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Sample records for chronic neurodegeneration models

  1. Chronic Hypertension Leads to Neurodegeneration in the TgSwDI Mouse Model of Alzheimer's Disease.

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    Kruyer, Anna; Soplop, Nadine; Strickland, Sidney; Norris, Erin H

    2015-07-01

    Numerous epidemiological studies link vascular disorders, such as hypertension, diabetes mellitus, and stroke, with Alzheimer's disease (AD). Hypertension, specifically, is an important modifiable risk factor for late-onset AD. To examine the link between midlife hypertension and the onset of AD later in life, we chemically induced chronic hypertension in the TgSwDI mouse model of AD in early adulthood. Hypertension accelerated cognitive deficits in the Barnes maze test (Phypertension induced hippocampal neurodegeneration at an early age in this mouse line (43% reduction in the dorsal subiculum; P<0.05), establishing this as a useful research model of AD with mixed vascular and amyloid pathologies.

  2. Insights into Mechanisms of Chronic Neurodegeneration

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    Abigail B. Diack

    2016-01-01

    Full Text Available Chronic neurodegenerative diseases such as Alzheimer’s disease (AD, Parkinson’s disease (PD, and prion diseases are characterised by the accumulation of abnormal conformers of a host encoded protein in the central nervous system. The process leading to neurodegeneration is still poorly defined and thus development of early intervention strategies is challenging. Unique amongst these diseases are Transmissible Spongiform Encephalopathies (TSEs or prion diseases, which have the ability to transmit between individuals. The infectious nature of these diseases has permitted in vivo and in vitro modelling of the time course of the disease process in a highly reproducible manner, thus early events can be defined. Recent evidence has demonstrated that the cell-to-cell spread of protein aggregates by a “prion-like mechanism” is common among the protein misfolding diseases. Thus, the TSE models may provide insights into disease mechanisms and testable hypotheses for disease intervention, applicable to a number of these chronic neurodegenerative diseases.

  3. Neurodegeneration severity can be predicted from early microglia alterations monitored in vivo in a mouse model of chronic glaucoma

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    Alejandra Bosco

    2015-05-01

    Full Text Available Microglia serve key homeostatic roles, and respond to neuronal perturbation and decline with a high spatiotemporal resolution. The course of all chronic CNS pathologies is thus paralleled by local microgliosis and microglia activation, which begin at early stages of the disease. However, the possibility of using live monitoring of microglia during early disease progression to predict the severity of neurodegeneration has not been explored. Because the retina allows live tracking of fluorescent microglia in their intact niche, here we investigated their early changes in relation to later optic nerve neurodegeneration. To achieve this, we used the DBA/2J mouse model of inherited glaucoma, which develops progressive retinal ganglion cell degeneration of variable severity during aging, and represents a useful model to study pathogenic mechanisms of retinal ganglion cell decline that are similar to those in human glaucoma. We imaged CX3CR1+/GFP microglial cells in vivo at ages ranging from 1 to 5 months by confocal scanning laser ophthalmoscopy (cSLO and quantified cell density and morphological activation. We detected early microgliosis at the optic nerve head (ONH, where axonopathy first manifests, and could track attenuation of this microgliosis induced by minocycline. We also observed heterogeneous and dynamic patterns of early microglia activation in the retina. When the same animals were aged and analyzed for the severity of optic nerve pathology at 10 months of age, we found a strong correlation with the levels of ONH microgliosis at 3 to 4 months. Our findings indicate that live imaging and monitoring the time course and levels of early retinal microgliosis and microglia activation in glaucoma could serve as indicators of future neurodegeneration severity.

  4. Cerebrospinal fluid biomarkers of neurodegeneration in chronic neurological diseases.

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    Tumani, Hayrettin; Teunissen, Charlotte; Süssmuth, Sigurd; Otto, Markus; Ludolph, Albert C; Brettschneider, Johannes

    2008-07-01

    Chronic neurological diseases (CND) like amyotrophic lateral sclerosis (ALS), dementia or multiple sclerosis (MS) share a chronic progressive course of disease that frequently leads to the common pathological pathway of neurodegeneration, including neuroaxonal damage, apoptosis and gliosis. There is an ongoing search for biomarkers that could support early diagnosis of CND and help to identify responders to interventions in therapeutic treatment trials. Cerebrospinal fluid (CSF) is a promising source of biomarkers in CND, since the CSF compartment is in close anatomical contact with the brain interstitial fluid, where biochemical changes related to CND are reflected. We review recent advances in CSF biomarkers research in CND and thereby focus on markers associated with neurodegeneration.

  5. Restorative effect of endurance exercise on behavioral deficits in the chronic mouse model of Parkinson's disease with severe neurodegeneration

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    Lau Yuen-Sum

    2009-01-01

    Full Text Available Abstract Background Animal models of Parkinson's disease have been widely used for investigating the mechanisms of neurodegenerative process and for discovering alternative strategies for treating the disease. Following 10 injections with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 25 mg/kg and probenecid (250 mg/kg over 5 weeks in mice, we have established and characterized a chronic mouse model of Parkinson's disease (MPD, which displays severe long-term neurological and pathological defects resembling that of the human Parkinson's disease in the advanced stage. The behavioral manifestations in this chronic mouse model of Parkinson's syndrome remain uninvestigated. The health benefit of exercise in aging and in neurodegenerative disorders including the Parkinson's disease has been implicated; however, clinical and laboratory studies in this area are limited. In this research with the chronic MPD, we first conducted a series of behavioral tests and then investigated the impact of endurance exercise on the identified Parkinsonian behavioral deficits. Results We report here that the severe chronic MPD mice showed significant deficits in their gait pattern consistency and in learning the cued version of the Morris water maze. Their performances on the challenging beam and walking grid were considerably attenuated suggesting the lack of balance and motor coordination. Furthermore, their spontaneous and amphetamine-stimulated locomotor activities in the open field were significantly suppressed. The behavioral deficits in the chronic MPD lasted for at least 8 weeks after MPTP/probenecid treatment. When the chronic MPD mice were exercise-trained on a motorized treadmill 1 week before, 5 weeks during, and 8–12 weeks after MPTP/probenecid treatment, the behavioral deficits in gait pattern, spontaneous ambulatory movement, and balance performance were reversed; whereas neuronal loss and impairment in cognitive skill, motor coordination, and

  6. Transgenic Drosophila model to study apolipoprotein E4-induced neurodegeneration.

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    Haddadi, Mohammad; Nongthomba, Upendra; Jahromi, Samaneh Reiszadeh; Ramesh, S R

    2016-03-15

    The ε4 isoform of apolipoprotein E (ApoE4) that is involved in neuron-glial lipid metabolism has been demonstrated as the main genetic risk factor in late-onset of Alzheimer's disease. However, the mechanism underlying ApoE4-mediated neurodegeneration remains unclear. We created a transgenic model of neurodegenerative disorder by expressing ε3 and ε4 isoforms of human ApoE in the Drosophila melanogaster. The genetic models exhibited progressive neurodegeneration, shortened lifespan and memory impairment. Genetic interaction studies between amyloid precursor protein and ApoE in axon pathology of the disease revealed that over expression of hApoE in Appl-expressing neurons of Drosophila brain causes neurodegeneration. Moreover, acute oxidative damage in the hApoE transgenic flies triggered a neuroprotective response of hApoE3 while chronic induction of oxidative damage accelerated the rate of neurodegeneration. This Drosophila model may facilitate analysis of the molecular and cellular events implicated in hApoE4 neurotoxicity.

  7. Chronic Stress and Glucocorticoids: From Neuronal Plasticity to Neurodegeneration

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    Sheela Vyas

    2016-01-01

    Full Text Available Stress and stress hormones, glucocorticoids (GCs, exert widespread actions in central nervous system, ranging from the regulation of gene transcription, cellular signaling, modulation of synaptic structure, and transmission and glial function to behavior. Their actions are mediated by glucocorticoid and mineralocorticoid receptors which are nuclear receptors/transcription factors. While GCs primarily act to maintain homeostasis by inducing physiological and behavioral adaptation, prolonged exposure to stress and elevated GC levels may result in neuro- and psychopathology. There is now ample evidence for cause-effect relationships between prolonged stress, elevated GC levels, and cognitive and mood disorders while the evidence for a link between chronic stress/GC and neurodegenerative disorders such as Alzheimer’s (AD and Parkinson’s (PD diseases is growing. This brief review considers some of the cellular mechanisms through which stress and GC may contribute to the pathogenesis of AD and PD.

  8. Chromosome 13 dementia syndromes as models of neurodegeneration

    DEFF Research Database (Denmark)

    Ghiso, J.; Revesz, T.; Holton, J.;

    2001-01-01

    Two hereditary conditions, familial British dementia (FBD) and familial Danish dementia (FDD), are associated with amyloid deposition in the central nervous system and neurodegeneration. The two amyloid proteins, ABri and ADan, are degradation products of the same precursor molecule BriPP bearing....... These issues argue for the primary importance of the amyloid deposits in the mechanism(s) of neuronal cell loss. We propose FBD and FDD, the chromosome 13 dementia syndromes, as models to study the molecular basis of neurofibrillary degeneration, cell death and amyloid formation in the brain....

  9. Anticholinergics boost the pathological process of neurodegeneration with increased inflammation in a tauopathy mouse model.

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    Yoshiyama, Yasumasa; Kojima, Ayako; Itoh, Kimiko; Uchiyama, Tomoyuki; Arai, Kimihito

    2012-01-01

    Anticholinergics, and drugs with anticholinergic properties, are widely and frequently prescribed, especially to the elderly. It is well known that these drugs decrease cognitive function and increase the risk of dementia. Although the mechanism of anticholinergic drug-induced cognitive impairment has been assumed to be functionally reduced acetylcholine (ACh) neurotransmission, some data have indicated that anticholinergics might enhance the pathology of Alzheimer's disease. In this study, we investigated the pathological effects of anticholinergics on neurodegeneration. We chronically administered two anticholinergics, trihexyphenidyl (TP) and propiverine (PP) (the latter with less central anticholinergic action), to neurodegenerative tauopathy model mice 2 to 10 months old. Furthermore, because the ACh nervous system regulates both central and peripheral inflammation, we administered TP or PP to PS19 mice in which we had artificially induced inflammation by lipopolysaccharide injection. Tau pathology, synaptic loss, and neurodegeneration in the hippocampal region, as well as tau insolubility and phosphorylation, were markedly increased in TP-treated mice and mildly increased in PP-treated mice. Furthermore, immunohistochemical analysis revealed microglial proliferation and activation. Moreover, anticholinergics increased interleukin-1β expression in both the spleen and brain of the tauopathy model mice intraperitoneally injected with lipopolysaccharide to induce systemic inflammation. Interestingly, these alterations were more strongly observed in TP-treated mice than in PP-treated mice, consistent with the level of central anticholinergic action. Anticholinergic drugs not only impair cognitive function by decreased ACh neurotransmission, but also accelerate neurodegeneration by suppressing an ACh-dependent anti-inflammatory system. Anticholinergics should be less readily prescribed to reduce the risk of dementia.

  10. The Impact of Mathematical Modeling in Understanding the Mechanisms Underlying Neurodegeneration: Evolving Dimensions and Future Directions

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    Lloret‐Villas, A; Varusai, TM; Juty, N; Laibe, C; Le NovÈre, N; Hermjakob, H

    2017-01-01

    Neurodegenerative diseases are a heterogeneous group of disorders that are characterized by the progressive dysfunction and loss of neurons. Here, we distil and discuss the current state of modeling in the area of neurodegeneration, and objectively compare the gaps between existing clinical knowledge and the mechanistic understanding of the major pathological processes implicated in neurodegenerative disorders. We also discuss new directions in the field of neurodegeneration that hold potential for furthering therapeutic interventions and strategies. PMID:28063254

  11. Chronic glucocorticoids exposure enhances neurodegeneration in the frontal cortex and hippocampus via NLRP-1 inflammasome activation in male mice.

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    Hu, Wen; Zhang, Yaodong; Wu, Wenning; Yin, Yanyan; Huang, Dake; Wang, Yuchan; Li, Weiping; Li, Weizu

    2016-02-01

    Neuroinflammation plays an important role in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD) and depression. Chronic glucocorticoids (GCs) exposure has deleterious effects on the structure and function of neurons and is associated with development and progression of AD. However, little is known about the proinflammatory effects of chronic GCs exposure on neurodegeneration in brain. Therefore, the aim of this study was to evaluate the effects of chronic dexamethasone (DEX) treatment (5mg/kg, s.c. for 7, 14, 21 and 28 days) on behavior, neurodegeneration and neuroinflammatory parameters of nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 1 (NLRP-1) inflammasome in male mice. The results showed that DEX treatment for 21 and 28 days significantly reduced the spontaneous motor activity and exploratory behavior of the mice. In addition, these mice showed significant neurodegeneration and a decrease of microtubule-associated protein 2 (MAP2) in the frontal cortex and hippocampus CA3. DEX treatment for 7, 14, 21 and 28 days significantly decreased the mRNA and protein expression of glucocorticoid receptor (GR). Moreover, DEX treatment for 21 and 28 days significantly increased the proteins expression of NLRP-1, Caspase-1, Caspase-5, apoptosis associated speck-like protein (ASC), nuclear factor-κB (NF-κB), p-NF-κB, interleukin-1β (IL-1β), IL-18 and IL-6 in the frontal cortex and hippocampus brain tissue. DEX treatment for 28 days also significantly increased the mRNA expression levels of NLRP-1, Caspase-1, ASC and IL-1β. These results suggest that chronic GCs exposure may increase brain inflammation via NLRP-1 inflammasome activation and induce neurodegeneration.

  12. Neurodegeneration and chronic renal failure in methylmalonic aciduria--a pathophysiological approach.

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    Morath, M A; Okun, J G; Müller, I B; Sauer, S W; Hörster, F; Hoffmann, G F; Kölker, S

    2008-02-01

    In the last decades the survival of patients with methylmalonic aciduria has been improved. However, the overall outcome of affected patients remains disappointing. The disease course is often complicated by acute life-threatening metabolic crises, which can result in multiple organ failure or even death, resembling primary defects of mitochondrial energy metabolism. Biochemical abnormalities during metabolic derangement, such as metabolic acidosis, ketonaemia/ketonuria, lactic acidosis, hypoglycaemia and hyperammonaemia, suggest mitochondrial dysfunction. In addition, long-term complications such as chronic renal failure and neurological disease are frequently found. Neuropathophysiological studies have focused on various effects caused by accumulation of putatively toxic organic acids, the so-called 'toxic metabolite' hypothesis. In previous studies, methylmalonate (MMA) has been considered as the major neurotoxin in methylmalonic aciduria, whereas more recent studies have highlighted a synergistic inhibition of mitochondrial energy metabolism (pyruvate dehydrogenase complex, tricarboxylic acid cycle, respiratory chain, mitochondrial salvage pathway of deoxyribonucleoside triphosphate (dNTP)) induced by propionyl-CoA, 2-methylcitrate and MMA as the key pathomechanism of inherited disorders of propionate metabolism. Intracerebral accumulation of toxic metabolites ('trapping' hypothesis') is considered a biochemical risk factor for neurodegeneration. Secondary effects of mitochondrial dysfunction, such as oxidative stress and impaired mtDNA homeostasis, contribute to pathogenesis of these disorders. The underlying pathomechanisms of chronic renal insufficiency in methylmalonic acidurias are not yet understood. We hypothesize that renal and cerebral pathomechanisms share some similarities, such as an involvement of dicarboxylic acid transport. This review aims to give a comprehensive overview on recent pathomechanistic concepts for methylmalonic acidurias.

  13. [Calpains and their endo- and exogenous regulators in various neurodegeneration models].

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    Lysenko, L A; Kantserova, N P; Rendakov, N L; Nemova, N N

    2014-01-01

    On the basis of experimental series with murine models there was obtained the evidence on calcium-dependent protease activity changes in rat brain at induced neurodegeneration. The properties of the proteolytic and regulatory components of calpain system under the effect of neurotoxic stimuli--amyloid beta-peptide or glutamate--were characterized; the basic endogenous regulatory mechanisms of calcium-dependent proteolysis modulation were determined as well. Neuroprotective properties of exogenous calpain regulators differing in the mechanisms of action (sex steroids, calcium regulators) were tested on studied neurodegeneration models.

  14. Aging and Neurodegeneration: A Tangle of Models and Mechanisms

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    Chakrabarti, Sasanka; Mohanakumar, Kochupurackal P.

    2016-01-01

    The research on aging and age-related diseases, especially the neurodegenerative diseases, is on the fast track. However, the results have so far not been translated to actual benefit for the patients in terms of treatment or diagnosis of age-related degenerative diseases including those of the CNS. As far as the prevention of the cognitive decline during non-pathological aging is concerned, there is nothing much to offer other than calorie restriction and physical exercise. Needless to say, the benefits are not up to our expectations. However, over the years at the experimental level it has been possible to identify several cellular and molecular mechanisms that are intricately associated with aging in general and neurodegenerative diseases in particular. These include oxidative stress and altered redox-signaling, mitochondrial dysfunction, inflammation, proteotoxicity and altered gene expressions. These inter-dependent pathways mediate cellular senescence and often culminate in programmed cell death like apoptosis and autophagy, and in the context of brain these changes are manifested clinically as cognitive decline and pathologically as neurodegeneration. This special issue provides the readers with glimpses of this complex scenario from different angles primarily in the context of brain and also attempts to identify the potential drug targets against neurodegenerative diseases. PMID:27114843

  15. Mitochondrial optic neuropathy: In vivo model of neurodegeneration and neuroprotective strategies

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    Julio C Rojas

    2010-03-01

    Full Text Available Julio C Rojas, Francisco Gonzalez-LimaDepartments of Psychology, Pharmacology and Toxicology, University of Texas at Austin, Austin, TX, USAAbstract: This review summarizes the characteristics of a rodent toxicologic model of optic neuropathy induced by the mitochondrial complex I inhibitor rotenone. This model has been developed to fulfill the demand for a drug-screening tool providing a sound mechanistic context to address the role of mitochondrial dysfunction in the pathogenesis of neurodegenerative disorders. It features biochemical, structural, and functional retinal deficits that resemble those of patients with Leber’s hereditary optic neuropathy, a mitochondrial disease characterized by selective degeneration of retinal ganglion cells, and for which an environmental component is believed to play a major triggering role. The available data support the efficiency, sensitivity, and versatility of the model for providing insights into the mechanisms of neurodegeneration, including mitochondrial dysfunction, oxidative stress and excitotoxicity. Screening work with this model has provided proof-of-principle that interventions targeting the electron transport chain, such as USP methylene blue and near-infrared light therapy, are effective at preventing neurodegeneration induced by mitochondrial dysfunction in vivo. Prospective developments of this model include the use of neuronal reporter genes for in vivo non-invasive assessment of retinal degeneration at different time points, and its combination with genetic approaches to elucidate the synergism of environmental and genetic factors in neurodegeneration.Keywords: animal model, neuroprotection, mitochondrial dysfunction, visual function, oxidative stress, cytochrome oxidase

  16. Neuroprotective Effects of Citicoline in in Vitro Models of Retinal Neurodegeneration

    OpenAIRE

    Andrea Matteucci; Monica Varano; Lucia Gaddini; Cinzia Mallozzi; Marika Villa; Flavia Pricci; Fiorella Malchiodi-Albedi

    2014-01-01

    In recent years, citicoline has been the object of remarkable interest as a possible neuroprotectant. The aim of this study was to investigate if citicoline affected cell survival in primary retinal cultures and if it exerted neuroprotective activity in conditions modeling retinal neurodegeneration. Primary retinal cultures, obtained from rat embryos, were first treated with increasing concentrations of citicoline (up to 1000 µM) and analyzed in terms of apoptosis and caspase activation and c...

  17. Neuroprotective effects of citicoline in in vitro models of retinal neurodegeneration.

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    Matteucci, Andrea; Varano, Monica; Gaddini, Lucia; Mallozzi, Cinzia; Villa, Marika; Pricci, Flavia; Malchiodi-Albedi, Fiorella

    2014-04-14

    In recent years, citicoline has been the object of remarkable interest as a possible neuroprotectant. The aim of this study was to investigate if citicoline affected cell survival in primary retinal cultures and if it exerted neuroprotective activity in conditions modeling retinal neurodegeneration. Primary retinal cultures, obtained from rat embryos, were first treated with increasing concentrations of citicoline (up to 1000 µM) and analyzed in terms of apoptosis and caspase activation and characterized by immunocytochemistry to identify neuronal and glial cells. Subsequently, excitotoxic concentration of glutamate or High Glucose-containing cell culture medium (HG) was administered as well-known conditions modeling neurodegeneration. Glutamate or HG treatments were performed in the presence or not of citicoline. Neuronal degeneration was evaluated in terms of apoptosis and loss of synapses. The results showed that citicoline did not cause any damage to the retinal neuroglial population up to 1000 µM. At the concentration of 100 µM, it was able to counteract neuronal cell damage both in glutamate- and HG-treated retinal cultures by decreasing proapoptotic effects and contrasting synapse loss. These data confirm that citicoline can efficiently exert a neuroprotective activity. In addition, the results suggest that primary retinal cultures, under conditions inducing neurodegeneration, may represent a useful system to investigate citicoline neuroprotective mechanisms.

  18. Neuroprotective Effects of Citicoline in in Vitro Models of Retinal Neurodegeneration

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    Andrea Matteucci

    2014-04-01

    Full Text Available In recent years, citicoline has been the object of remarkable interest as a possible neuroprotectant. The aim of this study was to investigate if citicoline affected cell survival in primary retinal cultures and if it exerted neuroprotective activity in conditions modeling retinal neurodegeneration. Primary retinal cultures, obtained from rat embryos, were first treated with increasing concentrations of citicoline (up to 1000 µM and analyzed in terms of apoptosis and caspase activation and characterized by immunocytochemistry to identify neuronal and glial cells. Subsequently, excitotoxic concentration of glutamate or High Glucose-containing cell culture medium (HG was administered as well-known conditions modeling neurodegeneration. Glutamate or HG treatments were performed in the presence or not of citicoline. Neuronal degeneration was evaluated in terms of apoptosis and loss of synapses. The results showed that citicoline did not cause any damage to the retinal neuroglial population up to 1000 µM. At the concentration of 100 µM, it was able to counteract neuronal cell damage both in glutamate- and HG-treated retinal cultures by decreasing proapoptotic effects and contrasting synapse loss. These data confirm that citicoline can efficiently exert a neuroprotective activity. In addition, the results suggest that primary retinal cultures, under conditions inducing neurodegeneration, may represent a useful system to investigate citicoline neuroprotective mechanisms.

