λ-cyhalothrin, cyfluthrin, deltamethrin, and permethrin, the biocidal disinfectants C12-C14-alkyl(ethylbenzyl)dimethylammonium (BAC), benzalkonium chloride and barquat (dimethyl benzyl ammonium chloride), and piperonyl butoxide and DEET. Our study confirms potential developmental neurotoxicity of some pesticides and provides first evidence that azamethiphos has the potential to act as a developmental neurotoxic compound. We also demonstrate that inhibition of neurite outgrowth and transcriptional alterations of gap-43 expression correlate, which suggests the employment of gap-43 expression as a biomarker for detection and initial evaluation of potential DNT of chemicals

In Zucker Diabetic Fatty Rats, Subclinical Diabetic Neuropathy Increases In Vivo Lidocaine Block Duration But Not In Vitro Neurotoxicity

NARCIS (Netherlands)

Lirk, Philipp; Flatz, Magdalena; Haller, Ingrid; Hausott, Barbara; Blumenthal, Stephan; Stevens, Markus F.; Suzuki, Suzuko; Klimaschewski, Lars; Gerner, Peter

2012-01-01

Background and Objectives: Application of local anesthetics may lead to nerve damage. Increasing evidence suggests that risk of neurotoxicity is higher in patients with diabetic peripheral neuropathy. In addition, block duration may be prolonged in neuropathy. We sought to investigate neurotoxicity

1,1′-Binaphthyl-2,2′-dicarboxylic acid–urea (1/1

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Edwin Weber

2008-10-01

Full Text Available In the title co-crystal, C22H14O4·CH4N2O, the 1,1′-binaphthyl-2,2′-dicarboxylic acid (BNDA and urea molecules are connected via a system of hydrogen bonds into a chiral two-dimensional polymeric structure parallel to the (001 plane. As the crystal is centrosymmetric, it consists of alternately stacked BNDA–urea layers of opposite chirality. The urea H atoms trans to the C=O group are bonded in a chelating mode [R12(6] to the carbonyl O atom from one of the carboxylic acid groups which, in turn, acts as the donor of an O—H...O hydrogen bond to another urea molecule. The [010] chains thus formed are further connected via an R22(8 hydrogen-bond motif formed between urea and the second carboxylic acid group of BNDA.

Neurotoxicity induced by alkyl nitrites: Impairment in learning/memory and motor coordination.

Science.gov (United States)

Cha, Hye Jin; Kim, Yun Ji; Jeon, Seo Young; Kim, Young-Hoon; Shin, Jisoon; Yun, Jaesuk; Han, Kyoungmoon; Park, Hye-Kyung; Kim, Hyung Soo

2016-04-21

Although alkyl nitrites are used as recreational drugs, there is only little research data regarding their effects on the central nervous system including their neurotoxicity. This study investigated the neurotoxicity of three representative alkyl nitrites (isobutyl nitrite, isoamyl nitrite, and butyl nitrite), and whether it affected learning/memory function and motor coordination in rodents. Morris water maze test was performed in mice after administrating the mice with varying doses of the substances in two different injection schedules of memory acquisition and memory retention. A rota-rod test was then performed in rats. All tested alkyl nitrites lowered the rodents' capacity for learning and memory, as assessed by both the acquisition and retention tests. The results of the rota-rod test showed that isobutyl nitrite in particular impaired motor coordination in chronically treated rats. The mice chronically injected with isoamyl nitrite also showed impaired function, while butyl nitrite had no significant effect. The results of the water maze test suggest that alkyl nitrites may impair learning and memory. Additionally, isoamyl nitrite affected the rodents' motor coordination ability. Collectively, our findings suggest that alkyl nitrites may induce neurotoxicity, especially on the aspect of learning and memory function. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Botanical Polyphenols Mitigate Microglial Activation and Microglia-Induced Neurotoxicity: Role of Cytosolic Phospholipase A2.

Science.gov (United States)

Chuang, Dennis Y; Simonyi, Agnes; Cui, Jiankun; Lubahn, Dennis B; Gu, Zezong; Sun, Grace Y

2016-09-01

Microglia play a significant role in the generation and propagation of oxidative/nitrosative stress, and are the basis of neuroinflammatory responses in the central nervous system. Upon stimulation by endotoxins such as lipopolysaccharides (LPS), these cells release pro-inflammatory factors which can exert harmful effects on surrounding neurons, leading to secondary neuronal damage and cell death. Our previous studies demonstrated the effects of botanical polyphenols to mitigate inflammatory responses induced by LPS, and highlighted an important role for cytosolic phospholipase A2 (cPLA2) upstream of the pro-inflammatory pathways (Chuang et al. in J Neuroinflammation 12(1):199, 2015. doi: 10.1186/s12974-015-0419-0 ). In this study, we investigate the action of botanical compounds and assess whether suppression of cPLA2 in microglia is involved in the neurotoxic effects on neurons. Differentiated SH-SY5Y neuroblastoma cells were used to test the neurotoxicity of conditioned medium from stimulated microglial cells, and WST-1 assay was used to assess for the cell viability of SH-SY5Y cells. Botanicals such as quercetin and honokiol (but not cyanidin-3-O-glucoside, 3CG) were effective in inhibiting LPS-induced nitric oxide (NO) production and phosphorylation of cPLA2. Conditioned medium from BV-2 cells stimulated with LPS or IFNγ caused neurotoxicity to SH-SY5Y cells. Decrease in cell viability could be ameliorated by pharmacological inhibitors for cPLA2 as well as by down-regulating cPLA2 with siRNA. Botanicals effective in inhibition of LPS-induced NO and cPLA2 phosphorylation were also effective in ameliorating microglial-induced neurotoxicity. Results demonstrated cytotoxic factors from activated microglial cells to cause damaging effects to neurons and potential use of botanical polyphenols to ameliorate the neurotoxic effects.

Age dependence of organophosphate and carbamate neurotoxicity in the postnatal rat: extrapolation to the human

International Nuclear Information System (INIS)

Vidair, Charles A.

2004-01-01

One important aspect of risk assessment for the organophosphate and carbamate pesticides is to determine whether their neurotoxicity occurs at lower dose levels in human infants compared to adults. Because these compounds probably exert their neurotoxic effects through the inhibition of acetylcholinesterase (AChE), the above question can be narrowed to whether the cholinesterase inhibition and neurotoxicity they produce is age-dependent, both in terms of the effects produced and potency. The rat is the animal model system most commonly used to address these issues. This paper first discusses the adequacy of the postnatal rat to serve as a model for neurodevelopment in the postnatal human, concluding that the two species share numerous pathways of postnatal neurodevelopment, and that the rat in the third postnatal week is the neurodevelopmental equivalent of the newborn human. Then, studies are discussed in which young and adult rats were dosed by identical routes with organophosphates or carbamates. Four pesticides were tested in rat pups in their third postnatal week: aldicarb, chlorpyrifos, malathion, and methamidophos. The first three, but not methamidophos, caused neurotoxicity at dose levels that ranged from 1.8- to 5.1-fold lower (mean 2.6-fold lower) in the 2- to 3-week-old rat compared to the adult. This estimate in the rat, based on a limited data set of three organophosphates and a single carbamate, probably represents the minimum difference in the neurotoxicity of an untested cholinesterase-inhibiting pesticide that should be expected between the human neonate and adult. For the organophosphates, the greater sensitivity of postnatal rats, and, by analogy, that expected for human neonates, is correlated with generally lower levels of the enzymes involved in organophosphate deactivation

iTRAQ proteomics analysis reveals that PI3K is highly associated with bupivacaine-induced neurotoxicity pathways.

Science.gov (United States)

Zhao, Wei; Liu, Zhongjie; Yu, Xujiao; Lai, Luying; Li, Haobo; Liu, Zipeng; Li, Le; Jiang, Shan; Xia, Zhengyuan; Xu, Shi-yuan

2016-02-01

Bupivacaine, a commonly used local anesthetic, has potential neurotoxicity through diverse signaling pathways. However, the key mechanism of bupivacaine-induced neurotoxicity remains unclear. Cultured human SH-SY5Y neuroblastoma cells were treated (bupivacaine) or untreated (control) with bupivacaine for 24 h. Compared to the control group, bupivacaine significantly increased cyto-inhibition, cellular reactive oxygen species, DNA damage, mitochondrial injury, apoptosis (increased TUNEL-positive cells, cleaved caspase 3, and Bcl-2/Bax), and activated autophagy (enhanced LC3II/LC3I ratio). To explore changes in protein expression and intercommunication among the pathways involved in bupivacaine-induced neurotoxicity, an 8-plex iTRAQ proteomic technique and bioinformatics analysis were performed. Compared to the control group, 241 differentially expressed proteins were identified, of which, 145 were up-regulated and 96 were down-regulated. Bioinformatics analysis of the cross-talk between the significant proteins with altered expression in bupivacaine-induced neurotoxicity indicated that phosphatidyl-3-kinase (PI3K) was the most frequently targeted protein in each of the interactions. We further confirmed these results by determining the downstream targets of the identified signaling pathways (PI3K, Akt, FoxO1, Erk, and JNK). In conclusion, our study demonstrated that PI3K may play a central role in contacting and regulating the signaling pathways that contribute to bupivacaine-induced neurotoxicity. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Neurobehavioural and Neurotoxic Effects of L-ascorbic Acid and L ...

African Journals Online (AJOL)

Background: Lead is an environmental toxicant, occupational and environmental exposures remain a serious problem in developing and industrializing countries. Objective: This study is designed to investigate the effects of L-ascorbic acid and L-tryptophan on the neurotoxicity and neurobehavioural alterations in lead ...

Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity

International Nuclear Information System (INIS)

Vilela, Luciano R.; Gobira, Pedro H.; Viana, Thercia G.; Medeiros, Daniel C.; Ferreira-Vieira, Talita H.; Doria, Juliana G.; Rodrigues, Flávia; Aguiar, Daniele C.; Pereira, Grace S.; Massessini, André R.; Ribeiro, Fabíola M.; Oliveira, Antonio Carlos P. de; Moraes, Marcio F.D.; Moreira, Fabricio A.

2015-01-01

Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB 1 receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB 1 receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity. - Highlights: • Cocaine toxicity is characterized by seizures and hippocampal cell death. • The endocannabinoid anandamide acts as a brain protective mechanism. • Inhibition of anandamide hydrolysis attenuates

Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity

Energy Technology Data Exchange (ETDEWEB)

Vilela, Luciano R. [Graduate Program in Neuroscience, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Gobira, Pedro H.; Viana, Thercia G. [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Medeiros, Daniel C.; Ferreira-Vieira, Talita H. [Department of Physiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Doria, Juliana G. [Graduate Program in Neuroscience, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Rodrigues, Flávia [Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Aguiar, Daniele C. [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Pereira, Grace S.; Massessini, André R. [Department of Physiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Ribeiro, Fabíola M. [Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Oliveira, Antonio Carlos P. de [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Moraes, Marcio F.D., E-mail: mfdm@icb.ufmg.br [Department of Physiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Moreira, Fabricio A., E-mail: fabriciomoreira@icb.ufmg.br [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil)

2015-08-01

Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB{sub 1} receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB{sub 1} receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity. - Highlights: • Cocaine toxicity is characterized by seizures and hippocampal cell death. • The endocannabinoid anandamide acts as a brain protective mechanism. • Inhibition of anandamide hydrolysis

Atropa belladonna neurotoxicity: Implications to neurological disorders.

Science.gov (United States)

Kwakye, Gunnar F; Jiménez, Jennifer; Jiménez, Jessica A; Aschner, Michael

2018-06-01

Atropa belladonna, commonly known as belladonna or deadly nightshade, ranks among one of the most poisonous plants in Europe and other parts of the world. The plant contains tropane alkaloids including atropine, scopolamine, and hyoscyamine, which are used as anticholinergics in Food and Drug Administration (FDA) approved drugs and homeopathic remedies. These alkaloids can be very toxic at high dose. The FDA has recently reported that Hyland's baby teething tablets contain inconsistent amounts of Atropa belladonna that may have adverse effects on the nervous system and cause death in children, thus recalled the product in 2017. A greater understanding of the neurotoxicity of Atropa belladonna and its modification of genetic polymorphisms in the nervous system is critical in order to develop better treatment strategies, therapies, regulations, education of at-risk populations, and a more cohesive paradigm for future research. This review offers an integrated view of the homeopathy and neurotoxicity of Atropa belladonna in children, adults, and animal models as well as its implications to neurological disorders. Particular attention is dedicated to the pharmaco/toxicodynamics, pharmaco/toxicokinetics, pathophysiology, epidemiological cases, and animal studies associated with the effects of Atropa belladonna on the nervous system. Additionally, we discuss the influence of active tropane alkaloids in Atropa belladonna and other similar plants on FDA-approved therapeutic drugs for treatment of neurological disorders. Copyright © 2018. Published by Elsevier Ltd.

Two three-dimensional coordination polymers of lead(II) with iminodiacetate and naphthalene-dicarboxylate anions: Synthesis, characterization and luminescence behavior

Energy Technology Data Exchange (ETDEWEB)

Hazari, Debdoot; Jana, Swapan Kumar [Department of Chemistry and Chemical Technology, Vidyasagar University, Midnapore 721 102, West Bengal (India); Fleck, Michel [Institute of Mineralogy and Crystallography, University of Vienna, Geozentrum, Althanstr. 9, A-1090 Vienna (Austria); Zangrando, Ennio [Department of Chemical and Pharmaceutical Sciences, University of Trieste, 34127 Trieste (Italy); Dalai, Sudipta, E-mail: sudipta@mail.vidyasagar.ac.in [Department of Chemistry and Chemical Technology, Vidyasagar University, Midnapore 721 102, West Bengal (India)

2014-11-15

Two lead(II) compounds [Pb{sub 3}(idiac){sub 3}(phen){sub 2}(H{sub 2}O)]·2(H{sub 2}O) (1) and [Pb(ndc)]{sub n} (2), where H{sub 2}idiac=iminodiacetic acid, phen=1,10-phenanthroline and H{sub 2}ndc=naphthalene-2,6-dicarboxylic acid, have been synthesized and structurally characterized. Single crystal X-ray diffraction analysis showed that compound 1 is a discrete trinuclear complex (of two-fold symmetry) which evolves to a supramolecular 3D network via π–π interactions, while in compound 2 the naphthalene dicarboxylate anion act as a linker to form a three dimensional architecture, where the anion adopts a bis-(bidentate bridging) coordination mode connecting four Pb(II) centers. The photoluminescence property of the two complexes has been studied. - graphical abstract: Two new topologically different 1D coordination polymers formed by Pb{sub 4} clusters have been synthesized and characterized by x-ray analysis. The luminescence and thermal properties have been studied. - Highlights: • 1 is a trinuclear complex of Pb(II) growing to 3D network via weak interactions. • In 1, layers of (4,4) rhomboidal topology are identified. • In 2, the ndc anion adopts interesting bis-(bidentate bridging) coordination. • In 2, network is reinforced by C–H…π-ring interactions between the ndc rings.

Site-specific ligation of anthracene-1,8-dicarboxylates to an Mn12 core: a route to the controlled functionalisation of single-molecule magnets.

Science.gov (United States)

Pacchioni, Mirko; Cornia, Andrea; Fabretti, Antonio C; Zobbi, Laura; Bonacchi, Daniele; Caneschi, Andrea; Chastanet, Guillaume; Gatteschi, Dante; Sessoli, Roberta

2004-11-21

A novel single-molecule magnet of the Mn12 family, [Mn12O12(O2CC6H5)8(L)4(H2O)4].8CH2Cl2, has been synthesised by site-specific ligand exchange using a tailor-made dicarboxylate (L2-), which leads to selective occupation of axial binding sites.

Salt and cocrystals of sildenafil with dicarboxylic acids: solubility and pharmacokinetic advantage of the glutarate salt.

Science.gov (United States)

Sanphui, Palash; Tothadi, Srinu; Ganguly, Somnath; Desiraju, Gautam R

2013-12-02

Sildenafil is a drug used to treat erectile dysfunction and pulmonary arterial hypertension. Because of poor aqueous solubility of the drug, the citrate salt, with improved solubility and pharmacokinetics, has been marketed. However, the citrate salt requires an hour to reach its peak plasma concentration. Thus, to improve solubility and bioavailability characteristics, cocrystals and salts of the drug have been prepared by treating aliphatic dicarboxylic acids with sildenafil; the N-methylated piperazine of the drug molecule interacts with the carboxyl group of the acid to form a heterosynthon. Salts are formed with oxalic and fumaric acid; salt monoanions are formed with succinic and glutaric acid. Sildenafil forms cocrystals with longer chain dicarboxylic acids such as adipic, pimelic, suberic, and sebacic acids. Auxiliary stabilization via C-H···O interactions is also present in these cocrystals and salts. Solubility experiments of sildenafil cocrystal/salts were carried out in 0.1N HCl aqueous medium and compared with the solubility of the citrate salt. The glutarate salt and pimelic acid cocrystal dissolve faster than the citrate salt in a two hour dissolution experiment. The glutarate salt exhibits improved solubility (3.2-fold) compared to the citrate salt in water. Solubilities of the binary salts follow an inverse correlation with their melting points, while the solubilities of the cocrystals follow solubilities of the coformer. Pharmacokinetic studies on rats showed that the glutarate salt exhibits doubled plasma AUC values in a single dose within an hour compared to the citrate salt. The high solubility of glutaric acid, in part originating from the strained conformation of the molecule and its high permeability, may be the reason for higher plasma levels of the drug.

Dipropyl 3,6-diphenyl-1,2-dihydro-1,2,4,5-tetrazine-1,2-dicarboxylate.

Science.gov (United States)

Rao, Guo-Wu; Hu, Wei-Xiao

2003-05-01

The title compound, C(22)H(24)N(4)O(4), was prepared from propyl chloroformate and 3,6-diphenyl-1,2-dihydro-s-tetrazine. This reaction yields the title compound rather than dipropyl 3,6-diphenyl-1,4-dihydro-s-tetrazine-1,4-dicarboxylate. The 2,3-diazabutadiene group in the central six-membered ring is not planar; the C=N double-bond length is 1.285 (2) A, and the average N-N single-bond length is 1.401 (3) A, indicating a lack of conjugation. The ring has a twist conformation, in which adjacent N atoms lie +/- 0.3268 (17) A from the plane of the ring. The molecule has twofold crystallographic symmetry.

In-vitro Neurotoxicity of Two Malaysian Krait Species (Bungarus candidus and Bungarus fasciatus Venoms: Neutralization by Monovalent and Polyvalent Antivenoms from Thailand

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Muhamad Rusdi Ahmad Rusmili

2014-03-01

Full Text Available Bungarus candidus and Bungarus fasciatus are two species of krait found in Southeast Asia. Envenoming by these snakes is often characterized by neurotoxicity and, without treatment, causes considerable morbidity and mortality. In this study, the in vitro neurotoxicity of each species, and the effectiveness of two monovalent antivenoms and a polyvalent antivenom, against the neurotoxic effects of the venoms, were examined in a skeletal muscle preparation. Both venoms caused concentration-dependent inhibition of indirect twitches, and attenuated responses to exogenous nicotinic receptor agonists, in the chick biventer preparation, with B. candidus venom being more potent than B. fasciatus venom. SDS-PAGE and western blot analysis indicated different profiles between the venoms. Despite these differences, most proteins bands were recognized by all three antivenoms. Antivenom, added prior to the venoms, attenuated the neurotoxic effect of the venoms. Interestingly, the respective monovalent antivenoms did not neutralize the effects of the venom from the other Bungarus species indicating a relative absence of cross-neutralization. Addition of a high concentration of polyvalent antivenom, at the t90 time point after addition of venom, partially reversed the neurotoxicity of B. fasciatus venom but not B. candidus venom. The monovalent antivenoms had no significant effect when added at the t90 time point. This study showed that B. candidus and B. fasciatus venoms display marked in vitro neurotoxicity in the chick biventer preparation and administration of antivenoms at high dose is necessary to prevent or reverse neurotoxicity.

Delayed neurotoxicity - do trichlorphon and/or dichlorvos cause delayed neuropathy in man or in test animals?

Science.gov (United States)

Johnson, M K

1981-01-01

Many, but not all, reports of delayed neuropathy associated with acute poisoning by trichlorphon refer to cases in U.S.S.R. Adulteration of technical trichlorphon with the ethyl analogue would greatly increase the neurotoxic hazard but analysis of a few samples has not revealed such impurities. Simultaneous ingestion of alcohol does not appear to increase neuropathic hazard. In hens double doses of trichlorphon each exceeding unprotected LD50 can produce moderate neuropathy associated with appropriately high inhibitions of neurotoxic esterase. Similar results are obtained with 2 doses of 10 x LD50 of dichlorvos. In vitro the inhibitory power of dichlorvos against neurotoxic esterase of hen brain is 0.02 x the power against acetylcholinesterase. This ratio correlates reasonably with the ratio of LD50/neuropathic dose. The factor for human brain enzymes is 0.06 suggesting that man is more susceptible to neuropathic effects of near-lethal doses of circulating dichlorvos. It is concluded that the only neuropathic hazard to man from good quality trichlorphon arises from rapid ingestion of massive doses. To obtain critical levels of inhibition of neurotoxic esterase and to cause neuropathy in man by repeated doses would require each dose to be severely toxic. Dichlorvos ingested in large doses is likely to kill rather than to cause neuropathy.

Ellagic acid promotes A{beta}42 fibrillization and inhibits A{beta}42-induced neurotoxicity

Energy Technology Data Exchange (ETDEWEB)

Feng, Ying [Department of Histology and Embryology, College of Basic Medical Science, China Medical University, Shenyang 110001 (China); Tsinghua University School of Medicine, Haidian District, Beijing 100084 (China); Yang, Shi-gao; Du, Xue-ting; Zhang, Xi; Sun, Xiao-xia; Zhao, Min [Tsinghua University School of Medicine, Haidian District, Beijing 100084 (China); Sun, Gui-yuan, E-mail: sungy2004@sohu.com [Department of Histology and Embryology, College of Basic Medical Science, China Medical University, Shenyang 110001 (China); Liu, Rui-tian, E-mail: rtliu@tsinghua.edu.cn [Tsinghua University School of Medicine, Haidian District, Beijing 100084 (China)

2009-12-25

Smaller, soluble oligomers of {beta}-amyloid (A{beta}) play a critical role in the pathogenesis of Alzheimer's disease (AD). Selective inhibition of A{beta} oligomer formation provides an optimum target for AD therapy. Some polyphenols have potent anti-amyloidogenic activities and protect against A{beta} neurotoxicity. Here, we tested the effects of ellagic acid (EA), a polyphenolic compound, on A{beta}42 aggregation and neurotoxicity in vitro. EA promoted A{beta} fibril formation and significant oligomer loss, contrary to previous results that polyphenols inhibited A{beta} aggregation. The results of transmission electron microscopy (TEM) and Western blot displayed more fibrils in A{beta}42 samples co-incubated with EA in earlier phases of aggregation. Consistent with the hypothesis that plaque formation may represent a protective mechanism in which the body sequesters toxic A{beta} aggregates to render them harmless, our MTT results showed that EA could significantly reduce A{beta}42-induced neurotoxicity toward SH-SY5Y cells. Taken together, our results suggest that EA, an active ingredient in many fruits and nuts, may have therapeutic potential in AD.

Liu Jun Zi Tang—A Potential, Multi-Herbal Complementary Therapy for Chemotherapy-Induced Neurotoxicity

Directory of Open Access Journals (Sweden)

Chun-Tang Chiou

2018-04-01

Full Text Available Liu Jun Zi Tang (LJZT has been used to treat functional dyspepsia and depression, suggesting its effects on gastrointestinal and neurological functions. LJZT is currently used as a complementary therapy to attenuate cisplatin-induced side effects, such as dyspepsia. However, its effect on chemotherapy-induced neuropathic pain or neurotoxicity has rarely been studied. Thus, we explored potential mechanisms underlying LJZT protection against cisplatin-induced neurotoxicity. We observed that LJZT attenuated cisplatin-induced thermal hyperalgesia in mice and apoptosis in human neuroblastoma SH-SY5Y cells. Furthermore, it also attenuated cisplatin-induced cytosolic and mitochondrial free radical formation, reversed the cisplatin-induced decrease in mitochondrial membrane potential, and increased the release of mitochondrial pro-apoptotic factors. LJZT not only activated the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α promoter region, but also attenuated the cisplatin-induced reduction of PGC-1α expression. Silencing of the PGC-1α gene counteracted the protection of LJZT. Taken together, LJZT mediated, through anti-oxidative effect and mitochondrial function regulation, to prevent cisplatin-induced neurotoxicity.

Increased interleukin-1β levels following low dose MDMA induces tolerance against the 5-HT neurotoxicity produced by challenge MDMA

Science.gov (United States)

2011-01-01

Background Preconditioning is a phenomenon by which tolerance develops to injury by previous exposure to a stressor of mild severity. Previous studies have shown that single or repeated low dose MDMA can attenuate 5-HT transporter loss produced by a subsequent neurotoxic dose of the drug. We have explored the mechanism of delayed preconditioning by low dose MDMA. Methods Male Dark Agouti rats were given low dose MDMA (3 mg/kg, i.p.) 96 h before receiving neurotoxic MDMA (12.5 mg/kg, i.p.). IL-1β and IL1ra levels and 5-HT transporter density in frontal cortex were quantified at 1 h, 3 h or 7 days. IL-1β, IL-1ra and IL-1RI were determined between 3 h and 96 h after low dose MDMA. sIL-1RI combined with low dose MDMA or IL-1β were given 96 h before neurotoxic MDMA and toxicity assessed 7 days later. Results Pretreatment with low dose MDMA attenuated both the 5-HT transporter loss and elevated IL-1β levels induced by neurotoxic MDMA while producing an increase in IL-1ra levels. Low dose MDMA produced an increase in IL-1β at 3 h and in IL-1ra at 96 h. sIL-1RI expression was also increased after low dose MDMA. Coadministration of sIL-1RI (3 μg, i.c.v.) prevented the protection against neurotoxic MDMA provided by low dose MDMA. Furthermore, IL-1β (2.5 pg, intracortical) given 96 h before neurotoxic MDMA protected against the 5-HT neurotoxicity produced by the drug, thus mimicking preconditioning. Conclusions These results suggest that IL-1β plays an important role in the development of delayed preconditioning by low dose MDMA. PMID:22114930

Increased interleukin-1β levels following low dose MDMA induces tolerance against the 5-HT neurotoxicity produced by challenge MDMA

Directory of Open Access Journals (Sweden)

Mayado Andrea

2011-11-01

Full Text Available Abstract Background Preconditioning is a phenomenon by which tolerance develops to injury by previous exposure to a stressor of mild severity. Previous studies have shown that single or repeated low dose MDMA can attenuate 5-HT transporter loss produced by a subsequent neurotoxic dose of the drug. We have explored the mechanism of delayed preconditioning by low dose MDMA. Methods Male Dark Agouti rats were given low dose MDMA (3 mg/kg, i.p. 96 h before receiving neurotoxic MDMA (12.5 mg/kg, i.p.. IL-1β and IL1ra levels and 5-HT transporter density in frontal cortex were quantified at 1 h, 3 h or 7 days. IL-1β, IL-1ra and IL-1RI were determined between 3 h and 96 h after low dose MDMA. sIL-1RI combined with low dose MDMA or IL-1β were given 96 h before neurotoxic MDMA and toxicity assessed 7 days later. Results Pretreatment with low dose MDMA attenuated both the 5-HT transporter loss and elevated IL-1β levels induced by neurotoxic MDMA while producing an increase in IL-1ra levels. Low dose MDMA produced an increase in IL-1β at 3 h and in IL-1ra at 96 h. sIL-1RI expression was also increased after low dose MDMA. Coadministration of sIL-1RI (3 μg, i.c.v. prevented the protection against neurotoxic MDMA provided by low dose MDMA. Furthermore, IL-1β (2.5 pg, intracortical given 96 h before neurotoxic MDMA protected against the 5-HT neurotoxicity produced by the drug, thus mimicking preconditioning. Conclusions These results suggest that IL-1β plays an important role in the development of delayed preconditioning by low dose MDMA.

Amiodarone biokinetics, the formation of its major oxidative metabolite and neurotoxicity after acute and repeated exposure of brain cell cultures.

Science.gov (United States)

Pomponio, Giuliana; Zurich, Marie-Gabrielle; Schultz, Luise; Weiss, Dieter G; Romanelli, Luca; Gramowski-Voss, Alexandra; Di Consiglio, Emma; Testai, Emanuela

2015-12-25

The difficulty in mimicking nervous system complexity and cell-cell interactions as well as the lack of kinetics information has limited the use of in vitro neurotoxicity data. Here, we assessed the biokinetic profile as well as the neurotoxicity of Amiodarone after acute and repeated exposure in two advanced rodent brain cell culture models, consisting of both neurons and glial cells organized in 2 or 3 dimensions to mimic the brain histiotypic structure and function. A strategy was applied to evidence the abiotic processes possibly affecting Amiodarone in vitro bioavailability, showing its ability to adsorb to the plastic devices. At clinically relevant Amiodarone concentrations, known to induce neurotoxicity in some patients during therapeutic treatment, a complete uptake was observed in both models in 24 h, after single exposure. After repeated treatments, bioaccumulation was observed, especially in the 3D cell model, together with a greater alteration of neurotoxicity markers. After 14 days, Amiodarone major oxidative metabolite (mono-N-desethylamiodarone) was detected at limited levels, indicating the presence of active drug metabolism enzymes (i.e. cytochrome P450) in both models. The assessment of biokinetics provides useful information on the relevance of in vitro toxicity data and should be considered in the design of an Integrated Testing Strategy aimed to identify specific neurotoxic alerts, and to improve the neurotoxicity assay predictivity for human acute and repeated exposure. Copyright © 2015 Elsevier Ltd. All rights reserved.

Mutual enhancement of central neurotoxicity induced by ketamine followed by methamphetamine

International Nuclear Information System (INIS)

Ke, J.-J.; Chen, H.-I.; Jen, C.J.; Kuo, Y.-M.; Cherng, C.G.; Tsai, Y.-P.N.; Ho, M.-C.; Tsai, C.-W.; Lung Yu

2008-01-01

We hereby report that repeated administration of ketamine (350 mg/kg in total) and methamphetamine (30 mg/kg in total) causes specific glutamatergic and dopaminergic neuron deficits, respectively, in adult mouse brain. Acute ketamine did not affect basal body temperature or the later methamphetamine-induced hyperthermia. However, pretreatment with repeated doses of ketamine aggravated methamphetamine-induced dopaminergic terminal loss as evidenced by a drastic decrease in the levels of dopamine, 3,4-dihydroxyphenylacetic acid, and dopamine transporter density as well as poor gait balance performance. In contrast, methamphetamine-induced serotonergic depletion was not altered by ketamine pretreatment. Likewise, the subsequent treatment with methamphetamine exacerbated the ketamine-induced glutamatergic damage as indicated by reduced levels of the vesicular glutamate transporter in hippocampus and striatum and poor memory performance in the Morris water maze. Finally, since activation of the D1 and AMPA/kainate receptors has been known to be involved in the release of glutamate and dopamine, we examined the effects of co-administration of SCH23390, a D1 antagonist, and CNQX, an AMPA/kainate antagonist. Intraventricular CNQX infusion abolished ketamine's potentiation of methamphetamine-induced dopamine neurotoxicity, while systemic SCH23390 mitigated methamphetamine's potentiation of ketamine-induced glutamatergic toxicity. We conclude that repeated doses of ketamine potentiate methamphetamine-induced dopamine neurotoxicity via AMPA/kainate activation and that conjunctive use of methamphetamine aggravates ketamine-induced glutamatergic neurotoxicity possibly via D1 receptor activation

Neuro-protective effect of rutin against Cisplatin-induced neurotoxic rat model.

Science.gov (United States)

Almutairi, Mashal M; Alanazi, Wael A; Alshammari, Musaad A; Alotaibi, Moureq Rashed; Alhoshani, Ali R; Al-Rejaie, Salim Salah; Hafez, Mohamed M; Al-Shabanah, Othman A

2017-09-29

Cisplatin is widely used chemotherapeutic agent for cancer treatment with limited uses due to its neurotoxic side effect. The aim of this study was to determine the potential preventive effects of rutin on the brain of cisplatin- neurotoxic rat model. Forty rats were divided into four groups. Group-1 (control group) was intra-peritoneal (IP) injected with 2.5 ml/kg saline. Group-2 (rutin group) was orally administrated 30 mg/kg rutin dissolved in water for 14 days. Group-3 (cisplatin group) was IP received 5 mg/kg cisplatin single dose. Group-4 (rutin and cisplatin group) was orally administrated 30 mg/kg rutin dissolved in water for 14 days with a single dose of 5 mg/kg cisplatin IP on day ten. Brain tissues from frontal cortex was used to extract RNA, the gene expression levels of paraoxonase-1 (PON-1), PON-2, PON-3, peroxisome proliferator-activated receptor delta (PPAR-δ), and glutathione peroxidase (GPx) was investigated by Real-time PCR. Cisplatin significantly decreased the expression levels of PON-1, PON-3, PPAR-δ and GPX whereas significantly increased PON-2 expression levels. Co-administration of Rutin prevented the cisplatin-induced toxicity by restoring the alteration in the studied genes to normal values as in the control group. This study showed that Rutin has neuroprotective effect and reduces cisplatin- neurotoxicity with possible mechanism via the antioxidant pathway.

Asiatic acid attenuates methamphetamine-induced neuroinflammation and neurotoxicity through blocking of NF-kB/STAT3/ERK and mitochondria-mediated apoptosis pathway

OpenAIRE

Park, Ji-Hyun; Seo, Young Ho; Jang, Jung-Hee; Jeong, Chul-Ho; Lee, Sooyeun; Park, Byoungduck

2017-01-01

Background Methamphetamine (METH) is a commonly abused drug that may result in neurotoxic effects. Recent studies have suggested that involvement of neuroinflammatory processes in brain dysfunction is induced by misuse of this drug. However, the mechanism underlying METH-induced inflammation and neurotoxicity in neurons is still unclear. In this study, we investigated whether asiatic acid (AA) effected METH-mediated neuroinflammation and neurotoxicity in dopaminergic neuronal cells. And we fu...

The classification of motor neuron defects in the zebrafish embryo toxicity test (ZFET) as an animal alternative approach to assess developmental neurotoxicity.

Science.gov (United States)

Muth-Köhne, Elke; Wichmann, Arne; Delov, Vera; Fenske, Martina

2012-07-01

Rodents are widely used to test the developmental neurotoxicity potential of chemical substances. The regulatory test procedures are elaborate and the requirement of numerous animals is ethically disputable. Therefore, non-animal alternatives are highly desirable, but appropriate test systems that meet regulatory demands are not yet available. Hence, we have developed a new developmental neurotoxicity assay based on specific whole-mount immunostainings of primary and secondary motor neurons (using the monoclonal antibodies znp1 and zn8) in zebrafish embryos. By classifying the motor neuron defects, we evaluated the severity of the neurotoxic damage to individual primary and secondary motor neurons caused by chemical exposure and determined the corresponding effect concentration values (EC₅₀). In a proof-of-principle study, we investigated the effects of three model compounds thiocyclam, cartap and disulfiram, which show some neurotoxicity-indicating effects in vertebrates, and the positive controls ethanol and nicotine and the negative controls 3,4-dichloroaniline (3,4-DCA) and triclosan. As a quantitative measure of the neurotoxic potential of the test compounds, we calculated the ratios of the EC₅₀ values for motor neuron defects and the cumulative malformations, as determined in a zebrafish embryo toxicity test (zFET). Based on this index, disulfiram was classified as the most potent and thiocyclam as the least potent developmental neurotoxin. The index also confirmed the control compounds as positive and negative neurotoxicants. Our findings demonstrate that this index can be used to reliably distinguish between neurotoxic and non-neurotoxic chemicals and provide a sound estimate for the neurodevelopmental hazard potential of a chemical. The demonstrated method can be a feasible approach to reduce the number of animals used in developmental neurotoxicity evaluation procedures. Copyright © 2012 Elsevier Inc. All rights reserved.

A dopamine receptor contributes to paraquat-induced neurotoxicity in Drosophila

Science.gov (United States)

Cassar, Marlène; Issa, Abdul-Raouf; Riemensperger, Thomas; Petitgas, Céline; Rival, Thomas; Coulom, Hélène; Iché-Torres, Magali; Han, Kyung-An; Birman, Serge

2015-01-01

Long-term exposure to environmental oxidative stressors, like the herbicide paraquat (PQ), has been linked to the development of Parkinson's disease (PD), the most frequent neurodegenerative movement disorder. Paraquat is thus frequently used in the fruit fly Drosophila melanogaster and other animal models to study PD and the degeneration of dopaminergic neurons (DNs) that characterizes this disease. Here, we show that a D1-like dopamine (DA) receptor, DAMB, actively contributes to the fast central nervous system (CNS) failure induced by PQ in the fly. First, we found that a long-term increase in neuronal DA synthesis reduced DAMB expression and protected against PQ neurotoxicity. Secondly, a striking age-related decrease in PQ resistance in young adult flies correlated with an augmentation of DAMB expression. This aging-associated increase in oxidative stress vulnerability was not observed in a DAMB-deficient mutant. Thirdly, targeted inactivation of this receptor in glutamatergic neurons (GNs) markedly enhanced the survival of Drosophila exposed to either PQ or neurotoxic levels of DA, whereas, conversely, DAMB overexpression in these cells made the flies more vulnerable to both compounds. Fourthly, a mutation in the Drosophila ryanodine receptor (RyR), which inhibits activity-induced increase in cytosolic Ca2+, also strongly enhanced PQ resistance. Finally, we found that DAMB overexpression in specific neuronal populations arrested development of the fly and that in vivo stimulation of either DNs or GNs increased PQ susceptibility. This suggests a model for DA receptor-mediated potentiation of PQ-induced neurotoxicity. Further studies of DAMB signaling in Drosophila could have implications for better understanding DA-related neurodegenerative disorders in humans. PMID:25158689

A neurotoxicity assessment of high flash aromatic naphtha.

Science.gov (United States)

Douglas, J F; McKee, R H; Cagen, S Z; Schmitt, S L; Beatty, P W; Swanson, M S; Schreiner, C A; Ulrich, C E; Cockrell, B Y

1993-01-01

Catalytic reforming is a refining process that converts naphthenes to aromatics by dehydrogenation to make higher octane gasoline blending components. A portion of this wide-boiling range hydrocarbon stream can be separated by distillation and used for other purposes. One such application is a mixture of predominantly 9-carbon aromatic molecules (C9 Aromatics, primarily isomers of ethyltoluene and trimethylbenzene), which is removed and used as a solvent also known as High Flash Aromatic Naphtha (HFAN). A program was initiated to assess the toxicological properties of HFAN since there may be human exposure, especially in the workplace. The current study was conducted to assess the potential for neurotoxicity in the rat. Adult male Sprague-Dawley rats of approximately 300 grams body weight, in groups of twenty, were exposed by inhalation to HFAN for 90 days at concentrations of 0, 100, 500, and 1500 ppm. During this period the animals were tested monthly for motor activity and in a functional observation battery. After three months of exposure, for 6 hours/day, 5 days/week, 10 animals/group/sex were sacrificed and selected nervous system tissue was examined histopathologically. No signs of neurotoxicity were seen in any of the evaluated parameters, nor was there evidence of pathologic changes in any of the examined tissues.

Gas adsorption properties of highly porous metal-organic frameworks containing functionalized naphthalene dicarboxylate linkers.

Science.gov (United States)

Sim, Jaeung; Yim, Haneul; Ko, Nakeun; Choi, Sang Beom; Oh, Youjin; Park, Hye Jeong; Park, SangYoun; Kim, Jaheon

2014-12-28

Three functionalized metal-organic frameworks (MOFs), MOF-205-NH2, MOF-205-NO2, and MOF-205-OBn, formulated as Zn4O(BTB)4/3(L), where BTB is benzene-1,3,5-tribenzoate and L is 1-aminonaphthalene-3,7-dicarboxylate (NDC-NH2), 1-nitronaphthalene-3,7-dicarboxylate (NDC-NO2) or 1,5-dibenzyloxy-2,6-naphthalenedicarboxylate (NDC-(OBn)2), were synthesized and their gas (H2, CO2, or CH4) adsorption properties were compared to those of the un-functionalized, parent MOF-205. Ordered structural models for MOF-205 and its derivatives were built based on the crystal structures and were subsequently used for predicting porosity properties. Although the Brunauer-Emmett-Teller (BET) surface areas of the three MOF-205 derivatives were reduced (MOF-205, 4460; MOF-205-NH2, 4330; MOF-205-NO2, 3980; MOF-205-OBn, 3470 m(2) g(-1)), all three derivatives were shown to have enhanced H2 adsorption capacities at 77 K and CO2 uptakes at 253, 273, and 298 K respectively at 1 bar in comparison with MOF-205. The results indicate the following trend in H2 adsorption: MOF-205 < MOF-205-NO2 < MOF-205-NH2 < MOF-205-OBn. MOF-205-OBn showed good ideal adsorbed solution theory (IAST) selectivity values of 6.5 for CO2/N2 (15/85 in v/v) and 2.7 for CO2/CH4 (50/50 in v/v) at 298 K. Despite the large reduction (-22%) in the surface area, MOF-205-OBn displayed comparable total volumetric CO2 (at 48 bar) and CH4 (at 35 bar) storage capacities with those of MOF-205 at 298 K: MOF-205-OBn, 305 (CO2) and 112 (CH4) cm(3) cm(-3), and for MOF-205, 307 (CO2) and 120 (CH4) cm(3) cm(-3), respectively.

Effect of crowding, temperature and age on glia activation and dopaminergic neurotoxicity induced by MDMA in the mouse brain.

Science.gov (United States)

Frau, Lucia; Simola, Nicola; Porceddu, Pier Francesca; Morelli, Micaela

2016-09-01

3,4-methylenedyoxymethamphetamine (MDMA or "ecstasy"), a recreational drug of abuse, can induce glia activation and dopaminergic neurotoxicity. Since MDMA is often consumed in crowded environments featuring high temperatures, we studied how these factors influenced glia activation and dopaminergic neurotoxicity induced by MDMA. C57BL/6J adolescent (4 weeks old) and adult (12 weeks old) mice received MDMA (4×20mg/kg) in different conditions: 1) while kept 1, 5, or 10×cage at room temperature (21°C); 2) while kept 5×cage at either room (21°C) or high (27°C) temperature. After the last MDMA administration, immunohistochemistry was performed in the caudate-putamen for CD11b and GFAP, to mark microglia and astroglia, and in the substantia nigra pars compacta for tyrosine hydroxylase, to mark dopaminergic neurons. MDMA induced glia activation and dopaminergic neurotoxicity, compared with vehicle administration. Crowding (5 or 10 mice×cage) amplified MDMA-induced glia activation (in adult and adolescent mice) and dopaminergic neurotoxicity (in adolescent mice). Conversely, exposure to a high environmental temperature (27°C) potentiated MDMA-induced glia activation in adult and adolescent mice kept 5×cage, but not dopaminergic neurotoxicity. Crowding and exposure to a high environmental temperature amplified MDMA-induced hyperthermia, and a positive correlation between body temperature and activation of either microglia or astroglia was found in adult and adolescent mice. These results provide further evidence that the administration setting influences the noxious effects of MDMA in the mouse brain. However, while crowding amplifies both glia activation and dopaminergic neurotoxicity, a high environmental temperature exacerbates glia activation only. Copyright © 2016 Elsevier B.V. All rights reserved.

Mephedrone does not damage dopamine nerve endings of the striatum, but enhances the neurotoxicity of methamphetamine, amphetamine, and MDMA.

Science.gov (United States)

Angoa-Pérez, Mariana; Kane, Michael J; Briggs, Denise I; Francescutti, Dina M; Sykes, Catherine E; Shah, Mrudang M; Thomas, David M; Kuhn, Donald M

2013-04-01

Mephedrone (4-methylmethcathinone) is a β-ketoamphetamine stimulant drug of abuse with close structural and mechanistic similarities to methamphetamine. One of the most powerful actions associated with mephedrone is the ability to stimulate dopamine (DA) release and block its re-uptake through its interaction with the dopamine transporter (DAT). Although mephedrone does not cause toxicity to DA nerve endings, its ability to serve as a DAT blocker could provide protection against methamphetamine-induced neurotoxicity like other DAT inhibitors. To test this possibility, mice were treated with mephedrone (10, 20, or 40 mg/kg) prior to each injection of a neurotoxic regimen of methamphetamine (four injections of 2.5 or 5.0 mg/kg at 2 h intervals). The integrity of DA nerve endings of the striatum was assessed through measures of DA, DAT, and tyrosine hydroxylase levels. The moderate to severe DA toxicity associated with the different doses of methamphetamine was not prevented by any dose of mephedrone but was, in fact, significantly enhanced. The hyperthermia caused by combined treatment with mephedrone and methamphetamine was the same as seen after either drug alone. Mephedrone also enhanced the neurotoxic effects of amphetamine and 3,4-methylenedioxymethamphetamine on DA nerve endings. In contrast, nomifensine protected against methamphetamine-induced neurotoxicity. As mephedrone increases methamphetamine neurotoxicity, the present results suggest that it interacts with the DAT in a manner unlike that of other typical DAT inhibitors. The relatively innocuous effects of mephedrone alone on DA nerve endings mask a potentially dangerous interaction with drugs that are often co-abused with it, leading to heightened neurotoxicity. © 2012 International Society for Neurochemistry.

3-Nitropropionic acid neurotoxicity in organotypic striatal and corticostriatal slice cultures is dependent on glucose and glutamate

DEFF Research Database (Denmark)

Storgaard, J; Kornblit, B T; Zimmer, J

2000-01-01

of lactate dehydrogenase in the medium and glutamic acid decarboxylase in tissue homogenates. 3-NPA toxicity (25-100 microM in 5 mM glucose, 24-48 h) appeared to be highly dependent on culture medium glucose levels. 3-NPA treatment caused also a dose-dependent lactate increase, reaching a maximum......Mitochondrial inhibition by 3-nitropropionic acid (3-NPA) causes striatal degeneration reminiscent of Huntington's disease. We studied 3-NPA neurotoxicity and possible indirect excitotoxicity in organotypic striatal and corticostriatal slice cultures. Neurotoxicity was quantified by assay...... of threefold increase above control at 100 microM. Both a high dose of glutamate (5 mM) and glutamate uptake blockade by dl-threo-beta-hydroxyaspartate potentiated 3-NPA neurotoxicity in corticostriatal slice cultures. Furthermore, striatum from corticostriatal cocultures was more sensitive to 3-NPA than...

Neurophysiological evidence of methylmercury neurotoxicity

DEFF Research Database (Denmark)

Murata, Katsuyuki; Grandjean, Philippe; Dakeishi, Miwako

2007-01-01

neurotoxicity and to examine the usefulness of those measures. METHODS: The reports addressing both neurophysiological measures and methylmercury exposure in humans were identified and evaluated. RESULTS: The neurological signs and symptoms of MD included paresthesias, constriction of visual fields, impairment...... disease (MD; methylmercury poisoning). In recent years, some of these methods have been used for the risk assessment of low-level methylmercury exposure in asymptomatic children. The objectives of this article were to present an overview of neurophysiological findings involved in methylmercury...... of hearing and speech, mental disturbances, excessive sweating, and hypersalivation. Neuropathological lesions involved visual, auditory, and post- and pre-central cortex areas. Neurophysiological changes involved in methylmercury, as assessed by EPs and HRV, were found to be in accordance with both clinical...

Methamphetamine generates peroxynitrite and produces dopaminergic neurotoxicity in mice: protective effects of peroxynitrite decomposition catalyst.

Science.gov (United States)

Imam, S Z; Crow, J P; Newport, G D; Islam, F; Slikker, W; Ali, S F

1999-08-07

Methamphetamine (METH)-induced dopaminergic neurotoxicity is believed to be produced by oxidative stress and free radical generation. The present study was undertaken to investigate if METH generates peroxynitrite and produces dopaminergic neurotoxicity. We also investigated if this generation of peroxynitrite can be blocked by a selective peroxynitrite decomposition catalyst, 5, 10,15, 20-tetrakis(N-methyl-4'-pyridyl)porphyrinato iron III (FeTMPyP) and protect against METH-induced dopaminergic neurotoxicity. Administration of METH resulted in the significant formation of 3-nitrotyrosine (3-NT), an in vivo marker of peroxynitrite generation, in the striatum and also caused a significant increase in the body temperature. METH injection also caused a significant decrease in the concentration of dopamine (DA), 3, 4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) by 76%, 53% and 40%, respectively, in the striatum compared with the control group. Treatment with FeTMPyP blocked the formation of 3-NT by 66% when compared with the METH group. FeTMPyP treatment also provided significant protection against the METH-induced hyperthermia and depletion of DA, DOPAC and HVA. Administration of FeTMPyP alone neither resulted in 3-NT formation nor had any significant effect on DA or its metabolite concentrations. These findings indicate that peroxynitrite plays a role in METH-induced dopaminergic neurotoxicity and also suggests that peroxynitrite decomposition catalysts may be beneficial for the management of psychostimulant abuse. Copyright 1999 Published by Elsevier Science B.V.

Neurotoxicity Induced by Bupivacaine via T-Type Calcium Channels in SH-SY5Y Cells

Science.gov (United States)

Wen, Xianjie; Xu, Shiyuan; Liu, Hongzhen; Zhang, Quinguo; Liang, Hua; Yang, Chenxiang; Wang, Hanbing

2013-01-01

There is concern regarding neurotoxicity induced by the use of local anesthetics. A previous study showed that an overload of intracellular calcium is involved in the neurotoxic effect of some anesthetics. T-type calcium channels, which lower the threshold of action potentials, can regulate the influx of calcium ions. We hypothesized that T-type calcium channels are involved in bupivacaine-induced neurotoxicity. In this study, we first investigated the effects of different concentrations of bupivacaine on SH-SY5Y cell viability, and established a cell injury model with 1 mM bupivacaine. The cell viability of SH-SY5Y cells was measured following treatment with 1 mM bupivacaine and/or different dosages (10, 50, or 100 µM) of NNC 55-0396 dihydrochloride, an antagonist of T-type calcium channels for 24 h. In addition, we monitored the release of lactate dehydrogenase, cytosolic Ca2+ ([Ca2+]i), cell apoptosis and caspase-3 expression. SH-SY5Y cells pretreated with different dosages (10, 50, or 100 µM) of NNC 55-0396 dihydrochloride improved cell viability, reduced lactate dehydrogenase release, inhibited apoptosis, and reduced caspase-3 expression following bupivacaine exposure. However, the protective effect of NNC 55-0396 dihydrochloride plateaued. Overall, our results suggest that T-type calcium channels may be involved in bupivacaine neurotoxicity. However, identification of the specific subtype of T calcium channels involved requires further investigation. PMID:23658789

Neurotoxicity induced by bupivacaine via T-type calcium channels in SH-SY5Y cells.

Directory of Open Access Journals (Sweden)

Xianjie Wen

Full Text Available There is concern regarding neurotoxicity induced by the use of local anesthetics. A previous study showed that an overload of intracellular calcium is involved in the neurotoxic effect of some anesthetics. T-type calcium channels, which lower the threshold of action potentials, can regulate the influx of calcium ions. We hypothesized that T-type calcium channels are involved in bupivacaine-induced neurotoxicity. In this study, we first investigated the effects of different concentrations of bupivacaine on SH-SY5Y cell viability, and established a cell injury model with 1 mM bupivacaine. The cell viability of SH-SY5Y cells was measured following treatment with 1 mM bupivacaine and/or different dosages (10, 50, or 100 µM of NNC 55-0396 dihydrochloride, an antagonist of T-type calcium channels for 24 h. In addition, we monitored the release of lactate dehydrogenase, cytosolic Ca(2+ ([Ca2+]i, cell apoptosis and caspase-3 expression. SH-SY5Y cells pretreated with different dosages (10, 50, or 100 µM of NNC 55-0396 dihydrochloride improved cell viability, reduced lactate dehydrogenase release, inhibited apoptosis, and reduced caspase-3 expression following bupivacaine exposure. However, the protective effect of NNC 55-0396 dihydrochloride plateaued. Overall, our results suggest that T-type calcium channels may be involved in bupivacaine neurotoxicity. However, identification of the specific subtype of T calcium channels involved requires further investigation.

Naphthalene Bis(4,8-diamino-1,5-dicarboxyl)amide Building Block for Semiconducting Polymers.

Science.gov (United States)

Eckstein, Brian J; Melkonyan, Ferdinand S; Manley, Eric F; Fabiano, Simone; Mouat, Aidan R; Chen, Lin X; Facchetti, Antonio; Marks, Tobin J

2017-10-18

We report a new naphthalene bis(4,8-diamino-1,5-dicarboxyl)amide (NBA) building block for polymeric semiconductors. Computational modeling suggests that regio-connectivity at the 2,6- or 3,7-NBA positions strongly modulates polymer backbone torsion and, therefore, intramolecular π-conjugation and aggregation. Optical, electrochemical, and X-ray diffraction characterization of 3,7- and 2,6-dithienyl-substituted NBA molecules and corresponding isomeric NBA-bithiophene copolymers P1 and P2, respectively, reveals the key role of regio-connectivity. Charge transport measurements demonstrate that while the twisted 3,7-NDA-based P1 is a poor semiconductor, the planar 2,6-functionalized NBA polymers (P2-P4) exhibit ambipolarity, with μ e and μ h of up to 0.39 and 0.32 cm 2 /(V·s), respectively.

The protective effect of Physalis peruviana L. against cadmium-induced neurotoxicity in rats.

Science.gov (United States)

Abdel Moneim, Ahmed E; Bauomy, Amira A; Diab, Marwa M S; Shata, Mohamed Tarek M; Al-Olayan, Ebtesam M; El-Khadragy, Manal F

2014-09-01

The present study was carried out to investigate the protective effect of Physalis peruviana L. (family Solanaceae) against cadmium-induced neurotoxicity in rats. Adult male Wistar rats were randomly divided into four groups. Group 1 was used as control. Group 2 was intraperitoneally injected with 6.5 mg/kg bwt of cadmium chloride for 5 days. Group 3 was treated with 200 mg/kg bwt of methanolic extract of Physalis (MEPh). Group 4 was pretreated with MEPh 1 h before cadmium for 5 days. Cadmium treatment induced marked disturbances in neurochemical parameters as indicating by significant (p Physalis has a beneficial effect in ameliorating the cadmium-induced oxidative neurotoxicity in the brain of rats.

Studies of (±)-3,4-methylenedioxymethamphetamine (MDMA) metabolism and disposition in rats and mice: relationship to neuroprotection and neurotoxicity profile.

Science.gov (United States)

Mueller, Melanie; Maldonado-Adrian, Concepcion; Yuan, Jie; McCann, Una D; Ricaurte, George A

2013-02-01

The neurotoxicity of (±)-3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") is influenced by temperature and varies according to species. The mechanisms underlying these two features of MDMA neurotoxicity are unknown, but differences in MDMA metabolism have recently been implicated in both. The present study was designed to 1) assess the effect of hypothermia on MDMA metabolism, 2) determine whether the neuroprotective effect of hypothermia is related to inhibition of MDMA metabolism, and 3) determine if different neurotoxicity profiles in mice and rats are related to differences in MDMA metabolism and/or disposition in the two species. Rats and mice received single neurotoxic oral doses of MDMA at 25°C and 4°C, and body temperature, pharmacokinetic parameters, and serotonergic and dopaminergic neuronal markers were measured. Hypothermia did not alter MDMA metabolism in rats and only modestly inhibited MDMA metabolism in mice; however, it afforded complete neuroprotection in both species. Rats and mice metabolized MDMA in a similar pattern, with 3,4-methylenedioxyamphetamine being the major metabolite, followed by 4-hydroxy-3-methoxymethamphetamine and 3,4-dihydroxymethamphetamine, respectively. Differences between MDMA pharmacokinetics in rats and mice, including faster elimination in mice, did not account for the different profile of MDMA neurotoxicity in the two species. Taken together, the results of these studies indicate that inhibition of MDMA metabolism is not responsible for the neuroprotective effect of hypothermia in rodents, and that different neurotoxicity profiles in rats and mice are not readily explained by differences in MDMA metabolism or disposition.

Acetylcholinesterase activities in marine snail (Cronia contracta) as a biomarker of neurotoxic contaminants along the Goa coast, West coast of India

Digital Repository Service at National Institute of Oceanography (India)

Gaitonde, D.; Sarkar, A.; Kaisary, S.; DeSilva, C.; Dias, C.F.M.; Rao, P.V.S.S.D.P.; Ray; Nagarajan, R.; DeSousa, S.N.; Sarkar, S.; Patill, D.

can be attributed to neurotoxic substances prevalent in those regions. The high concentration of different neurotoxic metals (lead, cadmium, copper, manganese and iron) and petroleum hydrocarbons in the tissues of the marine snails at Dona Paula, Vasco...

The Neurotoxicity of Nitrous Oxide: The Facts and “Putative” Mechanisms

Science.gov (United States)

Savage, Sinead; Ma, Daqing

2014-01-01

Nitrous oxide is a widely used analgesic agent, used also in combination with anaesthetics during surgery. Recent research has raised concerns about possible neurotoxicity of nitrous oxide, particularly in the developing brain. Nitrous oxide is an N-methyl-d-aspartate (NMDA)-antagonist drug, similar in nature to ketamine, another anaesthetic agent. It has been linked to post-operative cardiovascular problems in clinical studies. It is also widely known that exposure to nitrous oxide during surgery results in elevated homocysteine levels in many patients, but very little work has investigated the long term effect of these increased homocysteine levels. Now research in rodent models has found that homocysteine can be linked to neuronal death and possibly even cognitive deficits. This review aims to examine the current knowledge of mechanisms of action of nitrous oxide, and to describe some pathways by which it may have neurotoxic effects. PMID:24961701

Protection against methamphetamine-induced neurotoxicity to neostriatal dopaminergic neurons by adenosine receptor activation.

Science.gov (United States)

Delle Donne, K T; Sonsalla, P K

1994-12-01

Methamphetamine (METH)-induced neurotoxicity to nigrostriatal dopaminergic neurons in experimental animals appears to have a glutamatergic component because blockade of N-methyl-D-aspartate receptors prevents the neuropathologic consequences. Because adenosine affords neuroprotection against various forms of glutamate-mediated neuronal damage, the present studies were performed to investigate whether adenosine plays a protective role in METH-induced toxicity. METH-induced decrements in neostriatal dopamine content and tyrosine hydroxylase activity in mice were potentiated by concurrent treatment with caffeine, a nonselective adenosine antagonist that blocks both A1 and A2 adenosine receptors. In contrast, chronic treatment of mice with caffeine through their drinking water for 4 weeks, which increased the number of adenosine A1 receptors in the neostriatum and frontal cortex, followed by drug washout, prevented the neurochemical changes produced by the treatment of mice with METH treatment. In contrast, this treatment did not prevent 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine-induced dopaminergic neurotoxicity. Furthermore, concurrent administration of cyclopentyladenosine, an adenosine A1 receptor agonist, attenuated the METH-induced neurochemical changes. This protection by cyclopentyladenosine was blocked by cyclopentyltheophylline, an A1 receptor antagonist. These results indicate that activation of A1 receptors can protect against METH-induced neurotoxicity in mice.

7, 8, 3′-Trihydroxyflavone Promotes Neurite Outgrowth and Protects Against Bupivacaine-Induced Neurotoxicity in Mouse Dorsal Root Ganglion Neurons

Science.gov (United States)

Shi, Haohong; Luo, Xingjing

2016-01-01

Background 7, 8, 3′-trihydroxyflavone (THF) is a novel pro-neuronal small molecule that acts as a TrkB agonist. In this study, we examined the effect of THF on promoting neuronal growth and protecting anesthetics-induced neurotoxicity in dorsal root ganglion (DRG) neurons in vitro. Material/Methods Neonatal mouse DRG neurons were cultured in vitro and treated with various concentrations of THF. The effect of THF on neuronal growth was investigated by neurite outgrowth assay and Western blot. In addition, the protective effects of THF on bupivacaine-induced neurotoxicity were investigated by apoptosis TUNEL assay, neurite outgrowth assay, and Western blot, respectively. Results THF promoted neurite outgrowth of DRG neurons in dose-dependent manner, with an EC50 concentration of 67.4 nM. Western blot analysis showed THF activated TrkB signaling pathway by inducing TrkB phosphorylation. THF also rescued bupivacaine-induced neurotoxicity by reducing apoptosis and protecting neurite retraction in DRG neurons. Furthermore, the protection of THF in bupivacaine-injured neurotoxicity was directly associated with TrkB phosphorylation in a concentration-dependent manner in DRG neurons. Conclusions THF has pro-neuronal effect on DRG neurons by promoting neurite growth and protecting against bupivacaine-induced neurotoxicity, likely through TrkB activation. PMID:27371503

Co-exposure to an ortho-substituted PCB (PCB 153) and methylmercury enhances developmental neurotoxic effects

Energy Technology Data Exchange (ETDEWEB)

Fischer, C.; Fredriksson, A.; Eriksson, P. [Dept. Environment. Toxicol., Uppsala Univ. (Sweden)

2004-09-15

In our environment there are innumerable hazardous contaminants. Many of these compounds are the well-known persistent organic pollutants (POPs) like PCB and DDT. Another persistent agent in our environment is methylmercury (MeHg). These agents are known to be neurotoxic in laboratory animals and humans. Fetuses and neonates are known to be high-risk groups for exposure to these agents. A naturally occurring circumstance is the exposure to a combination of different persistent compounds. The knowledge of interaction between different toxic agents during development is sparse. In several studies we have shown that low-dose exposure of environmental toxic agents such as PCBs, DDT, BFRs (brominated flame retardants) as well as well-known neurotoxic agents such as nicotine, organophosphorous compounds and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), during the ''BGS'', in neonatal mice can lead to disruption of the adult brain function, and to an increased susceptibility to toxic agents as adults. Our studies concerning developmental neurotoxic effects after neonatal exposure to single PCB congeners have shown that some orthosubstituted PCBs (such as PCB 28, PCB 52, PCB 153) and some co-planar PCBs (such as PCB 77, PCB 126, PCB 169) cause derangement of adult behaviour that can worsen with age. Furthermore, the cholinergic receptors in the brain were also found to be affected8. Just recently we have seen that neonatal co-exposure to an ortho-substituted PCB, 2,2',5,5'-tetrachlorobiphenyl (PCB 52), together with a brominated flame retardant, 2,2',4,4',5-pentabromodiphenylether (PBDE 99), can enhance developmental neurotoxic effects when the exposure occurs during a critical stage of neonatal brain development. The present study was carried out in order to see whether PCB and MeHg could interact to cause enhanced developmental neurotoxic effects on spontaneous behaviour and habituation capability when given to neonatal mice.

Ozone (O{sub 3}) elicits neurotoxicity in spinal cord neurons (SCNs) by inducing ER Ca{sup 2+} release and activating the CaMKII/MAPK signaling pathway

Energy Technology Data Exchange (ETDEWEB)

Li, Yun; Lin, Xiaowen; Zhao, XueJun; Xie, Juntian; JunNan, Wang; Sun, Tao; Fu, Zhijian, E-mail: zhijian_fu@163.com

2014-11-01

Ozone (O{sub 3}) is widely used in the treatment of spinal cord related diseases. Excess or accumulation of this photochemical air can however be neurotoxic. In this study, in vitro cultured Wister rat spinal cord neurons (SCNs) were used to investigate the detrimental effects and underlying mechanisms of O{sub 3}. Ozone in a dose-dependent manner inhibited cell viability at a range of 20 to 500 μg/ml, with the dose at 40 μg/ml resulting in a decrease of cell viability to 75%. The cell death after O{sub 3} exposure was related to endoplasmic reticulum (ER) calcium (Ca{sup 2+}) release. Intracellular Ca{sup 2+} chelator, ER stabilizer (inositol 1,4,5-trisphosphate receptor (IP3R) antagonist and ryanodine receptor (RyR) antagonist) and calcium/calmodulin-dependent protein kinase II (CaMKII) antagonist could effectively block Ca{sup 2+} mobilization and inhibit cell death following 40 μg/ml O{sub 3} exposure. In addition, ER Ca{sup 2+} release due to O{sub 3} exposure enhanced phospho-p38 and phospho-JNK levels and apoptosis of SCNs through activating CaMKII. Based on these results, we confirm that ozone elicits neurotoxicity in SCNs via inducing ER Ca{sup 2+} release and activating CaMKII/MAPK signaling pathway. Therefore, physicians should get attention to the selection of treatment concentrations of oxygen/ozone. And, approaches, such as chelating intracellular Ca{sup 2+} and stabilizing neuronal Ca{sup 2+} homeostasis could effectively ameliorate the neurotoxicity of O{sub 3}. - Highlights: • Exposure to O{sub 3} can reduce the viability of SCNs and cause the cell death. • Exposure to O{sub 3} can trigger RyR and IP3R dependent intracellular Ca{sup 2+} release. • Exposure to O{sub 3} can enhance the phospho-CaMKII, phospho-JNK and phospho-p38 levels.

Influence of CYP3A5 and ABCB1 gene polymorphisms on calcineurin inhibitor-related neurotoxicity after hematopoietic stem cell transplantation.

Science.gov (United States)

Yanagimachi, Masakatsu; Naruto, Takuya; Tanoshima, Reo; Kato, Hiromi; Yokosuka, Tomoko; Kajiwara, Ryosuke; Fujii, Hisaki; Tanaka, Fumiko; Goto, Hiroaki; Yagihashi, Tatsuhiko; Kosaki, Kenjiro; Yokota, Shumpei

2010-01-01

One severe side effect of calcineurin inhibitors (CNIs: such as cyclosporine [CsA] and tacrolimus [FK506]) is neurotoxicity. CNIs are substrates for CYP3A5 and P-glycoprotein (P-gp), encoded by ABCB1 gene. In the present study, we hypothesized that genetic variability in CYP3A5 and ABCB1 genes may be associated with CNI-related neurotoxicity. The effects of the polymorphisms, such as CYP3A5 A6986G, ABCB1 C1236T, G2677T/A, and C3435T, associated with CNI-related neurotoxicity were evaluated in 63 patients with hematopoietic stem cell transplantation.   Of the 63 cases, 15 cases developed CNI-related neurotoxicity. In the CsA patient group (n = 30), age (p = 0.008), hypertension (p = 0.017), renal dysfunction (p < 0.001), ABCB1 C1236T (p < 0.001), and G2677T/A (p = 0.014) were associated with neurotoxicities. The CC genotype at ABCB1 C1236T was associated with it, but not significantly so (p = 0.07), adjusted for age, hypertension, and renal dysfunction. In the FK506 patient group (n = 33), CYP3A5 A6986G (p < 0.001), and ABCB1 C1236T (p = 0.002) were associated with neurotoxicity. At least one A allele at CYP3A5 A6986G (expressor genotype) was strongly associated with it according to logistic regression analysis (p = 0.01; OR, 8.5; 95% CI, 1.4-51.4).   The polymorphisms in CYP3A5 and ABCB1 genes were associated with CNI-related neurotoxicity. This outcome is probably because of CYP3A5 or P-gp functions or metabolites of CNIs. © 2009 John Wiley & Sons A/S.

From the Cover: Harmane-Induced Selective Dopaminergic Neurotoxicity in Caenorhabditis elegans.

Science.gov (United States)

Sammi, Shreesh Raj; Agim, Zeynep Sena; Cannon, Jason R

2018-02-01

Parkinson's disease (PD) is a debilitating neurodegenerative disease. Although numerous exposures have been linked to PD etiology, causative factors for most cases remain largely unknown. Emerging data on the neurotoxicity of heterocyclic amines suggest that this class of compounds should be examined for relevance to PD. Here, using Caenorhabditis elegans as a model system, we tested whether harmane exposure produced selective toxicity to dopamine neurons that is potentially relevant to PD. Harmane is a known tremorigenic β-carboline (a type of heterocyclic amine) found in cooked meat, roasted coffee beans, and tobacco. Thus, this compound represents a potentially important exposure. In the nematode model, we observed dopaminergic neurons to be selectively vulnerable, showing significant loss in terms of structure and function at lower doses than other neuronal populations. In examining mechanisms of toxicity, we observed significant harmane-induced decreases in mitochondrial viability and increased reactive oxygen species levels. Blocking transport through the dopamine transporter (DAT) was not neuroprotective, suggesting that harmane is unlikely to enter the cell through DAT. However, a mitochondrial complex I activator did partially ameliorate neurodegeneration. Further, mitochondrial complex I activator treatment reduced harmane-induced dopamine depletion, measured by the 1-nonanol assay. In summary, we have shown that harmane exposure in C. elegans produces selective dopaminergic neurotoxicity that may bear relevance to PD, and that neurotoxicity may be mediated through mitochondrial mechanisms. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

P1-11: Visual Function and Neurotoxic Symptoms Related to Exposure to Organic Solvents

Directory of Open Access Journals (Sweden)

Ingrid Jimenez Barbosa

2012-10-01

Full Text Available Aim: Exposure to Perchloroethylene (PERC, a solvent used in dry-cleaning, is associated with neurotoxicity and changes in colour vision (CV and contrast sensitivity (CS. However, PERCs' impact on other aspects of visual function (VF such as chromatic contrast sensitivity (CCS, glass pattern detection (GPP, visual search (VS, and global motion sensitivity (GMS remains unclear. This study compared VF and neurotoxicity in two populations at risk, dry-cleaners (cases from Colombia and Australia. Control groups of people with community levels of exposure to PERC were also assessed. Methods: A case-control study of VF in people who are working in the dry-cleaning industry for at least 1 year (n = 40 Colombia; n= 34 Australia with controls (n = 35 each site. VF measures assessed were CSF, CCS, the FM Hue 100 test, VS, GPP, and GMS. Neurotoxic symptoms were assessed using the Q16 modified version questionnaire. Results: Cases had poorer CCS, hue discrimination, GPP, GMS, and higher Q16 scores than controls (p < .05. There was no effect of country. CS function was poorer than controls (p < .05 for spatial frequencies≥0.50 cpd for Australian cases but for ≥1.0 cpd for Colombian cases. There were no significant differences between cases and controls for serial and parallel VS. Conclusion: Our CSF and CV findings indicate that the CS deficit extends to lower spatial frequencies. Furthermore we report a reduction in the detection of form, motion, and CCS. These deficits were associated with neurotoxic symptoms. Because VS was unaffected, it suggests that PERC affects lower order visual functions more severely than higher level cognition.

Methanogenic Paraffin Biodegradation: Alkylsuccinate Synthase Gene Quantification and Dicarboxylic Acid Production.

Science.gov (United States)

Oberding, Lisa K; Gieg, Lisa M

2018-01-01

Paraffinic n -alkanes (>C 17 ) that are solid at ambient temperature comprise a large fraction of many crude oils. The comparatively low water solubility and reactivity of these long-chain alkanes can lead to their persistence in the environment following fuel spills and pose serious problems for crude oil recovery operations by clogging oil production wells. However, the degradation of waxy paraffins under the anoxic conditions characterizing contaminated groundwater environments and deep subsurface energy reservoirs is poorly understood. Here, we assessed the ability of a methanogenic culture enriched from freshwater fuel-contaminated aquifer sediments to biodegrade the model paraffin n -octacosane (C 28 H 58 ). Compared with that in controls, the consumption of n -octacosane was coupled to methane production, demonstrating its biodegradation under these conditions. Smithella was postulated to be an important C 28 H 58 degrader in the culture on the basis of its high relative abundance as determined by 16S rRNA gene sequencing. An identified assA gene (known to encode the α subunit of alkylsuccinate synthase) aligned most closely with those from other Smithella organisms. Quantitative PCR (qPCR) and reverse transcription qPCR assays for assA demonstrated significant increases in the abundance and expression of this gene in C 28 H 58 -degrading cultures compared with that in controls, suggesting n -octacosane activation by fumarate addition. A metabolite analysis revealed the presence of several long-chain α,ω-dicarboxylic acids only in the C 28 H 58 -degrading cultures, a novel observation providing clues as to how methanogenic consortia access waxy hydrocarbons. The results of this study broaden our understanding of how waxy paraffins can be biodegraded in anoxic environments with an application toward bioremediation and improved oil recovery. IMPORTANCE Understanding the methanogenic biodegradation of different classes of hydrocarbons has important

Neurotoxicity of drugs of abuse - the case of methylenedioxy amphetamines (MDMA, ecstasy ), and amphetamines

Science.gov (United States)

Gouzoulis-Mayfrank, Euphrosyne; Daumann, Joerg

2009-01-01

Ecstasy (MDMA, 3,4-methylendioxymethamphetamine) and the stimulants methamphetamine (METH, speed) and amphetamine are popular drugs among young people, particularly in the dance scene. When given in high doses both MDMA and the stimulant amphetamines are clearly neurotoxic in laboratory animals. MDMA causes selective and persistent lesions of central serotonergic nerve terminals, whereas amphetamines damage both the serotonergic and dopaminergic systems. In recent years, the question of ecstasy-induced neurotoxicity and possible functional sequelae has been addressed in several studies in drug users. Despite large methodological problems, the bulk of evidence suggests residual alterations of serotonergic transmission in MDMA users, although at least partial recovery may occur after long-term abstinence. However, functional sequelae may persist even after longer periods of abstinence. To date, the most consistent findings associate subtle cognitive impairments with ecstasy use, particularly with memory. In contrast, studies on possible long-term neurotoxic effects of stimulant use have been relatively scarce. Preliminary evidence suggests that alterations of the dopaminergic system may persist even after years of abstinence from METH, and may be associated with deficits in motor and cognitive performance. In this paper, we will review the literature focusing on human studies. PMID:19877498

Candida antartica lipase-catalyzed hydrolysis of 4-substituted bis(ethoxycarbonylmethyl) 1,4-dihydropyridine-3,5-dicarboxylates as the key step in the synthesis of optically active dihydropyridines

NARCIS (Netherlands)

Sobolev, A.; Franssen, M.C.R.; Makarova, N.; Duburs, G.; Groot, de Æ.

2001-01-01

Prochiral bis(ethoxycarbonylmethyl) substituted 4-aryl-1,4-dihydropyridine-3,5-dicarboxylates were hydrolyzed enantioselectively by Candida antarctica lipase B (Novozym 435). The enantiomeric excesses varied from 68 to 93°depending on the substituent at position 4. In some cases, the e.e. could be

Effects of Personal Protective Equipment Use and Good Workplace Hygiene on Symptoms of Neurotoxicity in Solvent-Exposed Vehicle Spray Painters.

Science.gov (United States)

Keer, Sam; McLean, Dave; Glass, Bill; Douwes, Jeroen

2018-03-12

To assess the association between the use of personal protective equipment (PPE) and good workplace hygiene and symptoms of neurotoxicity in solvent-exposed vehicle spray painters. Exposure control measures including PPE-use and workplace hygiene practices and symptoms of neurotoxicity were assessed in 267 vehicle repair spray painters. Symptoms were assessed using an adapted version of the EUROQUEST Questionnaire. Frequent respirator and glove use was inversely and significantly associated with symptoms of neurotoxicity in a dose-dependent manner (P 80%. Poor hygiene workplace practices, such as solvent exposure to multiple body parts (OR 3.4, P = 0.11 for reporting ≥10 symptoms), were associated with an increased risk of symptoms. When using a general workplace hygiene score derived from a combination of PPE-use and (good) workplace practice factors an inverse and significant dose-response trend was observed for reporting ≥5 (P hygiene are associated with a strongly reduced risk of symptoms of neurotoxicity in solvent-exposed vehicle spray painters.

Evaluation of potential neurotoxic effects of occupational exposure to (L)-Lactates

NARCIS (Netherlands)

Clary, J.J.; Feron, V.J.; Velthuijsen, J.A. van

2001-01-01

Organo psycho syndrome (OPS) or chronic toxic encephalopathy (CTE) is a neurotoxic condition reported following long-term exposure to paints containing organic solvent and to other solvents. Lactate esters are finding wider use as solvents. Lactate esters have been well studied in standard toxicity

Morita-Baylis-Hillman Route to Dimethyl 2,3-Dihydrobenzo[b]oxepine-2,4- dicarboxylates and Methyl 2-(2-Carbomethoxybenzo[b]furan-3-yl)propanoates from Salicylaldehydes

International Nuclear Information System (INIS)

Ahn, Sang Hyun; Jang, Seung Soon; Kim, Young Keun; Lee, Kee Jung

2012-01-01

A new synthetic method for dimethyl 2,3-dihydrobenzo[b]oxepine-2,4-dicarboxylates and methyl 2-(2- carbomethoxybenzo[b]furan-3-yl)propanoates by an intramolecular conjugate displacement reaction or an S N 2 reaction of acetates of Morita-Baylis-Hillman adducts of methyl (2-formylphenoxy)acetates has been described

The dopamine transporter: role in neurotoxicity and human disease

International Nuclear Information System (INIS)

Bannon, Michael J.

2005-01-01

The dopamine transporter (DAT) is a plasma membrane transport protein expressed exclusively within a small subset of CNS neurons. It plays a crucial role in controlling dopamine-mediated neurotransmission and a number of associated behaviors. This review focuses on recent data elucidating the role of the dopamine transporter in neurotoxicity and a number of CNS disorders, including Parkinson disease, drug abuse, and attention deficit hyperactivity disorder (ADHD)

The dopamine transporter: role in neurotoxicity and human disease

Energy Technology Data Exchange (ETDEWEB)

Bannon, Michael J [Department of Psychiatry and Behavioral Neuroscience, Pharmacology, and Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201 (United States)

2005-05-01

The dopamine transporter (DAT) is a plasma membrane transport protein expressed exclusively within a small subset of CNS neurons. It plays a crucial role in controlling dopamine-mediated neurotransmission and a number of associated behaviors. This review focuses on recent data elucidating the role of the dopamine transporter in neurotoxicity and a number of CNS disorders, including Parkinson disease, drug abuse, and attention deficit hyperactivity disorder (ADHD)

Photo and Thermal Behavior of New Reinforced Polyamide-nanocomposite Montmorillonite on 2,3-Pyrazin Dicarboxylic Acid

Science.gov (United States)

Faghihi, Khalil; Samiei, Mojtaba; Hajibeygi, Mohsen

2012-06-01

Two new samples of reinforce polyamidemontmorillonite nanocomposites were synthesized by a convenient solution intercalation technique. Polyamide (PA) 3 as a source of polymer matrix was synthesized by the direct polycondensation reaction of pyrazine 2,3-dicarboxylic acid 1 with 4,4'-diamino diphenyl ether 2 in the presence of triphenyl phosphite (TPP), CaCl2, pyridine and N-methyl-2-pyrrolidone (NMP). The resulting nanocomposite films were characterized by Fourier transform infrared spectra (FT-IR), X-ray diffraction (XRD), scanning electron microscopy (SEM) and thermogravimetric analysis (TGA). The results showed that organo-modified clay was dispersed homogeneously in PA matrix. TGA indicated an enhancement of thermal stability of new nanocomposites compared with the pure polymer.

Solvent neurotoxicity in vehicle collision repair workers in New Zealand.

Science.gov (United States)

Keer, Samuel; Glass, Bill; Prezant, Bradley; McLean, David; Pearce, Neil; Harding, Elizabeth; Echeverria, Diana; McGlothlin, James; Babbage, Duncan R; Douwes, Jeroen

2016-12-01

To assess whether solvent use and workplace practices in the vehicle collision repair industry are associated with symptoms of neurotoxicity in spray painters and panel beaters (auto body repair workers). Neurobehavioural symptoms were assessed using a cross-sectional study design in 370 vehicle collision repair and 211 reference workers using the EUROQUEST questionnaire. Full-shift airborne solvent levels were measured in a subset (n=92) of collision repair workers. Solvent exposures were higher in spray painters than in panel beaters, but levels were below current international exposure standards. Collision repair workers were more likely to report symptoms of neurotoxicity than reference workers with ORs of 2.0, 2.4 and 6.4 (all p<0.05) for reporting ≥5, ≥10 and ≥15 symptoms respectively. This trend was generally strongest for panel beaters (ORs of 2.1, 3.3 and 8.2 for ≥5, ≥10 and ≥15 symptoms respectively). Associations with specific symptom domains showed increased risks for neurological (OR 4.2), psychosomatic (OR 3.2), mood (OR 2.1), memory (OR 2.9) and memory and concentration symptoms combined (OR 2.4; all p<0.05). Workers who had worked for 10-19 years or 20+ years in the collision repair industry reported consistently more symptoms than those who had only worked less than 10 years even after adjusting for age. However, those who worked more than 20 years generally reported fewer symptoms than those who worked 10-19 years, suggesting a possible healthy worker survivor bias. Despite low airborne solvent exposures, vehicle collision repair spray painters and panel beaters continue to be at risk of symptoms of neurotoxicity. Copyright © 2016 Elsevier B.V. All rights reserved.

Synthesis and physicochemical properties of the furan dicarboxylic acid, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, an inhibitor of plasma protein binding in uraemia.

Science.gov (United States)

Costigan, M G; Gilchrist, T L; Lindup, W E

1996-06-01

The furan dicarboxylic acid, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (5-propyl FPA) accumulates in the plasma of patients with chronic renal failure and is a major contributor to the drug binding defect of uraemic plasma. This acid has also been implicated in several other aspects of the uraemic syndrome: anaemia, irregularities of thyroid function, neurological symptoms and inhibition of active tubular secretion. The acid is not commercially available and its synthesis, starting with Meldrum's acid and methyl succinyl chloride, is described. The pKa values were measured by titration and values of 3.2 and 3.6 respectively were assigned to the carboxylic acid groups attached directly to the ring at position 3 and at position 2 (on the side-chain). The partition coefficient (log P) between hydrochloric acid and octanol was 1.2 and the distribution coefficient (log D; octanol-phosphate buffer pH 7.4) was -0.59. The pKa values and the degree of hydrophobic character of 5-propyl FPA are consistent with those of other protein-bound acids which undergo active tubular secretion by the kidney and this substance may serve as an endogenous marker for the effects of drugs and disease on this process.

Protective effect of arctigenin against MPP+ and MPTP-induced neurotoxicity.

Science.gov (United States)

Li, Dongwei; Liu, Qingping; Jia, Dong; Dou, Deqiang; Wang, Xiaofei; Kang, Tingguo

2014-01-01

The potential protective effects of arctigenin on 1-methyl-4-phenylpyridinium ion and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyride-induced neurotoxicity were examined, and the results indicated that arctigenin could improve the movement behaviors and upregulate dopamine and γ-aminobutyric acid levels in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyride-induced neurotoxicity mouse model. A further in vitro experiment showed that the pretreatment with arctigenin on cultured human neuroblastoma SH-SY5Y cells could obviously attenuate the decrease of cell survival rates caused by treatment with 1-methyl-4-phenylpyridinium ion by way of acting against cell apoptosis through the decrease of Bax/Bcl-2 and caspase-3, and by antioxidative action through reduction of the surplus reactive oxygen species production and downregulation of mitochondrial membrane potential. It is for the first time that a neuroprotective activity of arctigenin in both in vitro and in vivo experiments was reported, enlightening that arctigenin could be useful as a potential therapeutic agent for Parkinson's disease. Georg Thieme Verlag KG Stuttgart · New York.

catena-Poly[[[tetraaquazinc(II]-μ-4,4′-bipyridine-κ2N:N′] benzene-1,4-dicarboxylate

Directory of Open Access Journals (Sweden)

Ming-Bo Ruan

2009-07-01

Full Text Available In the title compound, {[Zn(C10H8N2(H2O4](C8H4O4}n, the ZnII atoms, lying on a twofold rotation axis, are bridged by 4,4′-bipyridine ligands, resulting in a linear chain along the b axis. In the chain, the ZnII atom adopts a slightly distorted octahedral coordination geometry involving four water molecules at the equatorial positions. The noncoordinated benzene-1,4-dicarboxylate anion, which is also located on a twofold rotation axis, bridges adjacent chains through O—H...O hydrogen bonds, forming a three-dimensional supramolecular network.

Research into esterification of mixture of lower dicarboxylic acids by 2-ethylhexan-1-ol in the presence of p-toluensulfonic acid

OpenAIRE

Melnyk, Stepan; Melnyk, Yuriy; Nykulyshyn, Irena; Shevchuk, Liliya

2017-01-01

Regularities of esterification of the mixture of lower dicarboxylic acids (succinic, glutaric, adipic) by 2-ethylhexan-1-ol in the presence of catalysts – p-toluensulfonic and sulfuric acids under non-stationary conditions were studied. It was found that in the presence of mineral acid, the reaction flows at a lower rate. Application of benzene as a substance that facilitates separation of water, formed in the esterification reaction, makes it possible, due to a lower reaction temperature, to...

Potentiometric studies on ternary complexes involving some divalent transition metal ions, gallic acid and biologically abundant aliphatic dicarboxylic acids in aqueous solutions

Directory of Open Access Journals (Sweden)

Abdelatty Mohamed Radalla

2015-06-01

Full Text Available Formation of binary and ternary complexes of the divalent transition metal ions, Cu2+, Ni2+, Co2+ and Zn2+ with gallic acid and the biologically important aliphatic dicarboxylic acids (adipic, succinic, malic, malonic, maleic, tartaric and oxalic acids were investigated by means of the potentiometric technique at 25 °C and I = 0.10 mol dm−3 NaNO3. The acid-base properties of the ligands were investigated and discussed. The acidity constants of gallic acid and aliphatic dicarboxylic acids were determined and used for determining the stability constants of the binary and ternary complexes formed in the aqueous medium under the above experimental conditions. The formation of the different 1:1 and 1:2 binary complexes and 1:1:1 ternary complexes are inferred from the corresponding potentiometric pH-metric titration curves. The ternary complex formation was found to occur in a stepwise manner. The stability constants of these binary and ternary systems were calculated. The values of Δ log K, percentage of relative stabilization (%R.S. and log X were evaluated and discussed. The concentration distribution of the various complex species formed in solution was evaluated and discussed. The mode of chelation of ternary complexes formed was ascertained by conductivity measurements.

Oxidation reduces the fibrillation but not the neurotoxicity of the prion peptide PrP106-126

DEFF Research Database (Denmark)

Bergstrøm, Linda Alice; Chabry, J.; Bastholm, L.

2007-01-01

There is increasing evidence that soluble oligomers of misfolded protein may play a role in the pathogenesis of protein misfolding diseases including the transmissible spongiform encephalopathies (TSE) where the protein involved is the prion protein, PrP. The effect of oxidation on fibrillation...... tendency and neurotoxicity of different molecular variants of the prion peptide PrP106-126 was investigated. It was found that methionine oxidation significantly reduced amyloid fibril formation and proteinase K resistance, but it did not reduce (but rather increase slightly) the neurotoxicity...

Delayed Neurotoxicity Associated with Therapy for Children with Acute Lymphoblastic Leukemia

Science.gov (United States)

Cole, Peter D.; Kamen, Barton A.

2006-01-01

Most children diagnosed today with acute lymphoblastic leukemia (ALL) will be cured. However, treatment entails risk of neurotoxicity, causing deficits in neurocognitive function that can persist in the years after treatment is completed. Many of the components of leukemia therapy can contribute to adverse neurologic sequelae, including…

Non-linear dose-response of aluminium hydroxide adjuvant particles: Selective low dose neurotoxicity

International Nuclear Information System (INIS)

Crépeaux, Guillemette; Eidi, Housam; David, Marie-Odile; Baba-Amer, Yasmine; Tzavara, Eleni; Giros, Bruno; Authier, François-Jérôme; Exley, Christopher; Shaw, Christopher A.; Cadusseau, Josette

2017-01-01

Aluminium (Al) oxyhydroxide (Alhydrogel ® ), the main adjuvant licensed for human and animal vaccines, consists of primary nanoparticles that spontaneously agglomerate. Concerns about its safety emerged following recognition of its unexpectedly long-lasting biopersistence within immune cells in some individuals, and reports of chronic fatigue syndrome, cognitive dysfunction, myalgia, dysautonomia and autoimmune/inflammatory features temporally linked to multiple Al-containing vaccine administrations. Mouse experiments have documented its capture and slow transportation by monocyte-lineage cells from the injected muscle to lymphoid organs and eventually the brain. The present study aimed at evaluating mouse brain function and Al concentration 180 days after injection of various doses of Alhydrogel ® (200, 400 and 800 μg Al/kg of body weight) in the tibialis anterior muscle in adult female CD1 mice. Cognitive and motor performances were assessed by 8 validated tests, microglial activation by Iba-1 immunohistochemistry, and Al level by graphite furnace atomic absorption spectroscopy. An unusual neuro-toxicological pattern limited to a low dose of Alhydrogel ® was observed. Neurobehavioural changes, including decreased activity levels and altered anxiety-like behaviour, were observed compared to controls in animals exposed to 200 μg Al/kg but not at 400 and 800 μg Al/kg. Consistently, microglial number appeared increased in the ventral forebrain of the 200 μg Al/kg group. Cerebral Al levels were selectively increased in animals exposed to the lowest dose, while muscle granulomas had almost Completely disappeared at 6 months in these animals. We conclude that Alhydrogel ® injected at low dose in mouse muscle may selectively induce long-term Al cerebral accumulation and neurotoxic effects. To explain this unexpected result, an avenue that could be explored in the future relates to the adjuvant size since the injected suspensions corresponding to the lowest dose

Age-dependent pattern of cerebellar susceptibility to bilirubin neurotoxicity in vivo in mice

Science.gov (United States)

Bortolussi, Giulia; Baj, Gabriele; Vodret, Simone; Viviani, Giulia; Bittolo, Tamara; Muro, Andrés F.

2014-01-01

Neonatal jaundice is caused by high levels of unconjugated bilirubin. It is usually a temporary condition caused by delayed induction of UGT1A1, which conjugates bilirubin in the liver. To reduce bilirubin levels, affected babies are exposed to phototherapy (PT), which converts toxic bilirubin into water-soluble photoisomers that are readily excreted out. However, in some cases uncontrolled hyperbilirubinemia leads to neurotoxicity. To study the mechanisms of bilirubin-induced neurological damage (BIND) in vivo, we generated a mouse model lacking the Ugt1a1 protein and, consequently, mutant mice developed jaundice as early as 36 hours after birth. The mutation was transferred into two genetic backgrounds (C57BL/6 and FVB/NJ). We exposed mutant mice to PT for different periods and analyzed the resulting phenotypes from the molecular, histological and behavioral points of view. Severity of BIND was associated with genetic background, with 50% survival of C57BL/6‑Ugt1−/− mutant mice at postnatal day 5 (P5), and of FVB/NJ-Ugt1−/− mice at P11. Life-long exposure to PT prevented cerebellar architecture alterations and rescued neuronal damage in FVB/NJ-Ugt1−/− but not in C57BL/6-Ugt1−/− mice. Survival of FVB/NJ-Ugt1−/− mice was directly related to the extent of PT treatment. PT treatment of FVB/NJ-Ugt1−/− mice from P0 to P8 did not prevent bilirubin-induced reduction in dendritic arborization and spine density of Purkinje cells. Moreover, PT treatment from P8 to P20 did not rescue BIND accumulated up to P8. However, PT treatment administered in the time-window P0–P15 was sufficient to obtain full rescue of cerebellar damage and motor impairment in FVB/NJ-Ugt1−/− mice. The possibility to modulate the severity of the phenotype by PT makes FVB/NJ-Ugt1−/− mice an excellent and versatile model to study bilirubin neurotoxicity, the role of modifier genes, alternative therapies and cerebellar development during high bilirubin conditions. PMID

Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy

Science.gov (United States)

Kramer, Rita; Bielawski, Jacek; Kistner-Griffin, Emily; Othman, Alaa; Alecu, Irina; Ernst, Daniela; Kornhauser, Drew; Hornemann, Thorsten; Spassieva, Stefka

2015-01-01

Peripheral neuropathy is a major dose-limiting side effect of paclitaxel and cisplatin chemotherapy. In the current study, we tested the involvement of a novel class of neurotoxic sphingolipids, the 1-deoxysphingolipids. 1-Deoxysphingolipids are produced when the enzyme serine palmitoyltransferase uses l-alanine instead of l-serine as its amino acid substrate. We tested whether treatment of cells with paclitaxel (250 nM, 1 µM) and cisplatin (250 nM, 1 µM) would result in elevated cellular levels of 1-deoxysphingolipids. Our results revealed that paclitaxel, but not cisplatin treatment, caused a dose-dependent elevation of 1-deoxysphingolipids levels and an increase in the message and activity of serine palmitoyltransferase (P peripheral neuropathy symptoms [evaluated by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-chemotherapy-induced peripheral neuropathy-20 (CIPN20) instrument] and the 1-deoxysphingolipid plasma levels (measured by mass spectrometry) in 27 patients with breast cancer who were treated with paclitaxel chemotherapy. Our results showed that there was an association between the incidence and severity of neuropathy and the levels of very-long-chain 1-deoxyceramides such as C24 (P neuropathy (P peripheral neuropathy.—Kramer, R., Bielawski, J., Kistner-Griffin, E., Othman, A., Alecu, I., Ernst, D., Kornhauser, D., Hornemann, T., Spassieva, S. Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy. PMID:26198449

Morita-Baylis-Hillman Route to Dimethyl 2,3-Dihydrobenzo[b]oxepine-2,4- dicarboxylates and Methyl 2-(2-Carbomethoxybenzo[b]furan-3-yl)propanoates from Salicylaldehydes

Energy Technology Data Exchange (ETDEWEB)

Ahn, Sang Hyun; Jang, Seung Soon; Kim, Young Keun; Lee, Kee Jung [Hanyang University, Seoul (Korea, Republic of)

2012-01-15

A new synthetic method for dimethyl 2,3-dihydrobenzo[b]oxepine-2,4-dicarboxylates and methyl 2-(2- carbomethoxybenzo[b]furan-3-yl)propanoates by an intramolecular conjugate displacement reaction or an S{sub N}2 reaction of acetates of Morita-Baylis-Hillman adducts of methyl (2-formylphenoxy)acetates has been described.

The Protective Effects of Nigella sativa and Its Constituents on Induced Neurotoxicity

Directory of Open Access Journals (Sweden)

Mohammad Reza Khazdair

2015-01-01

Full Text Available Nigella sativa (N. sativa is an annual plant and widely used as medicinal plant throughout the world. The seeds of the plant have been used traditionally in various disorders and as a spice to ranges of Persian foods. N. sativa has therapeutic effects on tracheal responsiveness (TR and lung inflammation on induced toxicity by Sulfur mustard. N. sativa has been widely used in treatment of various nervous system disorders such as Alzheimer disease, epilepsy, and neurotoxicity. Most of the therapeutic properties of this plant are due to the presence of some phenolic compounds especially thymoquinone (TQ, which is major bioactive component of the essential oil. The present review is an effort to provide a comprehensive study of the literature on scientific researches of pharmacological activities of the seeds of this plant on induced neurotoxicity.

Rational design and enantioselective synthesis of (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid - a novel inhibitor at human glutamate transporter subtypes 1, 2, and 3

DEFF Research Database (Denmark)

Bunch, Lennart; Nielsen, Birgitte; Jensen, Anders A.

2006-01-01

The natural product kainic acid is used as template for the rational design of a novel conformationally restricted (S)-glutamic acid (Glu) analogue, (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid (1a). The target structure 1a was synthesized from commercially available (S)-pyroglut......The natural product kainic acid is used as template for the rational design of a novel conformationally restricted (S)-glutamic acid (Glu) analogue, (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid (1a). The target structure 1a was synthesized from commercially available (S...

Carcinogenic and neurotoxic risks of acrylamide consumed through caffeinated beverages among the lebanese population.

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El-Zakhem Naous, Ghada; Merhi, Areej; Abboud, Martine I; Mroueh, Mohamad; Taleb, Robin I

2018-06-06

The present study aims to quantify acrylamide in caffeinated beverages including American coffee, Lebanese coffee, espresso, instant coffee and hot chocolate, and to determine their carcinogenic and neurotoxic risks. A survey was carried for this purpose whereby 78% of the Lebanese population was found to consume at least one type of caffeinated beverages. Gas Chromatography Mass Spectrometry analysis revealed that the average acrylamide level in caffeinated beverages is 29,176 μg/kg sample. The daily consumption of acrylamide from Lebanese coffee (10.9 μg/kg-bw/day), hot chocolate (1.2 μg/kg-bw/day) and Espresso (7.4 μg/kg-bw/day) was found to be higher than the risk intake for carcinogenicity and neurotoxicity as set by World Health Organization (WHO; 0.3-2 μg/kg-bw/day) at both the mean (average consumers) and high (high consumers) dietary exposures. On the other hand, American coffee (0.37 μg/kg-bw/day) was shown to pose no carcinogenic or neurotoxic risks among the Lebanese community for consumers with a mean dietary exposure. The study shows alarming results that call for regulating the caffeinated product industry by setting legislations and standard protocols for product preparation in order to limit the acrylamide content and protect consumers. In order to avoid carcinogenic and neurotoxic risks, we propose that WHO/FAO set acrylamide levels in caffeinated beverages to 7000 μg acrylamide/kg sample, a value which is 4-folds lower than the average acrylamide levels of 29,176 μg/kg sample found in caffeinated beverages sold in the Lebanese market. Alternatively, consumers of caffeinated products, especially Lebanese coffee and espresso, would have to lower their daily consumption to 0.3-0.4 cups/day. Copyright © 2018 Elsevier Ltd. All rights reserved.

An autophagic mechanism is involved in the 6-hydroxydopamine-induced neurotoxicity in vivo.

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He, Xin; Yuan, Wei; Li, Zijian; Feng, Juan

2017-10-05

6-hydroxydopamine (6-OHDA) is one of the most common agents for modeling dopaminergic neuron degeneration in Parkinson's disease (PD). So far, the role of autophagy in 6-OHDA-induced neurotoxicity remains controversial and most evidence is collected from in vitro studies. In this study, we determined the role of autophagy activation in 6-OHDA-induced neurotoxicity in a rat model of PD. Following 6-OHDA treatment, we observed a concomitant activation of autophagy and apoptosis. To further explore the interaction between autophagy and apoptosis induced by 6-OHDA, autophagy inhibitor 3-methylademine (3-MA) or cysteine protease inhibitor Z-FA-fmk was applied. We found that both 3-MA and Z-FA-fmk could not only exert immediate protection against 6-OHDA-induced neuronal apoptosis, but also prevent dopaminergic neuron loss in the long-term, which was related to reduced autophagosome formation. Furthermore, by monitoring the sequential changes of mTOR-related signaling pathways, we found that reactive oxygen species (ROS)-mediated AKT/AMPK-mTOR signaling pathway participated in but was not the initial cause of autophagy activation by 6-OHDA. Collectively, our data suggest that 6-OHDA-induced autophagy activation contributes to its neurotoxicity and targeting autophagy activation or cysteine proteases could be promising for developing neuroprotective agents for PD. Copyright © 2017 Elsevier B.V. All rights reserved.

Bilirubin-Induced Neurotoxicity in the Preterm Neonate.

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Watchko, Jon F

2016-06-01

Bilirubin-induced neurotoxicity in preterm neonates remains a clinical concern. Multiple cellular and molecular cascades likely underlie bilirubin-induced neuronal injury, including plasma membrane perturbations, excitotoxicity, neuroinflammation, oxidative stress, and cell cycle arrest. Preterm newborns are particularly vulnerable secondary to central nervous system immaturity and concurrent adverse clinical conditions that may potentiate bilirubin toxicity. Acute bilirubin encephalopathy in preterm neonates may be subtle and manifest primarily as recurrent symptomatic apneic events. Low-bilirubin kernicterus continues to be reported in preterm neonates, and although multifactorial in nature, is often associated with marked hypoalbuminemia. Copyright © 2016 Elsevier Inc. All rights reserved.