  19. Novel Mechanism for Reducing Acute and Chronic Neurodegeneration After Traumatic Brain Injury

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    2015-07-01

    DOCUMENTATION PAGE Form Approved OMB No. 0704-0188 Public reporting burden for this collection of information is estimated to average 1 hour per response...reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including...chronic neuronal cell loss, glial activation, and chronic traumatic encephalopathy (CTE) measure of β-amyloid and hyper-phosphorylated tau protein

  20. Implanted neural electrodes cause chronic, local inflammation that is correlated with local neurodegeneration

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    McConnell, George C.; Rees, Howard D.; Levey, Allan I.; Gutekunst, Claire-Anne; Gross, Robert E.; Bellamkonda, Ravi V.

    2009-10-01

    Prosthetic devices that are controlled by intracortical electrodes recording one's 'thoughts' are a reality today, and no longer merely in the realm of science fiction. However, widespread clinical use of implanted electrodes is hampered by a lack of reliability in chronic recordings, independent of the type of electrodes used. One major hypothesis has been that astroglial scar electrically impedes the electrodes. However, there is a temporal discrepancy between stabilization of scar's electrical properties and recording failure with recording failure lagging by 1 month. In this study, we test a possible explanation for this discrepancy: the hypothesis that chronic inflammation, due to the persistent presence of the electrode, causes a local neurodegenerative state in the immediate vicinity of the electrode. Through modulation of chronic inflammation via stab wound, electrode geometry and age-matched control, we found that after 16 weeks, animals with an increased level of chronic inflammation were associated with increased neuronal and dendritic, but not axonal, loss. We observed increased neuronal and dendritic loss 16 weeks after implantation compared to 8 weeks after implantation, suggesting that the local neurodegenerative state is progressive. After 16 weeks, we observed axonal pathology in the form of hyperphosphorylation of the protein tau in the immediate vicinity of the microelectrodes (as observed in Alzheimer's disease and other tauopathies). The results of this study suggest that a local, late onset neurodegenerative disease-like state surrounds the chronic electrodes and is a potential cause for chronic recording failure. These results also inform strategies to enhance our capability to attain reliable long-term recordings from implantable electrodes in the CNS.

  1. Transdermal delivery of cannabidiol attenuates binge alcohol-induced neurodegeneration in a rodent model of an alcohol use disorder.

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    Liput, Daniel J; Hammell, Dana C; Stinchcomb, Audra L; Nixon, Kimberly

    2013-10-01

    Excessive alcohol consumption, characteristic of alcohol use disorders, results in neurodegeneration and behavioral and cognitive impairments that are hypothesized to contribute to the chronic and relapsing nature of alcoholism. Therefore, the current study aimed to advance the preclinical development of transdermal delivery of cannabidiol (CBD) for the treatment of alcohol-induced neurodegeneration. In Experiment 1, 1.0%, 2.5% and 5.0% CBD gels were evaluated for neuroprotection. The 5.0% CBD gel resulted in a 48.8% reduction in neurodegeneration in the entorhinal cortex assessed by Fluoro-Jade B (FJB), which trended to statistical significance (p=0.069). Treatment with the 5.0% CBD gel resulted in day 3 CBD plasma concentrations of ~100.0 ng/mL so this level was used as a target concentration for development of an optimized gel formulation. Experiment 2 tested a next generation 2.5% CBD gel formulation, which was compared to CBD administration by intraperitoneal injection (IP; 40.0 mg/kg/day). This experiment found similar magnitudes of neuroprotection following both routes of administration; transdermal CBD decreased FJB+ cells in the entorhinal cortex by 56.1% (p<0.05), while IP CBD resulted in a 50.6% (p<0.05) reduction in FJB+ cells. These results demonstrate the feasibility of using CBD transdermal delivery systems for the treatment of alcohol-induced neurodegeneration.

  2. Correlated Inflammatory Responses and Neurodegeneration in Peptide-Injected Animal Models of Alzheimer’s Disease

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    James G. McLarnon

    2014-01-01

    Full Text Available Animal models of Alzheimer’s disease (AD which emphasize activation of microglia may have particular utility in correlating proinflammatory activity with neurodegeneration. This paper reviews injection of amyloid-β (Aβ into rat brain as an alternative AD animal model to the use of transgenic animals. In particular, intrahippocampal injection of Aβ1-42 peptide demonstrates prominent microglial mobilization and activation accompanied by a significant loss of granule cell neurons. Furthermore, pharmacological inhibition of inflammatory reactivity is demonstrated by a broad spectrum of drugs with a common endpoint in conferring neuroprotection in peptide-injected animals. Peptide-injection models provide a focus on glial cell responses to direct peptide injection in rat brain and offer advantages in the study of the mechanisms underlying neuroinflammation in AD brain.

  3. Prodromal Huntington disease as a model for functional compensation of early neurodegeneration.

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    Kathrin Malejko

    Full Text Available Functional compensation demonstrated as mechanism to offset neuronal loss in early Alzheimer disease may also occur in other adult-onset neurodegenerative diseases, particularly Huntington disease (HD with its genetic determination and gradual changes in structural integrity. In HD, neurodegeneration typically initiates in the dorsal striatum, successively affecting ventral striatal areas. Investigating carriers of the HD mutation with evident dorsal, but only minimal or no ventral striatal atrophy, we expected to find evidence for compensation of ventral striatal functioning. We investigated 14 pre- or early symptomatic carriers of the mutation leading to HD and 18 matched healthy controls. Participants underwent structural T1 magnetic resonance imaging (MRI and functional MRI during a reward task that probes ventral striatal functioning. Motor functioning and attention were assessed with reaction time (RT tasks. Structural images confirmed a specific decrease of dorsal striatal but only marginal ventral striatal volume in HD relative to control subjects, paralleling prolonged RT in the motor response tasks. While behavioral performance in the reward task during fMRI scanning was unimpaired, reward-related fMRI signaling in the HD group was differentially enhanced in the bilateral ventral striatum and in bilateral orbitofrontal cortex/anterior insula, as another region sensitive to reward processing. We provide evidence for the concept of functional compensation in premanifest HD which may suggest a defense mechanism in neurodegeneration. Given the so far inevitable course of HD with its genetically determined endpoint, this disease may provide another model to study the different aspects of the concept of functional compensation.

  4. TSPO in a murine model of Sandhoff disease: presymptomatic marker of neurodegeneration and disease pathophysiology.

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    Loth, Meredith K; Choi, Judy; McGlothan, Jennifer L; Pletnikov, Mikhail V; Pomper, Martin G; Guilarte, Tomás R

    2016-01-01

    Translocator protein (18 kDa), formerly known as the peripheral benzodiazepine receptor (PBR), has been extensively used as a biomarker of active brain disease and neuroinflammation. TSPO expression increases dramatically in glial cells, particularly in microglia and astrocytes, as a result of brain injury, and this phenomenon is a component of the hallmark response of the brain to injury. In this study, we used a mouse model of Sandhoff disease (SD) to assess the longitudinal expression of TSPO as a function of disease progression and its relationship to behavioral and neuropathological endpoints. Focusing on the presymptomatic period of the disease, we used ex vivo [(3)H]DPA-713 quantitative autoradiography and in vivo [(125)I]IodoDPA-713 small animal SPECT imaging to show that brain TSPO levels markedly increase prior to physical and behavioral manifestation of disease. We further show that TSPO upregulation coincides with early neuronal GM2 ganglioside aggregation and is associated with ongoing neurodegeneration and activation of both microglia and astrocytes. In brain regions with increased TSPO levels, there is a differential pattern of glial cell activation with astrocytes being activated earlier than microglia during the progression of disease. Immunofluorescent confocal imaging confirmed that TSPO colocalizes with both microglia and astrocyte markers, but the glial source of the TSPO response differs by brain region and age in SD mice. Notably, TSPO colocalization with the astrocyte marker GFAP was greater than with the microglia marker, Mac-1. Taken together, our findings have significant implications for understanding TSPO glial cell biology and for detecting neurodegeneration prior to clinical expression of disease.

  5. Moringa oleifera Mitigates Memory Impairment and Neurodegeneration in Animal Model of Age-Related Dementia

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    Chatchada Sutalangka

    2013-01-01

    Full Text Available To date, the preventive strategy against dementia is still essential due to the rapid growth of its prevalence and the limited therapeutic efficacy. Based on the crucial role of oxidative stress in age-related dementia and the antioxidant and nootropic activities of Moringa oleifera, the enhancement of spatial memory and neuroprotection of M. oleifera leaves extract in animal model of age-related dementia was determined. The possible underlying mechanism was also investigated. Male Wistar rats, weighing 180–220 g, were orally given M. oleifera leaves extract at doses of 100, 200, and 400 mg/kg at a period of 7 days before and 7 days after the intracerebroventricular administration of AF64A bilaterally. Then, they were assessed memory, neuron density, MDA level, and the activities of SOD, CAT, GSH-Px, and AChE in hippocampus. The results showed that the extract improved spatial memory and neurodegeneration in CA1, CA2, CA3, and dentate gyrus of hippocampus together with the decreased MDA level and AChE activity but increased SOD and CAT activities. Therefore, our data suggest that M. oleifera leaves extract is the potential cognitive enhancer and neuroprotectant. The possible mechanism might occur partly via the decreased oxidative stress and the enhanced cholinergic function. However, further explorations concerning active ingredient(s are still required.

  6. Moringa oleifera mitigates memory impairment and neurodegeneration in animal model of age-related dementia.

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    Sutalangka, Chatchada; Wattanathorn, Jintanaporn; Muchimapura, Supaporn; Thukham-mee, Wipawee

    2013-01-01

    To date, the preventive strategy against dementia is still essential due to the rapid growth of its prevalence and the limited therapeutic efficacy. Based on the crucial role of oxidative stress in age-related dementia and the antioxidant and nootropic activities of Moringa oleifera, the enhancement of spatial memory and neuroprotection of M. oleifera leaves extract in animal model of age-related dementia was determined. The possible underlying mechanism was also investigated. Male Wistar rats, weighing 180-220 g, were orally given M. oleifera leaves extract at doses of 100, 200, and 400 mg/kg at a period of 7 days before and 7 days after the intracerebroventricular administration of AF64A bilaterally. Then, they were assessed memory, neuron density, MDA level, and the activities of SOD, CAT, GSH-Px, and AChE in hippocampus. The results showed that the extract improved spatial memory and neurodegeneration in CA1, CA2, CA3, and dentate gyrus of hippocampus together with the decreased MDA level and AChE activity but increased SOD and CAT activities. Therefore, our data suggest that M. oleifera leaves extract is the potential cognitive enhancer and neuroprotectant. The possible mechanism might occur partly via the decreased oxidative stress and the enhanced cholinergic function. However, further explorations concerning active ingredient(s) are still required.

  7. Oral microbiome link to neurodegeneration in glaucoma.

    Directory of Open Access Journals (Sweden)

    Konstantin Astafurov

    Full Text Available BACKGROUND: Glaucoma is a progressive optic nerve degenerative disease that often leads to blindness. Local inflammatory responses are implicated in the pathology of glaucoma. Although inflammatory episodes outside the CNS, such as those due to acute systemic infections, have been linked to central neurodegeneration, they do not appear to be relevant to glaucoma. Based on clinical observations, we hypothesized that chronic subclinical peripheral inflammation contributes to neurodegeneration in glaucoma. METHODS: Mouthwash specimens from patients with glaucoma and control subjects were analyzed for the amount of bacteria. To determine a possible pathogenic mechanism, low-dose subcutaneous lipopolysaccharide (LPS was administered in two separate animal models of glaucoma. Glaucomatous neurodegeneration was assessed in the retina and optic nerve two months later. Changes in gene expression of toll-like receptor 4 (TLR4 signaling pathway and complement as well as changes in microglial numbers and morphology were analyzed in the retina and optic nerve. The effect of pharmacologic blockade of TLR4 with naloxone was determined. FINDINGS: Patients with glaucoma had higher bacterial oral counts compared to control subjects (p<0.017. Low-dose LPS administration in glaucoma animal models resulted in enhancement of axonal degeneration and neuronal loss. Microglial activation in the optic nerve and retina as well as upregulation of TLR4 signaling and complement system were observed. Pharmacologic blockade of TLR4 partially ameliorated the enhanced damage. CONCLUSIONS: The above findings suggest that the oral microbiome contributes to glaucoma pathophysiology. A plausible mechanism by which increased bacterial loads can lead to neurodegeneration is provided by experiments in animal models of the disease and involves activation of microglia in the retina and optic nerve, mediated through TLR4 signaling and complement upregulation. The finding that commensal

  8. 3-NP-induced neurodegeneration studies in experimental models of Huntington's disease : apoptosis in Huntington's disease

    NARCIS (Netherlands)

    Vis, Johanna Catharina

    2005-01-01

    This thesis investigates the possible role of apoptosis, or programmed cell death, in Huntington's disease (HD). HD is caused by an expanded CAG repeat in the N-terminal region of the huntingtin protein leading to specific neostriatal neurodegeneration. The sequence of events that leads to this sele

  9. Neuroprotective effect of a new DJ-1-binding compound against neurodegeneration in Parkinson's disease and stroke model rats

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    Yasui Hiroyuki

    2011-07-01

    Full Text Available Abstract Background Parkinson's disease (PD and cerebral ischemia are chronic and acute neurodegenerative diseases, respectively, and onsets of these diseases are thought to be induced at least by oxidative stress. PD is caused by decreased dopamine levels in the substantia nigra and striatum, and cerebral ischemia occurs as a result of local reduction or arrest of blood supply. Although a precursor of dopamine and inhibitors of dopamine degradation have been used for PD therapy and an anti-oxidant have been used for cerebral ischemia therapy, cell death progresses during treatment. Reagents that prevent oxidative stress-induced cell death are therefore necessary for fundamental therapies for PD and cerebral ischemia. DJ-1, a causative gene product of a familial form of PD, PARK7, plays roles in transcriptional regulation and anti-oxidative stress, and loss of its function is thought to result in the onset of PD. Superfluous oxidation of cysteine at amino acid 106 (C106 of DJ-1 renders DJ-1 inactive, and such oxidized DJ-1 has been observed in patients with the sporadic form of PD. Results In this study, a compound, comp-23, that binds to DJ-1 was isolated by virtual screening. Comp-23 prevented oxidative stress-induced death of SH-SY5Y cells and primary neuronal cells of the ventral mesencephalon but not that of DJ-1-knockdown SH-SY5Y cells, indicating that the effect of the compound is specific to DJ-1. Comp-23 inhibited the production of reactive oxygen species (ROS induced by oxidative stress and prevented excess oxidation of DJ-1. Furthermore, comp-23 prevented dopaminergic cell death in the substantia nigra and restored movement abnormality in 6-hydroxyldopamine-injected and rotenone-treated PD model rats and mice. Comp-23 also reduced infarct size of cerebral ischemia in rats that had been induced by middle cerebral artery occlusion. Protective activity of comp-23 seemed to be stronger than that of previously identified compound B

  10. Novel Food Supplement "CP1" Improves Motor Deficit, Cognitive Function, and Neurodegeneration in Animal Model of Parkinson's Disease.

    Science.gov (United States)

    Wattanathorn, Jintanaporn; Sutalangka, Chatchada

    2016-08-01

    Based on pivotal roles of oxidative stress, dopaminergic and cholinergic systems on the pathophysiology of Parkinson's disease (PD), the searching for functional food for patients attacked with PD from Cyperus rotundus and Zingiber officinale, the substances possessing antioxidant activity, and the suppression effects on monoamine oxidase B (MAO-B) and acetylcholinesterase (AChE) have been considered. In this study, we aimed to determine the effect of the combined extract of C. rotundus and Z. officinale (CP1) to improve motor and memory deficits, neurodegeneration, oxidative stress, and functions of both cholinergic and dopaminergic systems in the animal model of PD induced by 6-hydroxydopamine hydrochloride (6-OHDA). Male Wistar rats, weighing 180-220 g, were induced unilateral lesion at right substantia nigra by 6-OHDA and were orally given CP1 at doses of 100, 200, and 300 mg/kg body weight for 14 days after 6-OHDA injection. The results showed that the 6-OHDA rats treated with CP1 increased spatial memory, but decreased neurodegeneration, malondialdehyde level, and AChE activity in hippocampus. The decreased motor disorder and neurodegeneration in substantia nigra together with the enhanced catalase activity, but decreased MAO-B activity in striatum, were also observed. The memory enhancing effect of CP1 might occur through the improved oxidative stress and the enhanced cholinergic function, whereas the effect to improve motor disorder of CP1 might occur through the enhanced dopaminergic function in striatum by decreasing the degeneration of dopaminergic neurons and the suppression of MAO-B. Therefore, CP1 is the potential functional food against PD. However, further researches in clinical trial and drug interactions are essential.

  11. Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model.

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    Brunetti, Dario; Dusi, Sabrina; Giordano, Carla; Lamperti, Costanza; Morbin, Michela; Fugnanesi, Valeria; Marchet, Silvia; Fagiolari, Gigliola; Sibon, Ody; Moggio, Maurizio; d'Amati, Giulia; Tiranti, Valeria

    2014-01-01

    Pantothenate kinase-associated neurodegeneration, caused by mutations in the PANK2 gene, is an autosomal recessive disorder characterized by dystonia, dysarthria, rigidity, pigmentary retinal degeneration and brain iron accumulation. PANK2 encodes the mitochondrial enzyme pantothenate kinase type 2, responsible for the phosphorylation of pantothenate or vitamin B5 in the biosynthesis of co-enzyme A. A Pank2 knockout (Pank2(-/-)) mouse model did not recapitulate the human disease but showed azoospermia and mitochondrial dysfunctions. We challenged this mouse model with a low glucose and high lipid content diet (ketogenic diet) to stimulate lipid use by mitochondrial beta-oxidation. In the presence of a shortage of co-enzyme A, this diet could evoke a general impairment of bioenergetic metabolism. Only Pank2(-/-) mice fed with a ketogenic diet developed a pantothenate kinase-associated neurodegeneration-like syndrome characterized by severe motor dysfunction, neurodegeneration and severely altered mitochondria in the central and peripheral nervous systems. These mice also showed structural alteration of muscle morphology, which was comparable with that observed in a patient with pantothenate kinase-associated neurodegeneration. We here demonstrate that pantethine administration can prevent the onset of the neuromuscular phenotype in mice suggesting the possibility of experimental treatment in patients with pantothenate kinase-associated neurodegeneration.

  12. Genetic regulation of microglia activation, complement expression, and neurodegeneration in a rat model of traumatic brain injury.

    Science.gov (United States)

    Bellander, Bo-Michael; Lidman, Olle; Ohlsson, Marcus; Meijer, Britt; Piehl, Fredrik; Svensson, Mikael

    2010-08-01

    Secondary brain damage following traumatic brain injury in part depends on neuroinflammation, a process where genetic factors may play an important role. We examined the response to a standardized cortical contusion in two different inbred rat strains, Dark Agouti (DA) and Piebald Virol Glaxo (PVG). Both are well characterized in models of autoimmune neuroinflammation, where DA is susceptible and PVG resistant. We found that infiltration of polymorphonuclear granulocytes (PMN) at 3-day postinjury was more pronounced in PVG. DA was more infiltrated by T cells at 3-day postinjury, showed an enhanced glial activation at 7-day postinjury and higher expression of C3 complement at 7-day postinjury. Neurodegeneration, assessed by Fluoro-Jade, was also more pronounced in the DA strain at 30-day postinjury. These results demonstrate differences in the response to cortical contusion injury attributable to genetic influences and suggest a link between injury-induced inflammation and neurodegeneration. Genetic factors that regulate inflammation elicited by brain trauma may be important for the development of secondary brain damage.

  13. Pantothenate kinase-associated neurodegeneration: altered mitochondria membrane potential and defective respiration in Pank2 knock-out mouse model.

    Science.gov (United States)

    Brunetti, Dario; Dusi, Sabrina; Morbin, Michela; Uggetti, Andrea; Moda, Fabio; D'Amato, Ilaria; Giordano, Carla; d'Amati, Giulia; Cozzi, Anna; Levi, Sonia; Hayflick, Susan; Tiranti, Valeria

    2012-12-15

    Neurodegeneration with brain iron accumulation (NBIA) comprises a group of neurodegenerative disorders characterized by high brain content of iron and presence of axonal spheroids. Mutations in the PANK2 gene, which encodes pantothenate kinase 2, underlie an autosomal recessive inborn error of coenzyme A metabolism, called pantothenate kinase-associated neurodegeneration (PKAN). PKAN is characterized by dystonia, dysarthria, rigidity and pigmentary retinal degeneration. The pathogenesis of this disorder is poorly understood and, although PANK2 is a mitochondrial protein, perturbations in mitochondrial bioenergetics have not been reported. A knock-out (KO) mouse model of PKAN exhibits retinal degeneration and azoospermia, but lacks any neurological phenotype. The absence of a clinical phenotype has partially been explained by the different cellular localization of the human and murine PANK2 proteins. Here we demonstrate that the mouse Pank2 protein localizes to mitochondria, similar to its human orthologue. Moreover, we show that Pank2-defective neurons derived from KO mice have an altered mitochondrial membrane potential, a defect further corroborated by the observations of swollen mitochondria at the ultra-structural level and by the presence of defective respiration.

  14. A new in vivo model of pantothenate kinase-associated neurodegeneration reveals a surprising role for transcriptional regulation in pathogenesis.

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    Varun ePandey

    2013-09-01

    Full Text Available Pantothenate Kinase-Associated Neurodegeneration (PKAN is a neurodegenerative disorder with a poorly understood molecular mechanism. It is caused by mutations in Pantothenate Kinase, the first enzyme in the Coenzyme A (CoA biosynthetic pathway. Here, we developed a Drosophila model of PKAN (tim-fbl flies that allows us to continuously monitor the modeled disease in the brain. In tim-fbl flies, downregulation of fumble, the Drosophila PanK homologue in the cells containing a circadian clock results in characteristic features of PKAN such as developmental lethality, hypersensitivity to oxidative stress, and diminished life span. Despite quasi-normal circadian transcriptional rhythms, tim-fbl flies display brain-specific aberrant circadian locomotor rhythms, and a unique transcriptional signature. Comparison with expression data from flies exposed to paraquat demonstrates that, as previously suggested, pathways others than oxidative stress are affected by PANK downregulation. Surprisingly we found a significant decrease in the expression of key components of the photoreceptor recycling pathways, which could lead to retinal degeneration, a hallmark of PKAN. Importantly, these defects are not accompanied by changes in structural components in eye genes suggesting that changes in gene expression in the eye precede and may cause the retinal degeneration. Indeed tim-fbl flies have diminished response to light transitions, and their altered day/night patterns of activity demonstrates defects in light perception. This suggest that retinal lesions are not solely due to oxidative stress and demonstrates a role for the transcriptional response to CoA deficiency underlying the defects observed in dPanK deficient flies. Moreover, in the present study we developed a new fly model that can be applied to other diseases and that allows the assessment of neurodegeneration in the brains of living flies.