Caffeine Augments Anesthesia Neurotoxicity in the Fetal Macaque Brain.

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Noguchi, Kevin K; Johnson, Stephen A; Manzella, Francesca M; Masuoka, Kobe L; Williams, Sasha L; Martin, Lauren D; Dissen, Gregory A; Ikonomidou, Chrysanthy; Schenning, Katie J; Olney, John W; Brambrink, Ansgar M

2018-03-28

Caffeine is the most frequently used medication in premature infants. It is the respiratory stimulant of choice for apnea associated with prematurity and has been called the silver bullet in neonatology because of many proven benefits and few known risks. Research has revealed that sedative/anesthetic drugs trigger apoptotic death of neurons and oligodendrocytes in developing mammalian brains. Here we evaluated the influence of caffeine on the neurotoxicity of anesthesia in developing nonhuman primate brains. Fetal macaques (n = 7-8/group), at a neurodevelopmental age comparable to premature human infants, were exposed in utero for 5 hours to no drug (control), isoflurane, or isoflurane + caffeine and examined for evidence of apoptosis. Isoflurane exposure increased apoptosis 3.3 fold for neurons and 3.4 fold for oligodendrocytes compared to control brains. Isoflurane + caffeine caused neuronal apoptosis to increase 8.0 fold compared to control levels but did not augment oligoapoptosis. Neuronal death was particularly pronounced in the basal ganglia and cerebellum. Higher blood levels of caffeine within the range considered therapeutic and safe for human infants correlated with increased neuroapoptosis. Caffeine markedly augments neurotoxicity of isoflurane in the fetal macaque brain and challenges the assumption that caffeine is safe for premature infants.

Recombinant AAV8-mediated intrastriatal gene delivery of CDNF protects rats against methamphetamine neurotoxicity

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Wang, Lizheng; Wang, Zixuan; Xu, Xiaoyu; Zhu, Rui; Bi, Jinpeng; Liu, Wenmo; Feng, Xinyao; Wu, Hui; Zhang, Haihong; Wu, Jiaxin; Kong, Wei; Yu, Bin; Yu, Xianghui

2017-01-01

Methamphetamine (METH) exerts significant neurotoxicity in experimental animals and humans when taken at high doses or abused chronically. Long-term abusers have decreased dopamine levels, and they are more likely to develop Parkinson's disease (PD). To date, few medications are available to treat the METH-induced damage of neurons. Glial cell line-derived neurotrophic factor (GDNF) has been previously shown to reduce the dopamine-depleting effects of neurotoxic doses of METH. However, the effect of cerebral dopamine neurotrophic factor (CDNF), which has been reported to be more specific and efficient than GDNF in protecting dopaminergic neurons against 6-OHDA toxicity, in attenuating METH neurotoxicity has not been determined. Thus, the present study aimed to evaluate the neuroprotective effect of CDNF against METH-induced damage to the dopaminergic system in vitro and in vivo. In vitro, CDNF protein increased the survival rate and reduced the tyrosine hydroxylase (TH) loss of METH-treated PC12 cells. In vivo, METH was administered to rats following human CDNF overexpression mediated by the recombinant adeno-associated virus. Results demonstrated that CDNF overexpression in the brain could attenuate the METH-induced dopamine and TH loss in the striatum but could not lower METH-induced hyperthermia. PMID:28553166

Alternative plasticizer, 4-cyclohexene-1,2-dicarboxylic acid dinonyl ester, for blood containers with protective effects on red blood cells and improved cold resistance.

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Morishita, Yuki; Nomura, Yusuke; Fukui, Chie; Fujisawa, Ayano; Watanabe, Kayo; Fujimaki, Hideo; Kumada, Hidefumi; Inoue, Kaoru; Morikawa, Tomomi; Takahashi, Miwa; Kawakami, Tsuyoshi; Sakoda, Hideyuki; Mukai, Tomokazu; Yuba, Toshiyasu; Inamura, Ken-Ichi; Tanoue, Akito; Miyazaki, Ken-Ichi; Chung, Ung-Il; Ogawa, Kumiko; Yoshida, Midori; Haishima, Yuji

2018-04-01

Di (2-ethylhexyl) phthalate (DEHP), a typical plasticizer used for polyvinyl chloride (PVC), is eluted from PVC-made blood containers and protects against red blood cell (RBC) hemolysis. However, concerns have arisen regarding the reproductive and developmental risks of DEHP in humans, and the use of alternative plasticizers for medical devices has been recommended worldwide. In this study, we propose that the use of a novel plasticizer, 4-cyclohexene-1,2-dicarboxylic acid dinonyl ester (DL9TH), could help produce more useful and safe blood containers. PVC sheet containing DL9TH and di (2-ethylhexyl) 4-cyclohexene-1,2-dicarboxylate (DOTH) provides comparable or superior protective effects to RBCs relative to PVC sheet containing DEHP or di-isononyl-cyclohexane-1,2-dicarboxylate (DINCH ® , an alternative plasticizer that has been used in PVC sheets for blood containers). The total amount of plasticizer eluted from DOTH/DL9TH-PVC sheets is nearly the same as that eluted from DEHP-PVC sheets. In addition, DOTH/DL9TH-PVC has better cold resistance than DEHP- and DINCH ® -PVC sheets. In vitro and in vivo tests for biological safety based on International Organization for Standardization guidelines (10993 series) suggest that the DOTH/DL9TH-PVC sheet can be used safely. Subchronic toxicity testing of DL9TH in male rats in accordance with the principles of Organisation for Economic Co-operation and Development Test Guideline 408 showed that DL9TH did not induce adverse effects up to the highest dose level tested (717 mg/kg body weight/day). There were no effects on testicular histopathology and sperm counts, and no indications of endocrine effects: testosterone, thyroid-stimulating hormone, follicle-stimulating hormone, and 17β-estradiol were unchanged by the treatment, compared with the control group. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1052-1063, 2018. © 2017 Wiley Periodicals, Inc.

Neurotoxicity from prenatal and postnatal exposure to methylmercury

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Grandjean, Philippe; Weihe, Pal; Debes, Frodi

2014-01-01

exposure appeared to contribute to neurotoxic effects, in particular in regard to visuospatial processing and memory. Thus, addition in the regression analysis of exposure information obtained at a different point in time was not informative and should be avoided. Further studies with better information......, but visuospatial memory revealed a significant negative association. Mutual adjustment caused decreases of the apparent effect of the prenatal exposure. However, such adjustment may lead to underestimations due to the presence of correlated, error-prone exposure variables. In structural equation models, all...

Manganese: Recent advances in understanding its transport and neurotoxicity

International Nuclear Information System (INIS)

Aschner, Michael; Guilarte, Tomas R.; Schneider, Jay S.; Zheng Wei

2007-01-01

The present review is based on presentations from the meeting of the Society of Toxicology in San Diego, CA (March 2006). It addresses recent developments in the understanding of the transport of manganese (Mn) into the central nervous system (CNS), as well as brain imaging and neurocognitive studies in non-human primates aimed at improving our understanding of the mechanisms of Mn neurotoxicity. Finally, we discuss potential therapeutic modalities for treating Mn intoxication in humans

Effects of salicylate on 3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity in rats.

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Yeh, S Y

1997-11-01

The drug 3,4-methylenedioxymethamphetamine (MDMA) is a serotonergic neurotoxicant that causes hyperthermia and depletion of serotonin (5-HT) and 5-hydroxy-indole-3-acetic acid (5-HIAA) in the central nervous system. Formation of neurotoxic metabolites of MDMA, e.g., 2,4,5-trihydroxy-methamphetamine and 2,4,5-trihydroxyamphetamine, involves hydroxyl and/or superoxide free radicals. The present study was designed to determine whether the hydroxyl free-radical-trapping agent salicylate could provide protection against MDMA neurotoxicity in rats. In the acute studies, sodium salicylate (12.5-400 mg/kg, calculated as free acid) was injected interperitoneally (i.p.) 1 h before subcutaneous (s.c.) injections of MDMA (20 mg/kg as base). In the chronic studies, sodium salicylate (3.1-100 mg/kg) was injected i.p. 1 h before repeated s.c. injections of MDMA (10 mg/kg as base, twice daily, at 0830 and 1730 h for 4 consecutive days). Repeated MDMA administration depleted contents of 5-HT and 5-HIAA in the frontal cortex, hippocampus and striatum. Coadministration of salicylate plus MDMA did not significantly alter MDMA-induced depletion of 5-HT and 5-HIAA in these tissues. Thus, salicylate, a hydroxyl free-radical-trapping agent, does not protect against MDMA-induced hyperthermia and depletion of 5-HT and 5-HIAA. These observations suggest that MDMA-induced neurotoxicity may occur mainly through the production of superoxide or other radicals rather than hydroxyl free radicals. Salicylate actually potentiated MDMA-induced hyperthermia and lethality, findings that might be of clinical relevance.

A systems biology approach to predictive developmental neurotoxicity of a larvicide used in the prevention of Zika virus transmission

DEFF Research Database (Denmark)

Audouze, Karine; Taboureau, Olivier; Grandjean, Philippe

2018-01-01

The need to prevent developmental brain disorders has led to an increased interest in efficient neurotoxicity testing. When an epidemic of microcephaly occurred in Brazil, Zika virus infection was soon identified as the likely culprit. However, the pathogenesis appeared to be complex, and a larvi......The need to prevent developmental brain disorders has led to an increased interest in efficient neurotoxicity testing. When an epidemic of microcephaly occurred in Brazil, Zika virus infection was soon identified as the likely culprit. However, the pathogenesis appeared to be complex...... the potential developmental neurotoxicity, and we applied this method to examine the larvicide pyriproxyfen widely used in the prevention of Zika virus transmission. Our computational model covered a wide range of possible pathways providing mechanistic hypotheses between pyriproxyfen and neurological disorders...

Methylmercury and brain development: imprecision and underestimation of developmental neurotoxicity in humans

DEFF Research Database (Denmark)

Grandjean, Philippe; Herz, Katherine T

2011-01-01

Methylmercury is now recognized as an important developmental neurotoxicant, though this insight developed slowly over many decades. Developmental neurotoxicity was first reported in a Swedish case report in 1952, and from a serious outbreak in Minamata, Japan, a few years later. Whereas the infant...

Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds

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Voorhees, Jaymie R.; Rohlman, Diane S.; Lein, Pamela J.; Pieper, Andrew A.

2017-01-01

Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people. For example, multiple epidemiological studies have identified associations between occupational OP exposure and neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Rigorous scientific investigation of the basic science mechanisms underlying these epidemiological findings requires valid preclinical models in which tightly-regulated exposure paradigms can be correlated with neurotoxicity. Here, we review the experimental models of occupational OP exposure currently used in the field. We found that animal studies simulating occupational OP exposures do indeed show evidence of neurotoxicity, and that utilization of these models is helping illuminate the mechanisms underlying OP-induced neurological sequelae. Still, further work is necessary to evaluate exposure levels, protection methods, and treatment strategies, which taken together could serve to modify guidelines for improving workplace conditions globally. PMID:28149268

A one-dimensional ladder-like coordination polymer: poly[[hexa-aqua-bis(μ-5-nitro-benzene-1,3-dicarboxyl-ato-κO,O',O'')(μ-oxalato-κO,O':O'',O''')diyttrium(III)] trihydrate].

Science.gov (United States)

Fu, Zhong; Lin, Ying; Zhou, Yun-You; Zhang, Hong-Tao

2007-12-06

In the crystal structure of the title one-dimensional coordination polymer, [Y(2)(C(8)H(3)NO(6))(2)(C(2)O(4))(H(2)O)(6)]·3H(2)O, each Y(III) ion is bridged to its neighbours by two 5-nitro-benzene-1,3-dicarboxyl-ate (nbdc) dianions and one oxalate dianion (located on an inversion centre) to form a ladder-like polymeric structure. The two carboxylate groups of nbdc assume different modes of coordination, one is chelating whereas the other is monodentate. Three water mol-ecules coordinate to the Y(III) ion to complete an eight-coordinate distorted dodecahedral geometry. The ladder-like polymers are assembled together by hydrogen bonding and π-π stacking [centrio-centriod distance = 3.819 (9) Å] in the crystal structure.

Neurotoxicity of iodinated radiological contrast media

International Nuclear Information System (INIS)

Araujo Pinheiro, R.S. de

1988-01-01

We studied during the last ten years the neurotoxicity of artificial iodinated contrast media, with prospective clinical and experimental protocols. The experimental investigation in animals aimed to understand the relationship between the intracarotid injection, the subarachnoid application and the integrity of the blood-brain barrier function. The electro physiologic disturbances and the morphologic observation of pial circulation support the evidence that iodinated artificial contrast media induces significant alterations in brain metabolism and in the autoregulation of the blood flow of the encephalon. Even if many of such phenomena may not be apparent at the clinical level, we supposed that they are always present and that their clinical exteriorization is prevented by the immediate and effective action of homeostatic mechanisms. (author)

Vanadium induces dopaminergic neurotoxicity via protein kinase Cdelta dependent oxidative signaling mechanisms: Relevance to etiopathogenesis of Parkinson's disease

International Nuclear Information System (INIS)

Afeseh Ngwa, Hilary; Kanthasamy, Arthi; Anantharam, Vellareddy; Song, Chunjuan; Witte, Travis; Houk, Robert; Kanthasamy, Anumantha G.

2009-01-01

Environmental exposure to neurotoxic metals through various sources including exposure to welding fumes has been linked to an increased incidence of Parkinson's disease (PD). Welding fumes contain many different metals including vanadium typically present as particulates containing vanadium pentoxide (V 2 O 5 ). However, possible neurotoxic effects of this metal oxide on dopaminergic neuronal cells are not well studied. In the present study, we characterized vanadium-induced oxidative stress-dependent cellular events in cell culture models of PD. V 2 O 5 was neurotoxic to dopaminergic neuronal cells including primary nigral dopaminergic neurons and the EC 50 was determined to be 37 μM in N27 dopaminergic neuronal cell model. The neurotoxic effect was accompanied by a time-dependent uptake of vanadium and upregulation of metal transporter proteins Tf and DMT1 in N27 cells. Additionally, vanadium resulted in a threefold increase in reactive oxygen species generation, followed by release of mitochondrial cytochrome c into cytoplasm and subsequent activation of caspase-9 (> fourfold) and caspase-3 (> ninefold). Interestingly, vanadium exposure induced proteolytic cleavage of native protein kinase Cdelta (PKCδ, 72-74 kDa) to yield a 41 kDa catalytically active fragment resulting in a persistent increase in PKCδ kinase activity. Co-treatment with pan-caspase inhibitor Z-VAD-FMK significantly blocked vanadium-induced PKCδ proteolytic activation, indicating that caspases mediate PKCδ cleavage. Also, co-treatment with Z-VAD-FMK almost completely inhibited V 2 O 5 -induced DNA fragmentation. Furthermore, PKCδ knockdown using siRNA protected N27 cells from V 2 O 5 -induced apoptotic cell death. Collectively, these results demonstrate that vanadium can exert neurotoxic effects in dopaminergic neuronal cells via caspase-3-dependent PKCδ cleavage, suggesting that metal exposure may promote nigral dopaminergic degeneration.

Data set in support of neurotoxicity of trimethyltin chloride by morphological and protein analysis

Directory of Open Access Journals (Sweden)

C-Yoon Kim

2016-03-01

Full Text Available Trimethyltin chloride (TMT is a neurotoxicant widely present in the aquatic environment. Chronic exposure of embryos to TMT for 4 days post-fertilization (dpf elicited a concentration-related decrease in head & eye size and increase in axial malformation. In addition, Rohon-Beard sensory neurons and motor neurons showed decreased patterns of protein expression. These data coincide with previous research about the neurotoxicity of TMT on mRNA expression (Kim et al., 2016 [1]. These data demonstrates that TMT inhibits specific neurodevelopmental stages in zebrafish embryos and suggests a possible mechanism for the toxicity of TMT in vertebrate neurodevelopment. This paper contains data related to research concurrently published in Kim et al. (2016 [1]. Keywords: Trimethyltin chloride, Neurotoxicity, Zebrafish

Dopamine D(1) receptor deletion strongly reduces neurotoxic effects of methamphetamine.

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Ares-Santos, S; Granado, N; Oliva, I; O'Shea, E; Martin, E D; Colado, M I; Moratalla, R

2012-02-01

Methamphetamine (METH) is a potent, highly addictive psychostimulant consumed worldwide. In humans and experimental animals, repeated exposure to this drug induces persistent neurodegenerative changes. Damage occurs primarily to dopaminergic neurons, accompanied by gliosis. The toxic effects of METH involve excessive dopamine (DA) release, thus DA receptors are highly likely to play a role in this process. To define the role of D(1) receptors in the neurotoxic effects of METH we used D(1) receptor knock-out mice (D(1)R(-/-)) and their WT littermates. Inactivation of D(1)R prevented METH-induced dopamine fibre loss and hyperthermia, and increases in gliosis and pro-inflammatory molecules such as iNOS in the striatum. In addition, D(1)R inactivation prevented METH-induced loss of dopaminergic neurons in the substantia nigra. To explore the relationship between hyperthermia and neurotoxicity, METH was given at high ambient temperature (29 °C). In this condition, D(1)R(-/-) mice developed hyperthermia following drug delivery and the neuroprotection provided by D(1)R inactivation at 23 °C was no longer observed. However, reserpine, which empties vesicular dopamine stores, blocked hyperthermia and strongly potentiated dopamine toxicity in D(1)R(-/-) mice, suggesting that the protection afforded by D(1)R inactivation is due to both hypothermia and higher stored vesicular dopamine. Moreover, electrical stimulation evoked higher DA overflow in D(1)R(-/-) mice as demonstrated by fast scan cyclic voltammetry despite their lower basal DA content, suggesting higher vesicular DA content in D(1)R(-/-) than in WT mice. Altogether, these results indicate that the D(1)R plays a significant role in METH-induced neurotoxicity by mediating drug-induced hyperthermia and increasing the releasable cytosolic DA pool. Copyright © 2011. Published by Elsevier Inc.

Developmental neurotoxicity of different pesticides in PC-12 cells in vitro.

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Christen, Verena; Rusconi, Manuel; Crettaz, Pierre; Fent, Karl

2017-06-15

The detection of developmental neurotoxicity (DNT) of chemicals has high relevance for protection of human health. However, DNT of many pesticides is only little known. Furthermore, validated in vitro systems for assessment of DNT are not well established. Here we employed the rat phaeochromocytoma cell line PC-12 to evaluate DNT of 18 frequently used pesticides of different classes, including neonicotinoids, pyrethroids, organophosphates, organochlorines, as well as quaternary ammonium compounds, the organic compound used in pesticides, piperonyl butoxide, as well as the insect repellent diethyltoluamide (DEET). We determined the outgrowth of neurites in PC-12 cells co-treated with nerve growth factor and different concentrations of biocides for 5days. Furthermore, we determined transcriptional alterations of selected genes that may be associated with DNT, such as camk2α and camk2β, gap-43, neurofilament-h, tubulin-α and tubulin-β. Strong and dose- dependent inhibition of neurite outgrowth was induced by azamethiphos and chlorpyrifos, and dieldrin and heptachlor, which was correlated with up-regulation of gap-43. No or only weak effects on neurite outgrowth and transcriptional alterations occurred for neonicotinoids acetamiprid, clothianidin, imidacloprid and thiamethoxam, the pyrethroids λ-cyhalothrin, cyfluthrin, deltamethrin, and permethrin, the biocidal disinfectants C12-C14-alkyl(ethylbenzyl)dimethylammonium (BAC), benzalkonium chloride and barquat (dimethyl benzyl ammonium chloride), and piperonyl butoxide and DEET. Our study confirms potential developmental neurotoxicity of some pesticides and provides first evidence that azamethiphos has the potential to act as a developmental neurotoxic compound. We also demonstrate that inhibition of neurite outgrowth and transcriptional alterations of gap-43 expression correlate, which suggests the employment of gap-43 expression as a biomarker for detection and initial evaluation of potential DNT of chemicals

Neurotoxic effects of perfluoroalkylated compounds: mechanisms of action and environmental relevance.

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Mariussen, Espen

2012-09-01

Perfluoroalkylated compounds (PFCs) are used in fire-fighting foams, treatment of clothes, carpets and leather products, and as lubricants, pesticides, in paints and medicine. Recent developments in chemical analysis have revealed that fluorinated compounds have become ubiquitously spread and are regarded as a potential threats to the environment. Due to the carbon-fluorine bond, which has a very high bond strength, these chemicals are extremely persistent towards degradation and some PFCs have a potential for bioaccumulation in organisms. Of particular concern has been the developmental toxicity of PFOS and PFOA, which has been manifested in rodent studies as high mortality of prenatally exposed newborn rats and mice within 24 h after delivery. The nervous system appears to be one of the most sensitive targets of environmental contaminants. The serious developmental effects of PFCs have lead to the upcoming of studies that have investigated neurotoxic effects of these substances. In this review the major findings of the neurotoxicity of the main PFCs and their suggested mechanisms of action are presented. The neurotoxic effects are discussed in light of other toxic effects of PFCs to indicate the significance of PFCs as neurotoxicants. The main findings are that PFCs may induce neurobehavioral effects, particularly in developmentally exposed animals. The effects are, however, subtle and inconclusive and are often induced at concentrations where other toxic effects also are expected. Mechanistic studies have shown that PFCs may affect the thyroid system, influence the calcium homeostasis, protein kinase C, synaptic plasticity and cellular differentiation. Compared to other environmental toxicants the human blood levels of PFCs are high and of particular concern is that susceptible groups may be exposed to a cocktail of substances that in combination reach harmful concentrations.

Neuronal Nicotinic Receptors as New Targets for Amphetamine-Induced Oxidative Damage and Neurotoxicity

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Elena Escubedo

2011-06-01

Full Text Available Amphetamine derivatives such as methamphetamine (METH and 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy” are widely abused drugs in a recreational context. This has led to concern because of the evidence that they are neurotoxic in animal models and cognitive impairments have been described in heavy abusers. The main targets of these drugs are plasmalemmal and vesicular monoamine transporters, leading to reverse transport and increased monoamine efflux to the synapse. As far as neurotoxicity is concerned, increased reactive oxygen species (ROS production seems to be one of the main causes. Recent research has demonstrated that blockade of a7 nicotinic acetylcholine receptors (nAChR inhibits METH- and MDMA-induced ROS production in striatal synaptosomes which is dependent on calcium and on NO-synthase activation. Moreover, a7 nAChR antagonists (methyllycaconitine and memantine attenuated in vivo the neurotoxicity induced by METH and MDMA, and memantine prevented the cognitive impairment induced by these drugs. Radioligand binding experiments demonstrated that both drugs have affinity to a7 and heteromeric nAChR, with MDMA showing lower Ki values, while fluorescence calcium experiments indicated that MDMA behaves as a partial agonist on a7 and as an antagonist on heteromeric nAChR. Sustained Ca increase led to calpain and caspase-3 activation. In addition, modulatory effects of MDMA on a7 and heteromeric nAChR populations have been found.

Neuroprotection of Grape Seed Extract and Pyridoxine against Triton-Induced Neurotoxicity

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Heba M. Abdou

2016-01-01

Full Text Available Triton WR-1339 administration causes neurotoxicity. Natural products and herbal extracts can attenuate cerebral injury. In the present study, we investigated the neuroprotective role of grape seed extract and/or vitamin B6 against triton-induced neurotoxicity. Thirty-five adult male albino rats of the Sprague-Dawley strain, weighing 140–145 g, were divided into five groups: control, triton, grape seed extract + triton, grape seed extract + triton + vitamin B6, and vitamin B6 + triton. The hematological and biochemical analyses were carried out. Alteration in iNOS mRNA gene expression was determined using reverse-transcriptase PCR analysis. In addition, qualitative DNA fragmentation was examined using agarose gel electrophoresis. Triton-treatment caused significant disturbances in the hematological parameters, the neurological functions, and the antioxidant profile. Also, triton significantly increased the iNOS mRNA expression and DNA damage. Our results showed that grape seed extract and/or vitamin B6 could attenuate all the examined parameters. These natural substances could exhibit protective effects against triton-induced neurological damage because of their antioxidative and antiapoptotic capacities.

Assessment of Styrene Oxide Neurotoxicity Using In Vitro Auditory Cortex Networks

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Gopal, Kamakshi V.; Wu, Calvin; Moore, Ernest J.; Gross, Guenter W.

2011-01-01

Styrene oxide (SO) (C8H8O), the major metabolite of styrene (C6H5CH=CH2), is widely used in industrial applications. Styrene and SO are neurotoxic and cause damaging effects on the auditory system. However, little is known about their concentration-dependent electrophysiological and morphological effects. We used spontaneously active auditory cortex networks (ACNs) growing on microelectrode arrays (MEA) to characterize neurotoxic effects of SO. Acute application of 0.1 to 3.0 mM SO showed concentration-dependent inhibition of spike activity with no noticeable morphological changes. The spike rate IC50 (concentration inducing 50% inhibition) was 511 ± 60 μM (n = 10). Subchronic (5 hr) single applications of 0.5 mM SO also showed 50% activity reduction with no overt changes in morphology. The results imply that electrophysiological toxicity precedes cytotoxicity. Five-hour exposures to 2 mM SO revealed neuronal death, irreversible activity loss, and pronounced glial swelling. Paradoxical “protection” by 40 μM bicuculline suggests binding of SO to GABA receptors. PMID:23724250

Correlation of tissue concentrations of the pyrethroid bifenthrin with neurotoxicity in the rat

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Pyrethroids are neurotoxic insecticides used in a variety of agricultural and household products. Due to the phase-out oforganophosphate pesticides, the use of pyrethroids has increased. The potential for human exposure to pyrethroids has prompted pharmacodynamic and pharmacokine...

CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity

NARCIS (Netherlands)

A.J.M. de Graan (Anne-Joy); L. Elens (Laure); J.A. Sprowl (Jason); A. Sparreboom (Alex); L.E. Friberg (Lena); B. van der Holt (Bronno); P.J. de Raaf (Pleun); P. de Bruijn (Peter); F.K. Engels (Frederike); F.A.L.M. Eskens (Ferry); E.A.C. Wiemer (Erik); J. Verweij (Jaap); A.H.J. Mathijssen (Ron); R.H.N. van Schaik (Ron)

2013-01-01

textabstractPurpose: Paclitaxel is used for the treatment of several solid tumors and displays a high interindividual variation in exposure and toxicity. Neurotoxicity is one of the most prominent side effects of paclitaxel. This study explores potential predictive pharmacokinetic and

Prophylactic Neuroprotection of Total Glucosides of Paeoniae Radix Alba against Semen Strychni-Induced Neurotoxicity in Rats: Suppressing Oxidative Stress and Reducing the Absorption of Toxic Components.

Science.gov (United States)

Li, Shujuan; Chu, Yanjie; Zhang, Ruowen; Sun, Linjia; Chen, Xiaohui

2018-04-20

Strychnos alkaloids (SAs) are the main toxic constituents in Semen Strychni, a traditional Chinese medicine, which is known for its fatal neurotoxicity. Hence, the present study was carried out to evaluate the neurotoxicity induced by SAs and the pre-protective effects of the total glucosides of Paeoniae Radix Alba (TGP). An SA brain damage model was firstly established. The neurotoxicity induced by SAs and the pre-protective effects of TGP were confirmed by physical and behavioral testing, biochemical assay, and histological examination. Then, a liquid chromatography-tandem mass spectrometry method was developed and validated to investigate the time-course change and distribution of strychnine and brucine (two main SAs) in the brain after oral SA administration with or without TGP pretreatment. Biochemical analysis results indicated that TGP could ameliorate the oxidative stress status caused by SAs. Time-course change and distribution studies demonstrated that strychnine and brucine were rapidly absorbed into the brain, peaked early at 0.5 h, and were mainly located in the hippocampus and cerebellum. TGP showed a pre-protective effect against neurotoxicity by reducing the absorption of toxic alkaloids into the brain. These findings could provide beneficial information in facilitating future studies of Semen Strychni neurotoxicity and developing herbal medicines to alleviate neurotoxicity in the clinic.

Prophylactic Neuroprotection of Total Glucosides of Paeoniae Radix Alba against Semen Strychni-Induced Neurotoxicity in Rats: Suppressing Oxidative Stress and Reducing the Absorption of Toxic Components

Directory of Open Access Journals (Sweden)

Shujuan Li

2018-04-01

Full Text Available Strychnos alkaloids (SAs are the main toxic constituents in Semen Strychni, a traditional Chinese medicine, which is known for its fatal neurotoxicity. Hence, the present study was carried out to evaluate the neurotoxicity induced by SAs and the pre-protective effects of the total glucosides of Paeoniae Radix Alba (TGP. An SA brain damage model was firstly established. The neurotoxicity induced by SAs and the pre-protective effects of TGP were confirmed by physical and behavioral testing, biochemical assay, and histological examination. Then, a liquid chromatography-tandem mass spectrometry method was developed and validated to investigate the time-course change and distribution of strychnine and brucine (two main SAs in the brain after oral SA administration with or without TGP pretreatment. Biochemical analysis results indicated that TGP could ameliorate the oxidative stress status caused by SAs. Time-course change and distribution studies demonstrated that strychnine and brucine were rapidly absorbed into the brain, peaked early at 0.5 h, and were mainly located in the hippocampus and cerebellum. TGP showed a pre-protective effect against neurotoxicity by reducing the absorption of toxic alkaloids into the brain. These findings could provide beneficial information in facilitating future studies of Semen Strychni neurotoxicity and developing herbal medicines to alleviate neurotoxicity in the clinic.

Mercury-induced motor and sensory neurotoxicity: systematic review of workers currently exposed to mercury vapor.

Science.gov (United States)

Fields, Cheryl A; Borak, Jonathan; Louis, Elan D

2017-11-01

The neurotoxicity of elemental mercury (Hg 0 ) is well-recognized, but it is uncertain whether and for how long neurotoxicity persists; among studies that evaluated previously exposed workers, only one examined workers during and also years after exposure ceased. The aim of this review is to document the type, frequency, and dose-relatedness of objective neurological effects in currently exposed mercury workers and thereby provide first approximations of the effects one would have expected in previously exposed workers evaluated during exposure. We systematically reviewed studies of neurotoxicity in currently exposed mercury workers identified by searching MEDLINE (1950-2015), government reports, textbook chapters, and references cited therein; dental cohorts were not included. Outcomes on physical examination (PE), neurobehavioral (NB) tests, and electrophysiological studies were extracted and evaluated for consistency and dose-relatedness. Forty-five eligible studies were identified, comprising over 3000 workers chronically exposed to a range of Hg 0 concentrations (0.002-1.7 mg/m 3 ). Effects that demonstrated consistency across studies and increased frequency across urine mercury levels (200 μg/L, while NB testing is more appropriate for those with lower U Hg levels. They also provide benchmarks to which findings in workers with historical exposure can be compared.

Ruthenium water oxidation catalysts containing the non-planar tetradentate ligand, biisoquinoline dicarboxylic acid (biqaH2).

Science.gov (United States)

Scherrer, Dominik; Schilling, Mauro; Luber, Sandra; Fox, Thomas; Spingler, Bernhard; Alberto, Roger; Richmond, Craig J

2016-12-06

Two ruthenium complexes containing the tetradentate ligand [1,1'-biisoquinoline]-3,3'-dicarboxylic acid, and 4-picoline or 6-bromoisoquinoline as axial ligands have been prepared. The complexes have been fully characterised and initial studies on their potential to function as molecular water oxidation catalysts have been performed. Both complexes catalyse the oxidation of water in acidic media with Ce IV as a stoichiometric chemical oxidant, although turnover numbers and turnover frequencies are modest when compared with the closely related Ru-bda and Ru-pda analogues. Barriers for the water nucleophilic attack and intermolecular coupling pathways were obtained from density functional theory calculations and the crucial influence of the ligand framework in determining the most favourable reaction pathway was elucidated from a combined analysis of the theoretical and experimental results.

Non-Serotonergic Neurotoxicity by MDMA (Ecstasy in Neurons Derived from Mouse P19 Embryonal Carcinoma Cells.

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Dina Popova

Full Text Available 3,4-methylenedioxymethamphetamine (MDMA; ecstasy is a commonly abused recreational drug that causes neurotoxic effects in both humans and animals. The mechanism behind MDMA-induced neurotoxicity is suggested to be species-dependent and needs to be further investigated on the cellular level. In this study, the effects of MDMA in neuronally differentiated P19 mouse embryonal carcinoma cells have been examined. MDMA produces a concentration-, time- and temperature-dependent toxicity in differentiated P19 neurons, as measured by intracellular MTT reduction and extracellular LDH activity assays. The P19-derived neurons express both the serotonin reuptake transporter (SERT, that is functionally active, and the serotonin metabolizing enzyme monoamine oxidase A (MAO-A. The involvement of these proteins in the MDMA-induced toxicity was investigated by a pharmacological approach. The MAO inhibitors clorgyline and deprenyl, and the SERT inhibitor fluoxetine, per se or in combination, were not able to mimic the toxic effects of MDMA in the P19-derived neurons or block the MDMA-induced cell toxicity. Oxidative stress has been implicated in MDMA-induced neurotoxicity, but pre-treatment with the antioxidants α-tocopherol or N-acetylcysteine did not reveal any protective effects in the P19 neurons. Involvement of mitochondria in the MDMA-induced cytotoxicity was also examined, but MDMA did not alter the mitochondrial membrane potential (ΔΨm in the P19 neurons. We conclude that MDMA produce a concentration-, time- and temperature-dependent neurotoxicity and our results suggest that the mechanism behind MDMA-induced toxicity in mouse-derived neurons do not involve the serotonergic system, oxidative stress or mitochondrial dysfunction.

Non-Serotonergic Neurotoxicity by MDMA (Ecstasy) in Neurons Derived from Mouse P19 Embryonal Carcinoma Cells.

Science.gov (United States)

Popova, Dina; Forsblad, Andréas; Hashemian, Sanaz; Jacobsson, Stig O P

2016-01-01

3,4-methylenedioxymethamphetamine (MDMA; ecstasy) is a commonly abused recreational drug that causes neurotoxic effects in both humans and animals. The mechanism behind MDMA-induced neurotoxicity is suggested to be species-dependent and needs to be further investigated on the cellular level. In this study, the effects of MDMA in neuronally differentiated P19 mouse embryonal carcinoma cells have been examined. MDMA produces a concentration-, time- and temperature-dependent toxicity in differentiated P19 neurons, as measured by intracellular MTT reduction and extracellular LDH activity assays. The P19-derived neurons express both the serotonin reuptake transporter (SERT), that is functionally active, and the serotonin metabolizing enzyme monoamine oxidase A (MAO-A). The involvement of these proteins in the MDMA-induced toxicity was investigated by a pharmacological approach. The MAO inhibitors clorgyline and deprenyl, and the SERT inhibitor fluoxetine, per se or in combination, were not able to mimic the toxic effects of MDMA in the P19-derived neurons or block the MDMA-induced cell toxicity. Oxidative stress has been implicated in MDMA-induced neurotoxicity, but pre-treatment with the antioxidants α-tocopherol or N-acetylcysteine did not reveal any protective effects in the P19 neurons. Involvement of mitochondria in the MDMA-induced cytotoxicity was also examined, but MDMA did not alter the mitochondrial membrane potential (ΔΨm) in the P19 neurons. We conclude that MDMA produce a concentration-, time- and temperature-dependent neurotoxicity and our results suggest that the mechanism behind MDMA-induced toxicity in mouse-derived neurons do not involve the serotonergic system, oxidative stress or mitochondrial dysfunction.

Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar

Science.gov (United States)

Jevtovic-Todorovic, V.; Absalom, A. R.; Blomgren, K.; Brambrink, A.; Crosby, G.; Culley, D. J.; Fiskum, G.; Giffard, R. G.; Herold, K. F.; Loepke, A. W.; Ma, D.; Orser, B. A.; Planel, E.; Slikker, W.; Soriano, S. G.; Stratmann, G.; Vutskits, L.; Xie, Z.; Hemmings, H. C.

2013-01-01

Although previously considered entirely reversible, general anaesthesia is now being viewed as a potentially significant risk to cognitive performance at both extremes of age. A large body of preclinical as well as some retrospective clinical evidence suggest that exposure to general anaesthesia could be detrimental to cognitive development in young subjects, and might also contribute to accelerated cognitive decline in the elderly. A group of experts in anaesthetic neuropharmacology and neurotoxicity convened in Salzburg, Austria for the BJA Salzburg Seminar on Anaesthetic Neurotoxicity and Neuroplasticity. This focused workshop was sponsored by the British Journal of Anaesthesia to review and critically assess currently available evidence from animal and human studies, and to consider the direction of future research. It was concluded that mounting evidence from preclinical studies reveals general anaesthetics to be powerful modulators of neuronal development and function, which could contribute to detrimental behavioural outcomes. However, definitive clinical data remain elusive. Since general anaesthesia often cannot be avoided regardless of patient age, it is important to understand the complex mechanisms and effects involved in anaesthesia-induced neurotoxicity, and to develop strategies for avoiding or limiting potential brain injury through evidence-based approaches. PMID:23722106

(2,2'-Bipyridine-4,4'-dicarboxylic acid-κ2N,N')chlorido(2,2':6',2''-terpyridyl-κ3N,N',N'')ruthenium(II) perchlorate ethanol monosolvate monohydrate

DEFF Research Database (Denmark)

Nielsen, Anne; McKenzie, Christine Joy; Bond, Andrew David

2012-01-01

,4 '-dicarboxylic acid ligands, with interplanar separations of 3.65 (1) and 3.72 (1) angstrom. Three O atoms of the perchlorate ion are each disordered equally over two positions. The hydroxy group of the ethanol molecule is also disordered over two sites with refined occupancies of 0.794 (9) and 0.206 (9)....

Crystal engineering of novel cocrystals of a triazole drug with 1,4-dicarboxylic acids.

Science.gov (United States)

Remenar, Julius F; Morissette, Sherry L; Peterson, Matthew L; Moulton, Brian; MacPhee, J Michael; Guzmán, Héctor R; Almarsson, Orn

2003-07-16

Cocrystals of the poorly soluble antifungal drug cis-itraconazole (1) with 1,4-dicarboxylic acids have been prepared. The crystal structure of the succinic acid cocrystal with 1 was determined to be a trimer by single-crystal X-ray. The trimer is comprised of two molecules of 1 oriented in antiparallel fashion to form a pocket with a triazole at either end. The extended succinic acid molecule fills the pocket, bridging the triazole groups through hydrogen-bonding interactions rather than interacting with the more basic piperazine nitrogens. The solubility and dissolution rate of some of the cocrystals are approximately the same as those of the amorphous drug in the commercial formulation and are much higher than those for the crystalline free base. The results suggest that cocrystals of drug molecules have the possibility of achieving the higher oral bioavailability common for amorphous forms of water-insoluble drugs while maintaining the long-term chemical and physical stability that crystal forms provide.

Syntheses, structures and magnetic properties of four coordination polymers based on nitrobenzene dicarboxylate and various N-donor coligands

International Nuclear Information System (INIS)

Li, Gui-Lian; Yin, Wei-Dong; Liu, Guang-Zhen; Ma, Lu-Fang; Wang, Li-Ya

2014-01-01

Four new coordination polymers ([Ni(4-Nbdc)(bpa)(H 2 O)]) n (1), ([Co(4-Nbdc)(bpp) (H 2 O)]) n (2), ([Ni(4-Nbdc)(bpp)(H 2 O)]·H 2 O) n (3), and ([Mn 2 (3-Nbdc) 2 (bib) 3 ]·2H 2 O) n (4) (4-Nbdc=4-nitrobenzene-1,2-dicarboxylate, 3-Nbdc=3-nitrobenzene-1,2-dicarboxylate, bpa=1,2-bi(4-pyridyl)ethane, bpp=1,3-bis(4-pyridyl)propane, and bib=1,4-bis(1-imidazoly)benzene), were synthesized by hydrothermal reactions, and characterized by single-crystal X-ray diffractions, elemental analysis, FT-IR, PXRD, TGA and magnetic analysis. Complexes 1 and 2 display quasi-trapezoidal chain and brick-wall layer, and both of them contain metal–carboxylate binuclear units. Complexes 3 and 4 exhibit three-dimensional frameworks with the (6 6 ) dia topology and (4 4 .6 10 .8)(4 4 .6 2 ) fsc topology, and both of them contain metal–carboxylate chains. The carboxyl groups with syn-anti coordination mode mediate effectively the weak ferromagnetic coupling interaction within Ni(II)–carboxylate binuclear in 1 (J=1.27 cm −1 ) and Ni(II)–carboxylate chain in 3 (J=1.44 cm −1 ), respectively, and the carboxyl groups with anti-anti coordination mode leads to the classic antiferromagnetic coupling interaction within Mn(II)–carboxylate chain in 4 (J=−0.77 cm −1 ). - Highlights: • Four novel coordination polymers were hydrothermally synthesized. • 1 is 1D quasi-trapezoidal chain and 2 is brick-wall layer both with dinuclear units. • 3 and 4 show 3D frameworks both with 1D metal–carboxylate chains. • 1 and 3 exhibit ferromagnetic coupling, while 4 shows antiferromagnetic coupling

Molecular and polymeric uranyl and thorium hybrid materials featuring methyl substituted pyrazole dicarboxylates and heterocyclic 1,3-diketones

Science.gov (United States)

Carter, Korey P.; Kerr, Andrew T.; Taydakov, Ilya V.; Cahill, Christopher L.

2018-02-01

A series of seven novel f-element bearing hybrid materials have been prepared from either methyl substituted 3,4 and 4,5-pyrazoledicarboxylic acids, or heterocyclic 1,3- diketonate ligands using hydrothermal conditions. Compounds 1, [UO2(C6H4N2O4)2(H2O)], and 3, [Th(C6H4N2O4)4(H2O)5]·H2O feature 1-Methyl-1H-pyrazole-3,4-dicarboxylate ligands (SVI-COOH 3,4), whereas 2, [UO2(C6H4N2O4)2(H2O)], and 4, [Th(C6H5N2O4)(OH)(H2O)6]2·2(C6H5N2O4)·3H2O feature 1-Methyl-1H-pyrazole-4,5-dicarboxylate moieties (SVI-COOH 4,5). Compounds 5, [UO2(C13H15N4O2)2(H2O)]·2H2O and 6, [UO2(C11H11N4O2)2(H2O)]·4.5H2O feature 1,3-bis(4-N1-methyl-pyrazolyl)propane-1,3-dione and 1,3-bis(4-N1,3-dimethyl-pyrazolyl)propane-1,3-dione respectively, whereas the heterometallic 7, [UO2(C11H11N4O2)2(CuCl2)(H2O)]·2H2O is formed by using 6 as a metalloligand starting material. Single crystal X-ray diffraction indicates that all coordination to either [UO2]2+ or Th(IV) metal centers is through O-donation as anticipated. Room temperature, solid-state luminescence studies indicate characteristic uranyl emissive behavior for 1 and 2, whereas those for 5 and 6 are weak and poorly resolved.

Accumulation of Misfolded SOD1 in Dorsal Root Ganglion Degenerating Proprioceptive Sensory Neurons of Transgenic Mice with Amyotrophic Lateral Sclerosis

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Javier Sábado

2014-01-01

Full Text Available Amyotrophic lateral sclerosis (ALS is an adult-onset progressive neurodegenerative disease affecting upper and lower motoneurons (MNs. Although the motor phenotype is a hallmark for ALS, there is increasing evidence that systems other than the efferent MN system can be involved. Mutations of superoxide dismutase 1 (SOD1 gene cause a proportion of familial forms of this disease. Misfolding and aggregation of mutant SOD1 exert neurotoxicity in a noncell autonomous manner, as evidenced in studies using transgenic mouse models. Here, we used the SOD1G93A mouse model for ALS to detect, by means of conformational-specific anti-SOD1 antibodies, whether misfolded SOD1-mediated neurotoxicity extended to neuronal types other than MNs. We report that large dorsal root ganglion (DRG proprioceptive neurons accumulate misfolded SOD1 and suffer a degenerative process involving the inflammatory recruitment of macrophagic cells. Degenerating sensory axons were also detected in association with activated microglial cells in the spinal cord dorsal horn of diseased animals. As large proprioceptive DRG neurons project monosynaptically to ventral horn MNs, we hypothesise that a prion-like mechanism may be responsible for the transsynaptic propagation of SOD1 misfolding from ventral horn MNs to DRG sensory neurons.

An in vivo mechanism for the reduced peripheral neurotoxicity of NK105: a paclitaxel-incorporating polymeric micellar nanoparticle formulation

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Nakamura I

2017-02-01

Full Text Available Iwao Nakamura, Eiji Ichimura, Rika Goda, Hitomi Hayashi, Hiroko Mashiba, Daichi Nagai, Hirofumi Yokoyama, Takeshi Onda, Akira Masuda Nanomedicine Group, Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., Tokyo, Japan Abstract: In our previous rodent studies, the paclitaxel (PTX-incorporating polymeric micellar nanoparticle formulation NK105 had showed significantly stronger antitumor effects and reduced peripheral neurotoxicity than PTX dissolved in Cremophor® EL and ethanol (PTX/CRE. Thus, to elucidate the mechanisms underlying reduced peripheral neurotoxicity due to NK105, we performed pharmacokinetic analyses of NK105 and PTX/CRE in rats. Among neural tissues, the highest PTX concentrations were found in the dorsal root ganglion (DRG. Moreover, exposure of DRG to PTX (Cmax_PTX and AUC0-inf._PTX in the NK105 group was almost half that in the PTX/CRE group, whereas exposure of sciatic and sural nerves was greater in the NK105 group than in the PTX/CRE group. In histopathological analyses, damage to DRG and both peripheral nerves was less in the NK105 group than in the PTX/CRE group. The consistency of these pharmacokinetic and histopathological data suggests that high levels of PTX in the DRG play an important role in the induction of peripheral neurotoxicity, and reduced distribution of PTX to the DRG of NK105-treated rats limits the ensuing peripheral neurotoxicity. In further analyses of PTX distribution to the DRG, Evans blue (Eb was injected with BODIPY®-labeled NK105 into rats, and Eb fluorescence was observed only in the DRG. Following injection, most Eb dye bound to albumin particles of ~8 nm and had penetrated the DRG. In contrast, BODIPY®–NK105 particles of ~90 nm were not found in the DRG, suggesting differential penetration based on particle size. Because PTX also circulates as PTX–albumin particles of ~8 nm following injection of PTX/CRE, reduced peripheral neurotoxicity of NK105 may reflect exclusion from the

Advancing the Science of Developmental Neurotoxicity (DNT) Testing for Better Safety Evaluation

DEFF Research Database (Denmark)

Bal-Price, Anna; Coecke, Sandra; Costa, Lucio

2012-01-01

Bal-Price AK, Coecke S, Costa L, Crofton KM, Fritsche E, Goldberg A, Grandjean P, Lein PJ, Li A, Lucchini R, Mundy WR, Padilla S, Persico A, Seiler AEM, Kreysa J. Conference Report: Advancing the Science of Developmental Neurotoxicity (DNT) Testing for Better Safety Evaluation. Altex 2012: 29: 202-15....

Oxidative stress in MeHg-induced neurotoxicity

Energy Technology Data Exchange (ETDEWEB)

Farina, Marcelo, E-mail: farina@ccb.ufsc.br [Departamento de Bioquimica, Centro de Ciencias Biologicas, Universidade Federal de Santa Catarina, Florianopolis, SC (Brazil); Aschner, Michael [Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN (United States); Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN (United States); Rocha, Joao B.T., E-mail: jbtrocha@yahoo.com.br [Departamento de Quimica, Centro de Ciencias Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, RS (Brazil)

2011-11-15

Methylmercury (MeHg) is an environmental toxicant that leads to long-lasting neurological and developmental deficits in animals and humans. Although the molecular mechanisms mediating MeHg-induced neurotoxicity are not completely understood, several lines of evidence indicate that oxidative stress represents a critical event related to the neurotoxic effects elicited by this toxicant. The objective of this review is to summarize and discuss data from experimental and epidemiological studies that have been important in clarifying the molecular events which mediate MeHg-induced oxidative damage and, consequently, toxicity. Although unanswered questions remain, the electrophilic properties of MeHg and its ability to oxidize thiols have been reported to play decisive roles to the oxidative consequences observed after MeHg exposure. However, a close examination of the relationship between low levels of MeHg necessary to induce oxidative stress and the high amounts of sulfhydryl-containing antioxidants in mammalian cells (e.g., glutathione) have led to the hypothesis that nucleophilic groups with extremely high affinities for MeHg (e.g., selenols) might represent primary targets in MeHg-induced oxidative stress. Indeed, the inhibition of antioxidant selenoproteins during MeHg poisoning in experimental animals has corroborated this hypothesis. The levels of different reactive species (superoxide anion, hydrogen peroxide and nitric oxide) have been reported to be increased in MeHg-exposed systems, and the mechanisms concerning these increments seem to involve a complex sequence of cascading molecular events, such as mitochondrial dysfunction, excitotoxicity, intracellular calcium dyshomeostasis and decreased antioxidant capacity. This review also discusses potential therapeutic strategies to counteract MeHg-induced toxicity and oxidative stress, emphasizing the use of organic selenocompounds, which generally present higher affinity for MeHg when compared to the classically

Developmental Neurotoxicity of Traffic-Related Air Pollution: Focus on Autism.

Science.gov (United States)

Costa, Lucio G; Chang, Yu-Chi; Cole, Toby B

2017-06-01

Epidemiological and animal studies suggest that air pollution may negatively affect the central nervous system (CNS) and contribute to CNS diseases. Traffic-related air pollution is a major contributor to global air pollution, and diesel exhaust (DE) is its most important component. Several studies suggest that young individuals may be particularly susceptible to air pollution-induced neurotoxicity and that perinatal exposure may cause or contribute to developmental disabilities and behavioral abnormalities. In particular, a number of recent studies have found associations between exposures to traffic-related air pollution and autism spectrum disorders (ASD), which are characterized by impairment in socialization and in communication and by the presence of repetitive and unusual behaviors. The cause(s) of ASD are unknown, and while it may have a hereditary component, environmental factors are increasingly suspected as playing a pivotal role in its etiology, particularly in genetically susceptible individuals. Autistic children present higher levels of neuroinflammation and systemic inflammation, which are also hallmarks of exposure to traffic-related air pollution. Gene-environment interactions may play a relevant role in determining individual susceptibility to air pollution developmental neurotoxicity. Given the worldwide presence of elevated air pollution, studies on its effects and mechanisms on the developing brain, genetic susceptibility, role in neurodevelopmental disorders, and possible therapeutic interventions are certainly warranted.

Neurotoxicity of cerebro-spinal fluid from patients with Parkinson's disease on mesencephalic primary cultures as an in vitro model of dopaminergic neurons.

Science.gov (United States)

Kong, Ping; Zhang, Ben-Shu; Lei, Ping; Kong, Xiao-Dong; Zhang, Shi-Shuang; Li, Dai; Zhang, Yun

2015-08-01

Parkinson's disease is a degenerative disorder of the central nervous system. In spite of extensive research, neither the cause nor the mechanisms have been firmly established thus far. One assumption is that certain toxic substances may exist in the cerebro-spinal fluid (CSF) of Parkinson's disease patients. To confirm the neurotoxicity of CSF and study the potential correlation between neurotoxicity and the severity of Parkinson's disease, CSF was added to cultured cells. By observation of cell morphology, changes in the levels of lactate dehydrogenase, the ratio of tyrosine hydroxylase-positive cells, and the expression of tyrosine hydroxylase mRNA and protein, the differences between the two groups were shown. The created in vitro model of dopaminergic neurons using primary culture of mouse embryonic mesencephalic tissue is suitable for the study of neurotoxicity. The observations of the present study indicated that CSF from Parkinson's disease patients contains factors that can cause specific injury to cultured dopaminergic neurons. However, no obvious correlation was found between the neurotoxicity of CSF and the severity of Parkinson's disease.

The neurotoxicity of pyridinium metabolites of haloperidol

Directory of Open Access Journals (Sweden)

Agnieszka Górska

2015-10-01

Full Text Available Haloperydol is a butyrophenone, typical neuroleptic agent characterized as a high antipsychotics effects in the treatment of schizophrenia and in palliative care to alleviation many syndromes, such as naursea, vomiting and delirium. Clinical problems occurs during and after administration of the drug are side effects, particularly extrapyrramidal symptoms (EPS. The neurotoxicity of haloperydol may be initiated by the cationic metabolites of haloperydol, HPP+, RHPP+, formed by oxidation and reduction pathways. These metabolites are transported by human organic cation transporters (hOCT to several brain structures for exapmle, in substantia nigra, striatum, caudate nucleus, hippocampus. After reaching the dopaminergic neurons inhibits mitochondrial complex I, evidence for free radical involvement, thus leading to neurodegeneration.

Human embryonic stem cell-derived test systems for developmental neurotoxicity: A transcriptomics approach

NARCIS (Netherlands)

Krug, A.K.; Kolde, R.; Gaspar, J.A.; Rempel, E.; Balmer, N.V.; Meganathan, K.; Vojnits, K.; Baquié, M.; Waldmann, T.; Ensenat-Waser, R.; Jagtap, S.; Evans, R.M.; Julien, S.; Peterson, H.; Zagoura, D.; Kadereit, S.; Gerhard, D.; Sotiriadou, I.; Heke, M.; Natarajan, K.; Henry, M.; Winkler, J.; Marchan, R.; Stoppini, L.; Bosgra, S.; Westerhout, J.; Verwei, M.; Vilo, J.; Kortenkamp, A.; Hescheler, J.; Hothorn, L.; Bremer, S.; Thriel, C. van; Krause, K.-H.; Hengstler, J.G.; Rahnenführer, J.; Leist, M.; Sachinidis, A.

2013-01-01

Developmental neurotoxicity (DNT) and many forms of reproductive toxicity (RT) often manifest themselves in functional deficits that are not necessarily based on cell death, but rather on minor changes relating to cell differentiation or communication. The fields of DNT/RT would greatly benefit from

Neurotoxic effect of maneb in rats as studied by neurochemical and immunohistochemical parameters

DEFF Research Database (Denmark)

Nielsen, Brian Svend; Larsen, Erik Huusfeldt; Ladefoged, Ole

2006-01-01

) increased in a dose-related manner, as did the 5-HT concentrations in the rest of the brain indicating early sign of neurotoxicity. Striatal acetylcholinesterase activity was not affected. The concentrations of noradrenaline, dopamine, neurotransmitter amino acids and the levels of the proteins alpha...

Involvement of direct inhibition of NMDA receptors in the effects of sigma-receptor ligands on glutamate neurotoxicity in vitro.

Science.gov (United States)

Nishikawa, H; Hashino, A; Kume, T; Katsuki, H; Kaneko, S; Akaike, A

2000-09-15

This study was performed to examine the roles of the N-methyl-D-aspartate (NMDA) receptor/phencyclidine (PCP) channel complex in the protective effects of sigma-receptor ligands against glutamate neurotoxicity in cultured cortical neurons derived from fetal rats. A 1-h exposure of cultures to glutamate caused a marked loss of viability, as determined by Trypan blue exclusion. This acute neurotoxicity of glutamate was prevented by NMDA receptor antagonists. Expression of sigma(1) receptor mRNA in cortical cultures was confirmed by reverse transcription polymerase chain reaction (RT-PCR). sigma Receptor ligands with affinity for NMDA receptor channels including the PCP site, such as (+)-N-allylnormetazocine ((+)-SKF10,047), haloperidol, and R(-)-N-(3-phenyl-1-propyl)-1-phenyl-2-aminopropane ((-)-PPAP), prevented glutamate neurotoxicity in a concentration-dependent manner. In contrast, other sigma-receptor ligands without affinity for NMDA receptors, such as carbetapentane and R(+)-3-(3-hydroxyphenyl)-N-propylpiperidine ((+)-3-PPP), did not show neuroprotective effects. Putative endogenous sigma receptor ligands such as pregnenolone, progesterone, and dehydroepiandrosterone did not affect glutamate neurotoxicity. The protective effects of (+)-SKF10,047, haloperidol, and (-)-PPAP were not affected by the sigma(1) receptor antagonist rimcazole. These results suggested that a direct interaction with NMDA receptors but not with sigma receptors plays a crucial role in the neuroprotective effects of sigma receptor ligands with affinity for NMDA receptors.

Insights into cytokine release syndrome and neurotoxicity after CD19-specific CAR-T cell therapy.

Science.gov (United States)

Gauthier, Jordan; Turtle, Cameron J

2018-04-03

T-cells engineered to express CD19-specific chimeric antigen receptors (CD19 CAR-T cells) can achieve high response rates in patients with refractory/relapsed (R/R) CD19+ hematologic malignancies. Nonetheless, the efficacy of CD19-specific CAR-T cell therapy can be offset by significant toxicities, such as cytokine release syndrome (CRS) and neurotoxicity. In this report of our presentation at the 2018 Second French International Symposium on CAR-T cells (CAR-T day), we describe the clinical presentations of CRS and neurotoxicity in a cohort of 133 adults treated with CD19 CAR-T cells at the Fred Hutchinson Cancer Research Center, and provide insights into the mechanisms contributing to these toxicities. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Rational design, synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid

DEFF Research Database (Denmark)

Bunch, Lennart; Liljefors, Tommy; Greenwood, Jeremy R

2003-01-01

conformationally restricted (S)-glutamic acid (Glu) analogue intended as a mimic of the folded Glu conformation. The synthesis of 1 was completed in its racemic form in eight steps from commercially available starting materials. As a key step, the first facially selective hydroboration of a 5-methylidene[2......The design and synthesis of conformationally restricted analogues of alpha-amino acids is an often used strategy in medicinal chemistry research. Here we present the rational design, synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid (1), a novel...... studies on native 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) (IC(50) > 300 microM, [(3)H]AMPA) or kainic acid (IC(50) > 160 microM, [(3)H]kainic acid) receptors nor in binding studies on the cloned iGluR5,6 subtypes (IC(50) > 300 microM, [(3)H]kainic acid)....

Chemical characterization of composites developed from glycerol and dicarboxylic acids rein forced with piassava fiber

International Nuclear Information System (INIS)

Miranda, Cleidiene S.; Oliveira, Jamerson C.; Guimaraes, Danilo H.; Jose, Nadia M.; Carvalho, Ricardo F.

2011-01-01

In search of alternative technologies that enable the use of products with lower environmental impact, This study aims to develop a composite polymer-based piassava fiber. The sludge, waste and byproduct of commercial uses currently being used as reinforcement in polymer matrices, due to presence of lignocellulosic materials. The matrix polymer used was synthesized from glycerol with dicarboxylic acids, in order to open future perspectives on the use of glycerin generated from purified biodiesel production plastics. Composites with 2, 5, 10 wt% of piassava fiber cut into 5 mm raw and treated were obtained a mixture of solution. The materials were characterized by TGA, DSC, XRD and SEM. It was observed that the material under study is promising for the industrial market, because it has good compatibility with natural fibers allowing wider application of fiber natural and glycerol, producing semicrystalline composites and with good thermal properties. (author)

Health assessment of gasoline and fuel oxygenate vapors: Neurotoxicity evaluation

OpenAIRE

O?Callaghan, James P.; Daughtrey, Wayne C.; Clark, Charles R.; Schreiner, Ceinwen A.; White, Russell

2014-01-01

Sprague?Dawley rats were exposed via inhalation to vapor condensates of either gasoline or gasoline combined with various fuel oxygenates to assess potential neurotoxicity of evaporative emissions. Test articles included vapor condensates prepared from ?baseline gasoline? (BGVC), or gasoline combined with methyl tertiary butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME), diisopropyl ether (G/DIPE), ethanol (G/EtOH), or t-butyl alcohol (G/TBA). Target concentrati...

Gamma-Secretase Inhibitors Attenuate Neurotrauma and Neurogenic Acute Lung Injury in Rats by Rescuing the Accumulation of Hypertrophic Microglia

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Hung-Jung Lin

2017-12-01

Full Text Available Background/Aims: In response to traumatic brain injury (TBI, activated microglia exhibit changes in their morphology from the resting ramified phenotype toward the activated hypertrophic or amoeboid phenotype. Here, we provide the first description of the mechanism underlying the neuroprotective effects of γ-secretase inhibitors on TBI outcomes in rats. Methods: The neuroprotective effects of γ-secretase inhibitors such as LY411575 or CHF5074 on TBI-induced neurotoxicity were analysed using a neurological motor function evaluation, cerebral contusion assay, immunohistochemical staining for microglia phenotypes, lung injury score and Evans Blue dye extravasation assay of brain and lung oedema. Results: Hypertrophic or amoeboid microglia accumulated in the injured cortex, the blood-brain-barrier was disrupted and neurological deficits and acute lung injury were observed 4 days after TBI in adult rats. However, a subcutaneous injection of LY411575 (5 mg/kg or CHF5074 (30 mg/kg immediately after TBI and once daily for 3 consecutive days post-TBI significantly attenutaed the accumulation of hypertrophic microglia in the injured brain, neurological injury, and neurogenic acute lung injury. Conclusion: Gamma-secretase inhibitors attenuated neurotrauma and neurogenic acute lung injury in rats by reducing the accumulation of hypertrophic microglia in the vicinity of the lesion.

UNDERTAKING POSITIVE CONTROL STUDIES AS PART OF DEVELOPMENTAL NEUROTOXICITY TESTING: A REPORT FROM THE ILSI RESEARCH FOUNDATION/RISK SCIENCE INSTITUTE EXPERT WORKING GROUP ON NEURODEVELOPMENTAL ENDPOINTS

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Developmental neurotoxicity testing involves functional and neurohistological assessments in offspring during and following maternal and/or neonatal exposure. Data from positive control studies are an integral component in developmental neurotoxicity risk assessments. Positive ...

Interaction of the 106-126 prion peptide with lipid membranes and potential implication for neurotoxicity

International Nuclear Information System (INIS)

Dupiereux, Ingrid; Zorzi, Willy; Lins, Laurence; Brasseur, Robert; Colson, Pierre; Heinen, Ernst; Elmoualij, Benaissa

2005-01-01

Prion diseases are fatal neurodegenerative disorders characterized by the accumulation in the brain of an abnormally misfolded, protease-resistant, and β-sheet rich pathogenic isoform (PrP sc ) of the cellular prion protein (PrP c ). In the present work, we were interested to study the mode of prion protein interaction with the membrane using the 106-126 peptide and small unilamellar lipid vesicles as model. As previously demonstrated, we showed by MTS assay that PrP 106-126 induces alterations in the human neuroblastoma SH-SY5Y cell line. We demonstrated for the first time by lipid-mixing assay and by the liposome vesicle leakage test that PrP 106-126, a non-tilted peptide, induces liposome fusion thus a potential cell membrane destabilization, as supported by membrane integrity assay (LDH). By circular dichroism (CD) analysis we showed that the fusogenic property of PrP 106-126 in the presence of liposome is associated with a predominantly β-sheet structure. These data suggest that the fusogenic property associated with a predominant β-sheet structure exhibited by the prion peptides contributes to the neurotoxicity of these peptides by destabilizing cellular membranes. The latter might be attached at the membrane surface in a parallel orientation as shown by molecular modeling

Deficient PKR in RAX/PKR Association Ameliorates Ethanol-Induced Neurotoxicity in the Developing Cerebellum.

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Li, Hui; Chen, Jian; Qi, Yuanlin; Dai, Lu; Zhang, Mingfang; Frank, Jacqueline A; Handshoe, Jonathan W; Cui, Jiajun; Xu, Wenhua; Chen, Gang

2015-08-01

Ethanol-induced neuronal loss is closely related to the pathogenesis of fetal alcohol spectrum disorders. The cerebellum is one of the brain areas that are most sensitive to ethanol. The mechanism underlying ethanol neurotoxicity remains unclear. Our previous in vitro studies have shown that the double-stranded RNA (dsRNA)-activated protein kinase (PKR) regulates neuronal apoptosis upon ethanol exposure and ethanol activates PKR through association with its intracellular activator RAX. However, the role of PKR and its interaction with RAX in vivo have not been investigated. In the current study, by utilizing N-PKR-/- mice, C57BL/6J mice with a deficient RAX-binding domain in PKR, we determined the critical role of RAX/PKR association in PKR-regulated ethanol neurotoxicity in the developing cerebellum. Our data indicate that while N-PKR-/- mice have a similar BAC profile as wild-type mice, ethanol induces less brain/body mass reduction as well as cerebellar neuronal loss. In addition, ethanol promotes interleukin-1β (IL-1β) secretion, and IL-1β is a master cytokine regulating inflammatory response. Importantly, ethanol-promoted IL-1β secretion is inhibited in the developing cerebellum of N-PKR-/- mice. Thus, RAX/PKR interaction and PKR activation regulate ethanol neurotoxicity in the developing cerebellum, which may involve ethanol-induced neuroinflammation. Further, PKR could be a possible target for pharmacological intervention to prevent or treat fetal alcohol spectrum disorder (FASD).

Accelerated oxygen consumption by catecholamines in the presence of aromatic nitro and nitroso compounds. Implications and neurotoxicity of nitro compounds

International Nuclear Information System (INIS)

Sridhar, K.

1981-01-01

The interactions of catecholamines with nitro and nitroso compounds are studied in view of the possible involvement of catecholamine type neurotransmitters in neurotoxicity caused by hypoxic cell sensitizers. The data reported suggest that neurotoxicity of nitro compounds may be due to depletion of oxygen, catecholamines and ascorbate in nerve tissue with concomitant generation of toxic species such as hydroxyl, hydronitroxyl and superoxide free radicals as well as nitroso and quinonoid derivatives. 5 references, 1 figure

A novel antagonistic role of natural compound icariin on neurotoxicity of amyloid β peptide

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Jianhui Liu

2015-01-01

Interpretation & conclusions: The results indicated a novel antagonistic role of icariin in the neurotoxicity of Aβ1-42 via inhibiting its aggregation, suggesting that icariin might have potential therapeutic benefits to delay or modify the progression of AD.

Neurotoxicity of developmental hypothyroxinemia and hypothyroidism in rats: Impairments of long-term potentiation are mediated by phosphatidylinositol 3-kinase signaling pathway

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Wang, Yi; Wei, Wei; Wang, Yuan; Dong, Jing; Song, Binbin; Min, Hui [Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang (China); Teng, Weiping, E-mail: twpendocrine@yahoo.com.cn [Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Hospital of China Medical University, Shenyang (China); Chen, Jie, E-mail: chenjie@mail.cmu.edu.cn [Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang (China)

2013-09-01

Neurotoxicity of iodine deficiency-induced hypothyroidism during developmental period results in serious impairments of brain function, such as learning and memory. These impairments are largely irreversible, and the underlying mechanisms remain unclear. In addition to hypothyroidism, iodine deficiency may cause hypothyroxinemia, a relatively subtle form of thyroid hormone deficiency. Neurotoxicity of developmental hypothyroxinemia also potentially impairs learning and memory. However, more direct evidence of the associations between developmental hypothyroxinemia and impairments of learning and memory should be provided, and the underlying mechanisms remain to be elucidated. Thus, in the present study, we investigated the effects of developmental hypothyroxinemia and hypothyroidism on long-term potentiation (LTP), a widely accepted cellular model of learning and memory, in the hippocampal CA1 region. The activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway – a pathway closely associated with synaptic plasticity and learning and memory – was also investigated. Wistar rats were treated with iodine deficient diet or methimazole (MMZ) to induce developmental hypothyroxinemia or hypothyroidism. The results showed that developmental hypothyroxinemia caused by mild iodine deficiency and developmental hypothyroidism caused by severe iodine deficiency or MMZ significantly reduced the field-excitatory postsynaptic potential (f-EPSP) slope and the population spike (PS) amplitude. Decreased activation of the PI3K signaling pathway was also observed in rats subjected to developmental hypothyroxinemia or hypothyroidism. Our results may support the hypothesis that neurotoxicity of both developmental hypothyroxinemia and hypothyroidism causes damages to learning and memory. Our results also suggest that decreased activation of the PI3K signaling pathway may contribute to impairments of LTP caused by neurotoxicity of both developmental hypothyroxinemia and

Neurotoxicity of developmental hypothyroxinemia and hypothyroidism in rats: Impairments of long-term potentiation are mediated by phosphatidylinositol 3-kinase signaling pathway

International Nuclear Information System (INIS)

Wang, Yi; Wei, Wei; Wang, Yuan; Dong, Jing; Song, Binbin; Min, Hui; Teng, Weiping; Chen, Jie

2013-01-01

Neurotoxicity of iodine deficiency-induced hypothyroidism during developmental period results in serious impairments of brain function, such as learning and memory. These impairments are largely irreversible, and the underlying mechanisms remain unclear. In addition to hypothyroidism, iodine deficiency may cause hypothyroxinemia, a relatively subtle form of thyroid hormone deficiency. Neurotoxicity of developmental hypothyroxinemia also potentially impairs learning and memory. However, more direct evidence of the associations between developmental hypothyroxinemia and impairments of learning and memory should be provided, and the underlying mechanisms remain to be elucidated. Thus, in the present study, we investigated the effects of developmental hypothyroxinemia and hypothyroidism on long-term potentiation (LTP), a widely accepted cellular model of learning and memory, in the hippocampal CA1 region. The activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway – a pathway closely associated with synaptic plasticity and learning and memory – was also investigated. Wistar rats were treated with iodine deficient diet or methimazole (MMZ) to induce developmental hypothyroxinemia or hypothyroidism. The results showed that developmental hypothyroxinemia caused by mild iodine deficiency and developmental hypothyroidism caused by severe iodine deficiency or MMZ significantly reduced the field-excitatory postsynaptic potential (f-EPSP) slope and the population spike (PS) amplitude. Decreased activation of the PI3K signaling pathway was also observed in rats subjected to developmental hypothyroxinemia or hypothyroidism. Our results may support the hypothesis that neurotoxicity of both developmental hypothyroxinemia and hypothyroidism causes damages to learning and memory. Our results also suggest that decreased activation of the PI3K signaling pathway may contribute to impairments of LTP caused by neurotoxicity of both developmental hypothyroxinemia and

Brain manganese, catecholamine turnover, and the development of startle in rats prenatally exposed to manganese

International Nuclear Information System (INIS)

Kontur, P.J.; Fechter, L.D.

1985-01-01

Manganese (Mn) can be neurotoxic when present in high concentrations. Neonatal animals show differential absorption, accumulation, and excretion of Mn relative to adults. If similar kinetic differences exist during gestation, then fetal animals may be susceptible to Mn neurotoxicity. The objective of this study was to examine maternal-fetal Mn transfer and the susceptibility of prenatal animals to Mn neurotoxicity. This was approached by studying the ability of Mn to cross the placenta and reach the fetal central nervous system using radiotracer and atomic absorption spectroscopy techniques. Manganese is thought to disrupt catecholamine neurotransmission in the central nervous system. This was examined in newborn rats by alpha-methyl-para-tyrosine induced catecholamine turnover and the development of the acoustic startle response. The results suggest that there are limits on fetal Mn accumulation under conditions of both normal and excessive dietary Mn levels. Manganese accumulation in the fetal brain after exposure to increased dietary Mn does not alter either dopamine or norepinephrine turnover or the development of the acoustic startle response. Excess Mn does not appear to be neurotoxic to fetal rats in spite of its limited accumulation in nervous tissue after gestational exposure

Mining the Virgin Land of Neurotoxicology: A Novel Paradigm of Neurotoxic Peptides Action on Glycosylated Voltage-Gated Sodium Channels

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Zhirui Liu

2012-01-01

Full Text Available Voltage-gated sodium channels (VGSCs are important membrane protein carrying on the molecular basis for action potentials (AP in neuronal firings. Even though the structure-function studies were the most pursued spots, the posttranslation modification processes, such as glycosylation, phosphorylation, and alternative splicing associating with channel functions captured less eyesights. The accumulative research suggested an interaction between the sialic acids chains and ion-permeable pores, giving rise to subtle but significant impacts on channel gating. Sodium channel-specific neurotoxic toxins, a family of long-chain polypeptides originated from venomous animals, are found to potentially share the binding sites adjacent to glycosylated region on VGSCs. Thus, an interaction between toxin and glycosylated VGSC might hopefully join the campaign to approach the role of glycosylation in modulating VGSCs-involved neuronal network activity. This paper will cover the state-of-the-art advances of researches on glycosylation-mediated VGSCs function and the possible underlying mechanisms of interactions between toxin and glycosylated VGSCs, which may therefore, fulfill the knowledge in identifying the pharmacological targets and therapeutic values of VGSCs.

Short-term use of antiepileptic drugs is neurotoxic to the immature brain

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Yu Liu

2015-01-01

Full Text Available Previous studies have shown that the long-term use of antiepileptic drugs can cause nervous system damage. However, short-term antiepileptic drug treatment is frequently given to infants, especially neonates, to control seizure. Whether the short-term use of antiepileptic drugs is neurotoxic remains unclear. In the present study, immature rats, 3-21 days of age, were intraperitoneally injected with phenobarbital and/or topiramate for 3 consecutive days. Hematoxylin-eosin and immunohistochemical staining revealed that phenobarbital and topiramate, individually or in combination, were cytotoxic to hippocampal CA1 neurons and inhibited the expression of GluR1 and NR2B, excitatory glutamate receptor subunits. Furthermore, the combination of the two drugs caused greater damage than either drug alone. The results demonstrate that the short-term use of antiepileptic drugs damages neurons in the immature brain and that the combined use of antiepileptic drugs exacerbates damage. Our findings suggest that clinicians should consider the potential neurotoxic risk associated with the combined use of antiepileptic drugs in the treatment of seizure.

Attenuation of methamphetamine-induced nigrostriatal dopaminergic neurotoxicity in mice by lipopolysaccharide pretreatment.

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Lin, Yin Chiu; Kuo, Yu-Min; Liao, Pao-Chi; Cherng, Chianfang G; Su, Su-Wen; Yu, Lung

2007-04-30

Immunological activation has been proposed to play a role in methamphetamine-induced dopaminergic terminal damage. In this study, we examined the roles of lipopolysaccharide, a pro-inflammatory and inflammatory factor, treatment in modulating the methamphetamine-induced nigrostriatal dopamine neurotoxicity. Lipopolysaccharide pretreatment did not affect the basal body temperature or methamphetamine-elicited hyperthermia three days later. Such systemic lipopolysaccharide treatment mitigated methamphetamine-induced striatal dopamine and 3,4-dihydroxyphenylacetic acid depletions in a dose-dependent manner. As the most potent dose (1 mg/kg) of lipopolysaccharide was administered two weeks, one day before or after the methamphetamine dosing regimen, methamphetamine-induced striatal dopamine and 3,4-dihydroxyphenylacetic acid depletions remained unaltered. Moreover, systemic lipopolysaccharide pretreatment (1 mg/kg) attenuated local methamphetamine infusion-produced dopamine and 3,4-dihydroxyphenylacetic acid depletions in the striatum, indicating that the protective effect of lipopolysaccharide is less likely due to interrupted peripheral distribution or metabolism of methamphetamine. We concluded a critical time window for systemic lipopolysaccharide pretreatment in exerting effective protection against methamphetamine-induced nigrostriatal dopamine neurotoxicity.

Studies on the assessment of neurotoxicity in children with acute lymphoblastic leukemia

International Nuclear Information System (INIS)

Muchi, H.; Satoh, T.; Yamamoto, K.; Karube, T.; Miyao, M.

1987-01-01

Central nervous system (CNS) prophylaxis caused a remarkable reduction in the incidence of CNS disease, however there has evolved a growing concern regarding the immediate or late toxicities to the developing CNS. Twenty-eight children with acute lymphoblastic leukemia who survived for more than 2 years were examined for the assessment of neurotoxicity induced by CNS prophylaxis and its treatment. The patients were stratified into three groups: Stratum I, prophylaxis with methotrexate; Stratum II, prophylaxis with cranial irradiation with methotrexate; and Stratum III, with CNS leukemia. Once CNS disease developed the sequelae were frequent and severe, due to the elevated methotrexate levels in the cerebrospinal fluid. CNS prophylaxis with intermediate-dose methotrexate was less toxic to the developing CNS than prophylactic cranial irradiation, especially in children under 5 years of age. Electroencephalograms and evoked potentials are likely to find increasing application in defining the CNS sequelae of acute lymphoblastic leukemia in children and its treatment. Although the sample size was small, the findings delineate specific areas of neurotoxicity

Severe neurotoxicity associated to the intrathecal of metotreaxate and cytanobina in patients with tenkenic or lymphoma

International Nuclear Information System (INIS)

Garcia Tena, J.; Lopez Andreu, J.A.; Verdeguer, A.; Menor, F.; Mulas, F.; Ferris, J.

1995-01-01

The prophylaxis and treatment of central nervous system leukemia and lymphoma with intrathecal chemotherapy have been related to severe neurotoxicity. At least 35 cases of subacute myeloencepthalopathy with transient a permanent paraplegia/quadriplegia have been reported. A comprehensive view of the literature and a description of a new case of intrathecal chemotherapy-related neurotoxicity is made. Among the cases reported in the literature, complete recovery was observed in 9 patients, partial recovery with variable sequelae in 6, no recovery in 8 and 13 patients died. Early cerebrospinal fluid exchange seems to be the only potentially effective approach although not universally accepted. The rarity of this toxicity and the proved efficacy of the intrathecal chemotherapy justify its use

A holistic view of anesthesia-related neurotoxicity in children

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Clausen NG

2015-11-01

Full Text Available Nicola G Clausen, Tom G Hansen Department of Anesthesia and Intensive Care, Odense University Hospital, Odense, Denmark Introduction: Animal studies (including in nonhuman primates have shown that most general anesthetics cause enhanced neuroapoptosis in the immature brain with subsequent long-term neurocognitive deficits later in life. Whether human neurons are equally affected is yet unknown, but a final answer to this issue is still pending. To date, most human studies within the field are of observational nature and the results are conflicting. Some studies indicate an association between exposure to anesthesia and surgery while others do not. Objective: This review summarizes results from preclinical and observational studies. Controversies and challenges regarding the interpretation of these results are presented. Crucial aspects of neurocognitive safety during pediatric anesthesia and surgery are highlighted. International initiatives aiming to improve the safe conductance of pediatric anesthesia are introduced. Conclusion: So far, anesthesia-related neurotoxicity in humans remains an area of concern but it cannot be completely excluded. Clinical practice should not be changed until there are definite proofs that anesthetic exposure causes neurocognitive impairment later in life. Withholding necessary and timely surgeries as a consequence of any such concerns could result in worse harm. Focus of current research should also be redirected to include other factors, than merely anesthetics and surgery, that influence the neurocognitive safety of children perioperatively. Keywords: pediatric anesthesia, neurotoxicity, anesthesia safety, neurocognitive development 

The acute and long-term neurotoxic effects of MDMA on marble burying behaviour in mice.

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Saadat, Kathryn S; Elliott, J Martin; Colado, M Isabel; Green, A Richard

2006-03-01

When mice are exposed to harmless objects such as marbles in their cage they bury them, a behaviour sometimes known as defensive burying. We investigated the effect of an acute dose of MDMA (èecstasy') and other psychoactive drugs on marble burying and also examined the effect of a prior neurotoxic dose of MDMA or p-chloroamphetamine (PCA) on burying. Acute administration of MDMA produced dose-dependent inhibition of marble burying (EC50: 7.6 micro mol/kg). Other drugs that enhance monoamine function also produced dose-dependent inhibition: methamphetamine PCA paroxetine MDMA GBR 12909 methylphenidate. None of these drugs altered locomotor activity at a dose that inhibited burying. A prior neurotoxic dose of MDMA, which decreased striatal dopamine content by 60%, but left striatal 5-HT content unaltered, did not alter spontaneous marble burying 18 or 40 days later. However, a neurotoxic dose of PCA which decreased striatal dopamine by 60% and striatal 5-HT by 70% attenuated marble burying 28 days later. Overall, these data suggest that MDMA, primarily by acutely increasing 5-HT function, acts like several anxiolytic drugs in this behavioural model. Long-term loss of cerebral 5-HT content also produced a similar effect. Since this change was observed only after 28 days, it is probably due to an adaptive response in the brain.

Treatment with Akebia Saponin D Ameliorates Aβ1–42-Induced Memory Impairment and Neurotoxicity in Rats

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Yongde Chen

2016-03-01

Full Text Available Amyloid-β peptide (Aβ is known to be directly associated with the progressive neuronal death observed in Alzheimer’s disease (AD. However, effective neuroprotective approaches against Aβ neurotoxicity are still unavailable. In the present study, we investigated the protective effects of Akebia saponin D (ASD, a typical compound isolated from the rhizome of Dipsacus asper Wall, on Aβ1–42-induced impairment of learning and memory formation and explored the probable underlying molecular mechanisms. We found that treatment with ASD (30, 90 or 270 mg/kg significantly ameliorated impaired spatial learning and memory in intracerebroventricularly (ICV Aβ1–42-injected rats, as evidenced by a decrease tendency in escape latency during acquisition trials and improvement in exploratory activities in the probe trial in Morris water maze (MWM. Further study showed that ASD reversed Aβ1–42-induced accumulation of Aβ1–42 and Aβ1–40 in the hippocampus through down-regulating the expression of BACE and Presenilin 2 accompanied with increased the expression of TACE, IDE and LRP-1. Taken together, our findings suggested that ASD exerted therapeutic effects on Aβ-induced cognitive deficits via amyloidogenic pathway.

Luminescence recognition of different organophosphorus pesticides by the luminescent Eu(III)-pyridine-2,6-dicarboxylic acid probe

Energy Technology Data Exchange (ETDEWEB)

Azab, Hassan A., E-mail: azab2@yahoo.com [Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522 (Egypt); Duerkop, Axel [Institute of Analytical Chemistry, Chemo and Biosensors, Regensburg University, D-93040 Regensburg (Germany); Anwar, Z.M.; Hussein, Belal H.M.; Rizk, Moustafa A.; Amin, Tarek [Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522 (Egypt)

2013-01-08

Highlights: Black-Right-Pointing-Pointer Europium (III) luminescence quenching has been used for sensing organophosphorous pesticides. Black-Right-Pointing-Pointer Four guest pesticides chlorfenvinphos, malathion, azinphos, and paraxon ethyl were used. Black-Right-Pointing-Pointer A sensitive rapid, cheap direct method for the determination of the pesticides has been developed. Black-Right-Pointing-Pointer The method was applied to the determination of the OPs in tap, river, mineral, and waste waters. - Abstract: Luminescence quenching of a novel long lived Eu(III)-pyridine-2,6-dicarboxylic acid probe of 1:2 stoichiometric ratio has been studied in 0.10 volume fraction ethanol-water mixture at pH 7.5 (HEPES buffer) in the presence of the organophosphorus pesticides chlorfenvinphos (P1), malathion (P2), azinphos (P3), and paraxon ethyl (P4). The luminescence intensity of Eu(III)-(PDCA){sub 2} probe decreases as the concentration of the pesticide increases. It was observed that the quenching due to P3 and P4 proceeds via both diffusional and static quenching processes. Direct methods for the determination of the pesticides under investigation have been developed using the luminescence quenching of Eu(III)-pyridine-2,6-dicarboxylic acid probe in solution. The linear range for determination of the selected pesticides is 1.0-35.0 {mu}M. The detection limits were 0.24-0.55 {mu}M for P3, P4, and P1 and 2.5 {mu}M for P2, respectively. The binding constants (K), and thermodynamic parameters of the OPs with Eu(III)-(PDCA){sub 2} were evaluated. Positive and negative values of entropy ({Delta}S) and enthalpy ({Delta}H) changes for Eu(III)-(PDCA){sub 2}-P1 ternary complex were calculated. As the waters in this study do not contain the above mentioned OPs over the limit detectable by the method, a recovery study was carried out after the addition of the adequate amounts of the organophosphorus pesticides under investigation.

Curcumin Attenuated Bupivacaine-Induced Neurotoxicity in SH-SY5Y Cells Via Activation of the Akt Signaling Pathway.

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Fan, You-Ling; Li, Heng-Chang; Zhao, Wei; Peng, Hui-Hua; Huang, Fang; Jiang, Wei-Hang; Xu, Shi-Yuan

2016-09-01

Bupivacaine is widely used for regional anesthesia, spinal anesthesia, and pain management. However, bupivacaine could cause neuronal injury. Curcumin, a low molecular weight polyphenol, has a variety of bioactivities and may exert neuroprotective effects against damage induced by some stimuli. In the present study, we tested whether curcumin could attenuate bupivacaine-induced neurotoxicity in SH-SY5Y cells. Cell injury was evaluated by examining cell viability, mitochondrial damage and apoptosis. We also investigated the levels of activation of the Akt signaling pathway and the effect of Akt inhibition by triciribine on cell injury following bupivacaine and curcumin treatment. Our findings showed that the bupivacaine treatment could induce neurotoxicity. Pretreatment of the SH-SY5Y cells with curcumin significantly attenuated bupivacaine-induced neurotoxicity. Interestingly, the curcumin treatment increased the levels of Akt phosphorylation. More significantly, the pharmacological inhibition of Akt abolished the cytoprotective effect of curcumin against bupivacaine-induced cell injury. Our data suggest that pretreating SH-SY5Y cells with curcumin provides a protective effect on bupivacaine-induced neuronal injury via activation of the Akt signaling pathway.

In vitro acute and developmental neurotoxicity screening: an overview of cellular platforms and high-throughput technical possibilities.

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Schmidt, Béla Z; Lehmann, Martin; Gutbier, Simon; Nembo, Erastus; Noel, Sabrina; Smirnova, Lena; Forsby, Anna; Hescheler, Jürgen; Avci, Hasan X; Hartung, Thomas; Leist, Marcel; Kobolák, Julianna; Dinnyés, András

2017-01-01

Neurotoxicity and developmental neurotoxicity are important issues of chemical hazard assessment. Since the interpretation of animal data and their extrapolation to man is challenging, and the amount of substances with information gaps exceeds present animal testing capacities, there is a big demand for in vitro tests to provide initial information and to prioritize for further evaluation. During the last decade, many in vitro tests emerged. These are based on animal cells, human tumour cell lines, primary cells, immortalized cell lines, embryonic stem cells, or induced pluripotent stem cells. They differ in their read-outs and range from simple viability assays to complex functional endpoints such as neural crest cell migration. Monitoring of toxicological effects on differentiation often requires multiomics approaches, while the acute disturbance of neuronal functions may be analysed by assessing electrophysiological features. Extrapolation from in vitro data to humans requires a deep understanding of the test system biology, of the endpoints used, and of the applicability domains of the tests. Moreover, it is important that these be combined in the right way to assess toxicity. Therefore, knowledge on the advantages and disadvantages of all cellular platforms, endpoints, and analytical methods is essential when establishing in vitro test systems for different aspects of neurotoxicity. The elements of a test, and their evaluation, are discussed here in the context of comprehensive prediction of potential hazardous effects of a compound. We summarize the main cellular characteristics underlying neurotoxicity, present an overview of cellular platforms and read-out combinations assessing distinct parts of acute and developmental neurotoxicology, and highlight especially the use of stem cell-based test systems to close gaps in the available battery of tests.

Pharmacological evaluation of SN79, a sigma (σ) receptor ligand, against methamphetamine-induced neurotoxicity in vivo.

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Kaushal, Nidhi; Seminerio, Michael J; Robson, Matthew J; McCurdy, Christopher R; Matsumoto, Rae R

2013-08-01

Methamphetamine is a highly addictive psychostimulant drug of abuse, causing hyperthermia and neurotoxicity at high doses. Currently, there is no clinically proven pharmacotherapy to treat these effects of methamphetamine, necessitating identification of potential novel therapeutic targets. Earlier studies showed that methamphetamine binds to sigma (σ) receptors in the brain at physiologically relevant concentrations, where it "acts in part as an agonist." SN79 (6-acetyl-3-(4-(4-(4-florophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one) was synthesized as a putative σ receptor antagonist with nanomolar affinity and selectivity for σ receptors over 57 other binding sites. SN79 pretreatment afforded protection against methamphetamine-induced hyperthermia and striatal dopaminergic and serotonergic neurotoxicity in male, Swiss Webster mice (measured as depletions in striatal dopamine and serotonin levels, and reductions in striatal dopamine and serotonin transporter expression levels). In contrast, di-o-tolylguanidine (DTG), a well established σ receptor agonist, increased the lethal effects of methamphetamine, although it did not further exacerbate methamphetamine-induced hyperthermia. Together, the data implicate σ receptors in the direct modulation of some effects of methamphetamine such as lethality, while having a modulatory role which can mitigate other methamphetamine-induced effects such as hyperthermia and neurotoxicity. Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.

Benzene-1,3-dicarboxylic acid 2,5-dimethylpyrrole derivatives as multiple inhibitors of bacterial Mur ligases (MurC-MurF).

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Perdih, Andrej; Hrast, Martina; Barreteau, Hélène; Gobec, Stanislav; Wolber, Gerhard; Solmajer, Tom

2014-08-01

Enzymes catalyzing the biosynthesis of bacterial peptidoglycan represent traditionally a collection of highly selective targets for novel antibacterial drug design. Four members of the bacterial Mur ligase family-MurC, MurD, MurE and MurF-are involved in the intracellular steps of peptidoglycan biosynthesis, catalyzing the synthesis of the peptide moiety of the Park's nucleotide. In our previous virtual screening campaign, a chemical class of benzene-1,3-dicarboxylic acid 2,5-dimethylpyrrole derivatives exhibiting dual MurD/MurE inhibition properties was discovered. In the present study we further investigated this class of compounds by performing inhibition assays on all four Mur ligases (MurC-MurF). Furthermore, molecular dynamics (MD) simulation studies of one of the initially discovered compound 1 were performed to explore its geometry as well as its energetic behavior based on the Linear Interaction Energy (LIE) method. Further in silico virtual screening (VS) experiments based on the parent active compound 1 were conducted to optimize the discovered series. Selected hits were assayed against all Escherichia coli MurC-MurF enzymes in biochemical inhibition assays and molecules 10-14 containing benzene-1,3-dicarboxylic acid 2,5-dimethylpyrrole coupled with five member-ring rhodanine moiety were found to be multiple inhibitors of the whole MurC-MurF cascade of bacterial enzymes in the micromolar range. Steady-state kinetics studies suggested this class to act as competitive inhibitors of the MurD enzyme towards d-Glu. These compounds represent novel valuable starting point in the development of novel antibacterial agents. Copyright © 2014 Elsevier Ltd. All rights reserved.

A coordination polymer of CdII with benzene-1,3-dicarboxylate and 1,4-bis[1-(2-pyridylmethylbenzimidazol-2-yl]butane

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Wei-Ping Zhang

2009-11-01

Full Text Available The title CdII coordination polymer, catena-poly[[{1,4-bis[1-(2-pyridylmethylbenzimidazol-2-yl]butane}cadmium(II]-μ-benzene-1,3-dicarboxylato], [Cd(C8H4O4(C30H28N6]n, was obtained by reaction of CdCO3, benzene-1,3-dicarboxylic acid (H2btc and 1,4-bis[1-(2-pyridylmethylbenzimidazol-2-yl]butane (L. The CdII cation is six-coordinated by an N2O4-donor set. L acts as a bidentate ligand and btc anions link CdII centers into a chain propagating parallel to [010].

Mitochondrial dysfunction contribute to diabetic neurotoxicity induced by streptozocin in mice: protective effect of Urtica dioica and pioglitazone.

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Shokrzadeh, Mohammad; Mirshafa, Atefeh; Yekta Moghaddam, Niusha; Birjandian, Behnoosh; Shaki, Fatemeh

2018-04-18

Uncontrolled chronic hyperglycemia in diabetic patients could result in various complications, including neurotoxicity. Urtica dioica L. (UD) is known for its hypoglycemic and antioxidant effects. In this study, we evaluated the efficacy of UD and pioglitazone (PIO) in reduction of neurotoxicity and oxidative stress in streptozocin-induced diabetic mice. Male mice were divided into seven groups: control, diabetic, dimethyl sulfoxide-treated control, PIO-treated, UD-treated, UD-PIO-treated, and vitamin E-treated. For induction of diabetes, streptozocin was injected in a single dose (65 mg/kg, i.p.). All treatments were performed for 5 weeks. Neurotoxicity was evaluated through hot plate and formalin test. Then, animals were killed, brain tissue was separated and the mitochondrial fraction was isolated with different centrifuge technique. Also, oxidative stress markers (reactive oxygen species, lipid peroxidation, protein carbonyl, glutathione) were measured in brain. Mitochondrial function was evaluated by MTT test in brain isolated mitochondria. Elevation of oxidative stress markers and mitochondrial damage were observed in diabetic mice compared to control group. Administration of PIO and UD ameliorated the oxidative stress and mitochondrial damage (p < 0.05) in diabetic mice. Also increase in pain score was shown in diabetic mice that treatment with UD and PIO diminished elevation of pain score in diabetic mice. Interestingly, simultaneous administration of PIO and UD showed synergism effect in attenuation of oxidative stress and hyperglycemia. UD showed a therapeutic potential for the attenuation of oxidative stress and diabetes-induced hyperglycemia that can be considered as co-treatment in treatment of diabetic neurotoxicity.

Curcumin Protects against Monosodium Glutamate Neurotoxicity and Decreasing NMDA2B and mGluR5 Expression in Rat Hippocampus

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Rania M. Khalil

2016-08-01

Full Text Available Background: Monosodium glutamate (MSG is a flavor enhancer used in food industries. MSG is well documented to induce neurotoxicity. Curcumin (CUR reportedly possesses beneficial effects against various neurotoxic insults. Hence, this present study has been designed to evaluate the neuroprotective effect of curcumin on MSG-induced neurotoxicity in rats. Methods: Thirty-two male Wister rats were divided into four groups (n=8: Control group, MSG group, CUR group and MSG + CUR group. CUR (Curcumin 150 mg/kg, orally was given day after day for four weeks along with MSG (4 mg/kg, orally. After 4 weeks, rats were sacrificed and brain hippocampus was isolated immediately on ice. Inflammatory marker TNFα and acetylcholinesterase (AChE activity (marker for cholinergic function were estimated. Gene expressions of metabotropic glutamate receptor 5 (mGluR5 and N-methyl-D-aspartate receptor 2B (NMDA2B along with glutamate concentration were assessed. Results: Treatment with CUR significantly attenuated AChE activity and TNFα in MSG-treated animals. The anti-inflammatory properties of CUR may be responsible for this observed neuroprotective action. A possible role of CUR to attenuate both glutamate level and gene expression of NMDA2B and mGLUR5 in brain hippocampus was established when compared to MSG group. Conclusion: We concluded that CUR as flavor enhancer protects against MSG-induced neurotoxicity in rats.

Usefulness of the bilirubin/albumin ratio for predicting bilirubin-induced neurotoxicity in premature infants

NARCIS (Netherlands)

Hulzebos, C. V.; van Imhoff, D. E.; Bos, A. F.; Ahlfors, C. E.; Verkade, H. J.; Dijk, P. H.

Unconjugated hyperbilirubinaemia occurs in almost all premature infants and is potentially neurotoxic. Treatment is based on total serum bilirubin (TSB), but treatment thresholds are not evidence based. Free bilirubin (Bf) - that is, not bound to albumin, seems a better parameter for bilirubin

CHLORPYRIFOS DEVELOPMENTAL NEUROTOXICITY: INTERACTION WITH GLUCOCORTICOIDS IN PC12 CELLS

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Slotkin, Theodore A.; Card, Jennifer; Seidler, Frederic J.

2012-01-01

Prenatal coexposures to glucocorticoids and organophosphate pesticides are widespread. Glucocorticoids are elevated by maternal stress and are commonly given in preterm labor; organophosphate exposures are virtually ubiquitous. We used PC12 cells undergoing neurodifferentiation in order to assess whether dexamethasone enhances the developmental neurotoxicity of chlorpyrifos, focusing on concentrations relevant to human exposures. By themselves, each agent reduced the number of cells and the combined exposure elicited a correspondingly greater effect than with either agent alone. There was no general cytotoxicity, as cell growth was actually enhanced, and again, the combined treatment evoked greater cellular hypertrophy than with the individual compounds. The effects on neurodifferentiation were more complex. Chlorpyrifos alone had a promotional effect on neuri to genesis whereas dexamethasone impaired it; combined treatment showed an overall impairment greater than that seen with dexamethasone alone. The effect of chlorpyrifos on differentiation into specific neurotransmitter phenotypes was shifted by dexamethasone. Either agent alone promoted differentiation into the dopaminergic phenotype at the expense of the cholinergic phenotype. However, in dexamethasone-primed cells, chlorpyrifos actually enhanced cholinergic neurodifferentiation instead of suppressing this phenotype. Our results indicate that developmental exposure to glucocorticoids, either in the context of stress or the therapy of preterm labor, could enhance the developmental neurotoxicity of organophosphates and potentially of other neurotoxicants, as well as producing neurobehavioral outcomes distinct from those seen with either individual agent. PMID:22796634

Astragalus Polysaccharide Suppresses 6-Hydroxydopamine-Induced Neurotoxicity in Caenorhabditis elegans

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Haifeng Li

2016-01-01

Full Text Available Astragalus membranaceus is a medicinal plant traditionally used in China for a variety of conditions, including inflammatory and neural diseases. Astragalus polysaccharides are shown to reduce the adverse effect of levodopa which is used to treat Parkinson’s disease (PD. However, the neuroprotective effect of Astragalus polysaccharides per se in PD is lacking. Using Caenorhabditis elegans models, we investigated the protective effect of astragalan, an acidic polysaccharide isolated from A. membranaceus, against the neurotoxicity of 6-hydroxydopamine (6-OHDA, a neurotoxin that can induce parkinsonism. We show that 6-OHDA is able to degenerate dopaminergic neurons and lead to the deficiency of food-sensing behavior and a shorter lifespan in C. elegans. Interestingly, these degenerative symptoms can be attenuated by astragalan treatment. Astragalan is also shown to alleviate oxidative stress through reducing reactive oxygen species level and malondialdehyde content and increasing superoxide dismutase and glutathione peroxidase activities and reduce the expression of proapoptotic gene egl-1 in 6-OHDA-intoxicated nematodes. Further studies reveal that astragalan is capable of elevating the decreased acetylcholinesterase activity induced by 6-OHDA. Together, our results demonstrate that the protective effect of astragalan against 6-OHDA neurotoxicity is likely due to the alleviation of oxidative stress and regulation of apoptosis pathway and cholinergic system and thus provide an important insight into the therapeutic potential of Astragalus polysaccharide in neurodegeneration.

Potentiation of 2,5-hexanedione neurotoxicity by methyl ethyl ketone

International Nuclear Information System (INIS)

Ralston, W.H.; Hilderbrand, R.L.; Uddin, D.E.; Andersen, M.E.; Gardier, R.W.

1985-01-01

Chronic oral administration of a combination of 2.2 mmol methyl ethyl ketone (MEK) and 2.2 mmol 2,5-hexanedione (2,5-HD)/kg/day, 5 days/week resulted in more rapid onset of motor deficits than did chronic dosing with 2.2 mmol 2,5-HD/kg/day alone. In kinetic studies blood time courses of 2,5-HD were determined in rats in the presence and absence of MEK. Concomitant administration of MEK reduced blood 2,5-HD clearance and increased the area under the curve (AUC) for the blood 2,5-HD. In companion experiments with 2,5-[1,6- 14 C]HD as a tracer, neural and nonneural tissues were examined 72 hr following the last treatment at Weeks 1, 2, and 3 of chronic administration of 2,5-HD alone or in combination with an equimolar dose of MEK. Rats treated with 2,5-[ 14 C]HD alone or in combination with MEK demonstrated no difference in total or trichloroacetic acid-precipitable radioactivity in blood, in liver homogenates, or in neurofilament-enriched fractions from sciatic nerve and spinal cord. The data support a suggestion that the potentiation of hexacarbon neurotoxicity by MEK is the result of the persistence of the neurotoxic metabolite in the blood and not the enhanced metabolism of parent hexacarbon to 2,5-HD

Quality of life (QoL) and neurotoxicity in germ-cell cancer survivors (GCCS)

DEFF Research Database (Denmark)

Lauritsen, J.; Bandak, Mikkel; Mortensen, M. S.