  15. Dual Role of Vitamin C on the Neuroinflammation Mediated Neurodegeneration and Memory Impairments in Colchicine Induced Rat Model of Alzheimer Disease.

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    Sil, Susmita; Ghosh, Tusharkanti; Gupta, Pritha; Ghosh, Rupsa; Kabir, Syed N; Roy, Avishek

    2016-12-01

    The neurodegeneration in colchicine induced AD rats (cAD) is mediated by cox-2 linked neuroinflammation. The importance of ROS in the inflammatory process in cAD has not been identified, which may be deciphered by blocking oxidative stress in this model by a well-known anti-oxidant vitamin C. Therefore, the present study was designed to investigate the role of vitamin C on colchicine induced oxidative stress linked neuroinflammation mediated neurodegeneration and memory impairments along with peripheral immune responses in cAD. The impairments of working and reference memory were associated with neuroinflammation and neurodegeneration in the hippocampus of cAD. Administration of vitamin C (200 and 400 mg/kg BW) in cAD resulted in recovery of memory impairments, with prevention of neurodegeneration and neuroinflammation in the hippocampus. The neuroinflammation in the hippocampus also influenced the peripheral immune responses and inflammation in the serum of cAD and all of these parameters were also recovered at 200 and 400 mg dose of vitamin C. However, cAD treated with 600 mg dose did not recover but resulted in increase of memory impairments, neurodegeneration and neuroinflammation in hippocampus along with alteration of peripheral immune responses in comparison to cAD of the present study. Therefore, the present study showed that ROS played an important role in the colchicine induced neuroinflammation linked neurodegeneration and memory impairments along with alteration of peripheral immune responses. It also appears from the results that vitamin C at lower doses showed anti-oxidant effect and at higher dose resulted in pro-oxidant effects in cAD.

  16. Ethanol-Induced Neurodegeneration and Glial Activation in the Developing Brain

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    Mariko Saito

    2016-08-01

    Full Text Available Ethanol induces neurodegeneration in the developing brain, which may partially explain the long-lasting adverse effects of prenatal ethanol exposure in fetal alcohol spectrum disorders (FASD. While animal models of FASD show that ethanol-induced neurodegeneration is associated with glial activation, the relationship between glial activation and neurodegeneration has not been clarified. This review focuses on the roles of activated microglia and astrocytes in neurodegeneration triggered by ethanol in rodents during the early postnatal period (equivalent to the third trimester of human pregnancy. Previous literature indicates that acute binge-like ethanol exposure in postnatal day 7 (P7 mice induces apoptotic neurodegeneration, transient activation of microglia resulting in phagocytosis of degenerating neurons, and a prolonged increase in glial fibrillary acidic protein-positive astrocytes. In our present study, systemic administration of a moderate dose of lipopolysaccharides, which causes glial activation, attenuates ethanol-induced neurodegeneration. These studies suggest that activation of microglia and astrocytes by acute ethanol in the neonatal brain may provide neuroprotection. However, repeated or chronic ethanol can induce significant proinflammatory glial reaction and neurotoxicity. Further studies are necessary to elucidate whether acute or sustained glial activation caused by ethanol exposure in the developing brain can affect long-lasting cellular and behavioral abnormalities observed in the adult brain.

  17. Chronic Neuroinflammation in Alzheimer’s Disease: New Perspectives on Animal Models and Promising Candidate Drugs

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    Christopher Millington

    2014-01-01

    Full Text Available Chronic neuroinflammation is now considered one of the major factors in the pathogenesis of Alzheimer’s disease (AD. However, the most widely used transgenic AD models (overexpressing mutated forms of amyloid precursor protein, presenilin, and/or tau do not demonstrate the degree of inflammation, neurodegeneration (particularly of the cholinergic system, and cognitive decline that is comparable with the human disease. Hence a more suitable animal model is needed to more closely mimic the resulting cognitive decline and memory loss in humans in order to investigate the effects of neuroinflammation on neurodegeneration. One of these models is the glial fibrillary acidic protein-interleukin 6 (GFAP-IL6 mouse, in which chronic neuroinflammation triggered constitutive expression of the cytokine interleukin-6 (IL-6 in astrocytes. These transgenic mice show substantial and progressive neurodegeneration as well as a decline in motor skills and cognitive function, starting from 6 months of age. This animal model could serve as an excellent tool for drug discovery and validation in vivo. In this review, we have also selected three potential anti-inflammatory drugs, curcumin, apigenin, and tenilsetam, as candidate drugs, which could be tested in this model.

  18. Pantothenate kinase-associated neurodegeneration: altered mitochondria membrane potential and defective respiration in Pank2 knock-out mouse model

    OpenAIRE

    2012-01-01

    Neurodegeneration with brain iron accumulation (NBIA) comprises a group of neurodegenerative disorders characterized by high brain content of iron and presence of axonal spheroids. Mutations in the PANK2 gene, which encodes pantothenate kinase 2, underlie an autosomal recessive inborn error of coenzyme A metabolism, called pantothenate kinase-associated neurodegeneration (PKAN). PKAN is characterized by dystonia, dysarthria, rigidity and pigmentary retinal degeneration. The pathogenesis of th...

  19. Gender effect on neurodegeneration and myelin markers in an animal model for multiple sclerosis

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    Massella Alessandro

    2012-01-01

    Full Text Available Abstract Background Multiple sclerosis (MS varies considerably in its incidence and progression in females and males. In spite of clinical evidence, relatively few studies have explored molecular mechanisms possibly involved in gender-related differences. The present study describes possible cellular- and molecular-involved markers which are differentially regulated in male and female rats and result in gender-dependent EAE evolution and progression. Attention was focused on markers of myelination (MBP and PDGFαR and neuronal distress and/or damage (GABA synthesis enzymes, GAD65 and GAD67, NGF, BDNF and related receptors, in two CNS areas, i.e. spinal cord and cerebellum, which are respectively severely and mildly affected by inflammation and demyelination. Tissues were sampled during acute, relapse/remission and chronic phases and results were analysed by two-way ANOVA. Results 1. A strong gender-dependent difference in myelin (MBP and myelin precursor (PDGFαR marker mRNA expression levels is observed in control animals in the spinal cord, but not in the cerebellum. This is the only gender-dependent difference in the expression level of the indicated markers in healthy animals; 2. both PDGFαR and MBP mRNAs in the spinal cord and MBP in the cerebellum are down-regulated during EAE in gender-dependent manner; 3. in the cerebellum, the expression profile of neuron-associated markers (GAD65, GAD67 is characterized by a substantial down-regulation during the inflammatory phase of the disease, which does not differ between male and female rats (two-way ANOVA; 4. there is an up-regulation of NGF, trkA and p75 mRNA expression in the early phases of the disease (14 and 21 days post-immunization, which is not different between male and female. Conclusions It is reported herein that the regulation of markers involved in demyelination and neuroprotection processes occurring during EAE, a well-established MS animal model, is gender- and time

  20. Serotonin Depletion Does not Modify the Short-Term Brain Hypometabolism and Hippocampal Neurodegeneration Induced by the Lithium-Pilocarpine Model of Status Epilepticus in Rats.

    Science.gov (United States)

    García-García, Luis; Shiha, Ahmed Anis; Bascuñana, Pablo; de Cristóbal, Javier; Fernández de la Rosa, Rubén; Delgado, Mercedes; Pozo, Miguel A

    2016-05-01

    It has been reported that fluoxetine, a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, has neuroprotective properties in the lithium-pilocarpine model of status epilepticus (SE) in rats. The aim of the present study was to investigate the effect of 5-HT depletion by short-term administration of p-chlorophenylalanine (PCPA), a specific tryptophan hydroxylase inhibitor, on the brain hypometabolism and neurodegeneration induced in the acute phase of this SE model. Our results show that 5-HT depletion did modify neither the brain basal metabolic activity nor the lithium-pilocarpine-induced hypometabolism when evaluated 3 days after the insult. In addition, hippocampal neurodegeneration and astrogliosis triggered by lithium-pilocarpine were not exacerbated by PCPA treatment. These findings point out that in the early latent phase of epileptogenesis, non-5-HT-mediated actions may contribute, at least in some extent, to the neuroprotective effects of fluoxetine in this model of SE.

  1. NAD+ salvage pathway proteins suppress proteotoxicity in yeast models of neurodegeneration by promoting the clearance of misfolded/oligomerized proteins.

    Science.gov (United States)

    Ocampo, Alejandro; Liu, Jingjing; Barrientos, Antoni

    2013-05-01

    Increased levels of nicotinamide/nicotinic acid mononucleotide adenylyltransferase (NMNAT) act as a powerful suppressor of Wallerian degeneration and ataxin- and tau-induced neurodegeneration in flies and mice. However, the nature of the suppression mechanism/s remains controversial. Here, we show that in yeast models of proteinopathies, overexpression of the NMNAT yeast homologs, NMA1 and NMA2, suppresses polyglutamine (PolyQ) and α-synuclein-induced cytotoxicities. Unexpectedly, overexpression of other genes in the salvage pathway for NAD(+) biosynthesis, including QNS1, NPT1 and PNC1 also protected against proteotoxicity. Our data revealed that in all cases, this mechanism involves extensive clearance of the non-native protein. Importantly, we demonstrate that suppression by NMA1 does not require the presence of a functional salvage pathway for NAD(+) biosynthesis, SIR2 or an active mitochondrial oxidative phosphorylation (OXPHOS) system. Our results imply the existence of histone deacetylase- and OXPHOS-independent crosstalk between the proteins in the salvage pathway for NAD(+) biosynthesis and the proteasome that can be manipulated to achieve cellular protection against proteotoxic stress.

  2. Paeoniflorin attenuates neuroinflammation and dopaminergic neurodegeneration in the MPTP model of Parkinson's disease by activation of adenosine A1 receptor.

    Science.gov (United States)

    Liu, Hua-Qing; Zhang, Wei-Yu; Luo, Xue-Ting; Ye, Yang; Zhu, Xing-Zu

    2006-06-01

    1. This study examined whether Paeoniflorin (PF), the major active components of Chinese herb Paeoniae alba Radix, has neuroprotective effect in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD). 2. Subcutaneous administration of PF (2.5 and 5 mg kg(-1)) for 11 days could protect tyrosine hydroxylase (TH)-positive substantia nigra neurons and striatal nerve fibers from death and bradykinesia induced by four-dose injection of MPTP (20 mg kg(-1)) on day 8. 3. When given at 1 h after the last dose of MPTP, and then administered once a day for the following 3 days, PF (2.5 and 5 mg kg(-1)) also significantly attenuated the dopaminergic neurodegeneration in a dose-dependent manner. Post-treatment with PF (5 mg kg(-1)) significantly attenuated MPTP-induced proinflammatory gene upregulation and microglial and astrocytic activation. 4. Pretreatment with 0.3 mg kg(-1) 8-cyclopentyl-1,3-dipropylxanthine, an adenosine A1 receptor (A1AR) antagonist, 15 min before each dose of PF, reversed the neuroprotective and antineuroinflammatory effects of PF. 5. In conclusion, this study demonstrated that PF could reduce the MPTP-induced toxicity by inhibition of neuroinflammation by activation of the A1AR, and suggested that PF might be a valuable neuroprotective agent for the treatment of PD.

  3. Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model

    OpenAIRE

    2013-01-01

    Pantothenate kinase-associated neurodegeneration, caused by mutations in the PANK2 gene, is an autosomal recessive disorder characterized by dystonia, dysarthria, rigidity, pigmentary retinal degeneration and brain iron accumulation. PANK2 encodes the mitochondrial enzyme pantothenate kinase type 2, responsible for the phosphorylation of pantothenate or vitamin B5 in the biosynthesis of co-enzyme A. A Pank2 knockout (Pank2−/− ) mouse model did not recapitulate the human disease but showed azo...

  4. Histone deacetylases suppress CGG repeat-induced neurodegeneration via transcriptional silencing in models of fragile X tremor ataxia syndrome.

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    Peter K Todd

    Full Text Available Fragile X Tremor Ataxia Syndrome (FXTAS is a common inherited neurodegenerative disorder caused by expansion of a CGG trinucleotide repeat in the 5'UTR of the fragile X syndrome (FXS gene, FMR1. The expanded CGG repeat is thought to induce toxicity as RNA, and in FXTAS patients mRNA levels for FMR1 are markedly increased. Despite the critical role of FMR1 mRNA in disease pathogenesis, the basis for the increase in FMR1 mRNA expression is unknown. Here we show that overexpressing any of three histone deacetylases (HDACs 3, 6, or 11 suppresses CGG repeat-induced neurodegeneration in a Drosophila model of FXTAS. This suppression results from selective transcriptional repression of the CGG repeat-containing transgene. These findings led us to evaluate the acetylation state of histones at the human FMR1 locus. In patient-derived lymphoblasts and fibroblasts, we determined by chromatin immunoprecipitation that there is increased acetylation of histones at the FMR1 locus in pre-mutation carriers compared to control or FXS derived cell lines. These epigenetic changes correlate with elevated FMR1 mRNA expression in pre-mutation cell lines. Consistent with this finding, histone acetyltransferase (HAT inhibitors repress FMR1 mRNA expression to control levels in pre-mutation carrier cell lines and extend lifespan in CGG repeat-expressing Drosophila. These findings support a disease model whereby the CGG repeat expansion in FXTAS promotes chromatin remodeling in cis, which in turn increases expression of the toxic FMR1 mRNA. Moreover, these results provide proof of principle that HAT inhibitors or HDAC activators might be used to selectively repress transcription at the FMR1 locus.

  5. Pituitary adenylate cyclase-activating polypeptide (PACAP) has a neuroprotective function in dopamine-based neurodegeneration in rat and snail parkinsonian models

    Science.gov (United States)

    Kiss, Tibor; Jungling, Adel

    2017-01-01

    ABSTRACT Pituitary adenylate cyclase-activating polypeptide (PACAP) rescues dopaminergic neurons from neurodegeneration and improves motor changes induced by 6-hydroxy-dopamine (6-OHDA) in rat parkinsonian models. Recently, we investigated the molecular background of the neuroprotective effect of PACAP in dopamine (DA)-based neurodegeneration using rotenone-induced snail and 6-OHDA-induced rat models of Parkinson's disease. Behavioural activity, monoamine (DA and serotonin), metabolic enzyme (S-COMT, MB-COMT and MAO-B) and PARK7 protein concentrations were measured before and after PACAP treatment in both models. Locomotion and feeding activity were decreased in rotenone-treated snails, which corresponded well to findings obtained in 6-OHDA-induced rat experiments. PACAP was able to prevent the behavioural malfunctions caused by the toxins. Monoamine levels decreased in both models and the decreased DA level induced by toxins was attenuated by ∼50% in the PACAP-treated animals. In contrast, PACAP had no effect on the decreased serotonin (5HT) levels. S-COMT metabolic enzyme was also reduced but a protective effect of PACAP was not observed in either of the models. Following toxin treatment, a significant increase in MB-COMT was observed in both models and was restored to normal levels by PACAP. A decrease in PARK7 was also observed in both toxin-induced models; however, PACAP had a beneficial effect only on 6-OHDA-treated animals. The neuroprotective effect of PACAP in different animal models of Parkinson's disease is thus well correlated with neurotransmitter, enzyme and protein levels. The models successfully mimic several, but not all etiological properties of the disease, allowing us to study the mechanisms of neurodegeneration as well as testing new drugs. The rotenone and 6-OHDA rat and snail in vivo parkinsonian models offer an alternative method for investigation of the molecular mechanisms of neuroprotective agents, including PACAP. PMID:28067625

  6. Pituitary adenylate cyclase-activating polypeptide (PACAP) has a neuroprotective function in dopamine-based neurodegeneration in rat and snail parkinsonian models.

    Science.gov (United States)

    Maasz, Gabor; Zrinyi, Zita; Reglodi, Dora; Petrovics, Dora; Rivnyak, Adam; Kiss, Tibor; Jungling, Adel; Tamas, Andrea; Pirger, Zsolt

    2017-02-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) rescues dopaminergic neurons from neurodegeneration and improves motor changes induced by 6-hydroxy-dopamine (6-OHDA) in rat parkinsonian models. Recently, we investigated the molecular background of the neuroprotective effect of PACAP in dopamine (DA)-based neurodegeneration using rotenone-induced snail and 6-OHDA-induced rat models of Parkinson's disease. Behavioural activity, monoamine (DA and serotonin), metabolic enzyme (S-COMT, MB-COMT and MAO-B) and PARK7 protein concentrations were measured before and after PACAP treatment in both models. Locomotion and feeding activity were decreased in rotenone-treated snails, which corresponded well to findings obtained in 6-OHDA-induced rat experiments. PACAP was able to prevent the behavioural malfunctions caused by the toxins. Monoamine levels decreased in both models and the decreased DA level induced by toxins was attenuated by ∼50% in the PACAP-treated animals. In contrast, PACAP had no effect on the decreased serotonin (5HT) levels. S-COMT metabolic enzyme was also reduced but a protective effect of PACAP was not observed in either of the models. Following toxin treatment, a significant increase in MB-COMT was observed in both models and was restored to normal levels by PACAP. A decrease in PARK7 was also observed in both toxin-induced models; however, PACAP had a beneficial effect only on 6-OHDA-treated animals. The neuroprotective effect of PACAP in different animal models of Parkinson's disease is thus well correlated with neurotransmitter, enzyme and protein levels. The models successfully mimic several, but not all etiological properties of the disease, allowing us to study the mechanisms of neurodegeneration as well as testing new drugs. The rotenone and 6-OHDA rat and snail in vivo parkinsonian models offer an alternative method for investigation of the molecular mechanisms of neuroprotective agents, including PACAP.

  7. dAtaxin-2 mediates expanded Ataxin-1-induced neurodegeneration in a Drosophila model of SCA1.

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    Ismael Al-Ramahi

    2007-12-01

    Full Text Available Spinocerebellar ataxias (SCAs are a genetically heterogeneous group of neurodegenerative disorders sharing atrophy of the cerebellum as a common feature. SCA1 and SCA2 are two ataxias caused by expansion of polyglutamine tracts in Ataxin-1 (ATXN1 and Ataxin-2 (ATXN2, respectively, two proteins that are otherwise unrelated. Here, we use a Drosophila model of SCA1 to unveil molecular mechanisms linking Ataxin-1 with Ataxin-2 during SCA1 pathogenesis. We show that wild-type Drosophila Ataxin-2 (dAtx2 is a major genetic modifier of human expanded Ataxin-1 (Ataxin-1[82Q] toxicity. Increased dAtx2 levels enhance, and more importantly, decreased dAtx2 levels suppress Ataxin-1[82Q]-induced neurodegeneration, thereby ruling out a pathogenic mechanism by depletion of dAtx2. Although Ataxin-2 is normally cytoplasmic and Ataxin-1 nuclear, we show that both dAtx2 and hAtaxin-2 physically interact with Ataxin-1. Furthermore, we show that expanded Ataxin-1 induces intranuclear accumulation of dAtx2/hAtaxin-2 in both Drosophila and SCA1 postmortem neurons. These observations suggest that nuclear accumulation of Ataxin-2 contributes to expanded Ataxin-1-induced toxicity. We tested this hypothesis engineering dAtx2 transgenes with nuclear localization signal (NLS and nuclear export signal (NES. We find that NLS-dAtx2, but not NES-dAtx2, mimics the neurodegenerative phenotypes caused by Ataxin-1[82Q], including repression of the proneural factor Senseless. Altogether, these findings reveal a previously unknown functional link between neurodegenerative disorders with common clinical features but different etiology.

  8. Establishment of an in vitro screening model for neurodegeneration induced by antimalarial drugs of the artemisinin-type..

    Science.gov (United States)

    Schmuck, G; Haynes, R K

    2000-01-01

    The establishment of an in vitro screening model for neurodegeneration inducing antimalarial drugs was conducted in stepwise fashion. Firstly, the in vivo selective neurotoxic potency of artemisinin was tested in neuronal cells in vitro in relation to the cytotoxic potency in other organ cell cultures such as liver and kidney or versus glial cells. Secondly, a comparison between different parts of the brain (cortex vs. brain stem) was performed and in the last step, a fast and sensitive screening endpoint was identified. In summary, non-neuronal cell lines such as hepatocytes (HEP-G2), liver epithelial cells (IAR), proximal tubular cells (LLC-PK(1)) and glial cells from the rat (C6) and human (GO-G-IJKT) displayed only moderate sensitivity to artemisinin and its derivatives. The same was found in undifferentiated neuronal cell lines from the mouse (N-18) and from human (Kelly), whereas during differentiation, these cells became much more sensitive. Primary astrocytes from the rat also were not specifically involved. In the comparison of primary neuronal cell cultures from the cortex and brain stem of the rat, the brain stem was found to be more sensitive than the cortex. The neurotoxic potential was determined by cytoskeleton elements (neurofilaments), which were degradated in vitro by diverse neurodegenerative compounds. In comparison of dog and rat primary brain stem cultures, the dog cells were found to be more sensitive to artemisinin than the rat cells. In addition to the primary brain stem cell cultures it was shown that the sprouting assay, which determines persistent delayed neurotoxic effects, is also useful for screening antimalarial drugs. To other compounds, artemether and artesunate, showed that use of the sprouting assay followed by primary brain stem cultures of the rat will be a good strategy to select candidate compounds.

  9. Neurodegeneration in schizophrenia.

    Science.gov (United States)

    Archer, Trevor

    2010-07-01

    The neurodegenerative aspect of schizophrenia presupposes gene-environmental interactions involving chromosomal abnormalities and obstetric/perinatal complications that culminate in predispositions that impart a particular vulnerability for drastic and unpredictable precipitating factors, such as stress or chemical agents. The notion of a neurodevelopmental progression to the disease state implies that early developmental insults, with neurodegenerative proclivities, evolve into structural brain abnormalities involving specific regional circuits and neurohumoral agents. This neurophysiological orchestration is expressed in the dysfunctionality observed in premorbid signs and symptoms arising in the eventual diagnosis, as well as the neurobehavioral deficits reported from animal models of the disorder. The relative contributions of perinatal insults, neonatal ventral hippocampus lesion, prenatal methylazoxymethanol acetate and early traumatic experience, as well as epigenetic contributions, are discussed from a neurodegenerative view of the essential neuropathology. It is implied that these considerations of factors that exert disruptive influences upon brain development, or normal aging, operationalize the central hub of developmental neuropathology around which the disease process may gain momentum. Nonetheless, the status of neurodegeneration in schizophrenia is somewhat tenuous and it is possible that brain imaging studies on animal models of the disorder, which may describe progressive alterations to cortical, limbic and ventricular structures similar to those of schizophrenic patients, are necessary to resolve the issue.