2016-01-01

Background: The majority of patients with testicular cancer become long-term survivors. However, treatment is associated with late effects which may hamper QoL. The aims of the present study were to assess the impact of treatment on long-term QoL and evaluate the influence of neurotoxicity on Qo...

3,4-Methylenedioxypyrovalerone prevents while methylone enhances methamphetamine-induced damage to dopamine nerve endings: β-ketoamphetamine modulation of neurotoxicity by the dopamine transporter

Science.gov (United States)

Anneken, John H.; Angoa-Pérez, Mariana; Kuhn, Donald M.

2016-01-01

Methylone, 3,4-methylenedioxypyrovalerone (MDPV), and mephedrone are psychoactive ingredients of ‘bath salts’ and their abuse represents a growing public health care concern. These drugs are cathinone derivatives and are classified chemically as β-ketoamphetamines. Because of their close structural similarity to the amphetamines, methylone, MDPV, and mephedrone share most of their pharmacological, neurochemical, and behavioral properties. One point of divergence in their actions is the ability to cause damage to the CNS. Unlike methamphetamine, the β-ketoamphetamines do not damage dopamine (DA) nerve endings. However, mephedrone has been shown to significantly accentuate methamphetamine neurotoxicity. Bath salt formulations contain numerous different psychoactive ingredients, and individuals who abuse bath salts also coabuse other illicit drugs. Therefore, we have evaluated the effects of methylone, MDPV, mephedrone, and methamphetamine on DA nerve endings. The β-ketoamphetamines alone or in all possible two-drug combinations do not result in damage to DA nerve endings but do cause hyperthermia. MDPV completely protects against the neurotoxic effects of methamphetamine while methylone accentuates it. Neither MDPV nor methylone attenuates the hyperthermic effects of methamphetamine. The potent neuroprotective effects of MDPV extend to amphetamine-, 3,4-methylenedioxymethamphetamine-, and MPTP-induced neurotoxicity. These results indicate that β-ketoamphetamine drugs that are non-substrate blockers of the DA transporter (i.e., MDPV) protect against methamphetamine neurotoxicity, whereas those that are substrates for uptake by the DA transporter and which cause DA release (i.e., methylone, mephedrone) accentuate neurotoxicity. PMID:25626880

A novel antibody-based biomarker for chronic algal toxin exposure and sub-acute neurotoxicity

Science.gov (United States)

Lefebvre, Kathi A.; Frame, Elizabeth R.; Gulland, Frances; Hansen, John D.; Kendrick, Preston S.; Beyer, Richard P.; Bammler, Theo K.; Farin, Frederico M.; Hiolski, Emma M.; Smith, Donald R.; Marcinek, David J.

2012-01-01

The neurotoxic amino acid, domoic acid (DA), is naturally produced by marine phytoplankton and presents a significant threat to the health of marine mammals, seabirds and humans via transfer of the toxin through the foodweb. In humans, acute exposure causes a neurotoxic illness known as amnesic shellfish poisoning characterized by seizures, memory loss, coma and death. Regular monitoring for high DA levels in edible shellfish tissues has been effective in protecting human consumers from acute DA exposure. However, chronic low-level DA exposure remains a concern, particularly in coastal and tribal communities that subsistence harvest shellfish known to contain low levels of the toxin. Domoic acid exposure via consumption of planktivorous fish also has a profound health impact on California sea lions (Zalophus californianus) affecting hundreds of animals yearly. Due to increasing algal toxin exposure threats globally, there is a critical need for reliable diagnostic tests for assessing chronic DA exposure in humans and wildlife. Here we report the discovery of a novel DA-specific antibody response that is a signature of chronic low-level exposure identified initially in a zebrafish exposure model and confirmed in naturally exposed wild sea lions. Additionally, we found that chronic exposure in zebrafish caused increased neurologic sensitivity to DA, revealing that repetitive exposure to DA well below the threshold for acute behavioral toxicity has underlying neurotoxic consequences. The discovery that chronic exposure to low levels of a small, water-soluble single amino acid triggers a detectable antibody response is surprising and has profound implications for the development of diagnostic tests for exposure to other pervasive environmental toxins.

A novel antibody-based biomarker for chronic algal toxin exposure and sub-acute neurotoxicity.

Science.gov (United States)

Lefebvre, Kathi A; Frame, Elizabeth R; Gulland, Frances; Hansen, John D; Kendrick, Preston S; Beyer, Richard P; Bammler, Theo K; Farin, Frederico M; Hiolski, Emma M; Smith, Donald R; Marcinek, David J

2012-01-01

The neurotoxic amino acid, domoic acid (DA), is naturally produced by marine phytoplankton and presents a significant threat to the health of marine mammals, seabirds and humans via transfer of the toxin through the foodweb. In humans, acute exposure causes a neurotoxic illness known as amnesic shellfish poisoning characterized by seizures, memory loss, coma and death. Regular monitoring for high DA levels in edible shellfish tissues has been effective in protecting human consumers from acute DA exposure. However, chronic low-level DA exposure remains a concern, particularly in coastal and tribal communities that subsistence harvest shellfish known to contain low levels of the toxin. Domoic acid exposure via consumption of planktivorous fish also has a profound health impact on California sea lions (Zalophus californianus) affecting hundreds of animals yearly. Due to increasing algal toxin exposure threats globally, there is a critical need for reliable diagnostic tests for assessing chronic DA exposure in humans and wildlife. Here we report the discovery of a novel DA-specific antibody response that is a signature of chronic low-level exposure identified initially in a zebrafish exposure model and confirmed in naturally exposed wild sea lions. Additionally, we found that chronic exposure in zebrafish caused increased neurologic sensitivity to DA, revealing that repetitive exposure to DA well below the threshold for acute behavioral toxicity has underlying neurotoxic consequences. The discovery that chronic exposure to low levels of a small, water-soluble single amino acid triggers a detectable antibody response is surprising and has profound implications for the development of diagnostic tests for exposure to other pervasive environmental toxins.

Differential response of nNOS knockout mice to MDMA ("ecstasy")- and methamphetamine-induced psychomotor sensitization and neurotoxicity.

Science.gov (United States)

Itzhak, Yossef; Anderson, Karen L; Ali, Syed F

2004-10-01

It has been shown that mice deficient in neuronal nitric oxide synthase (nNOS) gene are resistant to cocaine-induced psychomotor sensitization and methamphetamine (METH)-induced dopaminergic neurotoxicity. The present study was undertaken to investigate the hypothesis that nNOS has a major role in dopamine (DA)- but not serotonin (5-hydroxytryptamine; 5-HT)-mediated effects of psychostimulants. The response of nNOS knockout (KO) and wild-type (WT) mice to the psychomotor-stimulating and neurotoxic effects of 3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") and METH were investigated. Repeated administration of MDMA for 5 days resulted in psychomotor sensitization in both WT and nNOS KO mice, while repeated administration of METH caused psychomotor sensitization in WT but not in KO mice. Sensitization to both MDMA and METH was persistent for 40 days in WT mice, but not in nNOS KO mice. These findings suggest that the induction of psychomotor sensitization to MDMA and METH is NO independent and NO dependent, respectively, while the persistence of sensitization to both drugs is NO dependent. For the neurochemical studies, a high dose of MDMA caused marked depletion of 5-HT in several brain regions of both WT and KO mice, suggesting that the absence of the nNOS gene did not afford protection against MDMA-induced depletion of 5-HT. Striatal dopaminergic neurotoxicity caused by high doses of MDMA and METH in WT mice was partially prevented in KO mice administered with MDMA, but it was fully precluded in KO mice administered with METH. The differential response of nNOS KO mice to the behavioral and neurotoxic effects of MDMA and METH suggests that the nNOS gene is required for the expression and persistence of DA-mediated effects of METH and MDMA, while 5-HT-mediated effects of MDMA (induction of sensitization and 5-HT depletion) are not dependent on nNOS.

Neurotoxic Antibodies against the Prion Protein Do Not Trigger Prion Replication.

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Karl Frontzek

Full Text Available Prions are the infectious agents causing transmissible spongiform encephalopathies (TSE, progressive, inexorably lethal neurological diseases. Antibodies targeting the globular domain (GD of the cellular prion protein PrPC trigger a neurotoxic syndrome morphologically and molecularly similar to prion disease. This phenomenon raises the question whether such antibodies induce infectious prions de novo. Here we exposed cerebellar organotypic cultured slices (COCS to the neurotoxic antibody, POM1. We then inoculated COCS homogenates into tga20 mice, which overexpress PrPC and are commonly utilized as sensitive indicators of prion infectivity. None of the mice inoculated with COCS-derived lysates developed any signs of disease, and all mice survived for at least 200 days post-inoculation. In contrast, all mice inoculated with bona fide prions succumbed to TSE after 55-95 days. Post-mortem analyses did not reveal any signs of prion pathology in mice inoculated with POM1-COCS lysates. Also, lysates from POM1-exposed COCS were unable to convert PrP by quaking. Hence, anti-GD antibodies do not catalyze the generation of prion infectivity. These data indicate that prion replication can be separated from prion toxicity, and suggest that anti-GD antibodies exert toxicity by acting downstream of prion replication.

Assessment of neurotoxic effects of mercury in beluga whales (Delphinapterus leucas), ringed seals (Pusa hispida), and polar bears (Ursus maritimus) from the Canadian Arctic.

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Krey, Anke; Ostertag, Sonja K; Chan, Hing Man

2015-03-15

Marine mammals are indicator species of the Arctic ecosystem and an integral component of the traditional Inuit diet. The potential neurotoxic effects of increased mercury (Hg) in beluga whales (Delphinapterus leucas), ringed seals (Pusa hispida), and polar bears (Ursus maritimus) are not clear. We assessed the risk of Hg-associated neurotoxicity to these species by comparing their brain Hg concentrations with threshold concentrations for toxic endpoints detected in laboratory animals and field observations: clinical symptoms (>6.75 mg/kg wet weight (ww)), neuropathological signs (>4 mg/kg ww), neurochemical changes (>0.4 mg/kg ww), and neurobehavioral changes (>0.1mg/kg ww). The total Hg (THg) concentrations in the cerebellum and frontal lobe of ringed seals and polar bears were 3mg/kg ww. Our results suggest that brain THg levels in polar bears are below levels that induce neurobehavioral effects as reported in the literature, while THg concentrations in ringed seals are within the range that elicit neurobehavioral effects and individual ringed seals exceed the threshold for neurochemical changes. The relatively high THg concentration in beluga whales exceeds all of the neurotoxicity thresholds assessed. High brain selenium (Se):Hg molar ratios were observed in all three species, suggesting that Se could protect the animals from Hg-associated neurotoxicity. This assessment was limited by several factors that influence neurotoxic effects in animals, including: animal species; form of Hg in the brain; and interactions with modifiers of Hg-associated toxicity, such as Se. Comparing brain Hg concentrations in wildlife with concentrations of appropriate laboratory studies can be used as a tool for risk characterization of the neurotoxic effects of Hg in Arctic marine mammals. Copyright © 2014 Elsevier B.V. All rights reserved.

Neurotoxicity of amphetamine derivatives is mediated by caspase pathway activation in rat cerebellar granule cells

International Nuclear Information System (INIS)

Jimenez, Andres; Jorda, Elvira G.; Verdaguer, Ester; Pubill, David; Sureda, Francesc X.; Canudas, Anna M.; Escubedo, Elena; Camarasa, Jordi; Camins, Antoni; Pallas, Merce

2004-01-01

The neurotoxic action of the abuse drugs methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA) on cerebellar granule neurones (CGNs) culture was examined. Treatment for 48 h with METH or MDMA (1-5 mM) induced a higher decrease in viability than 24 h treatment. z.VAD.fmk (100 μM) but not MK-801 nor NBQX recovered control viability values. In both cases, cell death was characterised as apoptotic rather than necrotic by morphology cell observation. Apoptosis measured by flow cytometry indicated an increase in the hypodiploid population after 48 h treatment with METH and MDMA. Apoptosis was reverted by the presence of z.VAD.fmk (100 μM) but not by 10 μM MK-801 or NBQX. Similar results were obtained by analysing nuclear chromatine condensation. These results ruled out excitotoxic participation in amphetamine derivative-induced neurotoxicity in CGNs. Participation of radical oxygen species (ROS) was evaluated using α-tocopherol (1-15 μM) and cytometric studies. The co-treatment with 4 mM METH or MDMA for 48 h partially reverted neurotoxic action and apoptotic features, indicating ROS implication in CGNs death by amphetamine derivatives. Alteration of mitochondrial function induced cytochrome C (Cyt C) release after 48-h treatment with METH and MDMA (4 mM). There was also indication of caspase-3-like activation, measured by immunoanalysis and biochemically. Finally, neurodegenerative action caused by amphetamine derivatives may be prevented by using caspase inhibitors

Protective effects of ebselen (Ebs) and para-aminosalicylic acid (PAS) against manganese (Mn)-induced neurotoxicity

Energy Technology Data Exchange (ETDEWEB)

Marreilha dos Santos, A.P., E-mail: apsantos@ff.ul.pt [I-Med.UL, Department of Toxicology and Food Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon (Portugal); Lucas, Rui L.; Andrade, Vanda; Mateus, M. Luísa [I-Med.UL, Department of Toxicology and Food Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon (Portugal); Milatovic, Dejan; Aschner, Michael [Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Batoreu, M. Camila [I-Med.UL, Department of Toxicology and Food Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon (Portugal)

2012-02-01

Chronic, excessive exposure to manganese (Mn) may induce neurotoxicity and cause an irreversible brain disease, referred to as manganism. Efficacious therapies for the treatment of Mn are lacking, mandating the development of new interventions. The purpose of the present study was to investigate the efficacy of ebselen (Ebs) and para-aminosalicylic acid (PAS) in attenuating the neurotoxic effects of Mn in an in vivo rat model. Exposure biomarkers, inflammatory and oxidative stress biomarkers, as well as behavioral parameters were evaluated. Co-treatment with Mn plus Ebs or Mn plus PAS caused a significant decrease in blood and brain Mn concentrations (compared to rats treated with Mn alone), concomitant with reduced brain E{sub 2} prostaglandin (PGE{sub 2}) and enhanced brain glutathione (GSH) levels, decreased serum prolactin (PRL) levels, and increased ambulation and rearing activities. Taken together, these results establish that both PAS and Ebs are efficacious in reducing Mn body burden, neuroinflammation, oxidative stress and locomotor activity impairments in a rat model of Mn-induced toxicity. -- Highlights: ► The manuscript is unique in its approach to the neurotoxicity of Mn. ► The manuscript incorporates molecular, cellular and functional (behavioral) analyses. ► Both PAS and Ebs are effective in restoring Mn behavioral function. ► Both PAS and Ebs are effective in reducing Mn-induced oxidative stress. ► Both PAS and Ebs led to a decrease in Mn-induced neuro-inflammation.

Protective effects of ebselen (Ebs) and para-aminosalicylic acid (PAS) against manganese (Mn)-induced neurotoxicity

International Nuclear Information System (INIS)

Marreilha dos Santos, A.P.; Lucas, Rui L.; Andrade, Vanda; Mateus, M. Luísa; Milatovic, Dejan; Aschner, Michael; Batoreu, M. Camila

2012-01-01

Chronic, excessive exposure to manganese (Mn) may induce neurotoxicity and cause an irreversible brain disease, referred to as manganism. Efficacious therapies for the treatment of Mn are lacking, mandating the development of new interventions. The purpose of the present study was to investigate the efficacy of ebselen (Ebs) and para-aminosalicylic acid (PAS) in attenuating the neurotoxic effects of Mn in an in vivo rat model. Exposure biomarkers, inflammatory and oxidative stress biomarkers, as well as behavioral parameters were evaluated. Co-treatment with Mn plus Ebs or Mn plus PAS caused a significant decrease in blood and brain Mn concentrations (compared to rats treated with Mn alone), concomitant with reduced brain E 2 prostaglandin (PGE 2 ) and enhanced brain glutathione (GSH) levels, decreased serum prolactin (PRL) levels, and increased ambulation and rearing activities. Taken together, these results establish that both PAS and Ebs are efficacious in reducing Mn body burden, neuroinflammation, oxidative stress and locomotor activity impairments in a rat model of Mn-induced toxicity. -- Highlights: ► The manuscript is unique in its approach to the neurotoxicity of Mn. ► The manuscript incorporates molecular, cellular and functional (behavioral) analyses. ► Both PAS and Ebs are effective in restoring Mn behavioral function. ► Both PAS and Ebs are effective in reducing Mn-induced oxidative stress. ► Both PAS and Ebs led to a decrease in Mn-induced neuro-inflammation.

Silver nanoparticles reduce brain inflammation and related neurotoxicity through induction of H2S-synthesizing enzymes

Science.gov (United States)

Gonzalez-Carter, Daniel A.; Leo, Bey Fen; Ruenraroengsak, Pakatip; Chen, Shu; Goode, Angela E.; Theodorou, Ioannis G.; Chung, Kian Fan; Carzaniga, Raffaella; Shaffer, Milo S. P.; Dexter, David T.; Ryan, Mary P.; Porter, Alexandra E.

2017-03-01

Silver nanoparticles (AgNP) are known to penetrate into the brain and cause neuronal death. However, there is a paucity in studies examining the effect of AgNP on the resident immune cells of the brain, microglia. Given microglia are implicated in neurodegenerative disorders such as Parkinson’s disease (PD), it is important to examine how AgNPs affect microglial inflammation to fully assess AgNP neurotoxicity. In addition, understanding AgNP processing by microglia will allow better prediction of their long term bioreactivity. In the present study, the in vitro uptake and intracellular transformation of citrate-capped AgNPs by microglia, as well as their effects on microglial inflammation and related neurotoxicity were examined. Analytical microscopy demonstrated internalization and dissolution of AgNPs within microglia and formation of non-reactive silver sulphide (Ag2S) on the surface of AgNPs. Furthermore, AgNP-treatment up-regulated microglial expression of the hydrogen sulphide (H2S)-synthesizing enzyme cystathionine-γ-lyase (CSE). In addition, AgNPs showed significant anti-inflammatory effects, reducing lipopolysaccharide (LPS)-stimulated ROS, nitric oxide and TNFα production, which translated into reduced microglial toxicity towards dopaminergic neurons. Hence, the present results indicate that intracellular Ag2S formation, resulting from CSE-mediated H2S production in microglia, sequesters Ag+ ions released from AgNPs, significantly limiting their toxicity, concomitantly reducing microglial inflammation and related neurotoxicity.

Neurotoxicity induced by arsenic in Gallus Gallus: Regulation of oxidative stress and heat shock protein response.

Science.gov (United States)

Zhao, Panpan; Guo, Ying; Zhang, Wen; Chai, Hongliang; Xing, Houjuan; Xing, Mingwei

2017-01-01

Arsenic, a naturally occurring heavy metal pollutant, is one of the functioning risk factors for neurological toxicity in humans. However, little is known about the effects of arsenic on the nervous system of Gallus Gallus. To investigate whether arsenic induce neurotoxicity and influence the oxidative stress and heat shock proteins (Hsps) response in chickens, seventy-two 1-day-old male Hy-line chickens were treated with different doses of arsenic trioxide (As 2 O 3 ). The histological changes, antioxidant enzyme activity, and the expressions of Hsps were detected. Results showed slightly histology changes were obvious in the brain tissues exposure to arsenic. The activities of Glutathione peroxidase (GSH-Px) and catalase (CAT) were decreased compared to the control, whereas the malondialdehyde (MDA) content was increased gradually along with increase in diet-arsenic. The mRNA levels of Hsps and protein expressions of Hsp60 and Hsp70 were up-regulated. These results suggested that sub-chronic exposure to arsenic induced neurotoxicity in chickens. Arsenic exposure disturbed the balance of oxidants and antioxidants. Increased heat shock response tried to protect chicken brain tissues from tissues damage caused by oxidative stress. The mechanisms of neurotoxicity induced by arsenic include oxidative stress and heat shock protein response in chicken brain tissues. Copyright © 2016 Elsevier Ltd. All rights reserved.

Methamphetamine- and 1-methyl-4-phenyl- 1,2,3, 6-tetrahydropyridine-induced dopaminergic neurotoxicity in inducible nitric oxide synthase-deficient mice.

Science.gov (United States)

Itzhak, Y; Martin, J L; Ali, S F

1999-12-15

Previous studies have suggested a role for the retrograde messenger, nitric oxide (NO), in methamphetamine (METH)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- induced dopaminergic neurotoxicity. Since evidence supported the involvement of the neuronal nitric oxide synthase (nNOS) isoform in the dopaminergic neurotoxicity, the present study was undertaken to investigate whether the inducible nitric oxide synthase (iNOS) isoform is also associated with METH- and MPTP-induced neurotoxicity. The administration of METH (5mg/kg x 3) to iNOS deficient mice [homozygote iNOS(-/-)] and wild type mice (C57BL/6) resulted in significantly smaller depletion of striatal dopaminergic markers in the iNOS(-/-) mice compared with the wild-type mice. METH-induced hyperthermia was also significantly lower in the iNOS(-/-) mice than in wild-type mice. In contrast to the outcome of METH administration, MPTP injections (20 mg/kg x 3) resulted in a similar decrease in striatal dopaminergic markers in iNOS(-/-) and wild-type mice. In the set of behavioral experiments, METH-induced locomotor sensitization was investigated. The acute administration of METH (1.0 mg/kg) resulted in the same intensity of locomotor activity in iNOS(-/-) and wild-type mice. Moreover, 68 to 72 h after the exposure to the high-dose METH regimen (5 mg/kg x 3), a marked sensitized response to a challenge injection of METH (1.0 mg/kg) was observed in both the iNOS(-/-) and wild-type mice. The finding that iNOS(-/-) mice were unprotected from MPTP-induced neurotoxicity suggests that the partial protection against METH-induced neurotoxicity observed was primarily associated with the diminished hyperthermic effect of METH seen in the iNOS(-/-) mice. Moreover, in contrast to nNOS deficiency, iNOS deficiency did not affect METH-induced behavioral sensitization. Copyright 1999 Wiley-Liss, Inc.

Exercise does not protect against MPTP-induced neurotoxicity in BDNF haploinsufficient mice.

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Kim M Gerecke

Full Text Available Exercise has been demonstrated to potently protect substantia nigra pars compacta (SN dopaminergic neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-induced neurotoxicity. One mechanism proposed to account for this neuroprotection is the upregulation of neurotrophic factors. Several neurotrophic factors, including Brain Derived Neurotrophic Factor (BDNF, have been shown to upregulate in response to exercise. In order to determine if exercise-induced neuroprotection is dependent upon BDNF, we compared the neuroprotective effects of voluntary exercise in mice heterozygous for the BDNF gene (BDNF+/- with strain-matched wild-type (WT mice. Stereological estimates of SNpc DA neurons from WT mice allowed 90 days exercise via unrestricted running demonstrated complete protection against the MPTP-induced neurotoxicity. However, BDNF+/- mice allowed 90 days of unrestricted exercise were not protected from MPTP-induced SNpc DA neuron loss. Proteomic analysis comparing SN and striatum from 90 day exercised WT and BDNF+/- mice showed differential expression of proteins related to energy regulation, intracellular signaling and trafficking. These results suggest that a full genetic complement of BDNF is critical for the exercise-induced neuroprotection of SNpc DA neurons.

Acute Toxicity and Neurotoxicity of Chlorpyrifos in Black Tiger Shrimp, Penaeus monodon

Directory of Open Access Journals (Sweden)

Tassanee Eamkamon

2012-01-01

Full Text Available Acute toxicity and neurotoxicity of chlorpyrifos were determined in black tiger shrimp, P. monodon. LC50 values after 24 to 96 h of exposure were between 149.55 and 59.16 nmol/L. To determine the neurotoxicity of chlorpyrifos, the inhibition of acetylcholinesterase was monitored in the gill of the shrimps exposed to lethal (0.019, 0.194, and 1.942 µmol/L and sub-lethal (0.019, 0.194, and 1.942 nmol/L concentrations of chlorpyrifos. In lethal dose exposure, the AChE activities observed in shrimp exposed to 0.194, and 1.942 µmol/L of chlorpyrifos were significantly lower (1.7 and 3.3 times than that of control shrimp after 30 min of exposure (p<0.05. In sub-lethal exposure tests, the AChE activity of shrimp was significantly lower (1.9 times than that of control shrimp after exposure to 1.942 nmol/L of chlorpyrifos for 72 h (p<0.05. The sensitive reduction of AChE activity at the sub-lethal concentration, which was 30 times lower than 96 h LC50 value found in this study, indicates the potential use as a biomarker of chlorpyrifos exposure.

High molecular weight of polysaccharides from Hericium erinaceus against amyloid beta-induced neurotoxicity.

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Cheng, Jai-Hong; Tsai, Chia-Ling; Lien, Yi-Yang; Lee, Meng-Shiou; Sheu, Shyang-Chwen

2016-06-07

Hericium erinaceus (HE) is a well-known mushroom in traditional Chinese food and medicine. HE extracts from the fruiting body and mycelia not only exhibit immunomodulatory, antimutagenic and antitumor activity but also have neuroprotective properties. Here, we purified HE polysaccharides (HEPS), composed of two high molecular weight polysaccharides (1.7 × 10(5) Da and 1.1 × 10(5) Da), and evaluated their protective effects on amyloid beta (Aβ)-induced neurotoxicity in rat pheochromocytoma PC12 cells. HEPS were prepared and purified using a 95 % ethanol extraction method. The components of HEPS were analyzed and the molecular weights of the polysaccharides were determined using high-pressure liquid chromatography (HPLC). The neuroprotective effects of the polysaccharides were evaluated through a 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and an MTT assay and by quantifying reactive oxygen species (ROS) and mitochondrial membrane potentials (MMP) of Aβ-induced neurotoxicity in cells. Our results showed that 250 μg/ml HEPS was harmless and promoted cell viability with 1.2 μM Aβ treatment. We observed that the free radical scavenging rate exceeded 90 % when the concentration of HEPS was higher than 1 mg/mL in cells. The HEPS decreased the production of ROS from 80 to 58 % in a dose-dependent manner. Cell pretreatment with 250 μg/mL HEPS significantly reduced Aβ-induced high MMPs from 74 to 51 % and 94 to 62 % at 24 and 48 h, respectively. Finally, 250 μg/mL of HEPS prevented Aβ-induced cell shrinkage and nuclear degradation of PC12 cells. Our results demonstrate that HEPS exhibit antioxidant and neuroprotective effects on Aβ-induced neurotoxicity in neurons.

Protection against MPP(+)-induced neurotoxicity in SH-SY5Y cells by tormentic acid via the activation of PI3-K/Akt/GSK3β pathway.

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Zhao, Qing; Ye, Junli; Wei, Na; Fong, Chichun; Dong, Xiaoli

2016-07-01

The cause of Parkinson's disease (PD) could be ascribed to the progressive and selective loss of dopaminergic neurons in the substantia nigra pars compacta, and thus molecules with neuroprotective ability may have therapeutic value against PD. In the current study, the neuroprotective effects and underlying mechanisms of tormentic acid (TA), a naturally occurring triterpene extracted from medicinal plants such as Rosa rugosa and Potentilla chinensis, were evaluated in a widely used cellular PD model in which neurotoxicity was induced by MPP(+) in cultured SH-SY5Y cells. We found that TA at 1-30 μM substantially protected against MPP(+)-induced neurotoxicity, as evidenced by the increase in cell viability, decrease in lactate dehydrogenase release and the reduction in apoptotic nuclei. Moreover, TA effectively inhibited the elevated intracellular accumulation of reactive oxygen species as well as Bax/Bcl-2 ratio caused by MPP(+). Most importantly, TA markedly reversed the inhibition of protein expression of phosphorylated Akt (Ser 473) and phosphorylated GSK3β (Ser 9) caused by MPP(+). LY294002, the specific inhibitor of PI3-K, significantly abrogated the up-regulated phosphorylated Akt and phosphorylated GSK3β offered by TA, suggesting that the neuroprotection of TA was mainly dependent on the activation of PI3-K/Akt/GSK3β signaling pathway. The results taken together indicate that TA may be a potential candidate for further preclinical study aimed at the prevention and treatment of PD. Copyright © 2016 Elsevier Ltd. All rights reserved.

Syntheses, structures and magnetic properties of four coordination polymers based on nitrobenzene dicarboxylate and various N-donor coligands

Energy Technology Data Exchange (ETDEWEB)

Li, Gui-Lian; Yin, Wei-Dong; Liu, Guang-Zhen; Ma, Lu-Fang [College of Chemistry and Chemical Engineering, Luoyang Normal University, Luoyang 471022, Henan (China); Wang, Li-Ya, E-mail: gzliuly@126.com [College of Chemistry and Chemical Engineering, Luoyang Normal University, Luoyang 471022, Henan (China); College of Chemistry and Pharmacy Engineering, Nanyang Normal University, Nanyang 473061, Henan (China)

2014-12-15

Four new coordination polymers ([Ni(4-Nbdc)(bpa)(H{sub 2}O)]){sub n} (1), ([Co(4-Nbdc)(bpp) (H{sub 2}O)]){sub n} (2), ([Ni(4-Nbdc)(bpp)(H{sub 2}O)]·H{sub 2}O){sub n} (3), and ([Mn{sub 2}(3-Nbdc){sub 2}(bib){sub 3}]·2H{sub 2}O){sub n} (4) (4-Nbdc=4-nitrobenzene-1,2-dicarboxylate, 3-Nbdc=3-nitrobenzene-1,2-dicarboxylate, bpa=1,2-bi(4-pyridyl)ethane, bpp=1,3-bis(4-pyridyl)propane, and bib=1,4-bis(1-imidazoly)benzene), were synthesized by hydrothermal reactions, and characterized by single-crystal X-ray diffractions, elemental analysis, FT-IR, PXRD, TGA and magnetic analysis. Complexes 1 and 2 display quasi-trapezoidal chain and brick-wall layer, and both of them contain metal–carboxylate binuclear units. Complexes 3 and 4 exhibit three-dimensional frameworks with the (6{sup 6}) dia topology and (4{sup 4}.6{sup 10}.8)(4{sup 4}.6{sup 2}) fsc topology, and both of them contain metal–carboxylate chains. The carboxyl groups with syn-anti coordination mode mediate effectively the weak ferromagnetic coupling interaction within Ni(II)–carboxylate binuclear in 1 (J=1.27 cm{sup −1}) and Ni(II)–carboxylate chain in 3 (J=1.44 cm{sup −1}), respectively, and the carboxyl groups with anti-anti coordination mode leads to the classic antiferromagnetic coupling interaction within Mn(II)–carboxylate chain in 4 (J=−0.77 cm{sup −1}). - Highlights: • Four novel coordination polymers were hydrothermally synthesized. • 1 is 1D quasi-trapezoidal chain and 2 is brick-wall layer both with dinuclear units. • 3 and 4 show 3D frameworks both with 1D metal–carboxylate chains. • 1 and 3 exhibit ferromagnetic coupling, while 4 shows antiferromagnetic coupling.

Luminescence recognition of different organophosphorus pesticides by the luminescent Eu(III)–pyridine-2,6-dicarboxylic acid probe

International Nuclear Information System (INIS)

Azab, Hassan A.; Duerkop, Axel; Anwar, Z.M.; Hussein, Belal H.M.; Rizk, Moustafa A.; Amin, Tarek

2013-01-01

Highlights: ► Europium (III) luminescence quenching has been used for sensing organophosphorous pesticides. ► Four guest pesticides chlorfenvinphos, malathion, azinphos, and paraxon ethyl were used. ► A sensitive rapid, cheap direct method for the determination of the pesticides has been developed. ► The method was applied to the determination of the OPs in tap, river, mineral, and waste waters. - Abstract: Luminescence quenching of a novel long lived Eu(III)–pyridine-2,6-dicarboxylic acid probe of 1:2 stoichiometric ratio has been studied in 0.10 volume fraction ethanol–water mixture at pH 7.5 (HEPES buffer) in the presence of the organophosphorus pesticides chlorfenvinphos (P1), malathion (P2), azinphos (P3), and paraxon ethyl (P4). The luminescence intensity of Eu(III)–(PDCA) 2 probe decreases as the concentration of the pesticide increases. It was observed that the quenching due to P3 and P4 proceeds via both diffusional and static quenching processes. Direct methods for the determination of the pesticides under investigation have been developed using the luminescence quenching of Eu(III)–pyridine-2,6-dicarboxylic acid probe in solution. The linear range for determination of the selected pesticides is 1.0–35.0 μM. The detection limits were 0.24–0.55 μM for P3, P4, and P1 and 2.5 μM for P2, respectively. The binding constants (K), and thermodynamic parameters of the OPs with Eu(III)–(PDCA) 2 were evaluated. Positive and negative values of entropy (ΔS) and enthalpy (ΔH) changes for Eu(III)–(PDCA) 2 –P1 ternary complex were calculated. As the waters in this study do not contain the above mentioned OPs over the limit detectable by the method, a recovery study was carried out after the addition of the adequate amounts of the organophosphorus pesticides under investigation.

Akkumulation von L-Malat und D-Lactat in Arabidopsis thaliana und Laccase/HBT-vermittelte Delignifizierung von Spartina alterniflora und Phragmites australis

OpenAIRE

Heil, Alexander

2016-01-01

The current work contains two projects "Accumulation of L-malate and D-lactate in Arabidopsis thaliana" (A) "Laccase/HBT mediated delignification of Spartina alterniflora and Phragmites australis" (B). In project A, L-malate and D-lactate accumulated in A. thaliana plants. The accumulation of L-malate is carried out by modification of the plant metabolism with the enzymes PEPC, MDH and the tonoplast dicarboxylate transporter (TDT). Gene pepci2 (Hydrilla verticillata), mdh5 (Zea mays) and tdt ...

Neurotoxic and Cytotoxic Effects of Venom from Different Populations of the Egyptian Scorpio Maurus Palmatus

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Neurotoxic and cytotoxic effects of venoms from Scorpio maurus palmatus taken from different populations were assessed for geographic based variability in toxicity and to evaluate their insecticidal potency. Scorpions were collected from four regions. Three locations were mutually isolated pockets i...

Buyang Huanwu Decoction Vigorously Rescues PC12 Cells Against 6-OHDA-Induced Neurotoxicity via Akt/GSK3β Pathway Based on Serum Pharmacology Methodology.

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Li, Zeyan; Wang, Hui; Wang, Qian; Sun, Jinhao

2016-12-01

Buyang Huanwu decoction (BYHWD), as a popular traditional Chinese medicine formula, was widely used for treating ischemic diseases. However, in the area of neurodegenerative diseases, the researches focused on BYHWD are rare but promising, and molecular mechanisms underlying are largely elusive. 6-Hydroxydopamine (6-OHDA), a dopaminergic-specific neurotoxin, is extensively used to establish neurotoxic model in vivo and in vitro. In our present study, we prepared drug-containing serum of BYHWD (Buyang Huanwu drug-containing serum [BYHWS]) based on serum pharmacology methodology. Neurotoxic model in vitro was established in PC12 cells, and innovative experimental grouping method was adopted to investigate neuroprotective effects of BYHWS on neurotoxicity induced by 6-OHDA exposure. Remarkably, BYHWS vigorously rescued PC12 cells from 6-OHDA-induced neurotoxicity even to surpass 100% in cell viability. Moreover, Hoechst/propidium iodide (PI) staining revealed that cell apoptotic rate was reduced significantly after incubation of BYHWS. Besides, BYHWS effectively restored the disruption of mitochondrial membrane potential and attenuated the elevation of intracellular reactive oxygen species level caused by 6-OHDA insult. Furthermore, BYHWS remarkably reversed the dephosphorylation of Akt (protein kinase B) and glycogen synthase kinase-3β (GSK3β) evoked by 6-OHDA. The above protective effects were attenuated by coculturing with Akt inhibitor LY294002. In summary, we concluded that the BYHWS vigorously blocked 6-OHDA-induced neurotoxicity via Akt/GSK3β pathway and provided a novel insight into roles of BYHWD in the clinical practices on neurodegenerative diseases.

Effect of melatonin on methamphetamine- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity and methamphetamine-induced behavioral sensitization.

Science.gov (United States)

Itzhak, Y; Martin, J L; Black, M D; Ali, S F

1998-06-01

Methamphetamine (METH)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity is thought to be associated with the formation of free radicals. Since evidence suggests that melatonin may act as a free radical scavenger and antioxidant, the present study was undertaken to investigate the effect of melatonin on METH- and MPTP-induced neurotoxicity. In addition, the effect of melatonin on METH-induced locomotor sensitization was investigated. The administration of METH (5 mg kg(-1) x 3) or MPTP (20 mg kg(-1) x 3) to Swiss Webster mice resulted in 45-57% depletion in the content of striatal dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, and 57-59% depletion in dopamine transporter binding sites. The administration of melatonin (10 mg kg(-1)) before each of the three injections of the neurotoxic agents (on day 1), and thereafter for two additional days, afforded a full protection against METH-induced depletion of dopamine and its metabolites and dopamine transporter binding sites. In addition, melatonin significantly diminished METH-induced hyperthermia. However, the treatment with melatonin had no significant effect on MPTP-induced depletion of the dopaminergic markers tested. In the set of behavioral experiments, we found that the administration of 1 mg kg(-1) METH to Swiss Webster mice for 5 days resulted in marked locomotor sensitization to a subsequent challenge injection of METH, as well as context-dependent sensitization (conditioning). The pretreatment with melatonin (10 mg kg(-1)) prevented neither the sensitized response to METH nor the development of conditioned locomotion. Results of the present study indicate that melatonin has a differential effect on the dopaminergic neurotoxicity produced by METH and MPTP. Since it is postulated that METH-induced hyperthermia is related to its neurotoxic effect, while regulation of body temperature is unrelated to MPTP-induced neurotoxicity or METH

Structural modulation and luminescent properties of four Cd{sup II} coordination architectures based on 3-(pyridin-4-yl)-5-(pyrazin-2-yl)-1H-1,2,4-triazole and flexible/rigid dicarboxylate ligands

Energy Technology Data Exchange (ETDEWEB)

Xia, Liang; Dong, Wen-Wen, E-mail: dongww1@126.com; Ye, Xiao; Zhao, Jun; Li, Dong-Sheng, E-mail: lidongsheng1@126.com

2016-10-15

To systematically investigate the influence of the flexible or rigid auxiliary ligands on the structures and properties of transition metal compounds, we synthesized four new d{sup 10} coordination polymers (CPs) from 3-(pyridin-4-yl)-5-(pyrazin-2-yl)-1H-1,2,4-triazole (4-Hpzpt) and flexible/rigid dicarboxylate ligands, [Cd(4-pzpt){sub 2}]{sub n} (1), [Cd{sub 3}(4-pzpt){sub 2}(suc){sub 2}]{sub n} (2), [Cd{sub 2}(4-Hpzpt)(nbc){sub 2}(H{sub 2}O)]{sub n} (3) and ([Cd{sub 2}(4-pzpt){sub 2}(tfbdc)(H{sub 2}O){sub 4}]·H{sub 2}O){sub n} (4) (H{sub 2}suc=1,2-ethanedicarboxylic acid, H{sub 2}nbc=hthalene-1,4-dicarboxylic acid, H{sub 2}tfbdc =2,3,5,6-tetrafluoroterephthalic acid). Single crystal X-ray analysis indicates that compound 1 shows a 4{sup 4}-sql layer, which is extended to a 3D network via nonclassical C–H{sup …}N hydrogen bonds. Compound 2 possesses a 6-connected pcu-4{sup 12}0.6{sup 3} net composed of trinuclear Cd{sup II}-clusters. Compound 3 represents a rare 3D (3,4,4,5)-connected topology with a Schläfli symbol of (4·6·7)(4·5{sup 3}·7{sup 2})(5{sup 3}·6·7·9)(4{sup 2}·5{sup 5}·6·7{sup 2}). Compound 4 exhibits a 2D+2D→2D parallel interpenetrated 6{sup 3}-hcb network. The adjacent 2D networks are interdigitated with each other to form the resulting 3D supramolecular architecture through classical O–H{sup …}N and O–H{sup …}O hydrogen bonds. Structural diversities indicate that the nature of flexible/rigid-dicarboxlates plays crucial roles in modulating structures of these compounds. Moreover, the luminescent properties of them have been briefly investigated. - Graphical abstract: Four new Cd{sup II} coordination architectures constructed from the primary ligand 4-Hpzpt and flexible/rigid dicarboxylate coligands. Structural diversities indicate that the nature of flexible/rigid-dicarboxlates plays crucial roles in modulating structures of these compounds. And more, the thermal stability and luminescence are discussed. - Highlights: �

Maneb and Paraquat-Mediated Neurotoxicity: Involvement of Peroxiredoxin/Thioredoxin System

Science.gov (United States)

Roede, James R.; Hansen, Jason M.; Go, Young-Mi; Jones, Dean P.

2011-01-01

Epidemiological and in vivo studies have demonstrated that exposure to the pesticides paraquat (PQ) and maneb (MB) increase the risk of developing Parkinson’s disease (PD) and cause dopaminergic cell loss, respectively. PQ is a well-recognized cause of oxidative toxicity; therefore, the purpose of this study was to determine if MB potentiates oxidative stress caused by PQ, thus providing a mechanism for enhanced neurotoxicity by the combination. The results show that PQ alone at a moderately toxic dose (20–30% cell death in 24 h) caused increased reactive oxygen species (ROS) generation, oxidation of mitochondrial thioredoxin-2 and peroxiredoxin-3, lesser oxidation of cytoplasmic thioredoxin-1 and peroxiredoxin-1, and no oxidation of cellular GSH/GSSG. In contrast, MB alone at a similar toxic dose resulted in no ROS generation, no oxidation of thioredoxin and peroxiredoxin, and an increase in cellular GSH after 24 h. Together, MB increased GSH and inhibited ROS production and thioredoxin/peroxiredoxin oxidation observed with PQ alone, yet resulted in more extensive (> 50%) cell death. MB treatment resulted in increased abundance of nuclear Nrf2 and mRNA for phase II enzymes under the control of Nrf2, indicating activation of cell protective responses. The results show that MB potentiation of PQ neurotoxicity does not occur by enhancing oxidative stress and suggests that increased toxicity occurs by a combination of divergent mechanisms, perhaps involving alkylation by MB and oxidation by PQ. PMID:21402726

LEARNING AND MEMORY TESTS IN DEVELOPMENTAL NEUROTOXICITY TESTING: A CROSS-LABORATORY COMPARISON OF CONTROL DATA.

Science.gov (United States)

The US EPA Developmental Neurotoxicity (DNT) Study Test Guideline (OPPTS 870.6300) calls for functional tests to assess the impact of chemicals on cognitive function in offspring following maternal exposure. A test of associative learning and memory is to be conducted around th...

Design and validation of an ontology-driven animal-free testing strategy for developmental neurotoxicity testing.

NARCIS (Netherlands)

Hessel, Ellen V S; Staal, Yvonne C M; Piersma, Aldert H

2018-01-01

Developmental neurotoxicity entails one of the most complex areas in toxicology. Animal studies provide only limited information as to human relevance. A multitude of alternative models have been developed over the years, providing insights into mechanisms of action. We give an overview of

Developmental Neurotoxicity Study of Dietary Bisphenol A in Sprague-Dawley Rats

OpenAIRE

Stump, Donald G.; Beck, Melissa J.; Radovsky, Ann; Garman, Robert H.; Freshwater, Lester L.; Sheets, Larry P.; Marty, M. Sue; Waechter, John M.; Dimond, Stephen S.; Van Miller, John P.; Shiotsuka, Ronald N.; Beyer, Dieter; Chappelle, Anne H.; Hentges, Steven G.

2010-01-01

This study was conducted to determine the potential of bisphenol A (BPA) to induce functional and/or morphological effects to the nervous system of F1 offspring from dietary exposure during gestation and lactation according to the Organization for Economic Cooperation and Development and U.S. Environmental Protection Agency guidelines for the study of developmental neurotoxicity. BPA was offered to female Sprague-Dawley Crl:CD (SD) rats (24 per dose group) and their litters at dietary concent...

Neurotoxicity of Prosopis juliflora: from Natural Poisoning to Mechanism of Action of Its Piperidine Alkaloids.

Science.gov (United States)

da Silva, Victor Diogenes Amaral; da Silva, André Mario Mendes; E Silva, Juliana Helena Castro; Costa, Silvia Lima

2018-01-16

Prosopis juliflora was introduced in northeastern Brazil in the 1940s, and since then, it has been available as an alternative for animal nutrition. However, the consumption of P. juliflora as main or sole source of food causes an illness in animals known locally as "cara torta" disease. Cattle and goats experimentally intoxicated presents neurotoxic damage in the central nervous system. Histologic lesions were mainly characterized by vacuolation and loss of neurons in trigeminal motor nuclei. Furthermore, mitochondrial damage in neurons and gliosis was reported in trigeminal nuclei of intoxicated cattle. Studies, using neural cell cultures, have reproduced the main cellular alterations visualized in cara torta disease and contributed to understanding the mechanism of action piperidine alkaloids, the main neurotoxic compound in P. juliflora leaves and pods. Here, we will present aspects of the biological and toxicological properties of P. juliflora and its pharmacologically active compounds.

[The development of neurotoxic agents as chemical weapons during the National Socialist period in Germany].

Science.gov (United States)

López-Muñoz, F; Alamo, C; Guerra, J A; García-García, P

The discovery and development of the so-called 'nerve agents' (neurotoxic substances to be used as weapons) took place in the Third Reich, largely thanks to the vast amount of progress being made in pharmacology in Germany at that time, both in academic and industrial terms. Furthermore, successive National Socialist governments set up a collaborative network made up of the academia, the chemical industry and military chiefs that also favoured this line of research. The first neurotoxic substance to be incorporated into the category of 'chemical warfare agent' did so almost wholly by chance. As part of the work being carried out on organophosphate-type pesticides and insecticides, Gerald Schrader, a chemist at the I.G. Farben company, synthesised tabun (ethyl N,N-dimethylphosphoramidocyanidate) and an incident involving accidental contamination of laboratory staff with this substance highlighted its potential toxicity. The same group of researchers later synthesised another substance with the same properties, sarin (isopropyl methylphosphonofluoridate). Both agents were studied for use as chemical weapons by Wolfgang Wirth. At the same time, a group led by Richard Kuhn, who won the Nobel Prize in Chemistry in 1938, synthesised pinacolyl methylphosphonofluoridate, otherwise known as soman. Pharmacological studies confirmed that the neurotoxic mechanism of action of these substances was the irreversible inhibition of the enzyme acetylcholinesterase, which is responsible for metabolising acetylcholine. Results also showed that an excess of this neurotransmitter led to a continuous over-stimulation of the cholinergic (nicotinic and muscarinic) receptors, which is what triggers the appearance of the wide range of symptoms of poisoning and their swift fatal effect.

Protective role of Cynodon dactylon in ameliorating the aluminium-induced neurotoxicity in rat brain regions.

Science.gov (United States)

Sumathi, Thangarajan; Shobana, Chandrasekar; Kumari, Balasubramanian Rathina; Nandhini, Devarajulu Nisha

2011-12-01

Cynodon dactylon (Poaceae) is a creeping grass used as a traditional ayurvedic medicine in India. Aluminium-induced neurotoxicity is well known and different salts of aluminium have been reported to accelerate damage to biomolecules like lipids, proteins and nucleic acids. The objective of the present study was to investigate whether the aqueous extract of C. dactylon (AECD) could potentially prevent aluminium-induced neurotoxicity in the cerebral cortex, hippocampus and cerebellum of the rat brain. Male albino rats were administered with AlCl(3) at a dose of 4.2 mg/kg/day i.p. for 4 weeks. Experimental rats were given C. dactylon extract in two different doses of 300 mg and 750 mg/keg/day orally 1 h prior to the AlCl(3) administration for 4 weeks. At the end of the experiments, antioxidant status and activities of ATPases in cerebral cortex, hippocampus and cerebellum of rat brain were measured. Aluminium administration significantly decreased the level of GSH and the activities of SOD, GPx, GST, Na(+)/K(+) ATPase, and Mg(2+) ATPase and increased the level of lipid peroxidation (LPO) in all the brain regions when compared with control rats. Pre-treatment with AECD at a dose of 750 mg/kg b.w increased the antioxidant status and activities of membrane-bound enzymes (Na(+)/K(+) ATPase and Mg(2+) ATPase) and also decreased the level of LPO significantly, when compared with aluminium-induced rats. The results of this study indicated that AECD has potential to protect the various brain regions from aluminium-induced neurotoxicity.

D-deprenyl protects nigrostriatal neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity.

Science.gov (United States)

Muralikrishnan, Dhanasekharan; Samantaray, Supriti; Mohanakumar, Kochupurackal P

2003-10-01

Selegiline (L-deprenyl) is believed to render protection against l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-neurotoxicity to a significant extent via a free radical scavenging mechanism, which is independent of its ability to inhibit monoamine oxidase-B (MAO-B) in the brain. We investigated the hydroxyl radical (.OH) scavenging action and neuroprotective effect of D-deprenyl, its less active isomer, in MPTP-induced dopaminergic neurotoxicity in mice to test whether the chemical structure of the molecule or its biological effects contribute to this property. To achieve this goal we studied the effects of D-deprenyl on: (1).OH production in a Fenton reaction; (2) MPTP-induced.OH generation and dopamine (DA) depletion in vivo, employing a sensitive HPLC-electrochemical procedure; and (3) formation of MPP(+) in vivo in the striatum following systemic administration of MPTP, employing an HPLC-photodiode array detection system. D-deprenyl inhibited ferrous citrate-induced.OH in vitro (0.45 microM) and MPTP-induced.OH in vivo in substantia nigra (SN) and in the striatum (1.0 mg/kg, i.p.). D-deprenyl did not, but L-deprenyl (0.5 mg/kg dose) did significantly inhibit formation of MPP(+) in the striatum 90 min following systemic MPTP injection. It failed to affect MAO-B activity at 0.5 mg/kg in the striatum, but effectively blocked MPTP-induced striatal DA depletion. The potency of D-deprenyl to scavenge MPTP-induced.OH in vivo and to render protection against the dopaminergic neurotoxicity without affecting dopamine turnover, MAO-B activity, or formation of MPP(+) in the brain indicates a direct involvement of.OH in the neurotoxic action of MPTP and antioxidant effect in the neuroprotective action of deprenyl. Copyright 2003 Wiley-Liss, Inc.

The Protective Effects of IGF-1 on Different Subpopulations of DRG Neurons with Neurotoxicity Induced by gp120 and Dideoxycytidine In Vitro.

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Lu, Lin; Dong, Haixia; Liu, Guixiang; Yuan, Bin; Li, Yizhao; Liu, Huaxiang

2014-11-01

Peripheral neuropathy induced by human immunodeficiency virus (HIV) infection and antiretroviral therapy is not only difficult to distinguish in clinical practice, but also difficult to relieve the pain symptoms by analgesics because of the severity of the disease at the later stage. Hence, to explore the mechanisms of HIV-related neuropathy and find new therapeutic options are particularly important for relieving neuropathic pain symptoms of the patients. In the present study, primary cultured embryonic rat dorsal root ganglion (DRG) neurons were used to determine the neurotoxic effects of HIV-gp120 protein and/or antiretroviral drug dideoxycytidine (ddC) and the therapeutic actions of insulin-like growth factor-1 (IGF-1) on gp120- or ddC-induced neurotoxicity. DRG neurons were exposed to gp120 (500 pmol/L), ddC (50 μmol/L), gp120 (500 pmol/L) plus ddC (50 μmol/L), gp120 (500 pmol/L) plus IGF-1 (20 nmol/L), ddC (50 μmol/L) plus IGF-1 (20 nmol/L), gp120 (500 pmol/L) plus ddC (50 μmol/L) plus IGF-1 (20 nmol/L), respectively, for 72 hours. The results showed that gp120 and/or ddC caused neurotoxicity of primary cultured DRG neurons. Interestingly, the severity of neurotoxicity induced by gp120 and ddC was different in different subpopulation of DRG neurons. gp120 mainly affected large diameter DRG neurons (>25 μm), whereas ddC mainly affected small diameter DRG neurons (≤25 μm). IGF-1 could reverse the neurotoxicity induced by gp120 and/or ddC on small, but not large, DRG neurons. These data provide new insights in elucidating the pathogenesis of HIV infection- or antiretroviral therapy-related peripheral neuropathy and facilitating the development of novel treatment strategies.

Exercise Does Not Protect against MPTP-Induced Neurotoxicity in BDNF Happloinsufficent Mice

OpenAIRE

Gerecke, Kim M.; Jiao, Yun; Pagala, Viswajeeth; Smeyne, Richard J.

2012-01-01

Exercise has been demonstrated to potently protect substantia nigra pars compacta (SN) dopaminergic neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. One mechanism proposed to account for this neuroprotection is the upregulation of neurotrophic factors. Several neurotrophic factors, including Brain Derived Neurotrophic Factor (BDNF), have been shown to upregulate in response to exercise. In order to determine if exercise-induced neuroprotection is depende...

EEG with extreme delta brush in young female with methotrexate neurotoxicity supports NMDA receptor involvement

DEFF Research Database (Denmark)

Schmidt, Lisbeth Samsø; Kjær, Troels W; Schmiegelow, Kjeld

2017-01-01

Sub-acute neurotoxicity is a well-known complication to high-dose and intrathecal methotrexate (MTX) treatment of children with leukemia. Symptoms can be treated safely by dextromethorphan, a non-competitive antagonist to N-methyl-D-aspartic acid receptor (NMDAR). In a female with subacute MTX...

Pre-fibrillar α-synuclein variants with impaired β-structure increase neurotoxicity in Parkinson's disease models

NARCIS (Netherlands)

Karpinar, D.P.; Giller, K.; Becker, S.; Baldus, M.

2009-01-01

The relation of -synuclein (S) aggregation to Parkinson's disease (PD) has long been recognized, but the mechanism of toxicity, the pathogenic species and its molecular properties are yet to be identified. To obtain insight into the function different aggregated S species have in neurotoxicity in

Different Molecular Mechanisms Mediate Direct or Glia-Dependent Prion Protein Fragment 90-231 Neurotoxic Effects in Cerebellar Granule Neurons.

Science.gov (United States)

Thellung, Stefano; Gatta, Elena; Pellistri, Francesca; Villa, Valentina; Corsaro, Alessandro; Nizzari, Mario; Robello, Mauro; Florio, Tullio

2017-10-01

Glia over-stimulation associates with amyloid deposition contributing to the progression of central nervous system neurodegenerative disorders. Here we analyze the molecular mechanisms mediating microglia-dependent neurotoxicity induced by prion protein (PrP)90-231, an amyloidogenic polypeptide corresponding to the protease-resistant portion of the pathological prion protein scrapie (PrP Sc ). PrP90-231 neurotoxicity is enhanced by the presence of microglia within neuronal culture, and associated to a rapid neuronal [Ca ++ ] i increase. Indeed, while in "pure" cerebellar granule neuron cultures, PrP90-231 causes a delayed intracellular Ca ++ entry mediated by the activation of NMDA receptors; when neuron and glia are co-cultured, a transient increase of [Ca ++ ] i occurs within seconds after treatment in both granule neurons and glial cells, then followed by a delayed and sustained [Ca ++ ] i raise, associated with the induction of the expression of inducible nitric oxide synthase and phagocytic NADPH oxidase. [Ca ++ ] i fast increase in neurons is dependent on the activation of multiple pathways since it is not only inhibited by the blockade of voltage-gated channel activity and NMDA receptors but also prevented by the inhibition of nitric oxide and PGE 2 release from glial cells. Thus, Ca ++ homeostasis alteration, directly induced by PrP90-231 in cerebellar granule cells, requires the activation of NMDA receptors, but is greatly enhanced by soluble molecules released by activated glia. In glia-enriched cerebellar granule cultures, the activation of inducible nitric oxide (iNOS) and NADPH oxidase represents the main mechanism of toxicity since their pharmacological inhibition prevented PrP90-231 neurotoxicity, whereas NMDA blockade by D(-)-2-amino-5-phosphonopentanoic acid is ineffective; conversely, in pure cerebellar granule cultures, NMDA blockade but not iNOS inhibition strongly reduced PrP90-231 neurotoxicity. These data indicate that amyloidogenic peptides

Role of mitochondrial dysfunction in neurotoxicity of MPP+: partial protection of PC12 cells by acetyl-L-carnitine.

Science.gov (United States)

Virmani, Ashraf; Gaetani, Franco; Binienda, Zbigniew; Xu, Alex; Duhart, Helen; Ali, Syed F

2004-10-01

The damage to the central nervous system that is observed after administration of either methamphetamine (METH) or 1-methyl-4-phenylpyridinium (MPP+), the neurotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is known to be linked to dopamine (DA). The underlying neurotoxicity mechanism for both METH and MPP+ seem to involve free radical formation and impaired mitochondrial function. The MPP+ is thought to selectively kill nigrostriatal dopaminergic neurons by inhibiting mitochondrial complex I, with cell death being attributed to oxidative stress damage to these vulnerable DA neurons. In the present study, MPP+ was shown to significantly inhibit the response to MTT by cultured PC12 cells. This inhibitory action of MPP+ could be partially reversed by the co-incubation of the cells with the acetylated form of carnitine, acetyl-L-carnitine (ALC). Since at least part of the toxic action of MPP+ is related to mitochondrial inhibition, the partial reversal of the inhibition of MTT response by ALC could involve a partial restoration of mitochondrial function. The role carnitine derivatives, such as ALC, play in attenuating MPP+ and METH-evoked toxicity is still under investigation to elucidate the contribution of mitochondrial dysfunction in mechanisms of neurotoxicity.

Neurotoxicity following the Ingestion of Bilimbi Fruit (Averrhoa bilimbi) in an End-Stage Renal Disease Patient on Hemodialysis.

Science.gov (United States)

Caetano, Camille Pereira; de Sá, Cinara Barros; Faleiros, Bruno Antônio Paixão; Gomes, Marcelo Fonseca Coutinho Fernandes; Pereira, Edna Regina Silva

2017-01-01

The toxic effects of the ingestion of star fruit (Averrhoa carambola) in chronic kidney disease patients are well described in the literature. Recently, the compound caramboxin has been isolated, explaining the mechanisms of its neurotoxicity. Bilimbi fruit belongs to the family Oxalidaceae, Averrhoa bilimbi species, and exhibits similar biochemical characteristics to star fruit. To report the case of a patient with chronic kidney disease who developed a seizure disorder after the ingestion of bilimbi fruit. A 69-year-old man with chronic kidney disease on hemodialysis therapy had intractable hiccups, myoclonus, and generalized tonic-clonic seizures after the consumption of a moderate amount of bilimbi fruit. The electroencephalogram showed a pattern of seizure disorder despite the use of anticonvulsant drugs. Renal replacement therapy was maintained during the whole period and prescribed according to the patient's hemodynamic status. Despite showing clinical resolution of the seizure disorder, the patient died on the 27th day of hospitalization for infectious complications. The neurologic status without any other known cause and with clear temporal association with the ingestion of the fruit suggests the diagnosis of neurotoxicity. We propose the hypothesis that the bilimbi fruit has neurotoxic effects similar to those exhibited by the star fruit.

Dopamine transporter down-regulation following repeated cocaine: implications for 3,4-methylenedioxymethamphetamine-induced acute effects and long-term neurotoxicity in mice.

Science.gov (United States)

Peraile, I; Torres, E; Mayado, A; Izco, M; Lopez-Jimenez, A; Lopez-Moreno, J A; Colado, M I; O'Shea, E

2010-01-01

3,4-Methylenedioxymethamphetamine (MDMA) and cocaine are two widely abused psychostimulant drugs targeting the dopamine transporter (DAT). DAT availability regulates dopamine neurotransmission and uptake of MDMA-derived neurotoxic metabolites. We aimed to determine the effect of cocaine pre-exposure on the acute and long-term effects of MDMA in mice. Mice received a course of cocaine (20 mg*kg(-1), x2 for 3 days) followed by MDMA (20 mg*kg(-1), x2, 3 h apart). Locomotor activity, extracellular dopamine levels and dopaminergic neurotoxicity were determined. Furthermore, following the course of cocaine, DAT density in striatal plasma membrane and endosome fractions was measured. Four days after the course of cocaine, challenge with MDMA attenuated the MDMA-induced striatal dopaminergic neurotoxicity. Co-administration of the protein kinase C (PKC) inhibitor NPC 15437 prevented cocaine protection. At the same time, after the course of cocaine, DAT density was reduced in the plasma membrane and increased in the endosome fraction, and this effect was prevented by NPC 15437. The course of cocaine potentiated the MDMA-induced increase in extracellular dopamine and locomotor activity, following challenge 4 days later, compared with those pretreated with saline. Repeated cocaine treatment followed by withdrawal protected against MDMA-induced dopaminergic neurotoxicity by internalizing DAT via a mechanism which may involve PKC. Furthermore, repeated cocaine followed by withdrawal induced behavioural and neurochemical sensitization to MDMA, measures which could be indicative of increased rewarding effects of MDMA.

Resveratrol Protects Dopamine Neurons Against Lipopolysaccharide-Induced Neurotoxicity through Its Anti-Inflammatory Actions

Science.gov (United States)

Zhang, Feng; Shi, Jing-Shan; Zhou, Hui; Wilson, Belinda; Hong, Jau-Shyong

2010-01-01

Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by a progressive loss of dopamine (DA) neurons in the substantia nigra. Accumulating evidence indicates that inhibition of microglia-mediated neuroinflammation may become a reliable protective strategy for PD. Resveratrol, a nonflavonoid polyphenol naturally found in red wine and grapes, has been known to possess antioxidant, anticancer, and anti-inflammatory properties. Although recent studies have shown that resveratrol provided neuroprotective effects against ischemia, seizure, and neurodegenerative disorders, the mechanisms underlying its beneficial effects on dopaminergic neurodegeneration are poorly defined. In this study, rat primary midbrain neuron-glia cultures were used to elucidate the molecular mechanisms underlying resveratrol-mediated neuroprotection. The results clearly demonstrated that resveratrol protected DA neurons against lipopolysaccharide (LPS)-induced neurotoxicity in concentration- and time-dependent manners through the inhibition of microglial activation and the subsequent reduction of proinflammatory factor release. Mechanistically, resveratrol-mediated neuroprotection was attributed to the inhibition of NADPH oxidase. This conclusion is supported by the following observations. First, resveratrol reduced NADPH oxidase-mediated generation of reactive oxygen species. Second, LPS-induced translocation of NADPH oxidase cytosolic subunit p47 to the cell membrane was significantly attenuated by resveratrol. Third and most importantly, resveratrol failed to exhibit neuroprotection in cultures from NADPH oxidase-deficient mice. Furthermore, this neuroprotection was also related to an attenuation of the activation of mitogen-activated protein kinases and nuclear factor-κB signaling pathways in microglia. These findings suggest that resveratrol exerts neuroprotection against LPS-induced dopaminergic neurodegeneration, and NADPH oxidase may be a major player

Synthesis and luminescent spectroscopy of lanthanide complexes with dimethylpyridine-2,6-dicarboxylate (dmpc)

Energy Technology Data Exchange (ETDEWEB)

Taha, Ziyad A., E-mail: tahaz33@just.edu.jo [Department of Applied Chemical Sciences, Faculty of Arts and Sciences, Jordan University of Science and Technology, Irbid 22110 (Jordan); Ajlouni, Abdulaziz M.; Hijazi, Ahmed K. [Department of Applied Chemical Sciences, Faculty of Arts and Sciences, Jordan University of Science and Technology, Irbid 22110 (Jordan); Al-Rawashdeh, Nathir A. [Department of Applied Chemical Sciences, Faculty of Arts and Sciences, Jordan University of Science and Technology, Irbid 22110 (Jordan); Department of Chemistry, United Arab Emirates University, Al Ain 15551 (United Arab Emirates); Al-Hassan, Khader A.; Al-Haj, Yaser A. [Department of Chemistry, Faculty of Science, Yarmouk University, 1163 Irbid (Jordan); Ebqa' ai, Mohammad A. [Al-Qunfudah Center For Scientific Research, Umm Al-Qura University, College in Al-Qunfudah, Makkah (Saudi Arabia); Altalafha, Ammar Y. [Department of Chemistry, Faculty of Science, Yarmouk University, 1163 Irbid (Jordan)

2015-05-15

A series of lanthanide complexes with the general formulae [Ln(dmpc)(NO{sub 3}){sub 2}(H{sub 2}O){sub 2}]NO{sub 3} (Ln=Pr, Nd, Sm, Eu, Gd, Tb, Dy, and Er) and [La(dmpc)(NO{sub 3}){sub 2}(H{sub 2}O){sub 2}]NO{sub 3} were prepared by direct reaction between hydrated lanthanide(III) nitrate and dimethylpyridine-2,6-dicarboxylate (dmpc) in a 1:1 M ratio in ethylacetate–chloroform mixture. The luminescence properties of the dmpc and its Ln(III) complexes were investigated in solid state and in methanol, DMF and DMSO solutions. The Tb–dmpc, Eu–dmpc, Sm–dmpc and Dy–dmpc complexes exhibit characteristic luminescence of Tb(III), Eu(III), Sm(III) and Dy(III) ions indicating energy transfer from the dmpc to the Ln(III) ions. Scavenging activities of the dmpc and its Ln(III) complexes on DPPH{sup •} free radical were investigated in DMSO solution at a different concentrations ranges. - Highlights: • Nine new lanthanide complexes with dmpc ligand are prepared and characterized. • Ln–dmpc {Ln=Eu, Tb, Sm, Dy} complexes exhibit characteristic emissions of Ln ions. • The solvent effect on the luminescence intensity is investigated. • The antioxidant activity of the dmpc is enhanced upon complexation with lanthanide.

The effects of chronic stress on the human brain: From neurotoxicity, to vulnerability, to opportunity.

Science.gov (United States)

Lupien, Sonia J; Juster, Robert-Paul; Raymond, Catherine; Marin, Marie-France

2018-04-01

For the last five decades, science has managed to delineate the mechanisms by which stress hormones can impact on the human brain. Receptors for glucocorticoids are found in the hippocampus, amygdala and frontal cortex, three brain regions involved in memory processing and emotional regulation. Studies have shown that chronic exposure to stress is associated with reduced volume of the hippocampus and that chronic stress can modulate volumes of both the amygdala and frontal cortex, suggesting neurotoxic effects of stress hormones on the brain. Yet, other studies report that exposure to early adversity and/or familial/social stressors can increase vulnerability to stress in adulthood. Models have been recently developed to describe the roles that neurotoxic and vulnerability effects can have on the developing brain. These models suggest that developing early stress interventions could potentially counteract the effects of chronic stress on the brain and results going along with this hypothesis are summarized. Copyright © 2018 Elsevier Inc. All rights reserved.

Comparison between EEG and observation of rabbit behaviour in evaluation of subarachnoid neurotoxicity of metrizamide

International Nuclear Information System (INIS)

Maly, P.; Elmqvist, D.; Almen, T.; Golman, K.; Lund Univ. Hospital; Nyegaard and Co. A/S, Oslo

1986-01-01

The non-ionic contrast medium metrizamide (370 mg I/ml) was injected into the cisterna magna of rabbits at 2 dose levels (0.1 ml/kg and 0.5 ml/kg) to investigate whether visually evaluated EEG can detect neutrotoxicity at a lower dose level than a method based on observation and ranking of signs of excitation and depression in animal behaviour. Half of the metrizamide injections were made without anaesthesia, whereas the remaining injections were made during a short alphadolon/alphaxolon anaesthesia. EEG and animal behaviour were followed for 24 h after the injection of metrizamide. At the low 'clinical' dose, EEG could not detect statistically significant neurotoxicity, neither in anaesthetized nor in non-anaesthetized rabbits. Observation of animal behaviour, however, could detect statistically significant signs of depression in animals that had been anaesthetized. At the high dose level, both methods could detect significantly more serious symptoms of neurotoxicity than at the low dose level. (orig.)

EGCG Protects against 6-OHDA-Induced Neurotoxicity in a Cell Culture Model

OpenAIRE

Chen, Dan; Kanthasamy, Anumantha G.; Reddy, Manju B.

2015-01-01

Background. Parkinson's disease (PD) is a progressive neurodegenerative disease that causes severe brain dopamine depletion. Disruption of iron metabolism may be involved in the PD progression. Objective. To test the protective effect of (?)-epigallocatechin-3-gallate (EGCG) against 6-hydroxydopamine- (6-OHDA-) induced neurotoxicity by regulating iron metabolism in N27 cells. Methods. Protection by EGCG in N27 cells was assessed by SYTOX green assay, MTT, and caspase-3 activity. Iron regulato...

Methylmercury Induced Neurotoxicity and the Influence of Selenium in the Brains of Adult Zebrafish (Danio rerio

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Josef Daniel Rasinger

2017-03-01

Full Text Available The neurotoxicity of methylmercury (MeHg is well characterised, and the ameliorating effects of selenium have been described. However, little is known about the molecular mechanisms behind this contaminant-nutrient interaction. We investigated the influence of selenium (as selenomethionine, SeMet and MeHg on mercury accumulation and protein expression in the brain of adult zebrafish (Danio rerio. Fish were fed diets containing elevated levels of MeHg and/or SeMet in a 2 × 2 full factorial design for eight weeks. Mercury concentrations were highest in the brain tissue of MeHg-exposed fish compared to the controls, whereas lower levels of mercury were found in the brain of zebrafish fed both MeHg and SeMet compared with the fish fed MeHg alone. The expression levels of proteins associated with gap junction signalling, oxidative phosphorylation, and mitochondrial dysfunction were significantly (p < 0.05 altered in the brain of zebrafish after exposure to MeHg and SeMet alone or in combination. Analysis of upstream regulators indicated that these changes were linked to the mammalian target of rapamycin (mTOR pathways, which were activated by MeHg and inhibited by SeMet, possibly through a reactive oxygen species mediated differential activation of RICTOR, the rapamycin-insensitive binding partner of mTOR.

Fragment C Domain of Tetanus Toxin Mitigates Methamphetamine Neurotoxicity and Its Motor Consequences in Mice.

Science.gov (United States)

Mendieta, Liliana; Granado, Noelia; Aguilera, José; Tizabi, Yousef; Moratalla, Rosario

2016-08-01

The C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) is a nontoxic peptide with demonstrated in vitro and in vivo neuroprotective effects against striatal dopaminergic damage induced by 1-methyl-4-phenylpyridinium and 6-hydoxydopamine, suggesting its possible therapeutic potential in Parkinson's disease. Methamphetamine, a widely abused psychostimulant, has selective dopaminergic neurotoxicity in rodents, monkeys, and humans. This study was undertaken to determine whether Hc-TeTx might also protect against methamphetamine-induced dopaminergic neurotoxicity and the consequent motor impairment. For this purpose, we treated mice with a toxic regimen of methamphetamine (4mg/kg, 3 consecutive i.p. injections, 3 hours apart) followed by 3 injections of 40 ug/kg of Hc-TeTx into grastrocnemius muscle at 1, 24, and 48 hours post methamphetamine treatment. We found that Hc-TeTx significantly reduced the loss of dopaminergic markers tyrosine hydroxylase and dopamine transporter and the increases in silver staining (a well stablished degeneration marker) induced by methamphetamine in the striatum. Moreover, Hc-TeTx prevented the increase of neuronal nitric oxide synthase but did not affect microglia activation induced by methamphetamine. Stereological neuronal count in the substantia nigra indicated loss of tyrosine hydroxylase-positive neurons after methamphetamine that was partially prevented by Hc-TeTx. Importantly, impairment in motor behaviors post methamphetamine treatment were significantly reduced by Hc-TeTx. Here we demonstrate that Hc-TeTx can provide significant protection against acute methamphetamine-induced neurotoxicity and motor impairment, suggesting its therapeutic potential in methamphetamine abusers. © The Author 2016. Published by Oxford University Press on behalf of CINP.

Induced pluripotent stem cell-derived neuron as a human model for testing environmentally induced developmental neurotoxicity

Science.gov (United States)

Induced pluripotent stem cell-derived neurons as a human model for testing environmentally induced developmental neurotoxicity Ingrid L. Druwe1, Timothy J. Shafer2, Kathleen Wallace2, Pablo Valdivia3 ,and William R. Mundy2. 1University of North Carolina, Curriculum in Toxicology...

Developmental origins of adult diseases and neurotoxicity: Epidemiological and experimental studies

DEFF Research Database (Denmark)

Fox, Donald A; Grandjean, Philippe; de Groot, Didima

2012-01-01

and short-term memory in aged Rhesus monkeys following acute 24 h exposure to ketamine during early development. Overall, these presentations addressed fundamental issues in the emerging areas of lifetime neurotoxicity testing, differential vulnerable periods of exposure, nonmonotonic dose-response effects...... with neurodegeneration. Didima de Groot presented results on prenatal exposure of rats to methylazoxymethanol and discussed the results in light of the etiology of western Pacific amyotrophic lateral sclerosis and Parkinson-dementia complex. Merle G. Paule addressed the long-term changes in learning, motivation...

Detecting acute neurotoxicity during platinum chemotherapy by neurophysiological assessment of motor nerve hyperexcitability

International Nuclear Information System (INIS)

Hill, Andrew; Bergin, Peter; Hanning, Fritha; Thompson, Paul; Findlay, Michael; Damianovich, Dragan; McKeage, Mark J

2010-01-01

Platinum-based drugs, such as cisplatin and oxaliplatin, are well-known for inducing chronic sensory neuropathies but their acute and motor neurotoxicities are less well characterised. Use was made of nerve conduction studies and needle electromyography (EMG) to assess motor nerve excitability in cancer patients during their first treatment cycle with platinum-based chemotherapy in this study. Twenty-nine adult cancer patients had a neurophysiological assessment either before oxaliplatin plus capecitabine, on days 2 to 4 or 14 to 20 after oxaliplatin plus capecitabine, or on days 2 to 4 after carboplatin plus paclitaxel or cisplatin, undertaken by a neurophysiologist who was blinded to patient and treatment details. Patients completed a symptom questionnaire at the end of the treatment cycle. Abnormal spontaneous high frequency motor fibre action potentials were detected in 100% of patients (n = 6) and 72% of muscles (n = 22) on days 2 to 4 post-oxaliplatin, and in 25% of patients (n = 8) and 13% of muscles (n = 32) on days 14 to 20 post-oxaliplatin, but in none of the patients (n = 14) or muscles (n = 56) tested prior to oxaliplatin or on days 2 to 4 after carboplatin plus paclitaxel or cisplatin. Repetitive compound motor action potentials were less sensitive and less specific than spontaneous high frequency motor fibre action potentials for detection of acute oxaliplatin-induced motor nerve hyperexcitability but were present in 71% of patients (n = 7) and 32% of muscles (n = 32) on days 2 to 4 after oxaliplatin treatment. Acute neurotoxicity symptoms, most commonly cold-induced paraesthesiae and jaw or throat tightness, were reported by all patients treated with oxaliplatin (n = 22) and none of those treated with carboplatin plus paclitaxel or cisplatin (n = 6). Abnormal spontaneous high frequency motor fibre activity is a sensitive and specific endpoint of acute oxaliplatin-induced motor nerve hyperexcitability, detectable on EMG on days 2 to 4 post

Detecting acute neurotoxicity during platinum chemotherapy by neurophysiological assessment of motor nerve hyperexcitability

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Hill Andrew

2010-08-01

Full Text Available Abstract Background Platinum-based drugs, such as cisplatin and oxaliplatin, are well-known for inducing chronic sensory neuropathies but their acute and motor neurotoxicities are less well characterised. Use was made of nerve conduction studies and needle electromyography (EMG to assess motor nerve excitability in cancer patients during their first treatment cycle with platinum-based chemotherapy in this study. Methods Twenty-nine adult cancer patients had a neurophysiological assessment either before oxaliplatin plus capecitabine, on days 2 to 4 or 14 to 20 after oxaliplatin plus capecitabine, or on days 2 to 4 after carboplatin plus paclitaxel or cisplatin, undertaken by a neurophysiologist who was blinded to patient and treatment details. Patients completed a symptom questionnaire at the end of the treatment cycle. Results Abnormal spontaneous high frequency motor fibre action potentials were detected in 100% of patients (n = 6 and 72% of muscles (n = 22 on days 2 to 4 post-oxaliplatin, and in 25% of patients (n = 8 and 13% of muscles (n = 32 on days 14 to 20 post-oxaliplatin, but in none of the patients (n = 14 or muscles (n = 56 tested prior to oxaliplatin or on days 2 to 4 after carboplatin plus paclitaxel or cisplatin. Repetitive compound motor action potentials were less sensitive and less specific than spontaneous high frequency motor fibre action potentials for detection of acute oxaliplatin-induced motor nerve hyperexcitability but were present in 71% of patients (n = 7 and 32% of muscles (n = 32 on days 2 to 4 after oxaliplatin treatment. Acute neurotoxicity symptoms, most commonly cold-induced paraesthesiae and jaw or throat tightness, were reported by all patients treated with oxaliplatin (n = 22 and none of those treated with carboplatin plus paclitaxel or cisplatin (n = 6. Conclusions Abnormal spontaneous high frequency motor fibre activity is a sensitive and specific endpoint of acute oxaliplatin-induced motor nerve

Naringenin protects against 6-OHDA-induced neurotoxicity via activation of the Nrf2/ARE signaling pathway.

Science.gov (United States)

Lou, Haiyan; Jing, Xu; Wei, Xinbing; Shi, Huanying; Ren, Dongmei; Zhang, Xiumei

2014-04-01

There is increasing evidence that oxidative stress is critically involved in the pathogenesis of Parkinson's disease (PD), suggesting that pharmacological targeting of the antioxidant machinery may have therapeutic value. Naringenin, a natural flavonoid compound, has been reported to possess neuroprotective effect against PD related pathology; however the mechanisms underlying its beneficial effects are poorly defined. Thus, the purpose of the present study was to investigate the potential neuroprotective role of naringenin and to delineate its mechanism of action against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in models of PD both in vitro and in vivo. Naringenin treatment resulted in an increase in nuclear factor E2-related factor 2 (Nrf2) protein levels and subsequent activation of antioxidant response element (ARE) pathway genes in SH-SY5Y cells and in mice. Exposure of SH-SY5Y cells to naringenin provided protection against 6-OHDA-induced oxidative insults that was dependent on Nrf2, since treatment with Nrf2 siRNA failed to block against 6-OHDA neurotoxicity or induce Nrf2-dependent cytoprotective genes in SH-SY5Y cells. In mice, oral administration of naringenin resulted in significant protection against 6-OHDA-induced nigrostriatal dopaminergic neurodegeneration and oxidative damage. Our results indicate that activation of Nrf2/ARE signaling by naringenin is strongly associated with its neuroprotective effects against 6-OHDA neurotoxicity and suggest that targeting the Nrf2/ARE pathway may be a promising approach for therapeutic intervention in PD. Copyright © 2013 Elsevier Ltd. All rights reserved.

Gonadal steroids differentially modulate neurotoxicity of HIV and cocaine: testosterone and ICI 182,780 sensitive mechanism

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Mactutus Charles F

2005-06-01

Full Text Available Abstract Background HIV Associated Dementia (HAD is a common complication of human immunodeficiency virus (HIV infection that erodes the quality of life for patients and burdens health care providers. Intravenous drug use is a major route of HIV transmission, and drug use is associated with increased HAD. Specific proteins released as a consequence of HIV infection (e.g., gp120, the HIV envelope protein and Tat, the nuclear transactivating protein have been implicated in the pathogenesis of HAD. In primary cultures of human fetal brain tissue, subtoxic doses of gp120 and Tat are capable of interacting with a physiologically relevant dose of cocaine, to produce a significant synergistic neurotoxicity. Using this model system, the neuroprotective potential of gonadal steroids was investigated. Results 17β-Estradiol (17β-E2, but not 17α-estradiol (17α-E2, was protective against this combined neurotoxicity. Progesterone (PROG afforded limited neuroprotection, as did dihydrotestosterone (DHT. The efficacy of 5α-testosterone (T-mediated neuroprotection was robust, similar to that provided by 17β-E2. In the presence of the specific estrogen receptor (ER antagonist, ICI-182,780, T's neuroprotection was completely blocked. Thus, T acts through the ER to provide neuroprotection against HIV proteins and cocaine. Interestingly, cholesterol also demonstrated concentration-dependent neuroprotection, possibly attributable to cholesterol's serving as a steroid hormone precursor in neurons. Conclusion Collectively, the present data indicate that cocaine has a robust interaction with the HIV proteins gp120 and Tat that produces severe neurotoxicity, and this toxicity can be blocked through pretreatment with ER agonists.

Neural progenitor cells as models for high-throughput screens of developmental neurotoxicity: State of the science

NARCIS (Netherlands)

Breier, J.M.; Gassmann, K.; Kayser, R.; Stegeman, H.; Groot, D.de; Fritsche, E.; Shafer, T.J.

2010-01-01

In vitro, high-throughput methods have been widely recommended as an approach to screen chemicals for the potential to cause developmental neurotoxicity and prioritize them for additional testing. The choice of cellular models for such an approach will have important ramifications for the accuracy,

Evaluation of methods for the assessment of in vitro neurotoxicity : Calcium homeostasis as target for insecticides

NARCIS (Netherlands)

Meijer, M.

2016-01-01

Due to the REACH regulation, more animal studies for regulatory safety studies are needed in the coming years unless suitable alternatives become available. In addition, regulatory neurotoxicity tests have been criticized for their low sensitivity and the large amount of animals, time and money that

In vitro, inhibition of mitogen-activated protein kinase pathways protects against bupivacaine- and ropivacaine-induced neurotoxicity

NARCIS (Netherlands)

Lirk, Philipp; Haller, Ingrid; Colvin, Hans Peter; Lang, Leopold; Tomaselli, Bettina; Klimaschewski, Lars; Gerner, Peter

2008-01-01

Animal models show us that specific activation of the p38 mitogen-activated protein kinase (MAPK) may be a pivotal step in lidocaine neurotoxicity, but this has not been investigated in the case of two very widely used local anesthetics, bupivacaine and ropivacaine. We investigated the hypotheses

Amphetamine-metabolites of deprenyl involved in protection against neurotoxicity induced by MPTP and 2'-methyl-MPTP.

Science.gov (United States)

Sziráki, I; Kardos, V; Patthy, M; Pátfalusi, M; Gaál, J; Solti, M; Kollár, E; Singer, J

1994-01-01

The ability of 1-deprenyl to protect against the parkinsonian effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been attributed to the inhibition of conversion of MPTP to MPP+ (1-methyl-4-phenylpyridinium) catalyzed by MAO-B. We report here that deprenyl-treatment in mice has an additional neuroprotective element associated with the rapid metabolization of 1-deprenyl to 1-methamphetamine and 1-amphetamine. 1-Methamphetamine and 1-amphetamine inhibit MPP(+)-uptake into striatal synaptosomes prepared from rats. Post-treatment by 1-deprenyl, 1-methamphetamine, 1-amphetamine (at times when MPTP is no longer present in the striatum of mice) protects against neurotoxicity in C57BL mice by blocking the uptake of MPP+ into dopaminergic neurons, and even against the neurotoxicity induced by 2'CH3-MPTP, which is partly bioactivated by MAO-A. These findings may have clinical implications since deprenyl has recently been found to delay the progression of Parkinson's disease.

Hyperforin prevents beta-amyloid neurotoxicity and spatial memory impairments by disaggregation of Alzheimer's amyloid-beta-deposits.

Science.gov (United States)

Dinamarca, M C; Cerpa, W; Garrido, J; Hancke, J L; Inestrosa, N C

2006-11-01

The major protein constituent of amyloid deposits in Alzheimer's disease (AD) is the amyloid beta-peptide (Abeta). In the present work, we have determined the effect of hyperforin an acylphloroglucinol compound isolated from Hypericum perforatum (St John's Wort), on Abeta-induced spatial memory impairments and on Abeta neurotoxicity. We report here that hyperforin: (1) decreases amyloid deposit formation in rats injected with amyloid fibrils in the hippocampus; (2) decreases the neuropathological changes and behavioral impairments in a rat model of amyloidosis; (3) prevents Abeta-induced neurotoxicity in hippocampal neurons both from amyloid fibrils and Abeta oligomers, avoiding the increase in reactive oxidative species associated with amyloid toxicity. Both effects could be explained by the capacity of hyperforin to disaggregate amyloid deposits in a dose and time-dependent manner and to decrease Abeta aggregation and amyloid formation. Altogether these evidences suggest that hyperforin may be useful to decrease amyloid burden and toxicity in AD patients, and may be a putative therapeutic agent to fight the disease.

Barium coordination polymers based on fluorinated and fluorine-free benzene-dicarboxylates: Mechanochemical synthesis and spectroscopic characterization

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Al-Terkawi, Abdal-Azim; Scholz, Gudrun; Emmerling, Franziska; Kemnitz, Erhard

2018-05-01

A series of new Ba-based coordination polymers (CPs) were mechanochemically synthesized by milling Ba-hydroxide samples with perfluorinated and fluorine-free benzene-dicarboxylic acids, including tetrafluoroisophthalic acid (H2mBDC-F4), tetrafluorophthalic acid (H2oBDC-F4), isophthalic acid (H2mBDC) and phthalic acid (H2oBDC). The new fluorinated CPs: [Ba(mBDC-F4)·0.5H2O] (1) and [Ba(oBDC-F4)·1.5H2O] (2) are compared to their nonfluorinated counterparts: [Ba(mBDC)·2.5H2O] (3), and [Ba(oBDC)·1H2O] (4). These materials are thoroughly characterized using powder X-ray diffraction. The products obtained by milling are all hydrated but vary in their water contents. Compositions and local structures are investigated by elemental analysis, thermal analysis, MAS NMR and attenuated total reflection-infrared spectroscopy. These materials exhibit high thermal stabilities but small surface areas that remain unchanged even after thermal treatments.

Severe neurotoxicity following ingestion of tetraethyl lead.

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Wills, Brandon K; Christensen, Jason; Mazzoncini, Joe; Miller, Michael

2010-03-01

Organic lead compounds are potent neurotoxins which can result in death even from small exposures. Traditionally, these compounds are found in fuel stabilizers, anti-knock agents, and leaded gasoline. Cases of acute organic lead intoxication have not been reported for several decades. We report a case of a 13-year-old Iraqi male who unintentionally ingested a fuel stabilizer containing 80-90% tetraethyl lead, managed at our combat support hospital. The patient developed severe neurologic symptoms including agitation, hallucinations, weakness, and tremor. These symptoms were refractory to escalating doses of benzodiazepines and ultimately required endotracheal intubation and a propofol infusion. Adjunctive therapies included chelation, baclofen, and nutrition provided through a gastrostomy tube. The patient slowly recovered and was discharged in a wheelchair 20 days after ingestion, still requiring tube feeding. Follow-up at 62 days post-ingestion revealed near-resolution of symptoms with residual slurred speech and slight limp. This case highlights the profound neurotoxic manifestations of acute organic lead compounds.

Neurotoxic effects of levobupivacaine and fentanyl on rat spinal cord

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Yesim Cokay Abut

2015-02-01

Full Text Available BACKGROUND: The purpose of the study was to compare the neurotoxic effects of intrathecally administered levobupivacaine, fentanyl and their mixture on rat spinal cord. METHODS: In experiment, there were four groups with medication and a control group. Rats were injected 15 µL saline or fentanyl 0.0005 µg/15 µL, levobupivacaine 0.25%/15 µL and fentanyl 0.0005 µg + levobupivacaine 0.25%/15 µL intrathecally for four days. Hot plate test was performed to assess neurologic function after each injection at 5th, 30th and 60th min. Five days after last lumbal injection, spinal cord sections between the T5 and T6 vertebral levels were obtained for histologic analysis. A score based on subjective assessment of number of eosinophilic neurons - Red neuron - which means irreversible neuronal degeneration. They reflect the approximate number of degenerating neurons present in the affected neuroanatomic areas as follows: 1, none; 2, 1-20%; 3, 21-40%; 4, 41-60%; and 5, 61-100% dead neurons. An overall neuropathologic score was calculated for each rat by summating the pathologic scores for all spinal cord areas examined. RESULTS: In the results of HPT, comparing the control group, analgesic latency statistically prolonged for all four groups.In neuropathologic investment, the fentanyl and fentanyl + levobupivacaine groups have statistically significant high degenerative neuron counts than control and saline groups. CONCLUSIONS: These results suggest that, when administered intrathecally in rats, fentanyl and levobupivacaine behave similar for analgesic action, but fentanyl may be neurotoxic for spinal cord. There was no significant degeneration with levobupivacaine, but fentanyl group has had significant degeneration.

2,1,3-benzothiadiazole-5,6-dicarboxylic imide - A versatile building block for additive- and annealing-free processing of organic solar cells with effi ciencies exceeding 8%

KAUST Repository

Nielsen, Christian Bergenstof

2014-12-15

A new photoactive polymer comprising benzo[1,2-b:3,4-b′:5,6-d′]trithiophene and 2,1,3-benzothiadiazole-5,6-dicarboxylic imide is reported. The synthetic design allows for alkyl chains to be introduced on both electron-rich and electron-deficient components, which in turn allows for rapid optimization of the alkyl chain substitution pattern. Consequently, the optimized polymer shows a maximum efficiency of 8.3% in organic photovoltaic devices processed in commercially viable fashion without solvent additives, annealing, or device engineering.

2,1,3-benzothiadiazole-5,6-dicarboxylic imide - A versatile building block for additive- and annealing-free processing of organic solar cells with effi ciencies exceeding 8%

KAUST Repository

Nielsen, Christian Bergenstof; Ashraf, Raja Shahid; Treat, Neil D.; Schroeder, Bob C.; Donaghey, Jenny E.; White, Andrew J P; Stingelin, Natalie; McCulloch, Iain

2014-01-01

A new photoactive polymer comprising benzo[1,2-b:3,4-b′:5,6-d′]trithiophene and 2,1,3-benzothiadiazole-5,6-dicarboxylic imide is reported. The synthetic design allows for alkyl chains to be introduced on both electron-rich and electron-deficient components, which in turn allows for rapid optimization of the alkyl chain substitution pattern. Consequently, the optimized polymer shows a maximum efficiency of 8.3% in organic photovoltaic devices processed in commercially viable fashion without solvent additives, annealing, or device engineering.

Luminescence of uranyl ion complexed with 2,6-pyridine dicarboxylic acid as ligand in acetonitrile medium. Observation of co-luminescence

Energy Technology Data Exchange (ETDEWEB)

Maji, Siuli; Kumar, Satendra; Sankaran, Kannan [Indira Ghandi Centre for Atomic Research, Tamil Nadu (India). Materials Chemistry Div.

2017-10-01

Luminescence from UO{sub 2}{sup 2+} (uranyl ion) complexed with 2,6-pyridine dicarboxylic acid (PDA) has been studied using acetonitrile (MeCN) as solvent between pH 1.0 and 6.0. The enhancement in luminescence intensity because of sensitization by PDA in the non-aqueous environment provided by the MeCN is found to be one order better than in aqueous medium. The luminescence is further enhanced by about four times following the addition of Y{sup 3+}; a process known as co-luminescence. This is the first study on co-luminescence of uranyl ion in its PDA complex. Lifetime studies indicate the presence of two species having different micro-environments. Formations of both intra and inter molecular complexes are believed to be responsible for enhancement due to co-luminescence.

Luminescence of uranyl ion complexed with 2,6-pyridine dicarboxylic acid as ligand in acetonitrile medium. Observation of co-luminescence

International Nuclear Information System (INIS)

Maji, Siuli; Kumar, Satendra; Sankaran, Kannan

2017-01-01

Luminescence from UO_2"2"+ (uranyl ion) complexed with 2,6-pyridine dicarboxylic acid (PDA) has been studied using acetonitrile (MeCN) as solvent between pH 1.0 and 6.0. The enhancement in luminescence intensity because of sensitization by PDA in the non-aqueous environment provided by the MeCN is found to be one order better than in aqueous medium. The luminescence is further enhanced by about four times following the addition of Y"3"+; a process known as co-luminescence. This is the first study on co-luminescence of uranyl ion in its PDA complex. Lifetime studies indicate the presence of two species having different micro-environments. Formations of both intra and inter molecular complexes are believed to be responsible for enhancement due to co-luminescence.

A 3-dimensional human embryonic stem cell (hESC)-derived model to detect developmental neurotoxicity of nanoparticles.

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Hoelting, Lisa; Scheinhardt, Benjamin; Bondarenko, Olesja; Schildknecht, Stefan; Kapitza, Marion; Tanavde, Vivek; Tan, Betty; Lee, Qian Yi; Mecking, Stefan; Leist, Marcel; Kadereit, Suzanne

2013-04-01

Nanoparticles (NPs) have been shown to accumulate in organs, cross the blood-brain barrier and placenta, and have the potential to elicit developmental neurotoxicity (DNT). Here, we developed a human embryonic stem cell (hESC)-derived 3-dimensional (3-D) in vitro model that allows for testing of potential developmental neurotoxicants. Early central nervous system PAX6(+) precursor cells were generated from hESCs and differentiated further within 3-D structures. The 3-D model was characterized for neural marker expression revealing robust differentiation toward neuronal precursor cells, and gene expression profiling suggested a predominantly forebrain-like development. Altered neural gene expression due to exposure to non-cytotoxic concentrations of the known developmental neurotoxicant, methylmercury, indicated that the 3-D model could detect DNT. To test for specific toxicity of NPs, chemically inert polyethylene NPs (PE-NPs) were chosen. They penetrated deep into the 3-D structures and impacted gene expression at non-cytotoxic concentrations. NOTCH pathway genes such as HES5 and NOTCH1 were reduced in expression, as well as downstream neuronal precursor genes such as NEUROD1 and ASCL1. FOXG1, a patterning marker, was also reduced. As loss of function of these genes results in severe nervous system impairments in mice, our data suggest that the 3-D hESC-derived model could be used to test for Nano-DNT.

Editor's Highlight: Congener-Specific Disposition of Chiral Polychlorinated Biphenyls in Lactating Mice and Their Offspring: Implications for PCB Developmental Neurotoxicity.

Science.gov (United States)

Kania-Korwel, Izabela; Lukasiewicz, Tracy; Barnhart, Christopher D; Stamou, Marianna; Chung, Haeun; Kelly, Kevin M; Bandiera, Stelvio; Lein, Pamela J; Lehmler, Hans-Joachim

2017-07-01

Chiral polychlorinated biphenyl (PCB) congeners have been implicated by laboratory and epidemiological studies in PCB developmental neurotoxicity. These congeners are metabolized by cytochrome P450 (P450) enzymes to potentially neurotoxic hydroxylated metabolites (OH-PCBs). The present study explores the enantioselective disposition and toxicity of 2 environmentally relevant, neurotoxic PCB congeners and their OH-PCB metabolites in lactating mice and their offspring following dietary exposure of the dam. Female C57BL/6N mice (8-weeks old) were fed daily, beginning 2 weeks prior to conception and continuing throughout gestation and lactation, with 3.1 µmol/kg bw/d of racemic 2,2',3,5',6-pentachlorobiphenyl (PCB 95) or 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) in peanut butter; controls received vehicle (peanut oil) in peanut butter. PCB 95 levels were higher than PCB 136 levels in both dams and pups, consistent with the more rapid metabolism of PCB 136 compared with PCB 95. In pups and dams, both congeners were enriched for the enantiomer eluting second on enantioselective gas chromatography columns. OH-PCB profiles in lactating mice and their offspring were complex and varied according to congener, tissue and age. Developmental exposure to PCB 95 versus PCB 136 differentially affected the expression of P450 enzymes as well as neural plasticity (arc and ppp1r9b) and thyroid hormone-responsive genes (nrgn and mbp). The results suggest that the enantioselective metabolism of PCBs to OH-PCBs may influence neurotoxic outcomes following developmental exposures, a hypothesis that warrants further investigation. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Developmental neurotoxicity: methylmercury and prenatal exposure protection in the context of the Minamata Convention

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Ana Boischio

2015-09-01

Full Text Available Mercury is a global pollutant of public environmental health concern due to its long-range atmospheric distribution, environmental distribution, and neurotoxic effects. Following biological methylation, methylmercury (MeHg can be un-evenly bioaccumulated within aquatic food chains. Fish consumption can be a significant route of human exposure to MeHg. MeHg exposure in the prenatal stage, at relatively low levels, has recently been established as harmful during neurological development, potentially leading to intellectual disability. The Minamata Convention on Mercury is a global agreement, currently under ratification, to protect human health and the environment from anthropogenic emissions and releases of mercury and mercury compounds. The resolution regarding the role of the World Health Organization and ministries of health in the implementation of the Convention includes protection of human health from critical exposures to MeHg. Riverside populations living in areas with artisanal small-scale gold mining, and relying heavily on fish consumption, have been identified as the most vulnerable population in terms of MeHg exposure and developmental neurotoxicity. This article focuses on the proper design and dissemination of fish advisories within the context of implementation of the Convention.

Identification and Functional Characterization of a Tonoplast Dicarboxylate Transporter in Tomato (Solanum lycopersicum).

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Liu, Ruiling; Li, Boqiang; Qin, Guozheng; Zhang, Zhanquan; Tian, Shiping

2017-01-01

Acidity plays an important role in flavor and overall organoleptic quality of fruit and is mainly due to the presence of organic acids. Understanding the molecular basis of organic acid metabolism is thus of primary importance for fruit quality improvement. Here, we cloned a putative tonoplast dicarboxylate transporter gene ( SlTDT ) from tomato, and submitted it to the NCBI database (GenBank accession number: KC733165). SlTDT protein contained 13 putative transmembrane domains in silico analysis. Confocal microscopic study using green fluorescent fusion proteins revealed that SlTDT was localized on tonoplast. The expression patterns of SlTDT in tomato were analyzed by RT-qPCR. The results indicated that SlTDT expressed in leaves, roots, flowers and fruits at different ripening stages, suggesting SlTDT may be associated with the development of different tissues. To further explore the function of SlTDT , we constructed both overexpression and RNAi vectors and obtained transgenic tomato plants by agrobacterium-mediated method. Gas chromatography-mass spectrometer (GC-MS) analysis showed that overexpression of SlTDT significantly increased malate content, and reduced citrate content in tomato fruit. By contrast, repression of SlTDT in tomato reduced malate content of and increased citrate content. These results indicated that SlTDT played an important role in remobilization of malate and citrate in fruit vacuoles.

Roles of Neuroglobin Binding to Mitochondrial Complex III Subunit Cytochrome c1 in Oxygen-Glucose Deprivation-Induced Neurotoxicity in Primary Neurons.