  10. Moringa oleifera Mitigates Memory Impairment and Neurodegeneration in Animal Model of Age-Related Dementia

    OpenAIRE

    2013-01-01

    To date, the preventive strategy against dementia is still essential due to the rapid growth of its prevalence and the limited therapeutic efficacy. Based on the crucial role of oxidative stress in age-related dementia and the antioxidant and nootropic activities of Moringa oleifera, the enhancement of spatial memory and neuroprotection of M. oleifera leaves extract in animal model of age-related dementia was determined. The possible underlying mechanism was also investigated. Male Wistar rat...

  11. Migration of bone marrow-derived cells into the central nervous system in models of neurodegeneration.

    Science.gov (United States)

    Lampron, Antoine; Pimentel-Coelho, Pedro M; Rivest, Serge

    2013-12-01

    Microglia are the brain-resident macrophages tasked with the defense and maintenance of the central nervous system (CNS). The hematopoietic origin of microglia has warranted a therapeutic potential for the hematopoietic system in treating diseases of the CNS. However, migration of bone marrow-derived cells (BMDC) into the CNS is a marginal event under normal, healthy conditions. A busulfan-based chemotherapy regimen was used for bone marrow transplantation in wild-type mice before subjecting them to a hypoxic-ischemic brain injury or in APP/PS1 mice prior to the formation of amyloid plaques. The cells were tracked and analyzed throughout the development of the pathology. The efficacy of a preventive macrophage colony-stimulating factor (M-CSF) treatment was also studied to highlight the effects of circulating monocytes in hypoxic-ischemic brain injury. Such an injury induces a strong migration of BMDC into the CNS, without the need for irradiation. These migrating cells do not replace the entire microglial pool but rather are confined to the sites of injury for several weeks, suggesting that they could perform specific functions. M-CSF showed neuroprotective effects as a preventive treatment. In APP/PS1 mice, the formation of amyloid plaques was sufficient to induce the entry of cells into the parenchyma, though in low numbers. This study confirms that BMDC infiltrate the CNS in animal models for stroke and Alzheimer's disease and that peripheral cells can be targeted to treat affected regions of the CNS.

  12. Induction of Neuron-Specific Degradation of Coenzyme A Models Pantothenate Kinase-Associated Neurodegeneration by Reducing Motor Coordination in Mice.

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    Stephanie A Shumar

    Full Text Available Pantothenate kinase-associated neurodegeneration, PKAN, is an inherited disorder characterized by progressive impairment in motor coordination and caused by mutations in PANK2, a human gene that encodes one of four pantothenate kinase (PanK isoforms. PanK initiates the synthesis of coenzyme A (CoA, an essential cofactor that plays a key role in energy metabolism and lipid synthesis. Most of the mutations in PANK2 reduce or abolish the activity of the enzyme. This evidence has led to the hypothesis that lower CoA might be the underlying cause of the neurodegeneration in PKAN patients; however, no mouse model of the disease is currently available to investigate the connection between neuronal CoA levels and neurodegeneration. Indeed, genetic and/or dietary manipulations aimed at reducing whole-body CoA synthesis have not produced a desirable PKAN model, and this has greatly hindered the discovery of a treatment for the disease.Cellular CoA levels are tightly regulated by a balance between synthesis and degradation. CoA degradation is catalyzed by two peroxisomal nudix hydrolases, Nudt7 and Nudt19. In this study we sought to reduce neuronal CoA in mice through the alternative approach of increasing Nudt7-mediated CoA degradation. This was achieved by combining the use of an adeno-associated virus-based expression system with the synapsin (Syn promoter. We show that mice with neuronal overexpression of a cytosolic version of Nudt7 (scAAV9-Syn-Nudt7cyt exhibit a significant decrease in brain CoA levels in conjunction with a reduction in motor coordination. These results strongly support the existence of a link between CoA levels and neuronal function and show that scAAV9-Syn-Nudt7cyt mice can be used to model PKAN.

  13. The mTOR Inhibitor Rapamycin Mitigates Perforant Pathway Neurodegeneration and Synapse Loss in a Mouse Model of Early-Stage Alzheimer-Type Tauopathy.

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    Robert Siman

    Full Text Available The perforant pathway projection from layer II of the entorhinal cortex to the hippocampal dentate gyrus is especially important for long-term memory formation, and is preferentially vulnerable to developing a degenerative tauopathy early in Alzheimer's disease (AD that may spread over time trans-synaptically. Despite the importance of the perforant pathway to the clinical onset and progression of AD, a therapeutic has not been identified yet that protects it from tau-mediated toxicity. Here, we used an adeno-associated viral vector-based mouse model of early-stage AD-type tauopathy to investigate effects of the mTOR inhibitor and autophagy stimulator rapamycin on the tau-driven loss of perforant pathway neurons and synapses. Focal expression of human tau carrying a P301L mutation but not eGFP as a control in layer II of the lateral entorhinal cortex triggered rapid degeneration of these neurons, loss of lateral perforant pathway synapses in the dentate gyrus outer molecular layer, and activation of neuroinflammatory microglia and astroglia in the two locations. Chronic systemic rapamycin treatment partially inhibited phosphorylation of a mechanistic target of rapamycin substrate in brain and stimulated LC3 cleavage, a marker of autophagic flux. Compared with vehicle-treated controls, rapamycin protected against the tau-induced neuronal loss, synaptotoxicity, reactive microgliosis and astrogliosis, and activation of innate neuroimmunity. It did not alter human tau mRNA or total protein levels. Finally, rapamycin inhibited trans-synaptic transfer of human tau expression to the dentate granule neuron targets for the perforant pathway, likely by preventing the synaptic spread of the AAV vector in response to pathway degeneration. These results identify systemic rapamycin as a treatment that protects the entorhinal cortex and perforant pathway projection from tau-mediated neurodegeneration, axonal and synapse loss, and neuroinflammatory reactive

  14. Partial BACE1 reduction in a Down syndrome mouse model blocks Alzheimer-related endosomal anomalies and cholinergic neurodegeneration: role of APP-CTF.

    Science.gov (United States)

    Jiang, Ying; Rigoglioso, Andrew; Peterhoff, Corrinne M; Pawlik, Monika; Sato, Yutaka; Bleiwas, Cynthia; Stavrides, Philip; Smiley, John F; Ginsberg, Stephen D; Mathews, Paul M; Levy, Efrat; Nixon, Ralph A

    2016-03-01

    β-amyloid precursor protein (APP) and amyloid beta peptide (Aβ) are strongly implicated in Alzheimer's disease (AD) pathogenesis, although recent evidence has linked APP-βCTF generated by BACE1 (β-APP cleaving enzyme 1) to the development of endocytic abnormalities and cholinergic neurodegeneration in early AD. We show that partial BACE1 genetic reduction prevents these AD-related pathological features in the Ts2 mouse model of Down syndrome. Partially reducing BACE1 by deleting one BACE1 allele blocked development of age-related endosome enlargement in the medial septal nucleus, cerebral cortex, and hippocampus and loss of choline acetyltransferase (ChAT)-positive medial septal nucleus neurons. BACE1 reduction normalized APP-βCTF elevation but did not alter Aβ40 and Aβ42 peptide levels in brain, supporting a critical role in vivo for APP-βCTF in the development of these abnormalities. Although ameliorative effects of BACE1 inhibition on β-amyloidosis and synaptic proteins levels have been previously noted in AD mouse models, our results highlight the additional potential value of BACE1 modulation in therapeutic targeting of endocytic dysfunction and cholinergic neurodegeneration in Down syndrome and AD.

  15. Piperine, the main alkaloid of Thai black pepper, protects against neurodegeneration and cognitive impairment in animal model of cognitive deficit like condition of Alzheimer's disease.

    Science.gov (United States)

    Chonpathompikunlert, Pennapa; Wattanathorn, Jintanaporn; Muchimapura, Supaporn

    2010-03-01

    Recently, numerous medicinal plants possessing profound central nervous system effects and antioxidant activity have received much attention as food supplement to improve cognitive function against cognitive deficit condition including in Alzheimer's disease condition. Based on this information, the effect of piperine, a main active alkaloid in fruit of Piper nigrum, on memory performance and neurodegeneration in animal model of Alzheimer's disease have been investigated. Adult male Wistar rats (180-220 g) were orally given piperine at various doses ranging from 5, 10 and 20mg/kg BW at a period of 2 weeks before and 1 week after the intracerebroventricular administration of ethylcholine aziridinium ion (AF64A) bilaterally. The results showed that piperine at all dosage range used in this study significantly improved memory impairment and neurodegeneration in hippocampus. The possible underlying mechanisms might be partly associated with the decrease lipid peroxidation and acetylcholinesterase enzyme. Moreover, piperine also demonstrated the neurotrophic effect in hippocampus. However, further researches about the precise underlying mechanism are still required.

  16. Oxidative Stress in Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Varsha Shukla

    2011-01-01

    Full Text Available It has been demonstrated that oxidative stress has a ubiquitous role in neurodegenerative diseases. Major source of oxidative stress due to reactive oxygen species (ROS is related to mitochondria as an endogenous source. Although there is ample evidence from tissues of patients with neurodegenerative disorders of morphological, biochemical, and molecular abnormalities in mitochondria, it is still not very clear whether the oxidative stress itself contributes to the onset of neurodegeneration or it is part of the neurodegenerative process as secondary manifestation. This paper begins with an overview of how oxidative stress occurs, discussing various oxidants and antioxidants, and role of oxidative stress in diseases in general. It highlights the role of oxidative stress in neurodegenerative diseases like Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis. The last part of the paper describes the role of oxidative stress causing deregulation of cyclin-dependent kinase 5 (Cdk5 hyperactivity associated with neurodegeneration.

  17. All-you-can-eat: autophagy in neurodegeneration and neuroprotection

    Directory of Open Access Journals (Sweden)

    Jaeger Philipp A

    2009-04-01

    Full Text Available Abstract Autophagy is the major pathway involved in the degradation of proteins and organelles, cellular remodeling, and survival during nutrient starvation. Autophagosomal dysfunction has been implicated in an increasing number of diseases from cancer to bacterial and viral infections and more recently in neurodegeneration. While a decrease in autophagic activity appears to interfere with protein degradation and possibly organelle turnover, increased autophagy has been shown to facilitate the clearance of aggregation-prone proteins and promote neuronal survival in a number of disease models. On the other hand, too much autophagic activity can be detrimental as well and lead to cell death, suggesting the regulation of autophagy has an important role in cell fate decisions. An increasing number of model systems are now available to study the role of autophagy in the central nervous system and how it might be exploited to treat disease. We will review here the current knowledge of autophagy in the central nervous system and provide an overview of the various models that have been used to study acute and chronic neurodegeneration.

  18. Neurostereology Protocol for Unbiased Quantification of Neuronal Injury and Neurodegeneration

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    Victoria M Golub

    2015-10-01

    Full Text Available Neuronal injury and neurodegeneration are the hallmark pathologies in a variety of neurological conditions such as epilepsy, stroke, traumatic brain injury, Parkinson’s disease and Alzheimer’s disease. Quantification of absolute neuron and interneuron counts in various brain regions is essential to understand the impact of neurological insults or neurodegenerative disease progression in animal models. However, conventional qualitative scoring-based protocols are superficial and less reliable for use in studies of neuroprotection evaluations. Here we describe an optimized stereology protocol for quantification of neuronal injury and neurodegeneration by unbiased counting of neurons and interneurons. Every 20th section in each series of 20 sections was processed for NeuN(+ total neuron and parvalbumin(+ interneuron immunostaining. The sections that contain the hippocampus were then delineated into five reliably predefined subregions. Each region was separately analyzed with a microscope driven by the stereology software. Regional tissue volume was determined by using the Cavalieri estimator, and cell density and cell number were determined by using the optical disector and optical fractionator. This protocol yielded an estimate of 1.5 million total neurons and 0.05 million PV(+ interneurons within the rat hippocampus. The protocol has greater predictive power for absolute counts as it is based on 3D features rather than 2D images. The total neuron counts were consistent with literature values from sophisticated systems, which are more expensive than our stereology system. This unbiased stereology protocol allows for sensitive, medium-throughput counting of total neurons in any brain region, and thus provides a quantitative tool for studies of neuronal injury and neurodegeneration in a variety of acute brain injury and chronic neurological models.

  19. Loss of Dendritic Complexity Precedes Neurodegeneration in a Mouse Model with Disrupted Mitochondrial Distribution in Mature Dendrites

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    Guillermo López-Doménech

    2016-10-01

    Full Text Available Correct mitochondrial distribution is critical for satisfying local energy demands and calcium buffering requirements and supporting key cellular processes. The mitochondrially targeted proteins Miro1 and Miro2 are important components of the mitochondrial transport machinery, but their specific roles in neuronal development, maintenance, and survival remain poorly understood. Using mouse knockout strategies, we demonstrate that Miro1, as opposed to Miro2, is the primary regulator of mitochondrial transport in both axons and dendrites. Miro1 deletion leads to depletion of mitochondria from distal dendrites but not axons, accompanied by a marked reduction in dendritic complexity. Disrupting postnatal mitochondrial distribution in vivo by deleting Miro1 in mature neurons causes a progressive loss of distal dendrites and compromises neuronal survival. Thus, the local availability of mitochondrial mass is critical for generating and sustaining dendritic arbors, and disruption of mitochondrial distribution in mature neurons is associated with neurodegeneration.

  20. Models of acute and chronic pancreatitis.

    Science.gov (United States)

    Lerch, Markus M; Gorelick, Fred S

    2013-06-01

    Animal models of acute and chronic pancreatitis have been created to examine mechanisms of pathogenesis, test therapeutic interventions, and study the influence of inflammation on the development of pancreatic cancer. In vitro models can be used to study early stage, short-term processes that involve acinar cell responses. Rodent models reproducibly develop mild or severe disease. One of the most commonly used pancreatitis models is created by administration of supraphysiologic concentrations of caerulein, an ortholog of cholecystokinin. Induction of chronic pancreatitis with factors thought to have a role in human disease, such as combinations of lipopolysaccharide and chronic ethanol feeding, might be relevant to human disease. Models of autoimmune chronic pancreatitis have also been developed. Most models, particularly of chronic pancreatitis, require further characterization to determine which features of human disease they include.

  1. Diabetic retinopathy: recent advances towards understanding neurodegeneration and vision loss.

    Science.gov (United States)

    Barber, Alistair J

    2015-06-01

    Diabetic retinopathy (DR) is one of the most common retinal diseases world-wide. It has a complex pathology that involves the vasculature of the inner retina and breakdown of the blood-retinal barrier. Extensive research has determined that DR is not only a vascular disease but also has a neurodegenerative component and that essentially all types of cells in the retina are affected, leading to chronic loss of visual function. A great deal of work using animal models of DR has established the loss of neurons and pathology of other cell types, including supporting glial cells. There has also been an increased emphasis on measuring retinal function in the models, as well as further validation and extension of the animal studies by clinical and translational research. This article will attempt to summarize the more recent developments in research towards understanding the complexities of retinal neurodegeneration and functional vision loss in DR.

  2. Neuroinflammation Induces Neurodegeneration

    Science.gov (United States)

    Kempuraj, D; Thangavel, R; Natteru, PA; Selvakumar, GP; Saeed, D; Zahoor, H; Zaheer, S; Iyer, SS; Zaheer, A

    2017-01-01

    Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Multiple Sclerosis (MS) are characterized by neuronal degeneration and neuronal death in specific regions of the central nervous system (CNS). In AD, neurons of the hippocampus and entorhinal cortex are the first to degenerate, whereas in PD, dopaminergic neurons in the substantia nigra degenerate. MS patients show destruction of the myelin sheath. Once the CNS neurons are damaged, they are unable to regenerate unlike any other tissue in the body. Neurodegeneration is mediated by inflammatory and neurotoxic mediators such as interleukin-1beta (IL-1β), IL-6, IL-8, IL-33, tumor necrosis factor-alpha (TNF-α), chemokine (C-C motif) ligand 2 (CCL2), CCL5, matrix metalloproteinase (MMPs), granulocyte macrophage colony-stimulating factor (GM-CSF), glia maturation factor (GMF), substance P, reactive oxygen species (ROS), reactive nitrogen species (RNS), mast cells-mediated histamine and proteases, protease activated receptor-2 (PAR-2), CD40, CD40L, CD88, intracellular Ca+ elevation, and activation of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa-B (NF-kB). Activated microglia, astrocytes, neurons, T-cells and mast cells release these inflammatory mediators and mediate neuroinflammation and neurodegeneration in a vicious manner. Further, immune and inflammatory cells and inflammatory mediators from the periphery cross the defective blood-brain-barrier (BBB) and augment neuroinflammation. Though inflammation is crucial in the onset and the progression of neurodegenerative diseases, anti-inflammatory drugs do not provide significant therapeutic effects in these patients till date, as the disease pathogenesis is not yet clearly understood. In this review, we discuss the possible factors involved in neuroinflammation-mediated neurodegeneration. PMID:28127589

  3. Inhibitors of LRRK2 kinase attenuate neurodegeneration and Parkinson-like phenotypes in Caenorhabditis elegans and Drosophila Parkinson's disease models

    Science.gov (United States)

    Liu, Zhaohui; Hamamichi, Shusei; Dae Lee, Byoung; Yang, Dejun; Ray, Arpita; Caldwell, Guy A.; Caldwell, Kim A.; Dawson, Ted M.; Smith, Wanli W.; Dawson, Valina L.

    2011-01-01

    Mutations in leucine-rich repeat kinase 2 (LRRK2) have been identified as a genetic cause of familial Parkinson's disease (PD) and have also been found in the more common sporadic form of PD, thus positioning LRRK2 as important in the pathogenesis of PD. Biochemical studies of the disease-causing mutants of LRRK2 implicates an enhancement of kinase activity as the basis of neuronal toxicity and thus possibly the pathogenesis of PD due to LRRK2 mutations. Previously, a chemical library screen identified inhibitors of LRRK2 kinase activity. Here, two of these inhibitors, GW5074 and sorafenib, are shown to protect against G2019S LRRK2-induced neurodegeneration in vivo in Caenorhabditis elegans and in Drosophila. These findings indicate that increased kinase activity of LRRK2 is neurotoxic and that inhibition of LRRK2 activity can have a disease-modifying effect. This suggests that inhibition of LRRK2 holds promise as a treatment for PD. PMID:21768216

  4. Calcium signaling in neurodegeneration

    Directory of Open Access Journals (Sweden)

    Dreses-Werringloer Ute

    2009-05-01

    Full Text Available Abstract Calcium is a key signaling ion involved in many different intracellular and extracellular processes ranging from synaptic activity to cell-cell communication and adhesion. The exact definition at the molecular level of the versatility of this ion has made overwhelming progress in the past several years and has been extensively reviewed. In the brain, calcium is fundamental in the control of synaptic activity and memory formation, a process that leads to the activation of specific calcium-dependent signal transduction pathways and implicates key protein effectors, such as CaMKs, MAPK/ERKs, and CREB. Properly controlled homeostasis of calcium signaling not only supports normal brain physiology but also maintains neuronal integrity and long-term cell survival. Emerging knowledge indicates that calcium homeostasis is not only critical for cell physiology and health, but also, when deregulated, can lead to neurodegeneration via complex and diverse mechanisms involved in selective neuronal impairments and death. The identification of several modulators of calcium homeostasis, such as presenilins and CALHM1, as potential factors involved in the pathogenesis of Alzheimer's disease, provides strong support for a role of calcium in neurodegeneration. These observations represent an important step towards understanding the molecular mechanisms of calcium signaling disturbances observed in different brain diseases such as Alzheimer's, Parkinson's, and Huntington's diseases.

  5. Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model

    NARCIS (Netherlands)

    Brunetti, Dario; Dusi, Sabrina; Giordano, Carla; Lamperti, Costanza; Morbin, Michela; Fugnanesi, Valeria; Marchet, Silvia; Fagiolari, Gigliola; Sibon, Ody; Moggio, Maurizio; d'Amati, Giulia; Tiranti, Valeria

    2014-01-01

    Pantothenate kinase-associated neurodegeneration, caused by mutations in the PANK2 gene, is an autosomal recessive disorder characterized by dystonia, dysarthria, rigidity, pigmentary retinal degeneration and brain iron accumulation. PANK2 encodes the mitochondrial enzyme pantothenate kinase type 2,

  6. Metals and Neurodegeneration.

    Science.gov (United States)

    Chen, Pan; Miah, Mahfuzur Rahman; Aschner, Michael

    2016-01-01

    Metals play important roles in the human body, maintaining cell structure and regulating gene expression, neurotransmission, and antioxidant response, to name a few. However, excessive metal accumulation in the nervous system may be toxic, inducing oxidative stress, disrupting mitochondrial function, and impairing the activity of numerous enzymes. Damage caused by metal accumulation may result in permanent injuries, including severe neurological disorders. Epidemiological and clinical studies have shown a strong correlation between aberrant metal exposure and a number of neurological diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, autism spectrum disorders, Guillain-Barré disease, Gulf War syndrome, Huntington's disease, multiple sclerosis, Parkinson's disease, and Wilson's disease. Here, we briefly survey the literature relating to the role of metals in neurodegeneration.

  7. Peroxiredoxins and Neurodegeneration

    Directory of Open Access Journals (Sweden)

    S.H. Lee

    2006-01-01

    Full Text Available Peroxiredoxins (Prxs are a family of novel antioxidant proteins that are found in a variety of species and participate in a number of vital biological processes such as proliferation, differentiation, response to oxidative stress and intracellular signaling. It has been proposed that they might participate in these cellular processes by playing a role in eliminating or regulating the intracellular concentration of peroxides produced during metabolism as well as in the signaling cascades of growth factors and cytokines. Mammalian cells express six isoforms of Prx (Prx I to VI, which are classified into three subgroups (typical 2-Cys, atypical 2-Cys and 1-Cys based on the number and position of cysteine (Cys residues that participate in catalysis and on amino acid sequences and the immunological reactivity. Members of the typical 2-Cys subgroup include Prx I through Prx IV and contain an additional conserved cysteine in the carboxyl-terminal region, whereas Prx V and Prx VI, members of the atypical 2-Cys and 1-Cys subgroups, respectively, do not contain this second conserved Cys. On the other hand, Prxs activity can be regulated by phosphorylation and proteolysis processes in addition to overoxidation. Taken together, this study suggest that the generation of the oxidative stress which caused neurodegeneration may couple with produced Prxs and the reverse is true. However, this argument is still unclear on account of the difficulties of the direct observation of the reactive oxygen species due to their biological lifetime is short. Thus, experiments will be required to solve these problems and to comprehend the actual role of Prxs in neurodegeneration.

  8. Linking aβ42-induced hyperexcitability to neurodegeneration, learning and motor deficits, and a shorter lifespan in an Alzheimer's model.

    Directory of Open Access Journals (Sweden)

    Yong Ping

    2015-03-01

    Full Text Available Alzheimer's disease (AD is the most prevalent form of dementia in the elderly. β-amyloid (Aβ accumulation in the brain is thought to be a primary event leading to eventual cognitive and motor dysfunction in AD. Aβ has been shown to promote neuronal hyperactivity, which is consistent with enhanced seizure activity in mouse models and AD patients. Little, however, is known about whether, and how, increased excitability contributes to downstream pathologies of AD. Here, we show that overexpression of human Aβ42 in a Drosophila model indeed induces increased neuronal activity. We found that the underlying mechanism involves the selective degradation of the A-type K+ channel, Kv4. An age-dependent loss of Kv4 leads to an increased probability of AP firing. Interestingly, we find that loss of Kv4 alone results in learning and locomotion defects, as well as a shortened lifespan. To test whether the Aβ42-induced increase in neuronal excitability contributes to, or exacerbates, downstream pathologies, we transgenically over-expressed Kv4 to near wild-type levels in Aβ42-expressing animals. We show that restoration of Kv4 attenuated age-dependent learning and locomotor deficits, slowed the onset of neurodegeneration, and partially rescued premature death seen in Aβ42-expressing animals. We conclude that Aβ42-induced hyperactivity plays a critical role in the age-dependent cognitive and motor decline of this Aβ42-Drosophila model, and possibly in AD.

  9. The role of Ser129 phosphorylation of α-synuclein in neurodegeneration of Parkinson's disease: a review of in vivo models.

    Science.gov (United States)

    Sato, Hiroyasu; Kato, Takeo; Arawaka, Shigeki

    2013-01-01

    Parkinson's disease is the most common neurodegenerative movement disorder. The motor impairments of Parkinson's disease are caused by the loss of dopaminergic neurons in the substantia nigra and associated with the appearance of fibrillar aggregates of α-synuclein (α-syn) called Lewy bodies. Approximately 90% of α-syn deposited in Lewy bodies is phosphorylated at serine 129 (Ser129). In contrast, only 4% or less of total α-syn is phosphorylated at this residue in the normal brain. This suggests that the accumulation of Ser129-phosphorylated α-syn leads to the formation of Lewy bodies and dopaminergic neurodegeneration in Parkinson's disease. Our laboratory and others have performed experiments using in vivo models of Parkinson's disease to elucidate the role of increased Ser129 phosphorylation in α-syn neurotoxicity. However, there has been a lack of consistency among these models. In this review, we summarize the main findings regarding the relationship between Ser129 phosphorylation and α-syn neurotoxicity, and examine the differences among models. We further discuss the role of Ser129 phosphorylation in α-syn aggregation and the future directions to test the potential of Ser129 phosphorylation as a therapeutic target for slowing the progression of Parkinson's disease.

  10. DNA damage in nasal and brain tissues of canines exposed to air pollutants is associated with evidence of chronic brain inflammation and neurodegeneration.

    Science.gov (United States)

    Calderón-Garcidueñas, Lilian; Maronpot, Robert R; Torres-Jardon, Ricardo; Henríquez-Roldán, Carlos; Schoonhoven, Robert; Acuña-Ayala, Hilda; Villarreal-Calderón, Anna; Nakamura, Jun; Fernando, Reshan; Reed, William; Azzarelli, Biagio; Swenberg, James A

    2003-01-01

    Acute, subchronic, or chronic exposures to particulate matter (PM) and pollutant gases affect people in urban areas and those exposed to fires, disasters, and wars. Respiratory tract inflammation, production of mediators of inflammation capable of reaching the brain, systemic circulation of PM, and disruption of the nasal respiratory and olfactory barriers are likely in these populations. DNA damage is crucial in aging and in age-associated diseases such as Alzheimer's disease. We evaluated apurinic/apyrimidinic (AP) sites in nasal and brain genomic DNA, and explored by immunohistochemistry the expression of nuclear factor NFkappaB p65, inducible nitric oxide synthase (iNOS), cyclo-oxygenase 2 (COX2), metallothionein I and II, apolipoprotein E, amyloid precursor protein (APP), and beta-amyloid(1-42) in healthy dogs naturally exposed to urban pollution in Mexico City. Nickel (Ni) and vanadium (V) were measured by inductively coupled plasma mass spectrometry (ICP-MS). Forty mongrel dogs, ages 7 days-10 years were studied (14 controls from Tlaxcala and 26 exposed to urban pollution in South West Metropolitan Mexico City (SWMMC)). Nasal respiratory and olfactory epithelium were found to be early pollutant targets. Olfactory bulb and hippocampal AP sites were significantly higher in exposed than in control age matched animals. Ni and V were present in a gradient from olfactory mucosa > olfactory bulb > frontal cortex. Exposed dogs had (a) nuclear neuronal NFkappaB p65, (b) endothelial, glial and neuronal iNOS, (c) endothelial and glial COX2, (d) ApoE in neuronal, glial and vascular cells, and (e) APP and beta amyloid(1-42) in neurons, diffuse plaques (the earliest at age 11 months), and in subarachnoid blood vessels. Increased AP sites and the inflammatory and stress protein brain responses were early and significant in dogs exposed to urban pollution. Oil combustion PM-associated metals Ni and V were detected in the brain. There was an acceleration of Alzheimer

  11. Reduction of brain mitochondrial β-oxidation impairs complex I and V in chronic alcohol intake: the underlying mechanism for neurodegeneration.

    Directory of Open Access Journals (Sweden)

    James Haorah

    Full Text Available Neuropathy and neurocognitive deficits are common among chronic alcohol users, which are believed to be associated with mitochondrial dysfunction in the brain. The specific type of brain mitochondrial respiratory chain complexes (mRCC that are adversely affected by alcohol abuse has not been studied. Thus, we examined the alterations of mRCC in freshly isolated mitochondria from mice brain that were pair-fed the ethanol (4% v/v and control liquid diets for 7-8 weeks. We observed that alcohol intake severely reduced the levels of complex I and V. A reduction in complex I was associated with a decrease in carnitine palmitoyltransferase 1 (cPT1 and cPT2 levels. The mitochondrial outer (cPT1 and inner (cPT2 membrane transporter enzymes are specialized in acylation of fatty acid from outer to inner membrane of mitochondria for ATP production. Thus, our results showed that alterations of cPT1 and cPT2 paralleled a decrease β-oxidation of palmitate and ATP production, suggesting that impairment of substrate entry step (complex I function can cause a negative impact on ATP production (complex V function. Disruption of cPT1/cPT2 was accompanied by an increase in cytochrome C leakage, while reduction of complex I and V paralleled a decrease in depolarization of mitochondrial membrane potential (ΔΨ, monitored by JC-1 fluorescence and ATP production in alcohol intake. We noted that acetyl-L-carnitine (ALC, a cofactor of cPT1 and cPT2 prevented the adverse effects of alcohol while coenzyme Q10 (CoQ10 was not very effective against alcohol insults. These results suggest that understanding the molecular, biochemical, and signaling mechanisms of the CNS mitochondrial β-oxidation such as ALC can mitigate alcohol related neurological disorders.

  12. The chronic diseases modelling approach

    NARCIS (Netherlands)

    Hoogenveen RT; Hollander AEM de; Genugten MLL van; CCM

    1998-01-01

    A mathematical model structure is described that can be used to simulate the changes of the Dutch public health state over time. The model is based on the concept of demographic and epidemiologic processes (events) and is mathematically based on the lifetable method. The population is divided over s

  13. Neurodegeneration in accelerated aging.

    Science.gov (United States)

    Scheibye-Knudsen, Moren

    2016-11-01

    The growing proportion of elderly people represents an increasing economic burden, not least because of age-associated diseases that pose a significant cost to the health service. Finding possible interventions to age-associated disorders therefore have wide ranging implications. A number of genetically defined accelerated aging diseases have been characterized that can aid in our understanding of aging. Interestingly, all these diseases are associated with defects in the maintenance of our genome. A subset of these disorders, Cockayne syndrome, Xeroderma pigmentosum group A and ataxia-telangiectasia, show neurological involvement reminiscent of what is seen in primary human mitochondrial diseases. Mitochondria are the power plants of the cells converting energy stored in oxygen, sugar, fat, and protein into ATP, the energetic currency of our body. Emerging evidence has linked this organelle to aging and finding mitochondrial dysfunction in accelerated aging disorders thereby strengthens the mitochondrial theory of aging. This theory states that an accumulation of damage to the mitochondria may underlie the process of aging. Indeed, it appears that some accelerated aging disorders that show neurodegeneration also have mitochondrial dysfunction. The mitochondrial alterations may be secondary to defects in nuclear DNA repair. Indeed, nuclear DNA damage may lead to increased energy consumption, alterations in mitochondrial ATP production and defects in mitochondrial recycling, a term called mitophagy. These changes may be caused by activation of poly-ADP-ribose-polymerase 1 (PARP1), an enzyme that responds to DNA damage. Upon activation PARP1 utilizes key metabolites that attenuate pathways that are normally protective for the cell. Notably, pharmacological inhibition of PARP1 or reconstitution of the metabolites rescues the changes caused by PARP1 hyperactivation and in many cases reverse the phenotypes associated with accelerated aging. This implies that modulation

  14. Animal models of chronic wound care

    DEFF Research Database (Denmark)

    Trostrup, Hannah; Thomsen, Kim; Calum, Henrik

    2016-01-01

    . An inhibiting effect of bacterial biofilms on wound healing is gaining significant clinical attention over the last few years. There is still a paucity of suitable animal models to recapitulate human chronic wounds. The etiology of the wound (venous insufficiency, ischemia, diabetes, pressure) has to be taken...... on nonhealing wounds. Relevant hypotheses based on clinical or in vitro observations can be tested in representative animal models, which provide crucial tools to uncover the pathophysiology of cutaneous skin repair in infectious environments. Disposing factors, species of the infectious agent(s), and time...... of establishment of the infection are well defined in suitable animal models. In addition, several endpoints can be involved for evaluation. Animals do not display chronic wounds in the way that humans do. However, in many cases, animal models can mirror the pathological conditions observed in humans, although...

  15. DNA repair deficiency in neurodegeneration

    DEFF Research Database (Denmark)

    Jeppesen, Dennis Kjølhede; Bohr, Vilhelm A; Stevnsner, Tinna V.

    2011-01-01

    : homologous recombination and non-homologous end-joining. Ataxia telangiectasia and related disorders with defects in these pathways illustrate that such defects can lead to early childhood neurodegeneration. Aging is a risk factor for neurodegeneration and accumulation of oxidative mitochondrial DNA damage......Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive...... neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix-distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative...

  16. Glucocerebrosidase deficiency accelerates the accumulation of proteinase K-resistant α-synuclein and aggravates neurodegeneration in a Drosophila model of Parkinson's disease.

    Science.gov (United States)

    Suzuki, Mari; Fujikake, Nobuhiro; Takeuchi, Toshihide; Kohyama-Koganeya, Ayako; Nakajima, Kazuki; Hirabayashi, Yoshio; Wada, Keiji; Nagai, Yoshitaka

    2015-12-01

    Alpha-synuclein (αSyn) plays a central role in the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Recent multicenter genetic studies have revealed that mutations in the glucocerebrosidase 1 (GBA1) gene, which are responsible for Gaucher's disease, are strong risk factors for PD and DLB. However, the mechanistic link between the functional loss of glucocerebrosidase (GCase) and the toxicity of αSyn in vivo is not fully understood. In this study, we employed Drosophila models to examine the effect of GCase deficiency on the neurotoxicity of αSyn and its molecular mechanism. Behavioral and histological analyses showed that knockdown of the Drosophila homolog of GBA1 (dGBA1) exacerbates the locomotor dysfunction, loss of dopaminergic neurons and retinal degeneration of αSyn-expressing flies. This phenotypic aggravation was associated with the accumulation of proteinase K (PK)-resistant αSyn, rather than with changes in the total amount of αSyn, raising the possibility that glucosylceramide (GlcCer), a substrate of GCase, accelerates the misfolding of αSyn. Indeed, in vitro experiments revealed that GlcCer directly promotes the conversion of recombinant αSyn into the PK-resistant form, representing a toxic conformational change. Similar to dGBA1 knockdown, knockdown of the Drosophila homolog of β-galactosidase (β-Gal) also aggravated locomotor dysfunction of the αSyn flies, and its substrate GM1 ganglioside accelerated the formation of PK-resistant αSyn. Our findings suggest that the functional loss of GCase or β-Gal promotes the toxic conversion of αSyn via aberrant interactions between αSyn and their substrate glycolipids, leading to the aggravation of αSyn-mediated neurodegeneration.

  17. Neurodegeneration in the diabetic eye

    DEFF Research Database (Denmark)

    Simó, Rafael; Hernández, Cristina; Bandello, F;

    2014-01-01

    Diabetic retinopathy (DR), one of the leading causes of preventable blindness, has been considered a microcirculatory disease of the retina. However, there is emerging evidence to suggest that retinal neurodegeneration is an early event in the pathogenesis of DR, which participates in the develop......Diabetic retinopathy (DR), one of the leading causes of preventable blindness, has been considered a microcirculatory disease of the retina. However, there is emerging evidence to suggest that retinal neurodegeneration is an early event in the pathogenesis of DR, which participates...

  18. Neurodegeneration med jernakkumulation i hjernen

    DEFF Research Database (Denmark)

    Bertelsen, Maria; Hansen, Lars Kjærsgaard

    2015-01-01

    Neurodegeneration with brain iron accumulation (NBIA) is a heterogeneous group of syndromes. Whereas NBIA1 (panto-thenate kinase-associated neurodegeneration) has been known since 1922, some of the other diseases in the NBIA group have just been known for a few years. We present the case of a 16-......-year-old man who recently was diagnosed with NBIA4. He had had neurodegenerative symptoms since he was eight years old. The typical MRI findings in the basal ganglia were important in diagnosing NBIA. Furthermore gait analysis and specific genetic testing were performed....

  19. Neuroinflammation, neurodegeneration and regeneration in multiple sclerosis: intercorrelated manifestations of the immune response

    Science.gov (United States)

    Koudriavtseva, Tatiana; Mainero, Caterina

    2016-01-01

    Multiple sclerosis (MS) is a chronic immune-mediated inflammatory-demyelinating disorder of the central nervous system, with a strong neurodegenerative component. The question whether neurodegeneration in MS is independent or related to neuroinflammation has been long debated, but not yet fully clarified. Furthermore, little is still known on how neuroinflammation and neurodegeneration in MS are related to potential regenerative processes. In this perspective, we briefly discuss main clinical, pathological and experimental evidence on the relationship between neuroinflammation and neurodegeneration in MS, and on their connection with regeneration. We discuss that these processes in MS might represent intercorrelated manifestations of the immune response, especially of the innate immunity. PMID:28123401

  20. Neuroinlfammation, neurodegeneration and regeneration in multiple sclerosis:intercorrelated manifestations of the immune response

    Institute of Scientific and Technical Information of China (English)

    Tatiana Koudriavtseva; Caterina Mainero

    2016-01-01

    Multiple sclerosis (MS) is a chronic immune-mediated inlfammatory-demyelinating disorder of the central nervous system, with a strong neurodegenerative component. The question whether neurodegeneration in MS is independent or related to neuroinlfammation has been long debated, but not yet fully clariifed. Furthermore, little is still known on how neuroinlfammation and neurodegeneration in MS are related to potential regenerative processes. In this perspective, we brielfy discuss main clinical, pathological and ex-perimental evidence on the relationship between neuroinlfammation and neurodegeneration in MS, and on their connection with regeneration. We discuss that these processes in MS might represent intercorrelated manifestations of the immune response, especially of the innate immunity.

  1. Murine neural stem cells model Hunter disease in vitro: glial cell-mediated neurodegeneration as a possible mechanism involved.

    Science.gov (United States)

    Fusar Poli, E; Zalfa, C; D'Avanzo, F; Tomanin, R; Carlessi, L; Bossi, M; Nodari, L Rota; Binda, E; Marmiroli, P; Scarpa, M; Delia, D; Vescovi, A L; De Filippis, L

    2013-11-07

    Mucopolysaccharidosis type II (MPSII or Hunter Syndrome) is a lysosomal storage disorder caused by the deficit of iduronate 2-sulfatase (IDS) activity and characterized by progressive systemic and neurological impairment. As the early mechanisms leading to neuronal degeneration remain elusive, we chose to examine the properties of neural stem cells (NSCs) isolated from an animal model of the disease in order to evaluate whether their neurogenic potential could be used to recapitulate the early phases of neurogenesis in the brain of Hunter disease patients. Experiments here reported show that NSCs derived from the subventricular zone (SVZ) of early symptomatic IDS-knockout (IDS-ko) mouse retained self-renewal capacity in vitro, but differentiated earlier than wild-type (wt) cells, displaying an evident lysosomal aggregation in oligodendroglial and astroglial cells. Consistently, the SVZ of IDS-ko mice appeared similar to the wt SVZ, whereas the cortex and striatum presented a disorganized neuronal pattern together with a significant increase of glial apoptotic cells, suggesting that glial degeneration likely precedes neuronal demise. Interestingly, a very similar pattern was observed in the brain cortex of a Hunter patient. These observations both in vitro, in our model, and in vivo suggest that IDS deficit seems to affect the late phases of neurogenesis and/or the survival of mature cells rather than NSC self-renewal. In particular, platelet-derived growth factor receptor-α-positive (PDGFR-α+) glial progenitors appeared reduced in both the IDS-ko NSCs and in the IDS-ko mouse and human Hunter brains, compared with the respective healthy controls. Treatment of mutant NSCs with IDS or PDGF throughout differentiation was able to increase the number of PDGFR-α+ cells and to reduce that of apoptotic cells to levels comparable to wt. This evidence supports IDS-ko NSCs as a reliable in vitro model of the disease, and suggests the rescue of PDGFR-α+ glial cells as a

  2. Paeoniflorin attenuates neuroinflammation and dopaminergic neurodegeneration in the MPTP model of Parkinson's disease by activation of adenosine A1 receptor

    OpenAIRE

    Liu, Hua-Qing; Zhang, Wei-Yu; Luo, Xue-Ting; Ye, Yang; Zhu, Xing-Zu

    2006-01-01

    This study examined whether Paeoniflorin (PF), the major active components of Chinese herb Paeoniae alba Radix, has neuroprotective effect in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD).Subcutaneous administration of PF (2.5 and 5 mg kg−1) for 11 days could protect tyrosine hydroxylase (TH)-positive substantia nigra neurons and striatal nerve fibers from death and bradykinesia induced by four-dose injection of MPTP (20 mg kg−1) on day 8.When...

  3. Peripheral Inflammation Increases the Damage in Animal Models of Nigrostriatal Dopaminergic Neurodegeneration: Possible Implication in Parkinson's Disease Incidence

    Directory of Open Access Journals (Sweden)

    A. Machado

    2011-01-01

    Full Text Available Inflammatory processes described in Parkinson’s disease (PD and its animal models appear to be important in the progression of the pathogenesis, or even a triggering factor. Here we review that peripheral inflammation enhances the degeneration of the nigrostriatal dopaminergic system induced by different insults; different peripheral inflammations have been used, such as IL-1β and the ulcerative colitis model, as well as insults to the dopaminergic system such as 6-hydroxydopamine or lipopolysaccharide. In all cases, an increased loss of dopaminergic neurons was described; inflammation in the substantia nigra increased, displaying a great activation of microglia along with an increase in the production of cytokines such as IL-1β and TNF-α. Increased permeability or disruption of the BBB, with overexpression of the ICAM-1 adhesion molecule and infiltration of circulating monocytes into the substantia nigra, is also involved, since the depletion of circulating monocytes prevents the effects of peripheral inflammation. Data are reviewed in relation to epidemiological studies of PD.

  4. Computational Biology: Modeling Chronic Renal Allograft Injury.

    Science.gov (United States)

    Stegall, Mark D; Borrows, Richard

    2015-01-01

    New approaches are needed to develop more effective interventions to prevent long-term rejection of organ allografts. Computational biology provides a powerful tool to assess the large amount of complex data that is generated in longitudinal studies in this area. This manuscript outlines how our two groups are using mathematical modeling to analyze predictors of graft loss using both clinical and experimental data and how we plan to expand this approach to investigate specific mechanisms of chronic renal allograft injury.

  5. Effects of Copper and/or Cholesterol Overload on Mitochondrial Function in a Rat Model of Incipient Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Nathalie Arnal

    2013-01-01

    Full Text Available Copper (Cu and cholesterol (Cho are both associated with neurodegenerative illnesses in humans and animals models. We studied the effect in Wistar rats of oral supplementation with trace amounts of Cu (3 ppm and/or Cho (2% in drinking water for 2 months. Increased amounts of nonceruloplasmin-bound Cu were observed in plasma and brain hippocampus together with a higher concentration of ceruloplasmin in plasma, cortex, and hippocampus. Cu, Cho, and the combined treatment Cu + Cho were able to induce a higher Cho/phospholipid ratio in mitochondrial membranes with a simultaneous decrease in glutathione content. The concentration of cardiolipin decreased and that of peroxidation products, conjugated dienes and lipoperoxides, increased. Treatments including Cho produced rigidization in both the outer and inner mitochondrial membranes with a simultaneous increase in permeability. No significant increase in Cyt C leakage to the cytosol was observed except in the case of cortex from rats treated with Cu and Cho nor were there any significant changes in caspase-3 activity and the Bax/Bcl2 ratio. However, the Aβ(1–42/(1–40 ratio was higher in cortex and hippocampus. These findings suggest an incipient neurodegenerative process induced by Cu or Cho that might be potentiated by the association of the two supplements.

  6. A Neurodegeneration-Specific Gene-Expression Signature of Acutely Isolated Microglia from an Amyotrophic Lateral Sclerosis Mouse Model

    Directory of Open Access Journals (Sweden)

    Isaac M. Chiu

    2013-07-01

    Full Text Available Microglia are resident immune cells of the CNS that are activated by infection, neuronal injury, and inflammation. Here, we utilize flow cytometry and deep RNA sequencing of acutely isolated spinal cord microglia to define their activation in vivo. Analysis of resting microglia identified 29 genes that distinguish microglia from other CNS cells and peripheral macrophages/monocytes. We then analyzed molecular changes in microglia during neurodegenerative disease activation using the SOD1G93A mouse model of amyotrophic lateral sclerosis (ALS. We found that SOD1G93A microglia are not derived from infiltrating monocytes, and that both potentially neuroprotective and toxic factors, including Alzheimer’s disease genes, are concurrently upregulated. Mutant microglia differed from SOD1WT, lipopolysaccharide-activated microglia, and M1/M2 macrophages, defining an ALS-specific phenotype. Concurrent messenger RNA/fluorescence-activated cell sorting analysis revealed posttranscriptional regulation of microglia surface receptors and T cell-associated changes in the transcriptome. These results provide insights into microglia biology and establish a resource for future studies of neuroinflammation.

  7. Neuroprotective and cognitive enhancing effects of a multi-targeted food intervention in an animal model of neurodegeneration and depression.