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Yu, Zhanyang; Zhang, Yu; Liu, Ning; Yuan, Jing; Lin, Li; Zhuge, Qichuan; Xiao, Jian; Wang, Xiaoying

2016-07-01

Neuroglobin (Ngb) is a tissue globin specifically expressed in brain neurons. Recent studies by our laboratory and others have demonstrated that Ngb is protective against stroke and related neurological disorders, but the mechanisms remain poorly understood. We previously identified cytochrome c1 (Cyc1) as an Ngb-interacting molecule by yeast two-hybrid screening. Cyc1 is a subunit of mitochondria complex III, which is a component of mitochondrial respiratory chain and a major source of reactive oxygen species (ROS) production under both physiological and pathological conditions. In this study, we for the first time defined Ngb-Cyc1 binding, and investigated its roles in oxygen-glucose deprivation (OGD)/reoxygenation-induced neurotoxicity and ROS production in primary neurons. Immunocytochemistry and co-immunoprecipitation validated Ngb-Cyc1 binding, which was significantly increased by OGD and Ngb overexpression. We found 4 h OGD with/without 4 h reoxygenation significantly increased complex III activity, but this activity elevation was significantly attenuated in three groups of neurons: Ngb overexpression, specific complex III inhibitor stigmatellin, or stigmatellin plus Ngb overexpression, whereas there was no significant differences between these three groups, suggesting Ngb-Cyc1 binding may function in suppressing OGD-mediated complex III activity elevation. Importantly, these three groups of neurons also showed significant decreases in OGD-induced superoxide anion generation and neurotoxicity. These results suggest that Ngb can bind to mitochondrial complex III subunit Cyc1, leading to suppression of OGD-mediated complex III activity and subsequent ROS production elevation, and eventually reduction of OGD-induced neurotoxicity. This molecular signaling cascade may be at least part of the mechanisms of Ngb neuroprotection against OGD-induced neurotoxicity.

Markers of murine embryonic and neural stem cells, neurons and astrocytes: reference points for developmental neurotoxicity testing

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Developmental neurotoxicity (DNT) is a significant concern for environmental chemicals, as well as for food and drug constituents. The sensitivity of animal-based DNT models is unclear, and they are expensive and time consuming. Murine embryonic stem cells (mESC) recapitulate sev...

Three new 5-fold interpenetrating diamondoid frameworks constructed by rigid diimidazole and dicarboxylate ligands

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Huo, Jianqiang; Yan, Shuai; Li, Haiqiang; Yu, Donghui; Arulsamy, Navamoney

2018-03-01

A series of three-dimensional coordination polymers, namely, [Cd(BIMB)(SCA)]n (1), [M(BIMB)(trans-CHDC)]n (2, M = Cd2+; 3, M = Co2+), where BIMB = 1,4-di(1H-imidazol-1-yl)benzene, SCA2- = succinate dianion, CHDC2- = cyclohexane-1,4-dicarboxylate dianion) are synthesized hydro/solvatothermal methods. The products are characterized by elemental analysis and single-crystal X-ray diffraction data. Both the dianion and BIMB bridge different pairs of the metal ions, the three complexes are polymeric and their three-dimensional topology feature a diamond-like metal-organic framework (MOF). Owing to the length of the two bridging ligands, moderate size voids are formed in the diamondoid networks. However, the voids are filled by mutual interpenetration of four independent equivalent frameworks in a 5-fold interpenetrating architecture, and there is no sufficient void volume available for any guest molecules. The phase purity and thermal stability of the compounds are verified by powder X-ray diffraction (PXRD) and thermogravimetric (TG) data. The solid-state fluorescence spectra for the 3d10 Cd2+ MOF's 1 and 2 reveal significant enhancement in their emission intensities in comparison to the non-metallated BIMB. The enhanced emission is attributed to perturbation of intra-ligand emission states due to Cd2+ coordination.

Neuroprotective and antioxidant effects of Thalassia testudinum extract BM-21, against acrylamide-induced neurotoxicity in mice

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Roberto Menéndez

2014-06-01

Full Text Available Context: Acrylamide (ACR neurotoxicity is associated with the enhancement of lipid peroxidation and the reduction of the antioxidative capacity distal axon and nerve terminal regions. The aqueous ethanolic extract of the marine plant Thalassia testudinum, named BM-21, have shown antioxidant, anti-inflammatory and analgesic properties. Aims: To determine the neuroprotective and the antioxidant effects of BM-21, standardized to thalassiolin B content (5.8 ± 0.9%, on acrylamide (ACR-induced distal axonopathy in male OF-1 mice. Methods: Animals were administered with ACR (70 mg/kg, s.c., 4 weeks, and BM-21 was co-administered p.o at the doses of 4, 40 and 400 mg/kg. The effect of BM-21 on neurobehavioral indexes (rota-rod test, compound muscle action potential (CMAP of the sciatic nerve and oxidative stress parameters were investigated. Results: BM-21 significantly prevented the neurobehavioral sings of neurotoxicity and the alteration of CMAP amplitude and velocity. The lowest dose (4 mg/kg failed to ameliorate these parameters whereas the highest dose (400 mg/kg was the most active. BM-21 (400 mg/kg significantly restored total hydroperoxides (THP and glutathione (GSH in the sciatic nerve as well as superoxide dismutase (SOD and glutathione peroxidase (GSH-Px activities. Additionally, the extract also modified THP, GSH and the activity of SOD in cerebellum and brain towards the standard values. Conclusions: BM-21 given at doses that prevented ACR-induced neurotoxicity also produced antioxidant effect in the sciatic nerve, cerebellum and brain. Thus, the neuroprotective activity of BM-21 in this model seems to be mediated at least partly by its antioxidative properties.

Feasibility assessment of Micro electrode chip assay (MEA as a method of detecting neurotoxicity in vitro

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Enrico eDefranchi

2011-04-01

Full Text Available Detection and characterization of chemically-induced toxic effects in the nervous system represent a challenge for the hazard assessment of chemicals. In vivo, neurotoxicological assessments exploit the fact that the activity of neurons in the central and peripheral nervous system has functional consequences. And so far, no in vitro method for evaluating the neurotoxic hazard has yet been validated and accepted for regulatory purpose.The microelectrode array (MEA assay consists of a culture chamber into which an integrated array of microelectrodes is capable of measuring extracellular electrophysiology (spikes and bursts from electro-active tissues. A wide variety of electrically excitable biological tissues may be placed onto the chips including primary cultures of nervous system tissue. Recordings from this type of in vitro cultured system are non invasive, give label free evaluations and provide a higher throughput than conventional electrophysiological techniques. In this paper, twenty substances were tested in a blinded study for their toxicity and dose-response curves were obtained from foetal rat cortical neuronal networks coupled to MEAs. The experimental procedure consisted of evaluating the firing activity (spiking rate and modification/reduction in response to chemical administration. Native/reference activity, 30 minutes of activity recording per dilution, plus the recovery points (after 24 hours were recorded. The preliminary data, using a set of chemicals with different mode-of-actions (13 known to be neurotoxic, 2 non-neuroactive and not toxic and 5 non-neuroactive but toxic show good predictivity (sensitivity: 0.77; specificity: 0.86; accuracy: 0.85. Thus, the MEA with a neuronal network has the potency to become an effective tool to evaluate the neurotoxicity of substances in vitro.

Three PbII coordination polymers based on 2-(pyridin-2-yl)-1H-imidazole-4,5-dicarboxylic acid: Syntheses, crystal structures, and fluorescent properties

International Nuclear Information System (INIS)

Yu, Xiao-Yang; Xin, Rui; Gao, Wei-Ping; Wang, Na; Zhang, Xiao; Yang, Yan-Yan; Qu, Xiao-Shu

2013-01-01

Three lead coordination polymers, [PbCl(C 10 H 6 N 3 O 4 )(H 2 O)·H 2 O] n (1), [Pb(C 10 H 6 N 3 O 4 ) 2 (H 2 O)] n (2) and [Pb 3 (C 10 H 5 N 3 O 4 ) 3 ] n (3) (C 10 H 7 N 3 O 4 =2-(pyridin-2-yl)-1H-imidazole-4,5-dicarboxylic acid), have been hydrothermally synthesized and structurally characterized by single-crystal X-ray diffraction. In 1, Cl anions connected neighboring wave-like 2D layers, which are constructed with left- and right-handed helical chains, into a 3D network structure with a (6 3 )(6 5 ·8) topology. In 2, Pb cations are linked into a 3D 6 6 network with left- and right-handed helixes by μ 2 -bridging C 10 H 6 N 3 O 4 − ligands. In 3, C 10 H 5 N 3 O 4 2− ligands link Pb 6 O 12 clusters into a 3D (4 12 ·6 3 ) network. Their fluorescent properties were also investigated. - Graphical abstract: Three 3D lead compounds based on 2-(pyridin-2-yl)-1H-imidazole-4,5-dicarboxylic acid have been hydrothermally synthesized. Four new coordination modes of the organic ligand are first reported. Display Omitted - Highlights: • Three new Pb(II) complexes have been synthesized and characterized. • Left- and right-handed helical chains can be found in the 3D networks of 1 and 2. • Pb 6 O 12 clusters are connected into (4 12 ·6 3 ) network in 3

Dopaminergic Neuron-Specific Deletion of p53 Gene Attenuates Methamphetamine Neurotoxicity.

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Lu, Tao; Kim, Paul P; Greig, Nigel H; Luo, Yu

2017-08-01

p53 plays an essential role in the regulation of cell death in dopaminergic (DA) neurons and its activation has been implicated in the neurotoxic effects of methamphetamine (MA). However, how p53 mediates MA neurotoxicity remains largely unknown. In this study, we examined the effect of DA-specific p53 gene deletion in DAT-p53KO mice. Whereas in vivo MA binge exposure reduced locomotor activity in wild-type (WT) mice, this was significantly attenuated in DAT-p53KO mice and associated with significant differences in the levels of the p53 target genes BAX and p21 between WT and DAT-p53KO. Notably, DA-specific deletion of p53 provided protection of substantia nigra pars reticulata (SNpr) tyrosine hydroxylase (TH) positive fibers following binge MA, with DAT-p53KO mice having less decline of TH protein levels in striatum versus WT mice. Whereas DAT-p53KO mice demonstrated a consistently higher density of TH fibers in striatum compared to WT mice at 10 days after MA exposure, DA neuron counts within the substantia nigra pars compacta (SNpc) were similar. Finally, supportive of these results, administration of a p53-specific inhibitor (PFT-α) provided a similarly protective effect on MA binge-induced behavioral deficits. Neither DA specific p53 deletion nor p53 pharmacological inhibition affected hyperthermia induced by MA binge. These findings demonstrate a specific contribution of p53 activation in behavioral deficits and DA neuronal terminal loss by MA binge exposure.

Application of stem cell derived neuronal cells to evaluate neurotoxic chemotherapy

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Claudia Wing

2017-07-01

Full Text Available The generation of induced pluripotent stem cells (iPSCs and differentiation to cells composing major organs has opened up the possibility for a new model system to study adverse toxicities associated with chemotherapy. Therefore, we used human iPSC-derived neurons to study peripheral neuropathy, one of the most common adverse effects of chemotherapy and cause for dose reduction. To determine the utility of these neurons in investigating the effects of neurotoxic chemotherapy, we measured morphological differences in neurite outgrowth, cell viability as determined by ATP levels and apoptosis through measures of caspase 3/7 activation following treatment with clinically relevant concentrations of platinating agents (cisplatin, oxaliplatin and carboplatin, taxanes (paclitaxel, docetaxel and nab-paclitaxel, a targeted proteasome inhibitor (bortezomib, an antiangiogenic compound (thalidomide, and 5-fluorouracil, a chemotherapeutic that does not cause neuropathy. We demonstrate differential sensitivity of neurons to mechanistically distinct classes of chemotherapeutics. We also show a dose-dependent reduction of electrical activity as measured by mean firing rate of the neurons following treatment with paclitaxel. We compared neurite outgrowth and cell viability of iPSC-derived cortical (iCell® Neurons and peripheral (Peri.4U neurons to cisplatin, paclitaxel and vincristine. Goshajinkigan, a Japanese herbal neuroprotectant medicine, was protective against paclitaxel-induced neurotoxicity but not oxaliplatin as measured by morphological phenotypes. Thus, we have demonstrated the utility of human iPSC-derived neurons as a useful model to distinguish drug class differences and for studies of a potential neuroprotectant for the prevention of chemotherapy-induced peripheral neuropathy.

Correlation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity with blood-brain barrier monoamine oxidase activity

International Nuclear Information System (INIS)

Kalaria, R.N.; Mitchell, M.J.; Harik, S.I.

1987-01-01

Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism in humans and subhuman primates, but not in rats and many other laboratory animals; mice are intermediate in their susceptibility. Since MPTP causes selective dopaminergic neurotoxicity when infused directly into rat substantia nigra, the authors hypothesized that systemic MPTP may be metabolized by monoamine oxidase and/or other enzymes in rat brain capillaries and possibly other peripheral organs and thus prevented from reaching its neuronal sites of toxicity. They tested this hypothesis by assessing monoamine oxidase in isolated cerebral microvessels of humans, rats, and mice by measuring the specific binding of [ 3 H]pargyline, an irreversible monoamine oxidase inhibitor, and by estimating the rates of MPTP and benzylamine oxidation. [ 3 H]Pargyline binding to rat cerebral microvessels was about 10-fold higher than to human or mouse microvessels. Also, MPTP oxidation by rat brain microvessels was about 30-fold greater than by human microvessels; mouse microvessels yielded intermediate values. These results may explain, at least in part, the marked species differences in susceptibility to systemic MPTP. They also suggest the potential importance of enzyme barriers at the blood-brain interface that can metabolize toxins not excluded by structural barriers, and may provide biological bases for developing therapeutic strategies for the prevention of MPTP-induced neurotoxicity and other neurotoxic conditions including, possibly, Parkinson's disease

Comparison of the Developmental and Acute Neurotoxicity of a Library of Organophosphorus Pesticides Using a Vertebrate Behavioral Assay

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The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize organophosphorus pesticides for neurotoxicity using behavioral tests in an in vivo, vertebrate, medium-throughput model (zebrafish; Danio rerio). Our behavioral testing paradigm assesses the e...

Striatal dopamine release in vivo following neurotoxic doses of methamphetamine and effect of the neuroprotective drugs, chlormethiazole and dizocilpine.

Science.gov (United States)

Baldwin, H A; Colado, M I; Murray, T K; De Souza, R J; Green, A R

1993-03-01

1. Administration to rats of methamphetamine (15 mg kg-1, i.p.) every 2 h to a total of 4 doses resulted in a neurotoxic loss of striatal dopamine of 36% and of 5-hydroxytryptamine (5-HT) in the cortex (43%) and hippocampus (47%) 3 days later. 2. Administration of chlormethiazole (50 mg kg-1, i.p.) 15 min before each dose of methamphetamine provided complete protection against the neurotoxic loss of monoamines while administration of dizocilpine (1 mg kg-1, i.p.) using the same dose schedule provided substantial protection. 3. Measurement of dopamine release in the striatum by in vivo microdialysis revealed that methamphetamine produced an approximate 7000% increase in dopamine release after the first injection. The enhanced release response was somewhat diminished after the third injection but still around 4000% above baseline. Dizocilpine (1 mg kg-1, i.p.) did not alter this response but chlormethiazole (50 mg kg-1, i.p.) attenuated the methamphetamine-induced release by approximately 40%. 4. Dizocilpine pretreatment did not influence the decrease in the dialysate concentration of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) produced by administration of methamphetamine while chlormethiazole pretreatment decreased the dialysate concentration of these metabolites still further. 5. The concentration of dopamine in the dialysate during basal conditions increased modestly during the course of the experiment. This increase did not occur in chlormethiazole-treated rats. HVA concentrations were unaltered by chlormethiazole administration. 6. Chlormethiazole (100-1000 microM) did not alter methamphetamine (100 microM) or K+ (35 mM)-evoked release of endogenous dopamine from striatal prisms in vitro. 7. Several NMDA antagonists prevent methamphetamine-induced neurotoxicity; however chlormethiazole is not an NMDA antagonist. Inhibition of striatal dopamine function prevents methamphetamine-induced toxicity of both dopamine and 5

Economic benefits of methylmercury exposure control in Europe: Monetary value of neurotoxicity prevention

Science.gov (United States)

2013-01-01

Background Due to global mercury pollution and the adverse health effects of prenatal exposure to methylmercury (MeHg), an assessment of the economic benefits of prevented developmental neurotoxicity is necessary for any cost-benefit analysis. Methods Distributions of hair-Hg concentrations among women of reproductive age were obtained from the DEMOCOPHES project (1,875 subjects in 17 countries) and literature data (6,820 subjects from 8 countries). The exposures were assumed to comply with log-normal distributions. Neurotoxicity effects were estimated from a linear dose-response function with a slope of 0.465 Intelligence Quotient (IQ) point reduction per μg/g increase in the maternal hair-Hg concentration during pregnancy, assuming no deficits below a hair-Hg limit of 0.58 μg/g thought to be safe. A logarithmic IQ response was used in sensitivity analyses. The estimated IQ benefit cost was based on lifetime income, adjusted for purchasing power parity. Results The hair-mercury concentrations were the highest in Southern Europe and lowest in Eastern Europe. The results suggest that, within the EU, more than 1.8 million children are born every year with MeHg exposures above the limit of 0.58 μg/g, and about 200,000 births exceed a higher limit of 2.5 μg/g proposed by the World Health Organization (WHO). The total annual benefits of exposure prevention within the EU were estimated at more than 600,000 IQ points per year, corresponding to a total economic benefit between €8,000 million and €9,000 million per year. About four-fold higher values were obtained when using the logarithmic response function, while adjustment for productivity resulted in slightly lower total benefits. These calculations do not include the less tangible advantages of protecting brain development against neurotoxicity or any other adverse effects. Conclusions These estimates document that efforts to combat mercury pollution and to reduce MeHg exposures will have very substantial

Tuning different kinds of entangled metal-organic frameworks by modifying the spacer group of aliphatic dicarboxylate ligands and the reactant ratio.

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Yang, Jin-Xia; Zhai, Ji-Quan; Zhang, Xin; Qin, Ye-Yan; Yao, Yuan-Gen

2016-01-14

Taking advantage of the conformational flexibility of the bpp ligand and aliphatic dicarboxylic acids, six interesting entangled coordination polymers, {[Cd(fum)(bpp)(H2O)]·(H2O)}n (), {[Cd(fum)(bpp)2]·(H2O)5}n (), {[Cd2(suc)1.5(bpp)2(NO3)(H2O)2]·6H2O}n (), {[Cd(suc)(bpp)2]·(H2O)1.5}n (), {[Cd2(glu)2(bpp)3]·10H2O}n (), and {Cd(adp)(bpp)(H2O)}n () have been prepared and structurally characterized (bpp = 1,3-bi(4-pyridyl)propane, fum = fumaric, suc = succinate, glu = glutaric, adp = adipic). Compounds and are comprised of undulated 2D 4(4)-sql networks. In the structure of compound , two identical undulated layers are parallelly interpenetrated with each other to give a 2D → 2D interpenetrating framework. For , the dangling arms projected from 2D layers are intercalated into the neighboring sheets, producing a 2D → 3D polythreading framework. Compound shows a rare example of a 2D self-penetrating framework with a (3,4)-connected (4(2)·6(3)·8)(4(2)·6) topology. Compound presents an unusual 2D self-threading network with a novel 4-connected {4(2)·6(3)·8} topology. Compound displays a 3D self-penetrating system based on a 2D → 3D parallel polycatenation array. Compound exhibits an unprecedented 3D self-penetrating structure having both 1D + 1D → 1D polycatenation and 3D + 3D → 3D interpenetration characteristics. A comparison of these six compounds demonstrates that both the different spacer lengths of the aliphatic dicarboxylates and reactant ratios appear to play a significant role in the assembly of entangled frameworks. In addition, thermal stabilities and photoluminescence properties of have been examined in the solid state at room temperature.

Methamphetamine-induced neurotoxicity linked to UPS dysfunction and autophagy related changes that can be modulated by PKCδ in dopaminergic neuronal cells

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Lin, Mengshien; Shivalingappa, Prashanth Chandramani; Jin, Huajun; Ghosh, Anamitra; Anantharam, Vellareddy; Ali, Syed; Kanthasamy, Anumantha G.; Kanthasamy, Arthi

2012-01-01

A compromised protein degradation machinery has been implicated in methamphetamine (MA)-induced neurodegeneration. However, the signaling mechanisms that induce autophagy and UPS dysfunction are not well understood. The present study investigates the contributions of PKC delta (PKCδ) mediated signaling events in MA-induced autophagy, UPS dysfunction and cell death. Using an in vitro mesencephalic dopaminergic cell culture model, we demonstrate that MA-induced early induction of autophagy is associated with reduction in proteasomal function and concomitant dissipation of mitochondrial membrane potential (MMP), followed by significantly increased of PKCδ activation, caspase-3 activation, accumulation of ubiquitin positive aggregates and microtubule associated light chain-3 (LC3-II) levels. Interestingly, siRNA mediated knockdown of PKCδ or overexpression of cleavage resistant mutant of PKCδ dramatically reduced MA-induced autophagy, proteasomal function, and associated accumulation of ubiquitinated protein aggregates, which closely paralleled cell survival. Importantly, when autophagy was inhibited either pharmacologically (3-MA) or genetically (siRNA mediated silencing of LC3), the dopaminergic cells became sensitized to MA-induced apoptosis through caspase-3 activation. Conversely, overexpression of LC3 partially protected against MA-induced apoptotic cell death, suggesting a neuroprotective role for autophagy in MA-induced neurotoxicity. Notably, rat striatal tissue isolated from MA treated rats also exhibited elevated LC3-II, ubiquitinated protein levels, and PKCδ cleavage. Taken together, our data demonstrate that MA-induced autophagy serves as an adaptive strategy for inhibiting mitochondria mediated apoptotic cell death and degradation of aggregated proteins. Our results also suggest that the sustained activation of PKCδ leads to UPS dysfunction, resulting in the activation of caspase-3 mediated apoptotic cell death in the nigrostriatal dopaminergic

An efficient analytical platform for on line microfluidic profiling of neurotoxic snake venoms towards nicotinic receptor like affinity.

NARCIS (Netherlands)

Heus, F.A.H.; Vonk, F.; Otvos, R.A.; Bruyneel, B.; Smit, A.B.; Lingeman, H.; Richardson, M.; Niessen, W.M.A.; Kool, J.

2013-01-01

Venomous snakes have evolved their efficient venomous arsenals mainly to immobilize prey. The highly variable toxic peptides in these venoms target a myriad of neurotoxic and haemotoxic receptors and enzymes and comprise highly interesting candidates for drug discovery. Discovery of bioactive

Erythropoietin in the treatment of carbon monoxide neurotoxicity in rat.

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Moallem, Seyed Adel; Mohamadpour, Amir Hooshang; Abnous, Khalil; Sankian, Mojtaba; Sadeghnia, Hamid Reza; Tsatsakis, Aristidis; Shahsavand, Shabnam

2015-12-01

Erythropoietin (EPO) plays a critical role in the development of the nervous system. In this study, the effects of EPO in carbon monoxide (CO) neurotoxicity were examined. Rats were exposed to 3000 ppm CO for 1 h and then different doses of EPO were administrated intraperitoneally. After 24 h, glial fibrillary acidic protein (GFAP) levels in the serum were determined and water content of brain and the extravasation of a tracer (Evans blue) were measured. Brain lipid peroxidation, myeloperoxidase activity Myelin basic protein (MBP) and BAX/BcL2 protein relative expressions were determined. Cation exchange chromatography was used to evaluate MBP alterations. Seven days after exposure, pathological assessment was performed after Klüver-Barrera staining. EPO reduced malondialdehyde levels at all doses (2500, 5000 and 10,000 u/kg). Lower doses of EPO (625, 1250, 2500 u/kg) significantly decreased the elevated serum levels of GFAP. EPO could not reduce the water content of the edematous poisoned brains. However, at 5000 and 10,000 u/kg it protected the blood brain barrier against integrity loss as a result of CO. EPO could significantly decrease the MPO activity. CO-mediated oxidative stress caused chemical alterations in MBP and EPO could partially prevent these biochemical changes. Fewer vacuoles and demyelinated fibers were found in the EPO-treated animals. EPO (5000 u/kg) could restore the MBP density. CO increased brain BAX/Bcl-2 ratio 38.78%. EPO reduced it 38.86%. These results reveal that EPO could relatively prevent different pathways of neurotoxicity by CO poisoning and thus has the potential to be used as a novel approach to manage this poisoning. Copyright © 2015 Elsevier Ltd. All rights reserved.

Protective effect of arctigenin on ethanol-induced neurotoxicity in PC12 cells.

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Huang, Jia; Xiao, Lan; Wei, Jing-Xiang; Shu, Ya-Hai; Fang, Shi-Qi; Wang, Yong-Tang; Lu, Xiu-Min

2017-04-01

As a neurotropic substance, ethanol can damage nerve cells through an increase in the production of free radicals, interference of neurotrophic factor signaling pathways, activation of endogenous apoptotic signals and other molecular mechanisms. Previous studies have revealed that a number of natural drugs extracted from plants offer protection of nerve cells from damage. Among these, arctigenin (ATG) is a lignine extracted from Arctium lappa (L.), which has been found to exert a neuroprotective effect on scopolamine‑induced memory deficits in mice with Alzheimer's disease and glutamate-induced neurotoxicity in primary neurons. As a result, it may offer beneficial effects on ethanol-induced neurotoxicity. However, the effects of ATG on ethanol‑induced nerve damage remain to be elucidated. To address this issue, the present study used rat pheochromocytoma PC12 cells to investigate the neuroprotective effects of ATG on ethanol-induced cell damage by performing an MTT reduction assay, cell cycle analysis, Hoechst33342/propidium iodide fluorescence staining and flow cytometry to examine apoptosis. The results showed that 10 µM ATG effectively promoted the proliferation of damaged cells, and increased the distribution ratio of the cells at the G2/M and S phases (P<0.05). In addition, the apoptosis and necrosis of the PC12 cells were significantly decreased following treatment with ATG. Therefore, it was concluded that 10 µM ATG had a protective effect on ethanol‑induced injury in PC12 cells.

EGCG Protects against 6-OHDA-Induced Neurotoxicity in a Cell Culture Model

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Dan Chen

2015-01-01

Full Text Available Background. Parkinson’s disease (PD is a progressive neurodegenerative disease that causes severe brain dopamine depletion. Disruption of iron metabolism may be involved in the PD progression. Objective. To test the protective effect of (−-epigallocatechin-3-gallate (EGCG against 6-hydroxydopamine- (6-OHDA- induced neurotoxicity by regulating iron metabolism in N27 cells. Methods. Protection by EGCG in N27 cells was assessed by SYTOX green assay, MTT, and caspase-3 activity. Iron regulatory gene and protein expression were measured by RT-PCR and Western blotting. Intracellular iron uptake was measured using 55Fe. The EGCG protection was further tested in primary mesencephalic dopaminergic neurons by immunocytochemistry. Results. EGCG protected against 6-OHDA-induced cell toxicity. 6-OHDA treatment significantly (p<0.05 increased divalent metal transporter-1 (DMT1 and hepcidin and decreased ferroportin 1 (Fpn1 level, whereas pretreatment with EGCG counteracted the effects. The increased 55Fe (by 96%, p<0.01 cell uptake confirmed the iron burden by 6-OHDA and was reduced by EGCG by 27% (p<0.05, supporting the DMT1 results. Pretreatment with EGCG and 6-OHDA significantly increased (p<0.0001 TH+ cell count (~3-fold and neurite length (~12-fold compared to 6-OHDA alone in primary mesencephalic neurons. Conclusions. Pretreatment with EGCG protected against 6-OHDA-induced neurotoxicity by regulating genes and proteins involved in brain iron homeostasis, especially modulating hepcidin levels.

Advanced Pre-clinical Research Approaches and Models to Studying Pediatric Anesthetic Neurotoxicity

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Cheng eWang

2012-10-01

Full Text Available Advances in pediatric and obstetric surgery have resulted in an increase in the duration and complexity of anesthetic procedures. A great deal of concern has recently arisen regarding the safety of anesthesia in infants and children. Because of obvious limitations, it is not possible to thoroughly explore the effects of anesthetic agents on neurons in vivo in human infants or children. However, the availability of some advanced pre-clinical research approaches and models, such as imaging technology both in vitro and in vivo, stem cell and nonhuman primate experimental models, have provided potentially invaluable tools for examining the developmental effects of anesthetic agents. This review discusses the potential application of some sophisticaled research approaches, e.g., calcium imaging, in stem cell-derived in vitro models, especially human embryonic neural stem cells, along with their capacity for proliferation and their potential for differentiation, to dissect relevant mechanisms underlying the etiology of the neurotoxicity associated with developmental exposures to anesthetic agents. Also, this review attempts to discuss several advantages for using the developing rhesus monkey models (in vivo, when combined with dynamic molecular imaging approaches, in addressing critical issues related to the topic of pediatric sedation/anesthesia. These include the relationships between anesthetic-induced neurotoxicity, dose response, time-course and developmental stage at time of exposure (in vivo studies, serving to provide the most expeditious platform toward decreasing the uncertainty in extrapolating pre-clinical data to the human condition.

The role of system Xc- in methamphetamine-induced dopaminergic neurotoxicity in mice.

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Dang, Duy-Khanh; Shin, Eun-Joo; Tran, Hai-Quyen; Kim, Dae-Joong; Jeong, Ji Hoon; Jang, Choon-Gon; Nah, Seung-Yeol; Sato, Hideyo; Nabeshima, Toshitaka; Yoneda, Yukio; Kim, Hyoung-Chun

2017-09-01

The cystine/glutamate antiporter (system Xc - , Sxc) transports cystine into cell in exchange for glutamate. Since xCT is a specific subunit of Sxc, we employed xCT knockout mice and investigated whether this antiporter affected methamphetamine (MA)-induced dopaminergic neurotoxicity. MA treatment significantly increased striatal oxidative burdens in wild type mice. xCT inhibitor [i.e., S-4-carboxy-phenylglycine (CPG), sulfasalazine] or an xCT knockout significantly protected against these oxidative burdens. MA-induced increases in Iba-1 expression and Iba-1-labeled microglial immunoreactivity (Iba-1-IR) were significantly attenuated by CPG or sulfasalazine administration or xCT knockout. CPG or sulfasalazine significantly attenuated MA-induced TUNEL-positive cell populations in the striatum of Taconic ICR mice. The decrease in excitatory amino acid transporter-2 (or glutamate transporter-1) expression and increase in glutamate release were attenuated by CPG, sulfasalazine or xCT knockout. In addition, CPG, sulfasalazine or xCT knockout significantly protected against dopaminergic loss (i.e., decreases in tyrosine hydroxylase expression and immunoreactivity, and an increase in dopamine turnover rate) induced by MA. However, CPG, sulfasalazine or xCT knockout did not significantly affect the impaired glutathione system [i.e., decrease in reduced glutathione (GSH) and increase in oxidized glutathione (GSSG)] induced by MA. Our results suggest that Sxc mediates MA-induced neurotoxicity via facilitating oxidative stress, microgliosis, proapoptosis, and glutamate-related toxicity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Therapeutic potency of bee pollen against biochemical autistic features induced through acute and sub-acute neurotoxicity of orally administered propionic acid.

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Al-Salem, Huda S; Bhat, Ramesa Shafi; Al-Ayadhi, Laila; El-Ansary, Afaf

2016-04-23

It is now well documented that postnatal exposure to certain chemicals has been reported to increase the risk of autism spectrum disorder. Propionic acid (PA), as a metabolic product of gut microbiotaandas a commonly used food additive, has been reported to mediate the effects of autism. Results from animal studies may help to identify environmental neurotoxic agents and drugs that can ameliorate neurotoxicity and may thereby aid in the treatment of autism. The present study investigated the ameliorative effects of natural bee pollen against acute and sub-acute brain intoxication induced by (PA) in rats. Twenty-four young male Western Albino ratswere enrolled in the present study. They were classified into four equal groups, eachwith6 rats. The control group received only phosphate buffered saline; the oral buffered PA-treated groups (II and III) received a neurotoxic dose of 750 mg/kg body weight divided in 3 dose of 250 mg/kg body weight/day serving asthe acute group and 750 mg/kg body weight divided in 10 equal dose of 75 mg/kg body weight/day as the sub-acute group. The fourth group received 50 mg bee pollen for 30 days after PA-acute intoxication. The obtained data showed that the PA-treated groups demonstrated multiple signs of brain toxicity, as indicated by a depletion of serotonin (5HT), dopamine and nor-adrenaline, together withan increase in IFN-γ and caspase 3. Bee pollen was effective in ameliorating the neurotoxic effect of PA. All measured parameters demonstrated minimal alteration in comparison with thecontrol animal than did those of acute and sub-acute PA-treated animals. In conclusion, bee pollen demonstrates anti-inflammatory and anti-apoptotic effects while ameliorating the impaired neurochemistry of PA-intoxicated rats.

Separating the agony from ecstasy: R(-)-3,4-methylenedioxymethamphetamine has prosocial and therapeutic-like effects without signs of neurotoxicity in mice.

Science.gov (United States)

Curry, Daniel W; Young, Matthew B; Tran, Andrew N; Daoud, Georges E; Howell, Leonard L

2018-01-01

S,R(+/-)-3,4-methylenedioxymethamphetamine (SR-MDMA) is an amphetamine derivative with prosocial and putative therapeutic effects. Ongoing clinical trials are investigating it as a treatment for post-traumatic stress disorder (PTSD) and other conditions. However, its potential for adverse effects such as hyperthermia and neurotoxicity may limit its clinical viability. We investigated the hypothesis that one of the two enantiomers of SR-MDMA, R-MDMA, would retain the prosocial and therapeutic effects but with fewer adverse effects. Using male Swiss Webster and C57BL/6 mice, the prosocial effects of R-MDMA were measured using a social interaction test, and the therapeutic-like effects were assessed using a Pavlovian fear conditioning and extinction paradigm relevant to PTSD. Locomotor activity and body temperature were tracked after administration, and neurotoxicity was evaluated post-mortem. R-MDMA significantly increased murine social interaction and facilitated extinction of conditioned freezing. Yet, unlike racemic MDMA, it did not increase locomotor activity, produce signs of neurotoxicity, or increase body temperature. A key pharmacological difference between R-MDMA and racemic MDMA is that R-MDMA has much lower potency as a dopamine releaser. Pretreatment with a selective dopamine D1 receptor antagonist prevented SR-MDMA-induced hyperthermia, suggesting that differential dopamine signaling may explain some of the observed differences between the treatments. Together, these results indicate that the prosocial and therapeutic effects of SR-MDMA may be separable from the stimulant, thermogenic, and potential neurotoxic effects. To what extent these findings translate to humans will require further investigation, but these data suggest that R-MDMA could be a more viable therapeutic option for the treatment of PTSD and other disorders for which SR-MDMA is currently being investigated. Copyright © 2017 Elsevier Ltd. All rights reserved.

Comparative non-cholinergic neurotoxic effects of paraoxon and diisopropyl fluorophosphate (DFP) on human neuroblastoma and astrocytoma cell lines

International Nuclear Information System (INIS)

Qian Yongchang; Venkatraj, Jijayanagaram; Barhoumi, Rola; Pal, Ranadip; Datta, Aniruddha; Wild, James R.; Tiffany-Castiglioni, Evelyn

2007-01-01

The objective of this study was to evaluate the comparative non-cholinergic neurotoxic effects of paraoxon, which is acutely neurotoxic, and diisopropyl fluorophosphate (DFP), which induces OPIDN, in the human neuroblastoma SY5Y and the human astrocytoma cell line CCF-STTG1. SY5Y cells have been studied extensively as a model for OP-induced neurotoxicity, but CCF cells have not previously been studied. We conducted a preliminary human gene array assay of OP-treated SY5Y cells in order to assess at the gene level whether these cells can distinguish between OP compounds that do and do not cause OPIDN. Paraoxon and DFP induced dramatically different profiles of gene expression. Two genes were upregulated and 13 downregulated by at least 2-fold in paraoxon-treated cells. In contrast, one gene was upregulated by DFP and none was downregulated at the 2-fold threshold. This finding is consistent with current and previous observations that SY5Y cells can distinguish between OPs that do or do not induce OPIDN. We also examined gene array results for possible novel target proteins or metabolic pathways for OP neurotoxicity. Protein levels of glucose regulated protein 78 (GRP78) revealed that paraoxon exposure at 3 μM for 24 h significantly reduced GRP78 levels by 30% in neuroblastoma cells, whereas DFP treatment had no effect. In comparison with SY5Y neuroblastoma cells, paraoxon and DFP (3 μM for 24 h) each significantly increased GRP78 levels by 23-24% in CCF astrocytoma cells. As we have previously evaluated intracellular changes in Ca 2+ levels in SY5Y cells, we investigated the effects of paraoxon and DFP on cellular Ca 2+ homeostasis in CCF by studying cytosolic and mitochondrial basal calcium levels. A significant decrease in the ratio of mitochondrial to cytosolic Ca 2+ fluorescence was detected in CCF cultures treated for either 1 or 3 days with 1, 3, 10, or 30 μM paraoxon. In contrast, treatment with DFP for 1 day had no significant effect on the ratio of

Evidence for hydroxyl radical scavenging action of nitric oxide donors in the protection against 1-methyl-4-phenylpyridinium-induced neurotoxicity in rats.

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Banerjee, Rebecca; Saravanan, Karuppagounder S; Thomas, Bobby; Sindhu, Kizhake M; Mohanakumar, Kochupurackal P

2008-06-01

In the present study we provide evidence for hydroxyl radical (*OH) scavenging action of nitric oxide (NO*), and subsequent dopaminergic neuroprotection in a hemiparkinsonian rat model. Reactive oxygen species are strongly implicated in the nigrostriatal dopaminergic neurotoxicity caused by the parkinsonian neurotoxin, 1-methyl-4-phenylpyridinium (MPP+). Since the role of this free radical as a neurotoxicant or neuroprotectant is debatable, we investigated the effects of some of the NO* donors such as S-nitroso-N-acetylpenicillamine (SNAP), 3-morpholinosydnonimine hydrochloride (SIN-1), sodium nitroprusside (SNP) and nitroglycerin (NG) on in vitro *OH generation in a Fenton-like reaction involving ferrous citrate, as well as in MPP+-induced *OH production in the mitochondria. We also tested whether co-administration of NO* donor and MPP+ could protect against MPP+-induced dopaminergic neurotoxicity in rats. While NG, SNAP and SIN-1 attenuated MPP+-induced *OH generation in the mitochondria, and in a Fenton-like reaction, SNP caused up to 18-fold increase in *OH production in the latter reaction. Striatal dopaminergic depletion following intranigral infusion of MPP+ in rats was significantly attenuated by NG, SNAP and SIN-1, but not by SNP. Solutions of NG, SNAP and SIN-1, exposed to air for 48 h to remove NO*, when administered similarly failed to attenuate MPP+-induced neurotoxicity in vivo. Conversely, long-time air-exposed SNP solution when administered in rats intranigrally, caused a dose-dependent depletion of the striatal dopamine. These results confirm the involvement of *OH in the nigrostriatal degeneration caused by MPP+, indicate the *OH scavenging ability of NO*, and demonstrate protection by NO* donors against MPP+-induced dopaminergic neurotoxicity in rats.

Epigenetic changes in T-cell and monocyte signatures and production of neurotoxic cytokines in ALS patients.

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Lam, Larry; Chin, Lydia; Halder, Ramesh C; Sagong, Bien; Famenini, Sam; Sayre, James; Montoya, Dennis; Rubbi, Liudmilla; Pellegrini, Matteo; Fiala, Milan

2016-10-01

We have investigated transcriptional and epigenetic differences in peripheral blood mononuclear cells (PBMCs) of monozygotic female twins discordant in the diagnosis of amyotrophic lateral sclerosis (ALS). Exploring DNA methylation differences by reduced representation bisulfite sequencing (RRBS), we determined that, over time, the ALS twin developed higher abundances of the CD14 macrophages and lower abundances of T cells compared to the non-ALS twin. Higher macrophage signature in the ALS twin was also shown by RNA sequencing (RNA-seq). Moreover, the twins differed in the methylome at loci near several genes, including EGFR and TNFRSF11A, and in the pathways related to the tretinoin and H3K27me3 markers. We also tested cytokine production by PBMCs. The ALS twin's PBMCs spontaneously produced IL-6 and TNF-α, whereas PBMCs of the healthy twin produced these cytokines only when stimulated by superoxide dismutase (SOD)-1. These results and flow cytometric detection of CD45 and CD127 suggest the presence of memory T cells in both twins, but effector T cells only in the ALS twin. The ALS twin's PBMC supernatants, but not the healthy twin's, were toxic to rat cortical neurons, and this toxicity was strongly inhibited by an IL-6 receptor antibody (tocilizumab) and less well by TNF-α and IL-1β antibodies. The putative neurotoxicity of IL-6 and TNF-α is in agreement with a high expression of these cytokines on infiltrating macrophages in the ALS spinal cord. We hypothesize that higher macrophage abundance and increased neurotoxic cytokines have a fundamental role in the phenotype and treatment of certain individuals with ALS.-Lam, L., Chin, L., Halder, R. C., Sagong, B., Famenini, S., Sayre, J., Montoya, D., Rubbi L., Pellegrini, M., Fiala, M. Epigenetic changes in T-cell and monocyte signatures and production of neurotoxic cytokines in ALS patients. © FASEB.

Cerebellum neurotransmission during postnatal development: [Pt(O,O'-acac)(γ-acac)(DMS)] vs cisplatin and neurotoxicity.

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Piccolini, Valeria Maria; Esposito, Alessandra; Dal Bo, Veronica; Insolia, Violetta; Bottone, Maria Grazia; De Pascali, Sandra Angelica; Fanizzi, Francesco Paolo; Bernocchi, Graziella

2015-02-01

Several chemotherapeutic drugs are known to cause neurotoxicity. Platinum-based agents in use or in clinical trials display neurotoxic potential accompanied by neurological complications; recent studies have identified a large number of behavioural issues in paediatric oncology patients. To understand the toxicity of platinum drugs at the molecular and cellular levels, this study compares the possible cytotoxic effects of an older platinum compound, cisplatin and a new platinum compound, [Pt(O,O'-acac)(γ-acac)(DMS)], on the CNS of postnatally developing rats, which is much more vulnerable to injury than the CNS of adult rats. Since several drugs interact with neurotransmitters during neuronal maturation, we performed immunostainings with antibodies raised against markers of glutamate and GABA, the major neurotransmitters in the cerebellum. After a single injection of cisplatin at postnatal day 10 (PD10), the labelling of Purkinje cells with the neurotransmitter markers evidenced alterations between PD11 and PD30, i.e. atrophy of the dendrite tree, changes in the distribution of synaptic contacts of parallel and climbing fibres, delay in the elimination of transient synapses on cell soma and severely impaired pinceau formation at the axon hillock. After treatment with [Pt(O,O'-acac)(γ-acac)(DMS)], the sole relevant change concerned the timing of climbing fibres elimination; the transient synapses disappearance on the Purkinje cell soma was delayed in some cells; instead, the growth of Purkinje cell dendrite tree was normal as was the formation of inhibitory synaptic contacts on these neurons. These findings add new evidence not only on the lower neurotoxicity of [Pt(O,O'-acac)(γ-acac)(DMS)] vs cisplatin but also on the involvement of neurotransmitters and relative synaptic connections in the maturation of central nerve tissue. Copyright © 2014 ISDN. Published by Elsevier Ltd. All rights reserved.

Determination of Acetylcholinesterase activities in marine gastropod (Morula granulata) as a biomarker of neurotoxic contaminants along the Goan coast.

Digital Repository Service at National Institute of Oceanography (India)

Sarkar, A.; Tegur, P.M.; Jana, S.; Rao, P.V.S.S.D.P.

diseases or even death. Hence it is considered as a suitable biomarker for detecting environmental pollution caused by the neurotoxic compounds. We have carried out experiments with marine gastropods (Morula granulate) at the selected sites, Arambol...

Functionalization of LDPE and mLLDPE via grafting trans-ethylene-1,2-dicarboxylic acid by reactive extrusion

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2010-03-01

Full Text Available An investigation was made of grafting trans-ethylene-1,2-dicarboxylic acid (TEDA onto metallocene-linear low-density polyethylene (mLLDPE and low-density polyethylene (LDPE in the course of reactive extrusion. The initiator was 1,3-bis-(tert-butyl-peroxyisopropylbenzene. The graft efficiency of TEDA has been shown to increase with increasing initiator concentration, irrespective of polyethylene type. The graft values for LDPE were higher than for mLLDPE over the initiator concentration range (0.05 to 0.4 wt%. The rheological properties of mLLDPE were found to undergo more tangible changes during functionalization than those of LDPE. These changes were caused by side reactions, mainly macromolecular crosslinking. It has been established that some carboxyl groups get transformed to anhydride groups in the grafted product. The concentration of end double bonds reduces, but intramolecular unsaturation in both polyethylenes increases. Data are presented on thermal and stress-strain (mechanical properties of virgin and functionalized polymers, as well as rheological and viscoelastic properties of their melts.

In vitro neurotoxic effects of 1 GeV/n iron particles assessed in retinal explants.

Science.gov (United States)

Vazquez, M E; Kirk, E

2000-01-01

The heavy ion component of the cosmic radiation remains problematic to the assessment of risk in manned space flight. The biological effectiveness of HZE particles has yet to be established, particularly with regard to nervous tissue. Using heavy ions accelerated at the AGS of Brookhaven National Laboratory, we study the neurotoxic effects of iron particles. We exposed retinal explants, taken from chick embryos, to determine the dose response relationships for neurite outgrowth. Morphometric techniques were used to evaluate the in vitro effects of 1 GeV/a iron particles (LET 148 keV/micrometer). Iron particles produced a dose-dependent reduction of neurite outgrowth with a maximal effect achieved with a dose of 100 cGy. Doses as low as 10-50 cGy were able to induce reductions of the neurite outgrowth as compared to the control group. Neurite generation is a more sensitive parameter than neurite elongation, suggesting different mechanism of radiation damage in our model. These results showed that low doses/fluences of iron particles could impair the retinal ganglion cells' capacity to generate neurites indicating the highly neurotoxic capability of this heavy charged particle.

Accidental hydroxychloroquine overdose resulting in neurotoxic vestibulopathy.

Science.gov (United States)

Chansky, Peter B; Werth, Victoria P

2017-04-12

Hydroxychloroquine is an oral antimalarial medication commonly used off-label for a variety of rheumatological conditions, including systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome and dermatomyositis. We present a case of a 64-year-old woman who presented with acute onset headache, bilateral tinnitus, and left-sided facial numbness and tingling in the setting of accidentally overdosing on hydroxychloroquine. By the next morning, the patient began to experience worsening in the tingling sensation and it eventually spread to her left arm, thigh and distal extremities. The patient also complained of new onset blurring of her peripheral vision and feeling 'off balance.' Despite a complete neurological and ophthalmological work-up with unremarkable imaging and blood work, the patient has had no improvement in her tinnitus, left-sided paresthesias, visual disturbance or ataxia. This is a unique case of hydroxychloroquine overdose resulting in permanent neurotoxic vestibulopathy. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Neurotoxicity of subarachnoid hyperbaric bupivacaine in dogs.

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Ganem, E M; Vianna, P T; Marques, M; Castiglia, Y M; Vane, L A

1996-01-01

The study investigated possible neurotoxic effects of increasing concentrations and doses of bupivacaine administered into the subarachnoid space in dogs. Fifty animals were allocated to five experimental groups: G1, control; G2, 5 mg 0.5 bupivacaine in 10% glucose solution; G3, 10 mg of 1% bupivacaine in 10% glucose solution; G4, 20 mg 2% bupivacaine in 10% glucose solution, and G5, 20 mg 2% bupivacaine in water. After 72 hours of observation, the animals were killed and the spinal cords removed for histologic examination by light microscopy. None of the animals showed any neurologic clinical disturbance following recovery from spinal anesthesia. One case of necrosis of nerve tissue was observed in G3 and four in G4. Increasing concentrations and doses of hyperbaric bupivacaine solutions increased the incidence of nerve tissue damage, which did not occur with hypobaric solutions. These results should contribute to the further understanding of neurologic complications following spinal anesthesia when large doses of local anesthetics in hyperbaric solutions are used.

Role of Prion Protein Aggregation in Neurotoxicity

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Tullio Florio

2012-07-01

Full Text Available In several neurodegenerative diseases, such as Parkinson, Alzheimer’s, Huntington, and prion diseases, the deposition of aggregated misfolded proteins is believed to be responsible for the neurotoxicity that characterizes these diseases. Prion protein (PrP, the protein responsible of prion diseases, has been deeply studied for the peculiar feature of its misfolded oligomers that are able to propagate within affected brains, inducing the conversion of the natively folded PrP into the pathological conformation. In this review, we summarize the available experimental evidence concerning the relationship between aggregation status of misfolded PrP and neuronal death in the course of prion diseases. In particular, we describe the main findings resulting from the use of different synthetic (mainly PrP106-126 and recombinant PrP-derived peptides, as far as mechanisms of aggregation and amyloid formation, and how these different spatial conformations can affect neuronal death. In particular, most data support the involvement of non-fibrillar oligomers rather than actual amyloid fibers as the determinant of neuronal death.

Correlation of tissue concentrations of the pyrethroid bifenthrin with neurotoxicity in the rat

OpenAIRE

Scollon, Edward J.; Starr, James M.; Crofton, Kevin M.; Wolansky, Marcelo J.; DeVito, Michael J.; Hughes, Michael F.

2011-01-01

The potential for human exposure to pyrethroid pesticides has prompted pharmacodynamic and pharmacokinetic research to better characterize risk. This work tested the hypothesis that blood and brain concentrations of the pyrethroid bifenthrin are predictive of neurotoxic effects. Adult male Long Evans rats received a single oral dose of bifenthrin dissolved in corn oil. Using figure-eight mazes, motor activity was measured for 1 h at 4- and 7-h following exposure to bifenthrin (0–16 mg/kg or 0...

Systematic review of the neurocognitive outcomes used in studies of paediatric anaesthesia neurotoxicity

DEFF Research Database (Denmark)

Clausen, Nicola Groes

2018-01-01

Summary Neurotoxicity of anaesthetics in developing brain cells is well documented in preclinical studies, yet results are conflicting in humans. The use of many and different outcome measures in human studies may contribute to this disagreement. We conducted a systematic review to identify all...... for studies investigating neurocognitive outcome after GA in children countries during 1990-2017. Most assessments were performed within cognition, sensory-motor development, academic achievement or neuropsychological diagnosis. Few studies assessed other...... Anaesthesia, General; Child Development; Infant; Review...