    Science.gov (United States)

    Borre, Yuliya E; Panagaki, Theodora; Koelink, Pim J; Morgan, Mary E; Hendriksen, Hendrikus; Garssen, Johan; Kraneveld, Aletta D; Olivier, Berend; Oosting, Ronald S

    2014-04-01

    Rising neurodegenerative and depressive disease prevalence combined with the lack of effective pharmaceutical treatments and dangerous side effects, has created an urgent need for the development of effective therapies. Considering that these disorders are multifactorial in origin, treatments designed to interfere at different mechanistic levels may be more effective than the traditional single-targeted pharmacological concepts. To that end, an experimental diet composed of zinc, melatonin, curcumin, piperine, eicosapentaenoic acid (EPA, 20:5, n-3), docosahexaenoic acid (DHA, 22:6, n-3), uridine, and choline was formulated. This diet was tested on the olfactory bulbectomized rat (OBX), an established animal model of depression and cognitive decline. The ingredients of the diet have been individually shown to attenuate glutamate excitoxicity, exert potent anti-oxidant/anti-inflammatory properties, and improve synaptogenesis; processes that all have been implicated in neurodegenerative diseases and in the cognitive deficits following OBX in rodents. Dietary treatment started 2 weeks before OBX surgery, continuing for 6 weeks in total. The diet attenuated OBX-induced cognitive and behavioral deficits, except long-term spatial memory. Ameliorating effects of the diet extended to the control animals. Furthermore, the experimental diet reduced hippocampal atrophy and decreased the peripheral immune activation in the OBX rats. The ameliorating effects of the diet on the OBX-induced changes were comparable to those of the NMDA receptor antagonist, memantine, a drug used for the management of Alzheimer's disease. This proof-of-concept study suggests that a diet, which simultaneously targets multiple disease etiologies, can prevent/impede the development of a neurodegenerative and depressive disorders and the concomitant cognitive deficits.

  8. Biopsychosocial model of chronic recurrent pain

    Directory of Open Access Journals (Sweden)

    Zlatka Rakovec-Felser

    2009-07-01

    Full Text Available Pain is not merely a symptom of disease but a complex independent phenomenon where psychological factors are always present (Sternberg, 1973. Especially by chronic, recurrent pain it's more constructive to think of chronic pain as a syndrome that evolves over time, involving a complex interaction of physiological/organic, psychological, and behavioural processes. Study of chronic recurrent functional pain covers tension form of headache. 50 suffering persons were accidentally chosen among those who had been seeking medical help over more than year ago. We tested their pain intensity and duration, extent of subjective experience of accommodation efforts, temperament characteristics, coping strategies, personal traits, the role of pain in intra- and interpersonal communication. At the end we compared this group with control group (without any manifest physical disorders and with analyse of variance (MANOVA. The typical person who suffers and expects medical help is mostly a woman, married, has elementary or secondary education, is about 40. Pain, seems to appear in the phase of stress-induced psychophysical fatigue, by persons with lower constitutional resistance to different influences, greater irritability and number of physiologic correlates of emotional tensions. Because of their ineffective style of coping, it seems they quickly exhausted their adaptation potential too. Through their higher level of social–field dependence, reactions of other persons (doctor, spouse could be important factors of reinforcement and social learning processes. In managing of chronic pain, especially such as tension headache is, it's very important to involve bio-psychosocial model of pain and integrative model of treatment. Intra- and inter-subjective psychological functions of pain must be recognised as soon as possible.

  9. Neurodegeneration and sport.

    Science.gov (United States)

    Davis, Gavin A; Castellani, Rudolph J; McCrory, Paul

    2015-06-01

    The recent interest in concussion in sport has resulted in significant media focus about chronic traumatic encephalopathy (CTE), although a direct causative link(s) between concussion and CTE is not established. Typically, sport-related CTE occurs in a retired athlete with or without a history of concussion(s) who presents with a constellation of cognitive, mood, and/or behavioral symptoms and who has postmortem findings of tau deposition within the brain. There are many confounding variables, however, that can account for brain tau deposition, including genetic mutations, drugs, normal aging, environmental factors, postmortem brain processing, and toxins. To understand the roles of such factors in neurodegenerative diseases that may occur in athletes, this article reviews some neurodegenerative diseases that may present with similar findings in nonathletes. The article also reviews pathological changes identified with normal aging, and reviews the pathological findings of CTE in light of all these factors. While many of these athletes have a history of exposure to head impacts as a part of contact sport, there is insufficient evidence to establish causation between sports concussion and CTE. It is likely that many of the cases with neuropathological findings represent the normal aging process, the effects of opiate abuse, or a variant of frontotemporal lobar degeneration. Whether particular genetic causes may place athletes at greater risk of neurodegenerative disease is yet to be determined.

  10. Models of chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Chung K Fan

    2004-11-01

    Full Text Available Abstract Chronic obstructive pulmonary disease (COPD is a major global health problem and is predicted to become the third most common cause of death by 2020. Apart from the important preventive steps of smoking cessation, there are no other specific treatments for COPD that are as effective in reversing the condition, and therefore there is a need to understand the pathophysiological mechanisms that could lead to new therapeutic strategies. The development of experimental models will help to dissect these mechanisms at the cellular and molecular level. COPD is a disease characterized by progressive airflow obstruction of the peripheral airways, associated with lung inflammation, emphysema and mucus hypersecretion. Different approaches to mimic COPD have been developed but are limited in comparison to models of allergic asthma. COPD models usually do not mimic the major features of human COPD and are commonly based on the induction of COPD-like lesions in the lungs and airways using noxious inhalants such as tobacco smoke, nitrogen dioxide, or sulfur dioxide. Depending on the duration and intensity of exposure, these noxious stimuli induce signs of chronic inflammation and airway remodelling. Emphysema can be achieved by combining such exposure with instillation of tissue-degrading enzymes. Other approaches are based on genetically-targeted mice which develop COPD-like lesions with emphysema, and such mice provide deep insights into pathophysiological mechanisms. Future approaches should aim to mimic irreversible airflow obstruction, associated with cough and sputum production, with the possibility of inducing exacerbations.

  11. Aluminum induces neurodegeneration and its toxicity arises from increased iron accumulation and reactive oxygen species (ROS) production.

    Science.gov (United States)

    Wu, Zhihao; Du, Yumei; Xue, Hua; Wu, Yongsheng; Zhou, Bing

    2012-01-01

    The neurotoxicity of aluminum (Al) - the most abundant metal element on earth - has been known for years. However, the mechanism of Al-induced neurodegeneration and its relationship to Alzheimer's disease are still controversial. In particular, in vivo functional data are lacking. In a Drosophila model with chronic dietary Al overloading, general neurodegeneration and several behavioral changes were observed. Al-induced neurodegeneration is independent of β-amyloid or tau-associated toxicity, suggesting they act in different molecular pathways. Interestingly, Drosophila frataxin (dfh), which causes Friedreich's ataxia if mutated in humans, displayed an interacting effect with Al, suggesting Friedreich's ataxia patients might be more susceptible to Al toxicity. Al-treated flies accumulated large amount of iron and reactive oxygen species (ROS), and exhibited elevated SOD2 activity. Genetic and pharmacological efforts to reduce ROS or chelate excess Fe significantly mitigated Al toxicity. Our results indicate that Al toxicity is mediated through ROS production and iron accumulation and suggest a remedial route to reduce toxicity due to Al exposure.

  12. Caffeine prevents d-galactose-induced cognitive deficits, oxidative stress, neuroinflammation and neurodegeneration in the adult rat brain.

    Science.gov (United States)

    Ullah, Faheem; Ali, Tahir; Ullah, Najeeb; Kim, Myeong Ok

    2015-11-01

    d-galactose has been considered a senescent model for age-related neurodegenerative disease. It induces oxidative stress which triggers memory impairment, neuroinflammation and neurodegeneration. Caffeine act as anti-oxidant and has been used in various model of neurodegenerative disease. Nevertheless, the effect of caffeine against d-galactose aging murine model of age-related neurodegenerative disease elucidated. Here, we investigated the neuroprotective effect of caffeine against d-galactose. We observed that chronic treatment of caffeine (3 mg/kg/day intraperitoneally (i.p) for 60 days) improved memory impairment and synaptic markers (Synaptophysin and PSD95) in the d-galactose treated rats. Chronic caffeine treatment reduced the oxidative stress via the reduction of 8-oxoguanine through immunofluorescence in the d-galactose-treated rats. Consequently caffeine treatment suppressed stress kinases p-JNK. Additionally, caffeine treatment significantly reduced the d-galactose-induced neuroinflammation through alleviation of COX-2, NOS-2, TNFα and IL-1β. Furthermore we also analyzed that caffeine reduced cytochrome C, Bax/Bcl2 ratio, caspase-9, caspase-3 and PARP-1 level. Moreover by evaluating the immunohistochemical results of Nissl and Fluro-Jade B staining showed that caffeine prevented the neurodegeneration in the d-galactose-treated rats. Our results showed that caffeine prevents the d-galactose-induced oxidative stress and consequently alleviated neuroinflammation and neurodegeneration; and synaptic dysfunction and memory impairment. Therefore, we could suggest that caffeine might be a dietary anti-oxidant agent and a good candidate for the age-related neurodegenerative disorders.

  13. Interleukin-1 and inflammatory neurodegeneration.

    Science.gov (United States)

    Simi, A; Tsakiri, N; Wang, P; Rothwell, N J

    2007-11-01

    Inflammation occurs rapidly in response to acute brain insults such as stroke, haemorrhage or trauma, and can be sustained for long periods of time, for example in Alzheimer's or Parkinson's diseases and multiple sclerosis. Experimental evidence indicates that inflammation plays a major role in neurodegeneration under these conditions, and that the cytokine IL-1 (interleukin-1) is a pivotal mediator. IL-1 is expressed rapidly in response to neuronal injury, predominantly by microglia, and elevated levels of endogenous or exogenous IL-1 markedly exacerbate injury. The naturally occurring IL-1RA (IL-1 receptor antagonist) markedly inhibits ischaemic, excitotoxic and traumatic brain injury in rodents, and has shown promise in a Phase II clinical trial in stroke patients. The mechanisms of IL-1 expression, release and action in neurodegeneration are not fully elucidated and appear multiple. Systemic IL-1 markedly enhances ischaemic brain injury via release of neutrophils into circulation, neutrophil adhesion to injured cerebrovasculature and CNS (central nervous system) invasion, and cell death via activation of matrix metalloproteinase-9. IL-1 also influences the release of toxins from glial and endothelial cells. Neuronal responses to excitotoxins and physiological factors may have an impact on neuronal survival. IL-1RA, delivered peripherally, can enter the CNS in animals and humans and has no adverse effects in stroke or subarachnoid haemorrhage patients, but shows potential benefit in acute stroke patients.

  14. MicroRNAs in neurodegeneration.

    Science.gov (United States)

    Bushati, Natascha; Cohen, Stephen M

    2008-06-01

    microRNAs (miRNAs) act as post-transcriptional regulators of gene expression in diverse cellular and developmental processes. Many miRNAs are expressed specifically in the central nervous system, where they have roles in differentiation, neuronal survival, and potentially also in plasticity and learning. The absence of miRNAs in a variety of specific postmitotic neurons can lead to progressive loss of these neurons and behavioral defects reminiscent of the phenotypes seen in the pathologies of neurodegenerative diseases. Here, we review recent studies which provide a link between miRNA function and neurodegeneration. We also discuss evidence which might suggest involvement of miRNAs in the emergence or progression of neurodegenerative diseases.

  15. Th17 cell-mediated neuroinflammation is involved in neurodegeneration of aβ1-42-induced Alzheimer's disease model rats.

    Directory of Open Access Journals (Sweden)

    Jun Zhang

    Full Text Available Neuroinflammation, especially innate immunocyte-mediated neuroinflammation, has been reported to participate in pathogenesis of Alzheimer's disease (AD. However, the involvement of adaptive immune cells, such as CD4(+ T lymphocytes, in pathogenesis of AD is not well clarified. Herein, we focus on T helper 17 (Th17 cells, a subpopulation of CD4(+ T cells with high proinflammation, and show the implication of the cells in neurodegeneration of AD. Amyloid β1-42 (Aβ1-42 was bilaterally injected into hippocampus of rats to induce AD. On days 7 and 14 following the Aβ1-42 administration, escape latency of the rats in Morris water maze was increased, expression of amyloid precursor protein was upregulated, but expression of protein phosphatase 2A was downregulated in the hippocampus, and Nissl stain showed neuronal loss and gliosis in CA1 region. Infusion of FITC-linked albumin in blood circulation and combination with immunostaining of hippocampal sections for RORγ, a specific transcriptional factor of Th17 cells, demonstrated blood-brain barrier (BBB disruption and Th17 cells' infiltration into brain parenchyma of AD rats. Expression of Th17 proinflammatory cytokines, interleukin (IL-17 and IL-22, was increased in the hippocampus, and concentrations of the two cytokines were elevated in both the cerebrospinal fluid and the serum in AD occurrence and development. Compared with intact or saline-treated control rats, AD animals indicated an upregulated expression of Fas and FasL in the hippocampus. Further, the immunofluorescent histochemistry on AD hippocampal sections with NeuN, RORγ, Fas and FasL displayed that Fas was principally expressed by neurons and FasL was predominantly expressed by Th17 cells, and that neuronal apoptosis shown by TUNEL and NeuN double-labeled cells increased. These results suggest that Th17 cells, which were infiltrated into AD brain parenchyma, participate in neuroinflammation and neurodegeneration of AD by release of

  16. Th17 cell-mediated neuroinflammation is involved in neurodegeneration of aβ1-42-induced Alzheimer's disease model rats.

    Science.gov (United States)

    Zhang, Jun; Ke, Kai-Fu; Liu, Zhan; Qiu, Yi-Hua; Peng, Yu-Ping

    2013-01-01

    Neuroinflammation, especially innate immunocyte-mediated neuroinflammation, has been reported to participate in pathogenesis of Alzheimer's disease (AD). However, the involvement of adaptive immune cells, such as CD4(+) T lymphocytes, in pathogenesis of AD is not well clarified. Herein, we focus on T helper 17 (Th17) cells, a subpopulation of CD4(+) T cells with high proinflammation, and show the implication of the cells in neurodegeneration of AD. Amyloid β1-42 (Aβ1-42) was bilaterally injected into hippocampus of rats to induce AD. On days 7 and 14 following the Aβ1-42 administration, escape latency of the rats in Morris water maze was increased, expression of amyloid precursor protein was upregulated, but expression of protein phosphatase 2A was downregulated in the hippocampus, and Nissl stain showed neuronal loss and gliosis in CA1 region. Infusion of FITC-linked albumin in blood circulation and combination with immunostaining of hippocampal sections for RORγ, a specific transcriptional factor of Th17 cells, demonstrated blood-brain barrier (BBB) disruption and Th17 cells' infiltration into brain parenchyma of AD rats. Expression of Th17 proinflammatory cytokines, interleukin (IL)-17 and IL-22, was increased in the hippocampus, and concentrations of the two cytokines were elevated in both the cerebrospinal fluid and the serum in AD occurrence and development. Compared with intact or saline-treated control rats, AD animals indicated an upregulated expression of Fas and FasL in the hippocampus. Further, the immunofluorescent histochemistry on AD hippocampal sections with NeuN, RORγ, Fas and FasL displayed that Fas was principally expressed by neurons and FasL was predominantly expressed by Th17 cells, and that neuronal apoptosis shown by TUNEL and NeuN double-labeled cells increased. These results suggest that Th17 cells, which were infiltrated into AD brain parenchyma, participate in neuroinflammation and neurodegeneration of AD by release of

  17. Development and application of chronic disease risk prediction models.

    Science.gov (United States)

    Oh, Sun Min; Stefani, Katherine M; Kim, Hyeon Chang

    2014-07-01

    Currently, non-communicable chronic diseases are a major cause of morbidity and mortality worldwide, and a large proportion of chronic diseases are preventable through risk factor management. However, the prevention efficacy at the individual level is not yet satisfactory. Chronic disease prediction models have been developed to assist physicians and individuals in clinical decision-making. A chronic disease prediction model assesses multiple risk factors together and estimates an absolute disease risk for the individual. Accurate prediction of an individual's future risk for a certain disease enables the comparison of benefits and risks of treatment, the costs of alternative prevention strategies, and selection of the most efficient strategy for the individual. A large number of chronic disease prediction models, especially targeting cardiovascular diseases and cancers, have been suggested, and some of them have been adopted in the clinical practice guidelines and recommendations of many countries. Although few chronic disease prediction tools have been suggested in the Korean population, their clinical utility is not as high as expected. This article reviews methodologies that are commonly used for developing and evaluating a chronic disease prediction model and discusses the current status of chronic disease prediction in Korea.

  18. Loss of fractalkine signaling exacerbates axon transport dysfunction in a chronic model of glaucoma

    Directory of Open Access Journals (Sweden)

    Kevin T Breen

    2016-11-01

    Full Text Available Neurodegeneration in glaucoma results in decline and loss of retinal ganglion cells (RGCs, and is associated with activation of myeloid cells such as microglia and macrophages. The chemokine fractalkine (FKN or Cx3cl1 mediates communication from neurons to myeloid cells. Signaling through its receptor Cx3cr1 has been implicated in multiple neurodegenerative diseases, but the effects on neuronal pathology are variable. Since it is unknown how FKN-mediated crosstalk influences RGC degeneration in glaucoma, we assessed this in a chronic mouse model, DBA/2J. We analyzed a DBA/2J substrain deficient in Cx3cr1, and compared compartmentalized RGC degeneration and myeloid cell responses to those in standard DBA/2J mice. We found that loss of FKN signaling exacerbates axon transport dysfunction, an early event in neurodegeneration, with a significant increase in RGCs with somal accumulation of the axonal protein phosphorylated neurofilament, and reduced retinal expression of genes involved in axon transport, Kif1b and Atp8a2. There was no change in the loss of Brn3-positive RGCs, and no difference in the extent of damage to the proximal optic nerve, suggesting that the loss of fractalkine signaling primarily affects axon transport. Since Cx3cr1 is specifically expressed in myeloid cells, we assessed changes in retinal microglial number and activation, changes in gene expression, and the extent of macrophage infiltration. We found that loss of fractalkine signaling led to innate immune changes within the retina, including increased infiltration of peripheral macrophages and upregulated nitric oxide synthase-2 (Nos-2 expression in myeloid cells, which contributes to the production of NO and can promote axon transport deficits. In contrast, resident retinal microglia appeared unchanged either in number, morphology, or expression of the myeloid activation marker ionized calcium binding adaptor molecule 1 (Iba1. There was also no significant increase in the

  19. NEURODEGENERATION WITH IRON ACCUMULATION TYPE1

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    Shrikhande D Y

    2010-03-01

    Full Text Available Neurodegeneration with iron accumulation type 1 is a rare degenerative disorder presenting with dementia and progressive extrapyramidal dysfunction. A 10 yrs old girl reported with complaints of difficulty in speech and involuntary movements. MRI Brain showed ‘eye of tiger appearance’ which is suggestive of neurodegeneration with iron accumulation type 1. Treatment is symptomatic and chelating agents have no effect. The disease is progressivelyfatal

  20. Neurodegeneration in Autoimmune Optic Neuritis Is Associated with Altered APP Cleavage in Neurons and Up-Regulation of p53.

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    Sabine Herold

    Full Text Available Multiple Sclerosis (MS is a chronic autoimmune inflammatory disease of the central nervous system (CNS. Histopathological and radiological analysis revealed that neurodegeneration occurs early in the disease course. However, the pathological mechanisms involved in neurodegeneration are poorly understood. Myelin oligodendrocyte glycoprotein (MOG-induced experimental autoimmune encephalomyelitis (EAE in Brown Norway rats (BN-rats is a well-established animal model, especially of the neurodegenerative aspects of MS. Previous studies in this animal model indicated that loss of retinal ganglion cells (RGCs, the neurons that form the axons of the optic nerve, occurs in the preclinical phase of the disease and is in part independent of overt histopathological changes of the optic nerve. Therefore, the aim of this study was to identify genes which are involved in neuronal cell loss at different disease stages of EAE. Furthermore, genes that are highly specific for autoimmune-driven neurodegeneration were compared to those regulated in RGCs after optic nerve axotomy at corresponding time points. Using laser capture micro dissection we isolated RNA from unfixed RGCs and performed global transcriptome analysis of retinal neurons. In total, we detected 582 genes sequentially expressed in the preclinical phase and 1150 genes in the clinical manifest EAE (P 1.5. Furthermore, using ingenuity pathway analysis (IPA, we identified amyloid precursor protein (APP as a potential upstream regulator of changes in gene expression in the preclinical EAE but neither in clinical EAE, nor at any time point after optic nerve transection. Therefore, the gene pathway analysis lead to the hypothesis that altered cleavage of APP in neurons in the preclinical phase of EAE leads to the enhanced production of APP intracellular domain (AICD, which in turn acts as a transcriptional regulator and thereby initiates an apoptotic signaling cascade via up-regulation of the target gene p

  1. Impaired glutathione synthesis in neurodegeneration.

    Science.gov (United States)

    Aoyama, Koji; Nakaki, Toshio

    2013-10-18

    Glutathione (GSH) was discovered in yeast cells in 1888. Studies of GSH in mammalian cells before the 1980s focused exclusively on its function for the detoxication of xenobiotics or for drug metabolism in the liver, in which GSH is present at its highest concentration in the body. Increasing evidence has demonstrated other important roles of GSH in the brain, not only for the detoxication of xenobiotics but also for antioxidant defense and the regulation of intracellular redox homeostasis. GSH also regulates cell signaling, protein function, gene expression, and cell differentiation/proliferation in the brain. Clinically, inborn errors in GSH-related enzymes are very rare, but disorders of GSH metabolism are common in major neurodegenerative diseases showing GSH depletion and increased levels of oxidative stress in the brain. GSH depletion would precipitate oxidative damage in the brain, leading to neurodegenerative diseases. This review focuses on the significance of GSH function, the synthesis of GSH and its metabolism, and clinical disorders of GSH metabolism. A potential approach to increase brain GSH levels against neurodegeneration is also discussed.

  2. Impaired Glutathione Synthesis in Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Toshio Nakaki

    2013-10-01

    Full Text Available Glutathione (GSH was discovered in yeast cells in 1888. Studies of GSH in mammalian cells before the 1980s focused exclusively on its function for the detoxication of xenobiotics or for drug metabolism in the liver, in which GSH is present at its highest concentration in the body. Increasing evidence has demonstrated other important roles of GSH in the brain, not only for the detoxication of xenobiotics but also for antioxidant defense and the regulation of intracellular redox homeostasis. GSH also regulates cell signaling, protein function, gene expression, and cell differentiation/proliferation in the brain. Clinically, inborn errors in GSH-related enzymes are very rare, but disorders of GSH metabolism are common in major neurodegenerative diseases showing GSH depletion and increased levels of oxidative stress in the brain. GSH depletion would precipitate oxidative damage in the brain, leading to neurodegenerative diseases. This review focuses on the significance of GSH function, the synthesis of GSH and its metabolism, and clinical disorders of GSH metabolism. A potential approach to increase brain GSH levels against neurodegeneration is also discussed.

  3. A Mouse Model of Chronic West Nile Virus Disease

    Science.gov (United States)

    Graham, Jessica B.; Swarts, Jessica L.; Wilkins, Courtney; Thomas, Sunil; Green, Richard; Sekine, Aimee; Voss, Kathleen M.; Mooney, Michael; Choonoo, Gabrielle; Miller, Darla R.; Pardo Manuel de Villena, Fernando; Gale, Michael

    2016-01-01

    Infection with West Nile virus (WNV) leads to a range of disease outcomes, including chronic infection, though lack of a robust mouse model of chronic WNV infection has precluded identification of the immune events contributing to persistent infection. Using the Collaborative Cross, a population of recombinant inbred mouse strains with high levels of standing genetic variation, we have identified a mouse model of persistent WNV disease, with persistence of viral loads within the brain. Compared to lines exhibiting no disease or marked disease, the F1 cross CC(032x013)F1 displays a strong immunoregulatory signature upon infection that correlates with restraint of the WNV-directed cytolytic response. We hypothesize that this regulatory T cell response sufficiently restrains the immune response such that a chronic infection can be maintained in the CNS. Use of this new mouse model of chronic neuroinvasive virus will be critical in developing improved strategies to prevent prolonged disease in humans. PMID:27806117

  4. The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain.

    Science.gov (United States)

    Haider, Lukas; Zrzavy, Tobias; Hametner, Simon; Höftberger, Romana; Bagnato, Francesca; Grabner, Günther; Trattnig, Siegfried; Pfeifenbring, Sabine; Brück, Wolfgang; Lassmann, Hans

    2016-03-01

    Multiple sclerosis is a chronic inflammatory disease with primary demyelination and neurodegeneration in the central nervous system. In our study we analysed demyelination and neurodegeneration in a large series of multiple sclerosis brains and provide a map that displays the frequency of different brain areas to be affected by these processes. Demyelination in the cerebral cortex was related to inflammatory infiltrates in the meninges, which was pronounced in invaginations of the brain surface (sulci) and possibly promoted by low flow of the cerebrospinal fluid in these areas. Focal demyelinated lesions in the white matter occurred at sites with high venous density and additionally accumulated in watershed areas of low arterial blood supply. Two different patterns of neurodegeneration in the cortex were identified: oxidative injury of cortical neurons and retrograde neurodegeneration due to axonal injury in the white matter. While oxidative injury was related to the inflammatory process in the meninges and pronounced in actively demyelinating cortical lesions, retrograde degeneration was mainly related to demyelinated lesions and axonal loss in the white matter. Our data show that accumulation of lesions and neurodegeneration in the multiple sclerosis brain does not affect all brain regions equally and provides the pathological basis for the selection of brain areas for monitoring regional injury and atrophy development in future magnetic resonance imaging studies.

  5. A ferret model of COPD-related chronic bronchitis

    OpenAIRE

    Raju, S. Vamsee; Kim, Hyunki; Byzek, Stephen A.; Tang, Li Ping; Trombley, John E; Jackson, Patricia; Rasmussen, Lawrence; Wells, J. Michael; LIBBY, EMILY FALK; Dohm, Erik; Winter, Lindy; Samuel, Sharon L.; Kurt R. Zinn; Blalock, J. Edwin; Schoeb, Trenton R.

    2016-01-01

    Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the US. The majority of COPD patients have symptoms of chronic bronchitis, which lacks specific therapies. A major impediment to therapeutic development has been the absence of animal models that recapitulate key clinical and pathologic features of human disease. Ferrets are well suited for the investigation of the significance of respiratory diseases, given prior data indicating similarities to human airway p...

  6. Effects of hypothalamic neurodegeneration on energy balance.

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    Allison Wanting Xu

    2005-12-01

    Full Text Available Normal aging in humans and rodents is accompanied by a progressive increase in adiposity. To investigate the role of hypothalamic neuronal circuits in this process, we used a Cre-lox strategy to create mice with specific and progressive degeneration of hypothalamic neurons that express agouti-related protein (Agrp or proopiomelanocortin (Pomc, neuropeptides that promote positive or negative energy balance, respectively, through their opposing effects on melanocortin receptor signaling. In previous studies, Pomc mutant mice became obese, but Agrp mutant mice were surprisingly normal, suggesting potential compensation by neuronal circuits or genetic redundancy. Here we find that Pomc-ablation mice develop obesity similar to that described for Pomc knockout mice, but also exhibit defects in compensatory hyperphagia similar to what occurs during normal aging. Agrp-ablation female mice exhibit reduced adiposity with normal compensatory hyperphagia, while animals ablated for both Pomc and Agrp neurons exhibit an additive interaction phenotype. These findings provide new insight into the roles of hypothalamic neurons in energy balance regulation, and provide a model for understanding defects in human energy balance associated with neurodegeneration and aging.

  7. Military-related traumatic brain injury and neurodegeneration.

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    McKee, Ann C; Robinson, Meghan E

    2014-06-01

    Mild traumatic brain injury (mTBI) includes concussion, subconcussion, and most exposures to explosive blast from improvised explosive devices. mTBI is the most common traumatic brain injury affecting military personnel; however, it is the most difficult to diagnose and the least well understood. It is also recognized that some mTBIs have persistent, and sometimes progressive, long-term debilitating effects. Increasing evidence suggests that a single traumatic brain injury can produce long-term gray and white matter atrophy, precipitate or accelerate age-related neurodegeneration, and increase the risk of developing Alzheimer's disease, Parkinson's disease, and motor neuron disease. In addition, repetitive mTBIs can provoke the development of a tauopathy, chronic traumatic encephalopathy. We found early changes of chronic traumatic encephalopathy in four young veterans of the Iraq and Afghanistan conflict who were exposed to explosive blast and in another young veteran who was repetitively concussed. Four of the five veterans with early-stage chronic traumatic encephalopathy were also diagnosed with posttraumatic stress disorder. Advanced chronic traumatic encephalopathy has been found in veterans who experienced repetitive neurotrauma while in service and in others who were accomplished athletes. Clinically, chronic traumatic encephalopathy is associated with behavioral changes, executive dysfunction, memory loss, and cognitive impairments that begin insidiously and progress slowly over decades. Pathologically, chronic traumatic encephalopathy produces atrophy of the frontal and temporal lobes, thalamus, and hypothalamus; septal abnormalities; and abnormal deposits of hyperphosphorylated tau as neurofibrillary tangles and disordered neurites throughout the brain. The incidence and prevalence of chronic traumatic encephalopathy and the genetic risk factors critical to its development are currently unknown. Chronic traumatic encephalopathy has clinical and

  8. Molecular neurodegeneration: basic biology and disease pathways.

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    Vassar, Robert; Zheng, Hui

    2014-09-23

    The field of neurodegeneration research has been advancing rapidly over the past few years, and has provided intriguing new insights into the normal physiological functions and pathogenic roles of a wide range of molecules associated with several devastating neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease, and Down syndrome. Recent developments have also facilitated initial efforts to translate preclinical discoveries toward novel therapeutic approaches and clinical trials in humans. These recent developments are reviewed in the current Review Series on "Molecular Neurodegeneration: Basic Biology and Disease Pathways" in a number of state-of-the-art manuscripts that cover themes presented at the Third International Conference on Molecular Neurodegeneration: "Basic biology and disease pathways" held in Cannes, France, September, 2013.

  9. A chronic ulcerative colitis model in rats

    Institute of Scientific and Technical Information of China (English)

    Li Zheng; Zhen Qiang Gao; Shu Xian Wang

    2000-01-01

    @@ INTRODUCTION In recent years, there have been many reports about animal model to investigate drugs for inflammatory bowel diseases (IBD). The experimental animal model often used is acetic acid-induced damage of colonic muscosa. In the present study, this animal model was investigated by administering various concentrations of TNBS.

  10. Harpagoside attenuates MPTP/MPP⁺ induced dopaminergic neurodegeneration and movement disorder via elevating glial cell line-derived neurotrophic factor.

    Science.gov (United States)

    Sun, Xiaoyu; Xiong, Zhongkui; Zhang, Yongfang; Meng, Ya; Xu, Gang; Xia, Zhiming; Li, Jiamei; Zhang, Rui; Ke, Zunji; Xia, Zongqin; Hu, Yaer

    2012-03-01

    Parkinson's disease is a chronic neurodegenerative movement disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. New therapeutic approaches aiming at delaying or reversing the neurodegenerative process are under active investigations. In this work, we found that harpagoside, an iridoid purified from the Chinese medicinal herb Scrophularia ningpoensis, could not only prevent but also rescue the dopaminergic neurodegeneration in MPTP/MPP(+) intoxication with promising efficacy. Firstly, in cultured mesencephalic neurons, harpagoside significantly attenuated the loss of TH-positive neuron numbers and the shortening of axonal length. Secondly, in a chronic MPTP mouse model, harpagoside dose-dependently improved the loco-motor ability (rotarod test), increased the TH-positive neuron numbers in the substantia nigra pars compacta (unbiased stereological counting) and increased the striatal DAT density ((125) I-FP-CIT autoradiography). Thirdly, harpagoside markedly elevated the GDNF mRNA and GDNF protein levels in MPTP/MPP(+) lesioned models. However, the protecting effect of harpagoside on the dopaminergic degeneration disappeared when the intrinsic GDNF action was blocked by either the Ret inhibitor PP1 or the neutralizing anti-GDNF antibody. Taken together, we conclude that harpagoside attenuates the dopaminergic neurodegeneration and movement disorder mainly through elevating glial cell line-derived neurotrophic factor.

  11. Chronic subordinate colony housing (CSC as a model of chronic psychosocial stress in male rats.

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    Kewir D Nyuyki

    Full Text Available Chronic subordinate colony housing (CSC is an adequate and reliable mouse model of chronic psychosocial stress, resulting in reduced body weight gain, reduced thymus and increased adrenal weight, long-lasting anxiety-like behaviour, and spontaneous colitis. Furthermore, CSC mice show increased corticotrophin (ACTH responsiveness to acute heterotypic stressors, suggesting a general mechanism which allows a chronically-stressed organism to adequately respond to a novel threat. Therefore, the aim of the present study was to extend the CSC model to another rodent species, namely male Wistar rats, and to characterize relevant physiological, immunological, and behavioural consequences; placing particular emphasis on changes in hypothalamo-pituitary-adrenal (HPA axis responsiveness to an acute heterotypic stressor. In line with previous mouse data, exposure of Wistar rats to 19 days of CSC resulted in a decrease in body weight gain and absolute thymus mass, mild colonic barrier defects and intestinal immune activation. Moreover, no changes in stress-coping behaviour or social preference were seen; again in agreement with the mouse paradigm. Most importantly, CSC rats showed an increased plasma corticosterone response to an acute heterotypic stressor (open arm, 5 min despite displaying similar basal levels and similar basal and stressor-induced plasma ACTH levels. In contrast to CSC mice, anxiety-related behaviour and absolute, as well as relative adrenal weights remained unchanged in CSC rats. In summary, the CSC paradigm could be established as an adequate model of chronic psychosocial stress in male rats. Our data further support the initial hypothesis that adrenal hyper-responsiveness to ACTH during acute heterotypic stressors represents a general adaptation, which enables a chronically-stressed organism to adequately respond to novel challenges.

  12. Sex differences in the chronic mild stress model of depression.

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    Franceschelli, Anthony; Herchick, Samantha; Thelen, Connor; Papadopoulou-Daifoti, Zeta; Pitychoutis, Pothitos M

    2014-09-01

    A large volume of clinical and experimental evidence documents sex differences in brain anatomy, chemistry, and function, as well as in stress and drug responses. The chronic mild stress model (CMS) is one of the most extensively investigated animal models of chronic stress. However, only a limited number of studies have been conducted in female rodents despite the markedly higher prevalence of major depression among women. Herein, we review CMS studies conducted in rats and mice of both sexes and further discuss intriguing sex-dependent behavioral and neurobiological findings. The PubMed literature search engine was used to find and collect all relevant articles analyzed in this review. Specifically, a multitermed search was performed with 'chronic mild stress', 'chronic unpredictable stress' and 'chronic variable stress' as base terms and 'sex', 'gender', 'females' and 'depression' as secondary terms in various combinations. Male and female rodents appear to be differentially affected by CMS application, depending on the behavioral, physiological, and neurobiological indices that are being measured. Importantly, the CMS paradigm, despite its limitations, has been successfully used to assess a constellation of interdisciplinary research questions in the sex differences field and has served as a 'silver bullet' in assessing the role of sex in the neurobiology of major depression.

  13. A ferret model of COPD-related chronic bronchitis

    Science.gov (United States)

    Raju, S. Vamsee; Kim, Hyunki; Byzek, Stephen A.; Tang, Li Ping; Trombley, John E.; Jackson, Patricia; Rasmussen, Lawrence; Wells, J. Michael; Libby, Emily Falk; Winter, Lindy; Samuel, Sharon L.; Zinn, Kurt R.; Blalock, J. Edwin; Schoeb, Trenton R.; Dransfield, Mark T.; Rowe, Steven M.

    2016-01-01

    Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the US. The majority of COPD patients have symptoms of chronic bronchitis, which lacks specific therapies. A major impediment to therapeutic development has been the absence of animal models that recapitulate key clinical and pathologic features of human disease. Ferrets are well suited for the investigation of the significance of respiratory diseases, given prior data indicating similarities to human airway physiology and submucosal gland distribution. Here, we exposed ferrets to chronic cigarette smoke and found them to approximate complex clinical features of human COPD. Unlike mice, which develop solely emphysema, smoke-exposed ferrets exhibited markedly higher numbers of early-morning spontaneous coughs and sporadic infectious exacerbations as well as a higher level of airway obstruction accompanied by goblet cell metaplasia/hyperplasia and increased mucus expression in small airways, indicative of chronic bronchitis and bronchiolitis. Overall, we demonstrate the first COPD animal model exhibiting clinical and pathologic features of chronic bronchitis to our knowledge, providing a key advance that will greatly facilitate the preclinical development of novel treatments for this disease. PMID:27699245

  14. Bioengineered 3D Glial Cell Culture Systems and Applications for Neurodegeneration and Neuroinflammation.

    Science.gov (United States)

    Watson, P Marc D; Kavanagh, Edel; Allenby, Gary; Vassey, Matthew

    2017-02-01

    Neurodegeneration and neuroinflammation are key features in a range of chronic central nervous system (CNS) diseases such as Alzheimer's and Parkinson's disease, as well as acute conditions like stroke and traumatic brain injury, for which there remains significant unmet clinical need. It is now well recognized that current cell culture methodologies are limited in their ability to recapitulate the cellular environment that is present in vivo, and there is a growing body of evidence to show that three-dimensional (3D) culture systems represent a more physiologically accurate model than traditional two-dimensional (2D) cultures. Given the complexity of the environment from which cells originate, and their various cell-cell and cell-matrix interactions, it is important to develop models that can be controlled and reproducible for drug discovery. 3D cell models have now been developed for almost all CNS cell types, including neurons, astrocytes, microglia, and oligodendrocyte cells. This review will highlight a number of current and emerging techniques for the culture of astrocytes and microglia, glial cell types with a critical role in neurodegenerative and neuroinflammatory conditions. We describe recent advances in glial cell culture using electrospun polymers and hydrogel macromolecules, and highlight how these novel culture environments influence astrocyte and microglial phenotypes in vitro, as compared to traditional 2D systems. These models will be explored to illuminate current trends in the techniques used to create 3D environments for application in research and drug discovery focused on astrocytes and microglial cells.

  15. Epigenetic mechanisms governing the process of neurodegeneration.

    Science.gov (United States)

    Qureshi, Irfan A; Mehler, Mark F

    2013-01-01

    Studies elucidating how and why neurodegeneration unfolds suggest that a complex interplay between genetic and environmental factors is responsible for disease pathogenesis. Recent breakthroughs in the field of epigenetics promise to advance our understanding of these mechanisms and to promote the development of useful and effective pre-clinical risk stratification strategies, molecular diagnostic and prognostic methods, and disease-modifying treatments.

  16. A Canine Model of Chronic Graft-versus-Host Disease.

    Science.gov (United States)

    Graves, Scott S; Rezvani, Andrew; Sale, George; Stone, Diane; Parker, Maura; Rosinski, Steven; Spector, Michele; Swearingen, Bruce; Kean, Leslie; Storb, Rainer

    2017-03-01

    In long-term survivors of allogeneic hematopoietic cell transplantation (HCT), chronic graft-versus-host disease (GVHD) is the major cause of morbidity and mortality and a major determinant of quality of life. Chronic GVHD responds poorly to current immunosuppressive drugs, and while T cell depletion may be preventive, this gain is offset by increased relapse rates. A significant impediment to progress in treating chronic GVHD has been the limitations of existing animal models. The goal of this study was to develop a reproducible comprehensive model of chronic GVHD in the dog. Ten recipient dogs received 920 cGy total body irradiation, infusion of marrow, and an infusion of buffy coat cells from a dog leukocyte antigen (DLA)-mismatched unrelated donor. Postgrafting immunosuppression consisted of methotrexate (days 1, 3, 6, 11) and cyclosporine. The duration of cyclosporine administration was limited to 80 days instead of the clinically used 180 days. This was done to contain costs, as chronic GVHD was expected to develop at earlier time points. All recipients were given ursodiol for liver protection. One dog had graft failure and 9 dogs showed stable engraftment. Eight of the 9 developed de novo chronic GVHD. Dogs progressed with clinical signs of chronic GVHD over a period of 43 to 164 (median, 88) days after discontinuation of cyclosporine. Target organs showed the spectrum of chronic GVHD manifestations that are typically seen clinically. These included lichenoid changes of the skin, fasciitis, ocular involvement (xerophthalmia), conjunctivitis, bronchiolitis obliterans, salivary gland involvement, gingivitis, esophageal involvement, and hepatic involvement. Peripheral blood lymphocyte surface antigen expression of CD28 and inducible costimulator was elevated in dogs with GHVD compared with those in normal dogs, but not significantly so. Serum levels of IL-8 and monocyte chemotactic protein-1 in GVHD-affected dogs at time of euthanasia were elevated, whereas

  17. Regulated protein aggregation: stress granules and neurodegeneration

    Directory of Open Access Journals (Sweden)

    Wolozin Benjamin

    2012-11-01

    Full Text Available Abstract The protein aggregation that occurs in neurodegenerative diseases is classically thought to occur as an undesirable, nonfunctional byproduct of protein misfolding. This model contrasts with the biology of RNA binding proteins, many of which are linked to neurodegenerative diseases. RNA binding proteins use protein aggregation as part of a normal regulated, physiological mechanism controlling protein synthesis. The process of regulated protein aggregation is most evident in formation of stress granules. Stress granules assemble when RNA binding proteins aggregate through their glycine rich domains. Stress granules function to sequester, silence and/or degrade RNA transcripts as part of a mechanism that adapts patterns of local RNA translation to facilitate the stress response. Aggregation of RNA binding proteins is reversible and is tightly regulated through pathways, such as phosphorylation of elongation initiation factor 2α. Microtubule associated protein tau also appears to regulate stress granule formation. Conversely, stress granule formation stimulates pathological changes associated with tau. In this review, I propose that the aggregation of many pathological, intracellular proteins, including TDP-43, FUS or tau, proceeds through the stress granule pathway. Mutations in genes coding for stress granule associated proteins or prolonged physiological stress, lead to enhanced stress granule formation, which accelerates the pathophysiology of protein aggregation in neurodegenerative diseases. Over-active stress granule formation could act to sequester functional RNA binding proteins and/or interfere with mRNA transport and translation, each of which might potentiate neurodegeneration. The reversibility of the stress granule pathway also offers novel opportunities to stimulate endogenous biochemical pathways to disaggregate these pathological stress granules, and perhaps delay the progression of disease.

  18. Neuroprotective strategies against calpain-mediated neurodegeneration

    Directory of Open Access Journals (Sweden)

    Yildiz-Unal A

    2015-02-01

    Full Text Available Aysegul Yildiz-Unal,1 Sirin Korulu,2 Arzu Karabay3 1Department of Molecular Biology and Genetics, Faculty of Science, Mugla Sitki Koçman University, Kötekli, Mugla, Turkey; 2Department of Molecular Biology and Genetics, Istanbul Arel University, Istanbul Turkey; 3Department of Molecular Biology and Genetics, Faculty of Science and Letters, Istanbul Technical University, Maslak, Istanbul, Turkey Abstract: Calpains are calcium-dependent proteolytic enzymes that have deleterious effects on neurons upon their pathological over-activation. According to the results of numerous studies to date, there is no doubt that abnormal calpain activation triggers activation and progression of apoptotic processes in neurodegeneration, leading to neuronal death. Thus, it is very crucial to unravel all the aspects of calpain-mediated neurodegeneration in order to protect neurons through eliminating or at least minimizing its lethal effects. Protecting neurons against calpain-activated apoptosis basically requires developing effective, reliable, and most importantly, therapeutically applicable approaches to succeed. From this aspect, the most significant studies focusing on preventing calpain-mediated neurodegeneration include blocking the N-methyl-d-aspartate (NMDA-type glutamate receptor activities, which are closely related to calpain activation; directly inhibiting calpain itself via intrinsic or synthetic calpain inhibitors, or inhibiting its downstream processes; and utilizing the neuroprotectant steroid hormone estrogen and its receptors. In this review, the most remarkable neuroprotective strategies for calpain-mediated neurodegeneration are categorized and summarized with respect to their advantages and disadvantages over one another, in terms of their efficiency and applicability as a therapeutic regimen in the treatment of neurodegenerative diseases. Keywords: calpain, neurodegeneration, neuroprotection, calpain inhibitors, NMDAR, Speedy/RINGO

  19. Loss of presenilin function causes Alzheimer's disease-like neurodegeneration in the mouse.

    Science.gov (United States)

    Chen, Qian; Nakajima, Akira; Choi, Se Hoon; Xiong, Xiaoli; Tang, Ya-Ping

    2008-05-15

    Accumulating evidence has indicated that gain-of-function in beta-amyloid production may be not the necessary mechanism for mutant presenilin-1 (PS1) or PS2 to cause familial Alzheimer's disease (AD). In the present article, we show that conditional knockout of PS1 from the adult stage in the forebrain of mice with the PS2 null mutation triggers robust AD-like neurodegeneration including brain shrinkage, cortical and hippocampal atrophy,ventricular enlargement, severe neuronal loss, gliosis, tau hyperphosphorylation, neurofillament tangle-like structures, and intracellular filaments. Learning and memory functions in these mice are almost completely lost. Notably, there is no beta-amyloid deposition, indicating that presenilin dysfunction can directly cause neurodegeneration without the involvement of beta-amyloid. Furthermore, neurodegeneration occurs in a progressive manner following aging, suggesting that an accumulating effect of presenilin dysfunction over time might be a pathogenic mechanism for the involvement of mutant PS1/PS2 in causing AD. These results validate a mouse model characterized by the presence of many features of AD pathology. Furthermore, the demonstration of AD-like neurodegeneration in the absence of beta-amyloid deposition challenges the long-standing beta-amyloid cascade hypothesis and encourages an open debate on the role of beta-amyloid in causing AD. Most important, our results strongly suggest that to develop gamma-secretase inhibitors for the pharmacological treatment of AD may be not a reasonable strategy because antagonism of presenilin function may worsen neurodegeneration.