Lithium protects against methamphetamine-induced neurotoxicity in PC12 cells via Akt/GSK3β/mTOR pathway

International Nuclear Information System (INIS)

Wu, Jintao; Zhu, Dexiao; Zhang, Jing; Li, Guibao; Liu, Zengxun; Sun, Jinhao

2015-01-01

Methamphetamine (MA) is neurotoxic, especially in dopaminergic neurons. Long-lasting exposure to MA causes psychosis and increases the risk of Parkinson's disease. Lithium (Li) is a known mood stabilizer and has neuroprotective effects. Previous studies suggest that MA exposure decreases the phosphorylation of Akt/GSK3β pathway in vivo, whereas Li facilitates the phosphorylation of Akt/GSK3β pathway. Moreover, GSK3β and mTOR are implicated in the locomotor sensitization induced by psychostimulants and mTOR plays a critical role in MA induced toxicity. However, the effect of MA on Akt/GSK3β/mTOR pathway has not been fully investigated in vitro. Here, we found that MA exposure significantly dephosphorylated Akt/GSK3β/mTOR pathway in PC12 cells. In addition, Li remarkably attenuated the dephosphorylation effect of MA exposure on Akt/GSK3β/mTOR pathway. Furthermore, Li showed obvious protective effects against MA toxicity and LY294002 (Akt inhibitor) suppressed the protective effects of Li. Together, MA exposure dephosphorylates Akt/GSK3β/mTOR pathway in vitro, while lithium protects against MA-induced neurotoxicity via phosphorylation of Akt/GSK3β/mTOR pathway. - Highlights: • Lithium protects against methamphetamine-induced neurotoxicity in vitro. • Methamphetamine exposure dephosphorylates Akt/GSK3β/mTOR pathway. • Lithium attenuates methamphetamine-induced toxicity via phosphorylating Akt/GSK3β/mTOR pathway

Lithium protects against methamphetamine-induced neurotoxicity in PC12 cells via Akt/GSK3β/mTOR pathway

Energy Technology Data Exchange (ETDEWEB)

Wu, Jintao; Zhu, Dexiao; Zhang, Jing; Li, Guibao [Department of Anatomy, School of Medicine, Shandong University, Jinan, Shandong, 250012 (China); Liu, Zengxun [Department of Psychiatry, School of Medicine, Shandong University, Jinan, Shandong, 250012 China (China); Sun, Jinhao, E-mail: sunjinhao@gmail.com [Department of Anatomy, School of Medicine, Shandong University, Jinan, Shandong, 250012 (China)

2015-09-25

Methamphetamine (MA) is neurotoxic, especially in dopaminergic neurons. Long-lasting exposure to MA causes psychosis and increases the risk of Parkinson's disease. Lithium (Li) is a known mood stabilizer and has neuroprotective effects. Previous studies suggest that MA exposure decreases the phosphorylation of Akt/GSK3β pathway in vivo, whereas Li facilitates the phosphorylation of Akt/GSK3β pathway. Moreover, GSK3β and mTOR are implicated in the locomotor sensitization induced by psychostimulants and mTOR plays a critical role in MA induced toxicity. However, the effect of MA on Akt/GSK3β/mTOR pathway has not been fully investigated in vitro. Here, we found that MA exposure significantly dephosphorylated Akt/GSK3β/mTOR pathway in PC12 cells. In addition, Li remarkably attenuated the dephosphorylation effect of MA exposure on Akt/GSK3β/mTOR pathway. Furthermore, Li showed obvious protective effects against MA toxicity and LY294002 (Akt inhibitor) suppressed the protective effects of Li. Together, MA exposure dephosphorylates Akt/GSK3β/mTOR pathway in vitro, while lithium protects against MA-induced neurotoxicity via phosphorylation of Akt/GSK3β/mTOR pathway. - Highlights: • Lithium protects against methamphetamine-induced neurotoxicity in vitro. • Methamphetamine exposure dephosphorylates Akt/GSK3β/mTOR pathway. • Lithium attenuates methamphetamine-induced toxicity via phosphorylating Akt/GSK3β/mTOR pathway.

Novel one-pot synthesis of dicarboxylic acids mediated alginate-zirconium biopolymeric complex for defluoridation of water.

Science.gov (United States)

Prabhu, Subbaiah Muthu; Meenakshi, Sankaran

2015-04-20

The present investigation explains the fluoride removal from aqueous solution using alginate-zirconium complex prepared with respective dicarboxylic acids like oxalic acid (Ox), malonic acid (MA) and succinic acid (SA) as a medium. The complexes viz., alginate-oxalic acid-zirconium (Alg-Ox-Zr), alginate-malonic acid-zirconium (Alg-MA-Zr) and alginate-succinic acid-zirconium (Alg-SA-Zr) were synthesized and studied for fluoride removal. The synthesized complexes were characterized by FTIR, XRD, SEM with EDAX and mapping images. The effects of various operating parameters were optimized. The result showed that the maximum removal of fluoride 9653mgF(-)/kg was achieved by Alg-Ox-Zr complex at acidic pH in an ambient atmospheric condition. Equilibrium data of Alg-Ox-Zr complex was fitted well with Freundlich isotherm. The calculated values of thermodynamic parameters indicated that the fluoride adsorption is spontaneous and endothermic in nature. The mechanism of fluoride removal behind Alg-Ox-Zr complex has been proposed in detail. The suitability of the Alg-Ox-Zr complex has been tested with the field sample collected in a nearby fluoride endemic area. Copyright © 2014 Elsevier Ltd. All rights reserved.

HIV-1 gp120 neurotoxicity proximally and at a distance from the point of exposure: protection by rSV40 delivery of antioxidant enzymes.

Science.gov (United States)

Louboutin, Jean-Pierre; Agrawal, Lokesh; Reyes, Beverly A S; Van Bockstaele, Elisabeth J; Strayer, David S

2009-06-01

Toxicity of HIV-1 envelope glycoprotein (gp120) for substantia nigra (SN) neurons may contribute to the Parkinsonian manifestations often seen in HIV-1-associated dementia (HAD). We studied the neurotoxicity of gp120 for dopaminergic neurons and potential neuroprotection by antioxidant gene delivery. Rats were injected stereotaxically into their caudate-putamen (CP); CP and (substantia nigra) SN neuron loss was quantified. The area of neuron loss extended several millimeters from the injection site, approximately 35% of the CP area. SN neurons, outside of this area of direct neurotoxicity, were also severely affected. Dopaminergic SN neurons (expressing tyrosine hydroxylase, TH, in the SN and dopamine transporter, DAT, in the CP) were mostly affected: intra-CP gp120 caused approximately 50% DAT+ SN neuron loss. Prior intra-CP gene delivery of Cu/Zn superoxide dismutase (SOD1) or glutathione peroxidase (GPx1) protected SN neurons from intra-CP gp120. Thus, SN dopaminergic neurons are highly sensitive to HIV-1 gp120-induced neurotoxicity, and antioxidant gene delivery, even at a distance, is protective.

Protective Effects of N-Acetyl-L-cystein on 3,4-Methylene Dioxymethamphetamie-Induced Neurotoxicity in Cerebellum of Male Rats

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Sara Soleimani Asl

2011-10-01

Full Text Available Introduction: 3-4, methylenedioxymethamphetamine (MDMA causes apoptosis in nervous system and several studies suggest that oxidative stress contributes to MDMA-induced neurotoxicity. The aim of this study is to examine the effects of N-acetyl-L-Cystein (NAC as an antioxidant on MDMA-induced apoptosis. Methods: 21 Sprague dawley male rats (200-250mg were treated with MDMA (2×0,5mg/kg or MDMA plus NAC (100mg/kg IP for 7 day. After last administration of MDMA, rats were killed, cerebellum was removed and Bax and Bcl-2 expression was assessed by western blotting method. Results: The results of this study showed that MDMA causes up-regulation of Bax and down-regulation of Bcl-2 and NAC administration attenuated MDMA-induced apoptosis. Discussion: The present study suggests that NAC treatment may improve MDMA-induced neurotoxicity.

Concentrations of higher dicarboxylic acids C5–C13 in fresh snow samples collected at the High Alpine Research Station Jungfraujoch during CLACE 5 and 6

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K. Sieg

2009-03-01

Full Text Available Samples of freshly fallen snow were collected at the high alpine research station Jungfraujoch (Switzerland in February and March 2006 and 2007, during the Cloud and Aerosol Characterization Experiments (CLACE 5 and 6. In this study a new technique has been developed and demonstrated for the measurement of organic acids in fresh snow. The melted snow samples were subjected to solid phase extraction and resulting solutions analysed for organic acids by HPLC-MS-TOF using negative electrospray ionization. A series of linear dicarboxylic acids from C5 to C13 and phthalic acid, were identified and quantified. In several samples the biogenic acid pinonic acid was also observed. In fresh snow the median concentration of the most abundant acid, adipic acid, was 0.69 μg L−1 in 2006 and 0.70 μg L−1 in 2007. Glutaric acid was the second most abundant dicarboxylic acid found with median values of 0.46 μg L−1 in 2006 and 0.61 μg L−1 in 2007, while the aromatic acid phthalic acid showed a median concentration of 0.34 μg L−1 in 2006 and 0.45 μg L−1 in 2007. The concentrations in the samples from various snowfall events varied significantly, and were found to be dependent on the back trajectory of the air mass arriving at Jungfraujoch. Air masses of marine origin showed the lowest concentrations of acids whereas the highest concentrations were measured when the air mass was strongly influenced by boundary layer air.

One-step green synthesis of non-hazardous dicarboxyl cellulose flocculant and its flocculation activity evaluation

International Nuclear Information System (INIS)

Zhu, Hangcheng; Zhang, Yong; Yang, Xiaogang; Liu, Hongyi; Shao, Lan; Zhang, Xiumei; Yao, Juming

2015-01-01

The waste management of used flocculants is a thorny issue in the field of wastewater treatment. To natural cellulose based flocculants, utilization of hazardous cellulose solvent and simplification of synthetic procedure are the two urgent problems needing to be further improved. In this work, a series of natural dicarboxyl cellulose flocculants (DCCs) were one-step synthesized via Schiff-base route. The cellulose solvent (NaOH/Urea solution) was utilized during the synthesis process. The full-biodegradable flocculants avoid causing secondary pollution to environment. The chemical structure and solution property of the DCC products were characterized by FT-IR, 1 H NMR, 13 C NMR, TGA, FESEM, charge density and ζ-potential. Kaolin suspension and effluent from paper mill were selected to evaluate the flocculation activity of the DCCs. Their flocculation performance was compared with that of commercial cationic polyacrylamide and poly aluminium chloride flocculants. The positive results showed that the NaOH/Urea solvent effectively promoted the dialdehyde cellulose (DAC) conversion to DCC in the one-step synthesis reaction. The DCCs with the carboxylate content more than 1 mmol/g exhibited steady flocculation performance to kaolin suspension in the broad pH range from 4 to 10. Its flocculation capacity to the effluent from paper mill also showed excellent

Zebrafish embryotoxicity test for developmental (neuro)toxicity : Demo case of an integrated screening approach system using anti-epileptic drugs

NARCIS (Netherlands)

Beker van Woudenberg, Anna; Snel, Cor; Rijkmans, Eke; De Groot, Didima; Bouma, Marga; Hermsen, Sanne; Piersma, Aldert; Menke, Aswin; Wolterbeek, André

2014-01-01

To improve the predictability of the zebrafish embryotoxicity test (ZET) for developmental (neuro)toxicity screening, we used a multiple-endpoints strategy, including morphology, motor activity (MA), histopathology and kinetics. The model compounds used were antiepileptic drugs (AEDs): valproic acid

Zebrafish embryotoxicity test for developmental (neuro)toxicity: Demo case of an integrated screening approach system using anti-epileptic drugs

NARCIS (Netherlands)

Beker van Woudenberg, A.; Snel, C.; Rijkmans, E.; Groot, D. de; Bouma, M.; Hermsen, S.; Piersma, A.; Menke, A.; Wolterbeek, A.

2014-01-01

To improve the predictability of the zebrafish embryotoxicity test (ZET) for developmental (neuro)toxicity screening, we used a multiple-endpoints strategy, including morphology, motor activity (MA), histopathology and kinetics. The model compounds used were antiepileptic drugs (AEDs): valproic acid

Protection against 1-methyl-4-phenyl pyridinium-induced neurotoxicity in human neuroblastoma SH-SY5Y cells by Soyasaponin I by the activation of the phosphoinositide 3-kinase/AKT/GSK3β pathway.

Science.gov (United States)

Guo, Zheng; Cao, Wei; Zhao, Shifeng; Han, Zengtai; Han, Boxiang

2016-07-06

Parkinson's disease (PD) can be ascribed to the progressive and selective loss of dopaminergic neurons in the substantia nigra pars compacta, and thus molecules with neuroprotective ability may have therapeutic value against PD. In the current study, the neuroprotective effects and underlying mechanisms of Soyasaponin I (Soya-I), a naturally occurring triterpene extracted from a widely used ingredient in many foods, such as Glycine max (soybean), were evaluated in a widely used cellular PD model in which neurotoxicity was induced by 1-methyl-4-phenyl pyridinium (MPP) in cultured SH-SY5Y cells. We found that Soya-I at 10-40 μM considerably protected against MPP-induced neurotoxicity as evidenced by an increase in cell viability, a decrease in lactate dehydrogenase release, and a reduction in apoptotic nuclei. Moreover, Soya-I effectively inhibited the elevated intracellular accumulation of reactive oxygen species as well as the Bax/Bcl-2 ratio caused by MPP. Most importantly, Soya-I markedly reversed the inhibition of protein expression of phosphorylated AKT and phosphorylated GSK3β caused by MPP. LY294002, the specific inhibitor of phosphoinositide 3-kinase, significantly abrogated the upregulated phosphorylated AKT and phosphorylated GSK3β offered by Soya-I, suggesting that the neuroprotection of Soya-I was mainly dependent on the activation of the phosphoinositide 3-kinase/AKT/GSK3β signaling pathway. The results taken together indicate that Soya-I may be a potential candidate for further preclinical study aimed at the prevention and treatment of PD.

Clinical profile & complications of neurotoxic snake bite & comparison of two regimens of polyvalent anti-snake venom in its treatment

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Krishna Sarin

2017-01-01

Interpretation & conclusions: In this preliminary study, it was found that the national ASV protocol was as effective as the conventional regimen for neurotoxic snake bites. However, the findings need to be tested in a larger randomized controlled trial for definitive conclusions.

Relative Neurotoxicity of Ivermectin and Moxidectin in Mdr1ab (−/−) Mice and Effects on Mammalian GABA(A) Channel Activity

Science.gov (United States)

Ménez, Cécile; Sutra, Jean-François; Prichard, Roger; Lespine, Anne

2012-01-01

The anthelmintics ivermectin (IVM) and moxidectin (MOX) display differences in toxicity in several host species. Entrance into the brain is restricted by the P-glycoprotein (P-gp) efflux transporter, while toxicity is mediated through the brain GABA(A) receptors. This study compared the toxicity of IVM and MOX in vivo and their interaction with GABA(A) receptors in vitro. Drug toxicity was assessed in Mdr1ab(−/−) mice P-gp-deficient after subcutaneous administration of increasing doses (0.11–2.0 and 0.23–12.9 µmol/kg for IVM and MOX in P-gp-deficient mice and half lethal doses (LD50) in wild-type mice). Survival was evaluated over 14-days. In Mdr1ab(−/−) mice, LD50 was 0.46 and 2.3 µmol/kg for IVM and MOX, respectively, demonstrating that MOX was less toxic than IVM. In P-gp-deficient mice, MOX had a lower brain-to-plasma concentration ratio and entered into the brain more slowly than IVM. The brain sublethal drug concentrations determined after administration of doses close to LD50 were, in Mdr1ab(−/−) and wild-type mice, respectively, 270 and 210 pmol/g for IVM and 830 and 740–1380 pmol/g for MOX, indicating that higher brain concentrations are required for MOX toxicity than IVM. In rat α1β2γ2 GABA channels expressed in Xenopus oocytes, IVM and MOX were both allosteric activators of the GABA-induced response. The Hill coefficient was 1.52±0.45 for IVM and 0.34±0.56 for MOX (p<0.001), while the maximum potentiation caused by IVM and MOX relative to GABA alone was 413.7±66.1 and 257.4±40.6%, respectively (p<0.05), showing that IVM causes a greater potentiation of GABA action on this receptor. Differences in the accumulation of IVM and MOX in the brain and in the interaction of IVM and MOX with GABA(A) receptors account for differences in neurotoxicity seen in intact and Mdr1-deficient animals. These differences in neurotoxicity of IVM and MOX are important in considering their use in humans. PMID:23133688

Modeling chemotherapeutic neurotoxicity with human induced pluripotent stem cell-derived neuronal cells.

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Heather E Wheeler

Full Text Available There are no effective agents to prevent or treat chemotherapy-induced peripheral neuropathy (CIPN, the most common non-hematologic toxicity of chemotherapy. Therefore, we sought to evaluate the utility of human neuron-like cells derived from induced pluripotent stem cells (iPSCs as a means to study CIPN. We used high content imaging measurements of neurite outgrowth phenotypes to compare the changes that occur to iPSC-derived neuronal cells among drugs and among individuals in response to several classes of chemotherapeutics. Upon treatment of these neuronal cells with the neurotoxic drug paclitaxel, vincristine or cisplatin, we identified significant differences in five morphological phenotypes among drugs, including total outgrowth, mean/median/maximum process length, and mean outgrowth intensity (P < 0.05. The differences in damage among drugs reflect differences in their mechanisms of action and clinical CIPN manifestations. We show the potential of the model for gene perturbation studies by demonstrating decreased expression of TUBB2A results in significantly increased sensitivity of neurons to paclitaxel (0.23 ± 0.06 decrease in total neurite outgrowth, P = 0.011. The variance in several neurite outgrowth and apoptotic phenotypes upon treatment with one of the neurotoxic drugs is significantly greater between than within neurons derived from four different individuals (P < 0.05, demonstrating the potential of iPSC-derived neurons as a genetically diverse model for CIPN. The human neuron model will allow both for mechanistic studies of specific genes and genetic variants discovered in clinical studies and for screening of new drugs to prevent or treat CIPN.

Fragment C Domain of Tetanus Toxin Mitigates Methamphetamine Neurotoxicity and Its Motor Consequences in Mice.

OpenAIRE

Mendieta L; Granado, Noelia; Aguilera, J.; Tizabi Y; Moratalla, Rosario

2016-01-01

Background: The C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) is a nontoxic peptide with demonstrated in vitro and in vivo neuroprotective effects against striatal dopaminergic damage induced by 1-methyl-4-phenylpyridinium and 6-hydoxydopamine, suggesting its possible therapeutic potential in Parkinson?s disease. Methamphetamine, a widely abused psychostimulant, has selective dopaminergic neurotoxicity in rodents, monkeys, and humans. This study was undertaken to determine w...

Striatal dopamine D1 and D2 receptors: widespread influences on methamphetamine-induced dopamine and serotonin neurotoxicity.

Science.gov (United States)

Gross, Noah B; Duncker, Patrick C; Marshall, John F

2011-11-01

Methamphetamine (mAMPH) is an addictive psychostimulant drug that releases monoamines through nonexocytotic mechanisms. In animals, binge mAMPH dosing regimens deplete markers for monoamine nerve terminals, for example, dopamine and serotonin transporters (DAT and SERT), in striatum and cerebral cortex. Although the precise mechanism of mAMPH-induced damage to monoaminergic nerve terminals is uncertain, both dopamine D1 and D2 receptors are known to be important. Systemic administration of dopamine D1 or D2 receptor antagonists to rodents prevents mAMPH-induced damage to striatal dopamine nerve terminals. Because these studies employed systemic antagonist administration, the specific brain regions involved remain to be elucidated. The present study examined the contribution of dopamine D1 and D2 receptors in striatum to mAMPH-induced DAT and SERT neurotoxicities. In this experiment, either the dopamine D1 antagonist, SCH23390, or the dopamine D2 receptor antagonist, sulpiride, was intrastriatally infused during a binge mAMPH regimen. Striatal DAT and cortical, hippocampal, and amygdalar SERT were assessed as markers of mAMPH-induced neurotoxicity 1 week following binge mAMPH administration. Blockade of striatal dopamine D1 or D2 receptors during an otherwise neurotoxic binge mAMPH regimen produced widespread protection against mAMPH-induced striatal DAT loss and cortical, hippocampal, and amygdalar SERT loss. This study demonstrates that (1) dopamine D1 and D2 receptors in striatum, like nigral D1 receptors, are needed for mAMPH-induced striatal DAT reductions, (2) these same receptors are needed for mAMPH-induced SERT loss, and (3) these widespread influences of striatal dopamine receptor antagonists are likely attributable to circuits connecting basal ganglia to thalamus and cortex. Copyright © 2011 Wiley-Liss, Inc.

Protective Effects of N-Acetyl-L-cystein on 3,4-Methylene Dioxymethamphetamie-Induced Neurotoxicity in Cerebellum of Male Rats

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Sara Soleimani Asl

2011-10-01

Full Text Available Objective(s: 3-4, methylenedioxymethamphetamine (MDMA causes apoptosis in nervous system and several studies suggest that oxidative stress contributes to MDMA-induced neurotoxicity. The aim of this study is to examine the effects of N-acetyl-L-Cystein (NAC as an antioxidant on MDMA-induced apoptosis. Materials and Methods: 21 Sprague dawley male rats (200-250mg were treated with MDMA (2×0,5mg/kg or MDMA plus NAC (100mg/kg IP for 7 day. After last administration of MDMA, rats were killed, cerebellum was removed and Bax and Bcl-2 expression was assessed by western blotting method. Results: The results of this study showed that MDMA causes up-regulation of Bax and down-regulation of Bcl-2 and NAC administration attenuated MDMA-induced apoptosis. Conclusion: The present study suggests that NAC treatment may improve MDMA-induced neurotoxicity.

Fingolimod phosphate attenuates oligomeric amyloid β-induced neurotoxicity via increased brain-derived neurotrophic factor expression in neurons.

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Yukiko Doi

Full Text Available The neurodegenerative processes that underlie Alzheimer's disease are mediated, in part, by soluble oligomeric amyloid β, a neurotoxic protein that inhibits hippocampal long-term potentiation, disrupts synaptic plasticity, and induces the production of reactive oxygen species. Here we show that the sphingosine-1-phosphate (S1P receptor (S1PR agonist fingolimod phosphate (FTY720-P-a new oral drug for multiple sclerosis-protects neurons against oligomeric amyloid β-induced neurotoxicity. We confirmed that primary mouse cortical neurons express all of the S1P receptor subtypes and FTY720-P directly affects the neurons. Treatment with FTY720-P enhanced the expression of brain-derived neurotrophic factor (BDNF in neurons. Moreover, blocking BDNF-TrkB signaling with a BDNF scavenger, TrkB inhibitor, or ERK1/2 inhibitor almost completely ablated these neuroprotective effects. These results suggested that the neuroprotective effects of FTY720-P are mediated by upregulated neuronal BDNF levels. Therefore, FTY720-P may be a promising therapeutic agent for neurodegenerative diseases, such as Alzheimer's disease.

Human interleukin-10 delivered intrathecally by self-complementary adeno-associated virus 8 induces xenogeneic transgene immunity without clinical neurotoxicity in swine.

Science.gov (United States)

Unger, Mark D; Pleticha, Josef; Heilmann, Lukas F; Newman, Laura K; Maus, Timothy P; Beutler, Andreas S

2018-05-25

Intrathecal interleukin-10 delivered by plasmid or viral gene vectors has been proposed for clinical testing because it is effective for chronic pain in rodents, a potential therapeutic for various human diseases, and was found to be non-toxic in dogs, when the human interleukin-10 ortholog was tested. However, recent studies in swine testing porcine interleukin-10 demonstrated fatal neurotoxicity. To deliver vector-encoded human interleukin-10 in swine, measure expression of the transgene in cerebrospinal fluid, and monitor animals for signs of neurotoxicity. Human interleukin-10 levels peaked 2 weeks after vector administration followed by a rapid decline that occurred concomitant with the emergence of anti-human interleukin-10 antibodies in the cerebrospinal fluid and serum. Animals remained neurologically healthy throughout the study period. This study suggests that swine are not idiosyncratically sensitive to intrathecal interleukin-10 because, recapitulating previous reports in dogs, they suffered no clinical neurotoxicity from the human ortholog. These results strongly infer that toxicity of intrathecal interleukin-10 in large animal models was previously overlooked because of a species mismatch between transgene and host. The present study further suggests that swine were protected from interleukin-10 by a humoral immune response against the xenogeneic cytokine. Future safety studies of interleukin-10 or related therapeutics may require syngeneic large animal models. This article is protected by copyright. All rights reserved.

In Vivo 6-([18F]Fluoroacetamido-1-hexanoicanilide PET Imaging of Altered Histone Deacetylase Activity in Chemotherapy-Induced Neurotoxicity

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Nobuyoshi Fukumitsu

2018-01-01

Full Text Available Background. Histone deacetylases (HDACs regulate gene expression by changing histone deacetylation status. Neurotoxicity is one of the major side effects of cisplatin, which reacts with deoxyribonucleic acid (DNA and has excellent antitumor effects. Suberoylanilide hydroxamic acid (SAHA is an HDAC inhibitor with neuroprotective effects against cisplatin-induced neurotoxicity. Purpose. We investigated how cisplatin with and without SAHA pretreatment affects HDAC expression/activity in the brain by using 6-([18F]fluoroacetamido-1-hexanoicanilide ([18F]FAHA as a positron emission tomography (PET imaging agent for HDAC IIa. Materials and Methods. [18F]FAHA and [18F]fluoro-2-deoxy-2-D-glucose ([18F]FDG PET studies were done in 24 mice on 2 consecutive days and again 1 week later. The mice were divided into three groups according to drug administration between the first and second imaging sessions (Group A: cisplatin 2 mg/kg, twice; Group B: cisplatin 4 mg/kg, twice; Group C: cisplatin 4 mg/kg, twice, and SAHA 300 mg/kg pretreatment, 4 times. Results. The Ki value of [18F]FAHA was increased and the percentage of injected dose/tissue g (% ID/g of [18F]FDG was decreased in the brains of animals in Groups A and B. The Ki value of [18F]FAHA and % ID/g of [18F]FDG were not significantly different in Group C. Conclusions. [18F]FAHA PET clearly showed increased HDAC activity suggestive of cisplatin neurotoxicity in vivo, which was blocked by SAHA pretreatment.

Antidepressant Imipramine Protects Bupivacaine-Induced Neurotoxicity in Dorsal Root Ganglion Neurons Through Coactivation of TrkA and TrkB.

Science.gov (United States)

Guo, Jianrong; Wang, Huan; Tao, Qiang; Sun, Shiyu; Liu, Li; Zhang, Jianping; Yang, Dawei

2017-11-01

In our work, we used an in vitro culture model to investigate whether antidepressant imipramine (Ip) may protect bupivacaine (Bv)-induced neurotoxicity in mouse dorsal root ganglion (DRG). Adult mouse DRG was treated with 5 mM Bv in vitro to induce neurotoxicity. DRG was then pre-treated with Ip, prior to Bv, to examine its effects on protecting Bv-induced DRG apoptosis and neurite degeneration. Ip-induced dynamic changes in Trk receptors, including TrkA/B/C and phosphor (p-)TrkA/B/C, were examined by qPCR and Western blot. TrkA and TrkB were inhibited by siRNAs to further investigate their functional role in Ip- and Bv-treated DRG. Ip protected Bv-induced apoptosis and neurite loss in DRG. Ip did not alter TrkA/B/C expressions, whereas significantly augmented protein productions of p-TrkA and p-TrkB, but not p-TrkC. SiRNA-mediated TrkA or TrkB downregulation inhibited Trk receptors, and reduced p-TrkA and p-TrkB in DRG. TrkA or TrkB downregulation alone had no effect on Ip-induced protection in Bv-injured DRG. However, co-inhibition of TrkA and TrkB significantly ameliorated the protective effect of Ip on Bv-induced apoptosis and neurite loss in DRG. Imipramine protected bupivacaine-induced neurotoxicity in DRG, likely via the co-activation of TrkA and TrkB signaling pathways. J. Cell. Biochem. 118: 3960-3967, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Methamphetamine, d-amphetamine and p-chloroamphetamine induced neurotoxicity differentially effect impulsive responding on the stop-signal task in rats

Science.gov (United States)

Furlong, Teri M.; Leavitt, Lee S.; Keefe, Kristen A.; Son, Jong-Hyun

2016-01-01

Abused amphetamines, such as d-amphetamine (AMPH) and methamphetamine (METH), are highly addictive and destructive to health and productive lifestyles. The abuse of these drugs is associated with impulsive behavior, which is likely to contribute to addiction. The amphetamines also differentially damage dopamine (DA) and serotonin (5-HT) systems, which regulate impulsive behavior; therefore, exposure to these drugs may differentially alter impulsive behavior to effect the progression of addiction. We examined the impact of neurotoxicity induced by three amphetamines on impulsive action using a stop-signal task in rats. Animals were rewarded with a food pellet after lever pressing (i.e. a go trial), unless an auditory cue was presented and withholding lever press gained reward (i.e. a stop trial). Animals were trained on the task and then exposed to a neurotoxic regimen of either AMPH, p-chloroamphetamine (PCA), or METH. These regimens preferentially reduced DA transporter levels in striatum, 5-HT transporter levels in prefrontal cortex, or both, respectively. Assessment of performance on the stop-signal task beginning one week after the treatment revealed that AMPH produced a deficit in go-trial performance, whereas PCA did not alter performance on either trial type. In contrast, METH produced a deficit in stop-trial performance (i.e. impulsive action) but not go-trial performance. These findings suggest that the different neurotoxic consequences of substituted amphetamines are associated with different effects on inhibitory control over behavior. Thus, the course of addiction and maladaptive behavior resulting from exposure to these substances is likely to differ. PMID:26846719

Changes in interleukin-1 signal modulators induced by 3,4-methylenedioxymethamphetamine (MDMA: regulation by CB2 receptors and implications for neurotoxicity

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O'Shea Esther

2011-05-01

Full Text Available Abstract Background 3,4-Methylenedioxymethamphetamine (MDMA produces a neuroinflammatory reaction in rat brain characterized by an increase in interleukin-1 beta (IL-1β and microglial activation. The CB2 receptor agonist JWH-015 reduces both these changes and partially protects against MDMA-induced neurotoxicity. We have examined MDMA-induced changes in IL-1 receptor antagonist (IL-1ra levels and IL-1 receptor type I (IL-1RI expression and the effects of JWH-015. The cellular location of IL-1β and IL-1RI was also examined. MDMA-treated animals were given the soluble form of IL-1RI (sIL-1RI and neurotoxic effects examined. Methods Dark Agouti rats received MDMA (12.5 mg/kg, i.p. and levels of IL-1ra and expression of IL-1RI measured 1 h, 3 h or 6 h later. JWH-015 (2.4 mg/kg, i.p. was injected 48 h, 24 h and 0.5 h before MDMA and IL-1ra and IL-1RI measured. For localization studies, animals were sacrificed 1 h or 3 h following MDMA and stained for IL-1β or IL-1RI in combination with neuronal and microglial markers. sIL-1RI (3 μg/animal; i.c.v. was administered 5 min before MDMA and 3 h later. 5-HT transporter density was determined 7 days after MDMA injection. Results MDMA produced an increase in IL-ra levels and a decrease in IL-1RI expression in hypothalamus which was prevented by CB2 receptor activation. IL-1RI expression was localized on neuronal cell bodies while IL-1β expression was observed in microglial cells following MDMA. sIL-1RI potentiated MDMA-induced neurotoxicity. MDMA also increased IgG immunostaining indicating that blood brain-barrier permeability was compromised. Conclusions In summary, MDMA produces changes in IL-1 signal modulators which are modified by CB2 receptor activation. These results indicate that IL-1β may play a partial role in MDMA-induced neurotoxicity.

The downfall of TBA-354 - a possible explanation for its neurotoxicity via mass spectrometric imaging.

Science.gov (United States)

Ntshangase, Sphamandla; Shobo, Adeola; Kruger, Hendrik G; Asperger, Arndt; Niemeyer, Dagmar; Arvidsson, Per I; Govender, Thavendran; Baijnath, Sooraj

2017-10-13

1. TBA-354 was a promising antitubercular compound with activity against both replicating and static Mycobacterium tuberculosis (M.tb), making it the focal point of many clinical trials conducted by the TB Alliance. However, findings from these trials have shown that TBA-354 results in mild signs of reversible neurotoxicity; this left the TB Alliance with no other choice but to stop the research. 2. In this study, mass spectrometric methods were used to evaluate the pharmacokinetics and spatial distribution of TBA-354 in the brain using a validated liquid chromatography tandem-mass spectrometry (LCMS/MS) and mass spectrometric imaging (MSI), respectively. Healthy female Sprague-Dawley rats received intraperitoneal (i.p.) doses of TBA-354 (20 mg/kg bw). 3. The concentrationtime profiles showed a gradual absorption and tissue penetration of TBA-354 reaching the C max at 6 h post dose, followed by a rapid elimination. MSI analysis showed a time-dependent drug distribution, with highest drug concentration mainly in the neocortical regions of the brain. 4. The distribution of TBA-354 provides a possible explanation for the motor dysfunction observed in clinical trials. These results prove the importance of MSI as a potential tool in preclinical evaluations of suspected neurotoxic compounds.

Malaria Prevention, Mefloquine Neurotoxicity, Neuropsychiatric Illness, and Risk-Benefit Analysis in the Australian Defence Force

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Stuart McCarthy

2015-01-01

Full Text Available The Australian Defence Force (ADF has used mefloquine for malaria chemoprophylaxis since 1990. Mefloquine has been found to be a plausible cause of a chronic central nervous system toxicity syndrome and a confounding factor in the diagnosis of existing neuropsychiatric illnesses prevalent in the ADF such as posttraumatic stress disorder and traumatic brain injury. Overall health risks appear to have been mitigated by restricting the drug’s use; however serious risks were realised when significant numbers of ADF personnel were subjected to clinical trials involving the drug. The full extent of the exposure, health impacts for affected individuals, and consequences for ADF health management including mental health are not yet known, but mefloquine may have caused or aggravated neuropsychiatric illness in large numbers of patients who were subsequently misdiagnosed and mistreated or otherwise failed to receive proper care. Findings in relation to chronic mefloquine neurotoxicity were foreseeable, but this eventuality appears not to have been considered during risk-benefit analyses. Thorough analysis by the ADF would have identified this long-term risk as well as other qualitative risk factors. Historical exposure of ADF personnel to mefloquine neurotoxicity now also necessitates ongoing risk monitoring and management in the overall context of broader health policies.

An intermolecular Diels-Alder cycloaddition under various condition between 1,3-cyclohexadiene and 7-oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate

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Özgür Yılmaz

2017-10-01

Full Text Available The reaction between 1,3-cyclohexadiene and dimethyl 7-oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate both without a catalyst and with different catalysts, in both atmospheric and at high pressure, over 20 days were studied. At the end of the reactions, different products (retro Diels-Alder addition product 5 and Diels-Alder addition product 6 were obtained in different yields. When we look at the percentage of the addition product, it is observed that the yield of reaction at high pressure in water is the highest. All structures of these products were characterized by 1H-NMR, 13C-NMR, MS, and IR spectroscopy.

Curcumin attenuates glutamate neurotoxicity in the hippocampus by suppression of ER stress-associated TXNIP/NLRP3 inflammasome activation in a manner dependent on AMPK

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Li, Ying; Li, Jia; Li, Shanshan; Li, Yi; Wang, Xiangxiang; Liu, Baolin [Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, 639, Longmian Road, Nanjing 211198 (China); Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Research, China Pharmaceutical University, 639, Longmian Road, Nanjing 211198 (China); Fu, Qiang, E-mail: fuqiang@cpu.edu.cn [Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, 639, Longmian Road, Nanjing 211198 (China); Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Research, China Pharmaceutical University, 639, Longmian Road, Nanjing 211198 (China); Ma, Shiping, E-mail: spma@cpu.edu.cn [Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, 639, Longmian Road, Nanjing 211198 (China); Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Research, China Pharmaceutical University, 639, Longmian Road, Nanjing 211198 (China)

2015-07-01

Curcumin is a natural polyphenolic compound in Curcuma longa with beneficial effects on neuronal protection. This study aims to investigate the action of curcumin in the hippocampus subjected to glutamate neurotoxicity. Glutamate stimulation induced reactive oxygen species (ROS), endoplasmic reticulum stress (ER stress) and TXNIP/NLRP3 inflammasome activation, leading to damage in the hippocampus. Curcumin treatment in the hippocampus or SH-SY5Y cells inhibited IRE1α and PERK phosphorylation with suppression of intracellular ROS production. Curcumin increased AMPK activity and knockdown of AMPKα with specific siRNA abrogated its inhibitory effects on IRE1α and PERK phosphorylation, indicating that AMPK activity was essential for the suppression of ER stress. As a result, curcumin reduced TXNIP expression and inhibited NLRP3 inflammasome activation by downregulation of NLRP3 and cleaved caspase-1 induction, and thus reduced IL-1β secretion. Specific fluorescent probe and flow cytometry analysis showed that curcumin prevented mitochondrial malfunction and protected cell survival from glutamate neurotoxicity. Moreover, oral administration of curcumin reduced brain infarct volume and attenuated neuronal damage in rats subjected to middle cerebral artery occlusion. Immunohistochemistry showed that curcumin inhibited p-IRE1α, p-PERK and NLRP3 expression in hippocampus CA1 region. Together, these results showed that curcumin attenuated glutamate neurotoxicity by inhibiting ER stress-associated TXNIP/NLRP3 inflammasome activation via the regulation of AMPK, and thereby protected the hippocampus from ischemic insult. - Highlights: • Curcumin attenuates glutamate neurotoxicity in the hippocampus. • Curcumin suppresses ER stress in glutamate-induced hippocampus slices. • Curcumin inhibits TXNIP/NLRP3 inflammasome activation. • Regulation of AMPK by curcumin contributes to suppressing ER stress.

Curcumin attenuates glutamate neurotoxicity in the hippocampus by suppression of ER stress-associated TXNIP/NLRP3 inflammasome activation in a manner dependent on AMPK

International Nuclear Information System (INIS)

Li, Ying; Li, Jia; Li, Shanshan; Li, Yi; Wang, Xiangxiang; Liu, Baolin; Fu, Qiang; Ma, Shiping

2015-01-01

Curcumin is a natural polyphenolic compound in Curcuma longa with beneficial effects on neuronal protection. This study aims to investigate the action of curcumin in the hippocampus subjected to glutamate neurotoxicity. Glutamate stimulation induced reactive oxygen species (ROS), endoplasmic reticulum stress (ER stress) and TXNIP/NLRP3 inflammasome activation, leading to damage in the hippocampus. Curcumin treatment in the hippocampus or SH-SY5Y cells inhibited IRE1α and PERK phosphorylation with suppression of intracellular ROS production. Curcumin increased AMPK activity and knockdown of AMPKα with specific siRNA abrogated its inhibitory effects on IRE1α and PERK phosphorylation, indicating that AMPK activity was essential for the suppression of ER stress. As a result, curcumin reduced TXNIP expression and inhibited NLRP3 inflammasome activation by downregulation of NLRP3 and cleaved caspase-1 induction, and thus reduced IL-1β secretion. Specific fluorescent probe and flow cytometry analysis showed that curcumin prevented mitochondrial malfunction and protected cell survival from glutamate neurotoxicity. Moreover, oral administration of curcumin reduced brain infarct volume and attenuated neuronal damage in rats subjected to middle cerebral artery occlusion. Immunohistochemistry showed that curcumin inhibited p-IRE1α, p-PERK and NLRP3 expression in hippocampus CA1 region. Together, these results showed that curcumin attenuated glutamate neurotoxicity by inhibiting ER stress-associated TXNIP/NLRP3 inflammasome activation via the regulation of AMPK, and thereby protected the hippocampus from ischemic insult. - Highlights: • Curcumin attenuates glutamate neurotoxicity in the hippocampus. • Curcumin suppresses ER stress in glutamate-induced hippocampus slices. • Curcumin inhibits TXNIP/NLRP3 inflammasome activation. • Regulation of AMPK by curcumin contributes to suppressing ER stress

Dicarboxylic acids and levoglucosan in aerosols from Indo-Gangetic Plain: Inferences from day night variability during wintertime.

Science.gov (United States)

Sorathia, Fena; Rajput, Prashant; Gupta, Tarun

2018-05-15

This study assesses daytime and nighttime atmospheric abundance and molecular distribution of dicarboxylic acids (DCA: C 2 -C 10 ) and biomass burning tracers (levoglucosan and biomass burning derived potassium: K + BB ) in PM 10 (particulate matter with aerodynamic diameter≤10μm) from an urban location, Kanpur (in central Indo-Gangetic Plain: IGP) during wintertime (December 2015-February 2016). In this study, PM 10 varied from 130 to 242 and 175-388μgm -3 during daytime and nighttime, respectively. The average ratios of OC/EC (day: 12.3; night: 9.3) and WSOC/OC (day: 0.74; night: 0.48) were relatively high during daytime (OC: organic carbon; EC: elemental carbon; WSOC: water-soluble organic carbon). Strong linear correlations (R 2 ≥0.6; pformation involving aqueous-phase chemistry. Strong linear correlations of C 2 with C 3 and C 4 plausibly suggest that C 2 can have predominant formation pathways via decomposition of higher congeners of DCA. Overall, strong linear correlations of C 2 with levoglucosan and sulphate suggest that biomass burning emission and secondary transformations are predominant sources of DCA over IGP during wintertime. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of 7-nitroindazole, an NOS inhibitor on methamphetamine-induced dopaminergic and serotonergic neurotoxicity in mice.

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Ali, S F; Itzhak, Y

1998-05-30

Methamphetamine (METH) is one of the major drugs of abuse that is postulated to cause neurotoxicity by depleting dopamine (DA) and its metabolites, high-affinity DA uptake sites, and the activity of tyrosine hydroxylase. The present study was undertaken to investigate whether the relatively selective, neuronal nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7-NI), protects against METH-induced neurotoxicity. Male Swiss Webster mice received the following injections intraperitoneally (i.p.) 3 times (every 3 hr): (i) vehicle/saline, (ii) 7-NI (25 mg/kg)/saline, (iii) vehicle/METH (5 mg/kg), and (iv) 7-NI (25 mg/kg)/METH (5 mg/kg). On the second day, groups (i) and (iii) received two vehicle injections and groups (ii) and (iv) received two 7-NI injections (25 mg/kg each). The administration of vehicle/METH resulted in 68, 44 and 55% decreases in the concentration of DA, dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), respectively, and a 48% decrease in the number of [3H]mazindol binding sites in the striatum compared to control values. The treatment with 7-NI (group iv) provided a full protection against the depletion of DA and its metabolites, and the loss of dopamine transporter binding sites. Multiple injection of METH caused a significant decrease in the concentration of serotonin (5-HT) and its metabolite 5-hydroxyindole acetic acid (5-HIAA). Treatment with 7-NI partially blocked the depletion of 5-HT and completely blocked the reduction in 5-HIAA levels. The administration of 7-NI/saline (group ii) affected neither the tissue concentration of DA, 5-HT and their metabolites (DOPAC, HVA and 5-HIAA) nor the binding parameters of [3H]-mazindol compared to control (vehicle/saline) values. 7-NI had no significant effect on the animals' body temperature, and it did not affect METH-induced hyperthermia. These findings indicate a role for nitric oxide in METH-induced neurotoxicity and also suggest that blockage of NOS may be beneficial for the

Effects of 7-Nitroindazole, an NOS Inhibitor on Methamphetamine-Induced Dopaminergic and Serotonergic Neurotoxicity in Micea.

Science.gov (United States)

Ali, Syed F; Itzhak, Yossef

1998-05-01

Methamphetamine (METH) is one of the major drugs of abuse that is postulated to cause neurotoxicity by depleting dopamine (DA) and its metabolites, high-affinity DA uptake sites, and the activity of tyrosine hydroxylase. The present study was undertaken to investigate whether the relatively selective, neuronal nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7-NI), protects against METH-induced neurotoxicity. Male Swiss Webster mice received the following injections intraperitoneally (i.p.) 3 times (every 3 hr): (i) vehicle/saline, (ii) 7-NI (25 mg/kg)/saline, (iii) vehicle/METH (5 mg/kg), and (iv) 7-NI (25 mg/kg)/METH (5 mg/kg). On the second day, groups (i) and (iii) received two vehicle injections and groups (ii) and (iv) received two 7-NI injections (25 mg/kg each). The administration of vehicle/METH resulted in 68, 44 and 55% decreases in the concentration of DA, dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), respectively, and a 48% decrease in the number of [ 3 H]mazindol binding sites in the striatum compared to control values. The treatment with 7-NI (group iv) provided a full protection against the depletion of DA and its metabolites, and the loss of dopamine transporter binding sites. Multiple injection of METH caused a significant decrease in the concentration of serotonin (5-HT) and its metabolite 5-hydroxyindole acetic acid (5-HIAA). Treatment with 7-NI partially blocked the depletion of 5-HT and completely blocked the reduction in 5-HIAA levels. The administration of 7-NI/saline (group ii) affected neither the tissue concentration of DA, 5-HT and their metabolites (DOPAC, HVA and 5-HIAA) nor the binding parameters of [ 3 H]-mazindol compared to control (vehicle/saline) values. 7-NI had no significant effect on the animals' body temperature, and it did not affect METH-induced hyperthermia. These findings indicate a role for nitric oxide in METH-induced neurotoxicity and also suggest that blockage of NOS may be beneficial for

Neurotoxicity of brominated flame retardants

Science.gov (United States)

Polybrominated diphenyl ethers (PBDEs) have been commonly used as commercial flame retardants in a variety of products including plastics and textiles. Despite their decreasing usage worldwide, congeners continue to accumulate in the environment, including soil, dust, food, anima...

Effects of early and late diabetic neuropathy on sciatic nerve block duration and neurotoxicity in Zucker diabetic fatty rats

NARCIS (Netherlands)

Lirk, P.; Verhamme, C.; Boeckh, R.; Stevens, M. F.; ten Hoope, W.; Gerner, P.; Blumenthal, S.; de Girolami, U.; van Schaik, I. N.; Hollmann, M. W.; Picardi, S.

2015-01-01

The neuropathy of type II diabetes mellitus (DM) is increasing in prevalence worldwide. We aimed to test the hypothesis that in a rodent model of type II DM, neuropathy would lead to increased neurotoxicity and block duration after lidocaine-induced sciatic nerve block when compared with control

The Evolving Landscape of Neurotoxicity by Unconjugated Bilirubin: Role of Glial Cells and Inflammation

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Dora eBrites

2012-05-01

Full Text Available Unconjugated hyperbilirubinemia is a common condition in the first week of postnatal life. Although generally harmless, some neonates may develop very high levels of unconjugated bilirubin (UCB, which may surpass the protective mechanisms of the brain at preventing UCB accumulation. In this case, both short-term and long-term neurodevelopmental disabilities, such as acute and chronic UCB encephalopathy, known as kernicterus, or more subtle alterations designed as bilirubin-induced neurological dysfunction (BIND may be produced. There is a tremendous variability in babies’ vulnerability towards UCB for reasons not yet explained, but preterm birth, sepsis, hypoxia and haemolytic disease are comprised as risk factors. Therefore, UCB levels and neurological abnormalities are not strictly correlated. Even nowadays, the mechanisms of UCB neurotoxicity are still unclear, as are specific biomarkers, and little is known about lasting sequelae attributable to hyperbilirubinemia. On autopsy, UCB was shown to be within neurons, neuronal processes and microglia, and to produce loss of neurons, demyelination and gliosis. In isolated cell cultures, UCB was shown to impair neuronal arborization and to induce the release of proinflammatory cytokines from microglia and astrocytes. However, cell dependent-sensitivity to UCB toxicity and the role of each nerve cell type remain understood. This review provides a comprehensive insight into cell susceptibilities and molecular targets of UCB in neurons, astrocytes, and oligodendrocytes, and on phenotypic and functional responses of microglia to UCB. Interplay among glia elements and cross-talk with neurons, with a special emphasis in the UCB-induced immunostimulation, and the role of sepsis in BIND pathogenesis are highlighted. New and interesting data on the anti-inflammatory and antioxidant activities of different pharmacological agents are also presented, as novel and promising additional therapeutic approaches to

The neurotoxic effects of prenatal gabapentin and oxcarbazepine exposure on newborn rats.

Science.gov (United States)

Erisgin, Zuleyha; Ayas, Bulent; Nyengaard, Jens R; Ercument Beyhun, N; Terzi, Yuksel

2017-10-05

Teratogenicity is a problematic issue for pregnant women because of X-ray radiation, drugs, and genetic and unknown variables. First-generation antiepileptic drugs (AED) like valproic acid are well-known teratogens for developing fetuses. However, their usage is necessary in order to prevent maternal seizures. The underlying mechanism of birth defects associated with AED exposure remains unclear and information about the neurotoxic effects of prenatal exposure to AED is still limited. Oxcarbazepine (OXC) and gabapentin (GBP) are second-generation AED. It still remains unclear how much these drugs are safe during pregnancy. This study aimed to investigate whether any neurotoxic effect of OXC and GBP in utero exposure on the developing brain. Eighteen pregnant Wistar albino rats were divided into six groups. The first group was exposed to OXC at 100 mg/kg/day, the second to GBP at 50 mg/kg/day, and third to saline (0.9% NaCl) at 1.5 ml/day between the first and the fifth days of gestation. The same procedure was applied at the same dosages between the 6th and the 15th days of gestation for the 2nd three groups. Five female offspring (total n = 30, 45 days old) were taken from each group and stereological methods were applied in order to analyze the total and dopaminergic neuron number of the substantia nigra pars compacta (SNc). The result is that the OXC and GBP exposure at different gestational periods may not give rise to congenital malformation and it appears that the GBP exposure during the organogenesis period proliferatively affects the total number of neurons.