  20. Latent viral immune inflammatory response model for chronic multisymptom illness.

    Science.gov (United States)

    Maloney, Sean R; Jensen, Susan; Gil-Rivas, Virginia; Goolkasian, Paula

    2013-03-01

    A latent viral immune inflammatory response (LVIIR) model is presented which integrates factors that contribute to chronic multisymptom illness (CMI) in both the veteran and civilian populations. The LVIIR model for CMI results from an integration of clinical experience with a review of the literature in four distinct areas: (1) studies of idiopathic multisymptom illness in the veteran population including two decades of research on Gulf War I veterans with CMI, (2) new evidence supporting the existence of chronic inflammatory responses to latent viral antigens and the effect these responses may have on the nervous system, (3) recent discoveries concerning the role of vitamin D in maintaining normal innate and adaptive immunity including suppression of latent viruses and regulation of the immune inflammatory response, and (4) the detrimental effects of extreme chronic repetitive stress (ECRS) on the immune and nervous systems. The LVIIR model describes the pathophysiology of a pathway to CMI and presents a new direction for the clinical assessment of CMI that includes the use of neurological signs from a physical exam, objective laboratory data, and a new proposed latent viral antigen-antibody imaging technique for the peripheral and central nervous system. The LVIIR model predicts that CMI can be treated by a focus on reversal of immune system impairment, suppression of latent viruses and their antigens, and healing of nervous system tissue damaged by chronic inflammation associated with latent viral antigens and by ECRS. In addition, the LVIIR model suggests that maintaining optimal serum 25 OH vitamin D levels will maximize immune system suppression of latent viruses and their antigens and will minimize immune system inflammation. This model also emphasizes the importance of decreasing ECRS to improve immune system function and to minimize nervous system injury from excess serum glucocorticoid levels. The proposed model supports growing evidence that increasing

  1. Huntingtin interacting proteins are genetic modifiers of neurodegeneration.

    Directory of Open Access Journals (Sweden)

    Linda S Kaltenbach

    2007-05-01

    Full Text Available Huntington's disease (HD is a fatal neurodegenerative condition caused by expansion of the polyglutamine tract in the huntingtin (Htt protein. Neuronal toxicity in HD is thought to be, at least in part, a consequence of protein interactions involving mutant Htt. We therefore hypothesized that genetic modifiers of HD neurodegeneration should be enriched among Htt protein interactors. To test this idea, we identified a comprehensive set of Htt interactors using two complementary approaches: high-throughput yeast two-hybrid screening and affinity pull down followed by mass spectrometry. This effort led to the identification of 234 high-confidence Htt-associated proteins, 104 of which were found with the yeast method and 130 with the pull downs. We then tested an arbitrary set of 60 genes encoding interacting proteins for their ability to behave as genetic modifiers of neurodegeneration in a Drosophila model of HD. This high-content validation assay showed that 27 of 60 orthologs tested were high-confidence genetic modifiers, as modification was observed with more than one allele. The 45% hit rate for genetic modifiers seen among the interactors is an order of magnitude higher than the 1%-4% typically observed in unbiased genetic screens. Genetic modifiers were similarly represented among proteins discovered using yeast two-hybrid and pull-down/mass spectrometry methods, supporting the notion that these complementary technologies are equally useful in identifying biologically relevant proteins. Interacting proteins confirmed as modifiers of the neurodegeneration phenotype represent a diverse array of biological functions, including synaptic transmission, cytoskeletal organization, signal transduction, and transcription. Among the modifiers were 17 loss-of-function suppressors of neurodegeneration, which can be considered potential targets for therapeutic intervention. Finally, we show that seven interacting proteins from among 11 tested were able to

  2. Characterization of prefrontal cortex microstructure and antioxidant status in a rat model of neurodegeneration induced by aluminium chloride and multiple low-dose streptozotocin.

    Science.gov (United States)

    Akinola, Oluwole B; Biliaminu, Sikiru A; Adediran, Rianat A; Adeniye, Kehinde A; Abdulquadir, Fatimah C

    2015-12-01

    Diabetes mellitus (DM) is a risk factor for Alzheimer's disease (AD), and several individuals with AD are diabetic. Most non-transgenic animal models of AD make use of oral treatment with aluminium chloride (AlCl(3)) to induce brain lesions pathognomonic of the disease. Moreover, streptozotocin (STZ) can induce pathological features of either AD or DM depending on the mode of treatment. In the present study, we characterised prefrontal microanatomy and antioxidant defence system in a rat model of AD confounded by DM, with the objective of assessing the suitability of this model in the study of sporadic AD with DM co-morbidity. Adult Wistar rats were randomly assigned to receive either intraperitoneal STZ (30 mg/kg/day for 3 days; to induce DM), oral AlCl(3) (500 mg/kg/day for 4 weeks; to induce some brain lesions characteristic of AD); or both STZ and AlCl(3) (to induce AD with DM co-morbidity). Untreated rats served as controls. During treatment, blood glucose levels and body weights were evaluated repeatedly in all rats. At euthanasia, prefrontal cortex was homogenized in phosphate buffer solution and the supernatants assayed for some antioxidant enzymes (catalase, CAT; superoxide dismutase, SOD; and reduced glutathione, GSH). Moreover, following perfusion-fixation of the brain, frontal lobes were processed by the haematoxylin and eosin (H&E) or Congo red technique. Our findings showed that in rats co-administered AlCl(3) and STZ (AD + DM rats), prefrontal levels of GSH reduced significantly (p 0.05) compared with the controls. Moreover, in this model of AD with DM co-morbidity, extensive neuronal cell loss was observed in the prefrontal cortex, but Congophilic deposits were not present. The neurodegenerative lesions and antioxidant deficits characteristic of this AlCl(3) + STZ (AD + DM) rat model were more pronounced than similar lesions associated with mono-treatment with either STZ (DM) or AlCl(3) (AD) alone; and this makes the AlCl(3) + STZ model a suitable

  3. Hypersensitivity of the hippocampal CA3 region to stress-induced neurodegeneration and amyloidogenesis in a rat model of surgical menopause

    OpenAIRE

    2013-01-01

    Females who enter menopause prematurely via bilateral ovariectomy (surgical menopause) have a significantly increased risk for cognitive decline and dementia. To help elucidate the mechanisms underlying this phenomenon, we used an animal model of surgical menopause, long-term (10-week) bilateral ovariectomy in female rats. Herein, we demonstrate that long-term oestrogen deprivation dramatically increases sensitivity of the normally resistant hippocampal CA3 region to ischaemic stress, an effe...

  4. RNA binding proteins hnRNP A2/B1 and CUGBP1 suppress Fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS

    OpenAIRE

    Sofola, Oyinkan A.; Jin, Peng; QIN, YUNLONG; Duan, Ranhui; LIU, Huijie; de Haro, Maria; Nelson,David L.; Botas, Juan

    2007-01-01

    Fragile X associated tremor ataxia syndrome (FXTAS) is a recently described neurodegenerative disorder of older adult carriers of premutation alleles (60-200 CGG repeats) in the fragile-X mental retardation gene (FMR1). It has been proposed that FXTAS is an RNA mediated neurodegenerative disease caused by the titration of RNA binding proteins by the CGG repeats. To test this hypothesis, we utilize a transgenic Drosophila model of FXTAS that expresses premutation length repeat (90 CGG repeats)...

  5. Beyond pain: modeling decision-making deficits in chronic pain

    Science.gov (United States)

    Hess, Leonardo Emanuel; Haimovici, Ariel; Muñoz, Miguel Angel; Montoya, Pedro

    2014-01-01

    Risky decision-making seems to be markedly disrupted in patients with chronic pain, probably due to the high cost that impose pain and negative mood on executive control functions. Patients’ behavioral performance on decision-making tasks such as the Iowa Gambling Task (IGT) is characterized by selecting cards more frequently from disadvantageous than from advantageous decks, and by switching often between competing responses in comparison with healthy controls (HCs). In the present study, we developed a simple heuristic model to simulate individuals’ choice behavior by varying the level of decision randomness and the importance given to gains and losses. The findings revealed that the model was able to differentiate the behavioral performance of patients with chronic pain and HCs at the group, as well as at the individual level. The best fit of the model in patients with chronic pain was yielded when decisions were not based on previous choices and when gains were considered more relevant than losses. By contrast, the best account of the available data in HCs was obtained when decisions were based on previous experiences and losses loomed larger than gains. In conclusion, our model seems to provide useful information to measure each individual participant extensively, and to deal with the data on a participant-by-participant basis. PMID:25136301

  6. Beyond pain: modeling decision-making deficits in chronic pain

    Directory of Open Access Journals (Sweden)

    Leonardo Emanuel Hess

    2014-08-01

    Full Text Available Risky decision-making seems to be markedly disrupted in patients with chronic pain, probably due to the high cost that impose pain and negative mood on executive control functions. Patients’ behavioral performance on decision-making tasks such as the Iowa Gambling Task (IGT is characterized by selecting cards more frequently from disadvantageous than from advantageous decks, and by switching often between competing responses in comparison with healthy controls. In the present study, we developed a simple heuristic model to simulate individuals’ choice behavior by varying the level of decision randomness and the importance given to gains and losses. The findings revealed that the model was able to differentiate the behavioral performance of patients with chronic pain and healthy controls at the group, as well as at the individual level. The best fit of the model in patients with chronic pain was yielded when decisions were not based on previous choices and when gains were considered more relevant than losses. By contrast, the best account of the available data in healthy controls was obtained when decisions were based on previous experiences and losses loomed larger than gains. In conclusion, our model seems to provide useful information to measure each individual participant extensively, and to deal with the data on a participant-by-participant basis.

  7. Deletion of caspase-8 in mouse myeloid cells blocks microglia pro-inflammatory activation and confers protection in MPTP neurodegeneration model.

    Science.gov (United States)

    Kavanagh, Edel; Burguillos, Miguel Angel; Carrillo-Jimenez, Alejandro; Oliva-Martin, María José; Santiago, Martiniano; Rodhe, Johanna; Joseph, Bertrand; Venero, Jose Luis

    2015-09-01

    Increasing evidence involves sustained pro-inflammatory microglia activation in the pathogenesis of different neurodegenerative diseases, particularly Parkinson's disease (PD). We recently uncovered a completely novel and unexpected role for caspase-8 and its downstream substrates caspase-3/7 in the control of microglia activation and associated neurotoxicity to dopaminergic cells. To demonstrate the genetic evidence, mice bearing a floxed allele ofCASP8 were crossed onto a transgenic line expressing Cre under the control of Lysozyme 2 gene. Analysis of caspase-8 gene deletion in brain microglia demonstrated a high efficiency in activated but not in resident microglia. Mice were challenged with lipopolysaccharide, a potent inducer of microglia activation, or with MPTP, which promotes specific dopaminergic cell damage and consequent reactive microgliosis. In neither of these models, CASP8 deletion appeared to affect the overall number of microglia expressing the pan specific microglia marker, Iba1. In contrast, CD16/CD32 expression, a microglial pro-inflammatory marker, was found to be negatively affected upon CASP8 deletion. Expression of additional proinflammatory markers were also found to be reduced in response to lipopolysaccharide. Of importance, reduced pro-inflammatory microglia activation was accompanied by a significant protection of the nigro-striatal dopaminergic system in the MPTP mouse model of PD.

  8. Motivational, proteostatic and transcriptional deficits precede synapse loss, gliosis and neurodegeneration in the B6.HttQ111/+ model of Huntington’s disease

    Science.gov (United States)

    Bragg, Robert M.; Coffey, Sydney R.; Weston, Rory M.; Ament, Seth A.; Cantle, Jeffrey P.; Minnig, Shawn; Funk, Cory C.; Shuttleworth, Dominic D.; Woods, Emily L.; Sullivan, Bonnie R.; Jones, Lindsey; Glickenhaus, Anne; Anderson, John S.; Anderson, Michael D.; Dunnett, Stephen B.; Wheeler, Vanessa C.; MacDonald, Marcy E.; Brooks, Simon P.; Price, Nathan D.; Carroll, Jeffrey B.

    2017-01-01

    We investigated the appearance and progression of disease-relevant signs in the B6.HttQ111/+ mouse, a genetically precise model of the mutation that causes Huntington’s disease (HD). We find that B6.HttQ111/+ mice are healthy, show no overt signs of central or peripheral inflammation, and no gross motor impairment as late as 12 months of age. Behaviorally, we find that 4–9 month old B6.HttQ111/+ mice have normal activity levels and show no clear signs of anxiety or depression, but do show clear signs of reduced motivation. The neuronal density, neuronal size, synaptic density and number of glia is normal in B6.HttQ111/+ striatum, the most vulnerable brain region in HD, up to 12 months of age. Despite this preservation of the synaptic and cellular composition of the striatum, we observe clear progressive, striatal-specific transcriptional dysregulation and accumulation of neuronal intranuclear inclusions (NIIs). Simulation studies suggest these molecular endpoints are sufficiently robust for future preclinical studies, and that B6.HttQ111/+ mice are a useful tool for modeling disease-modifying or neuroprotective strategies for disease processes before the onset of overt phenotypes. PMID:28176805

  9. Chronic gastritis rat model and role of inducing factors

    Institute of Scientific and Technical Information of China (English)

    Zun Xiang; Jian-Min Si; Huai-De Huang

    2004-01-01

    AIM: To establish an experimental animal model of chronic gastritis in a short term and to investigate the effects of several potential inflammation-inducing factors on rat gastric mucosa.METHODS: Twenty-four healthy, male SD rats were treated with intragastric administration of 600 mL/L alcohol, 20mmol/L sodium deoxycholate and 0.5 g/L ammonia (factor A), forage containing low levels of vitamins (factor B), and/or indomethacin (factor C), according to an L8(27)orthogonal design. After 12 wk, gastric antral and body mucosae were pathologically examined.RESULTS: Chronic gastritis model was successfully induced in rats treated with factor A for 12 wk. After the treatment of animals, the gastric mucosal inflammation was significantly different from that in controls, and the number of pyloric glands at antrum and parietal cells at body were obviously reduced (P<0.01). Indomethacin induced gastritis but without atrophy, and short-term vitamin deficiency failed to induce chronic gastritis and gastric atrophy, In addition,indomethacin and vitamin deficiency had no synergistic effect in inducing gastritis with the factor A. No atypical hyperplasia and intestinal metaplasia in the gastric antrum and body were observed in all rats studied.CONCLUSION: Combined intragastric administration of 600 mL/L alcohol, 20 mmol/L sodium deoxycholate and 0.5 g/L ammonia induces chronic gastritis and gastric atrophy in rats. Indomethacin induces chronic gastritis only.The long-term roles of these factors in gastric inflammation and carcinogenesis need to be further elucidated.

  10. Does a loss of TDP-43 function cause neurodegeneration?

    Directory of Open Access Journals (Sweden)

    Xu Zuo-Shang

    2012-06-01

    Full Text Available Abstract In 2006, TAR-DNA binding protein 43 kDa (TDP-43 was discovered to be in the intracellular aggregates in the degenerating cells in amyotrophic lateral sclerosis (ALS and frontotemporal lobar degeneration (FTLD, two fatal neurodegenerative diseases [1,2]. ALS causes motor neuron degeneration leading to paralysis [3,4]. FTLD causes neuronal degeneration in the frontal and temporal cortices leading to personality changes and a loss of executive function [5]. The discovery triggered a flurry of research activity that led to the discovery of TDP-43 mutations in ALS patients and the widespread presence of TDP-43 aggregates in numerous neurodegenerative diseases. A key question regarding the role of TDP-43 is whether it causes neurotoxicity by a gain of function or a loss of function. The gain-of-function hypothesis has received much attention primarily based on the striking neurodegenerative phenotypes in numerous TDP-43-overexpression models. In this review, I will draw attention to the loss-of-function hypothesis, which postulates that mutant TDP-43 causes neurodegeneration by a loss of function, and in addition, by exerting a dominant-negative effect on the wild-type TDP-43 allele. Furthermore, I will discuss how a loss of function can cause neurodegeneration in patients where TDP-43 is not mutated, review the literature in model systems to discuss how the current data support the loss-of-function mechanism and highlight some key questions for testing this hypothesis in the future.

  11. Molecular neurodegeneration: basic biology and disease pathways

    OpenAIRE

    2014-01-01

    The field of neurodegeneration research has been advancing rapidly over the past few years, and has provided intriguing new insights into the normal physiological functions and pathogenic roles of a wide range of molecules associated with several devastating neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington’s disease, and Down syndrome. Recent developments have also facilitated initial efforts to...

  12. Neurodegeneration with Brain Iron Accumulation: An Overview

    Directory of Open Access Journals (Sweden)

    Seyed Hassan TONEKABONI*

    2014-12-01

    Full Text Available How to Cite This Article: Tonekaboni SH, Mollamohammadi M. Neurodegeneration with Brain Iron Accumulation: An Overview. Iran J Child Neurol. 2014 Autumn;8(4: 1-8.AbstractObjectiveNeurodegeneration with brain iron accumulation (NBIA is a group of neurodegenerative disorder with deposition of iron in the brain (mainly Basal Ganglia leading to a progressive Parkinsonism, spasticity, dystonia, retinal degeneration, optic atrophy often accompanied by psychiatric manifestations and cognitive decline. 8 of the 10 genetically defined NBIA types are inherited as autosomal recessive and the remaining two by autosomal dominant and X-linked dominant manner. Brain MRI findings are almost specific and show abnormal brain iron deposition in basal ganglia some other related anatomicallocations. In some types of NBIA cerebellar atrophy is the major finding in MRI.ReferencesShevel M. Racial hygiene, activeeuthanasia, and Julius Hallervorden. Neurology 1992;42:2214-2219.HayflickSJ. Neurodegeneration with brain Iron accumulation: from genes to pathogenesis.Semin Pediatr Neurol 2006;13:182-185.Zhou B, Westawy SK, Levinson B, et al. A novel pantothenate kinase gene(PANK2 is defective in Hallervorden-Spatzsyndrome. Nat Genet 2001;28:345- 349.www.ncbi.nlm.nihgov/NBK111Y/university of Washington, seattle. Allison Gregory and Susan Hayflick.Paisan-Ruiz C, Li A, Schneider SA, et al. Widesread Levy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations. Neurobiol Aging 2012;33:814-823.Dick KJ, Eckhardt M, Paison-Ruiz C, et al. Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia(SPG 35. Hum Mutat 31: E1251-E1260.Edvardson S, Hama H, Shaag A, et al. Mutation in the fatty acid 2-Hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia. Am I Hum Genet 2008;83:647-648.Schneider SA, Aggarwal A, Bhatt m, et al. Severe tongue protrusion dystonia: clinical syndromes

  13. Systemic Central Nervous System (CNS)-targeted Delivery of Neuropeptide Y (NPY) Reduces Neurodegeneration and Increases Neural Precursor Cell Proliferation in a Mouse Model of Alzheimer Disease.

    Science.gov (United States)

    Spencer, Brian; Potkar, Rewati; Metcalf, Jeff; Thrin, Ivy; Adame, Anthony; Rockenstein, Edward; Masliah, Eliezer

    2016-01-22

    Neuropeptide Y (NPY) is one of the most abundant protein transmitters in the central nervous system with roles in a variety of biological functions including: food intake, cardiovascular regulation, cognition, seizure activity, circadian rhythms, and neurogenesis. Reduced NPY and NPY receptor expression is associated with numerous neurodegenerative disorders including Alzheimer disease (AD). To determine whether replacement of NPY could ameliorate some of the neurodegenerative and behavioral pathology associated with AD, we generated a lentiviral vector expressing NPY fused to a brain transport peptide (apoB) for widespread CNS delivery in an APP-transgenic (tg) mouse model of AD. The recombinant NPY-apoB effectively reversed neurodegenerative pathology and behavioral deficits although it had no effect on accumulation of Aβ. The subgranular zone of the hippocampus showed a significant increase in proliferation of neural precursor cells without further differentiation into neurons. The neuroprotective and neurogenic effects of NPY-apoB appeared to involve signaling via ERK and Akt through the NPY R1 and NPY R2 receptors. Thus, widespread CNS-targeted delivery of NPY appears to be effective at reversing the neuronal and glial pathology associated with Aβ accumulation while also increasing NPC proliferation. Overall, increased delivery of NPY to the CNS for AD might be an effective therapy especially if combined with an anti-Aβ therapeutic.

  14. rAAV-mediated delivery of brain-derived neurotrophic factor promotes neurite outgrowth and protects neurodegeneration in focal ischemic model.

    Science.gov (United States)

    Zhang, Jingyu; Yu, Zhigang; Yu, Zhiqiang; Yang, Zichao; Zhao, Hong; Liu, Luran; Zhao, Jiexu

    2011-06-20

    Stroke is one of the neurological diseases which lead to permanently neuronal damage after temporary or long-term occlusion of vessels or after heart attack. However, there are few efficient strategies to prevent or treat this kind of insult in clinical because the consequence is irreversible and could be long-lasting after the onset of stroke. Gene therapy especially using viral system has long been addressed to be of great potential to reduce the damage. Here, we generated recombinant adeno-associated virus (rAAV) carrying brain-derived neurotrophic factor (BDNF) gene. Cells infected with rAAV-BDNF could be able to produce functional BDNF which promoted neurite outgrowth and protected neurons from apoptosis induced by serum deprivation. Further more, single injection of rAAV showed neuroprotection against cell death in focal ischemic model. These results showed that rAAV-mediated gene delivery is functional, which shed light to the future application of viral system-based gene therapy in clinical.

  15. Traumatization and chronic pain: a further model of interaction

    Directory of Open Access Journals (Sweden)

    Egloff N

    2013-11-01

    Full Text Available Niklaus Egloff,1 Anna Hirschi,2 Roland von Känel1 1Department of General Internal Medicine, Division of Psychosomatic Medicine, Inselspital, University Hospital, Bern, Switzerland; 2Outpatient Clinic for Victims of Torture and War, Swiss Red Cross, Bern-Wabern, Switzerland Abstract: Up to 80% of patients with severe posttraumatic stress disorder are suffering from “unexplained” chronic pain. Theories about the links between traumatization and chronic pain have become the subject of increased interest over the last several years. We will give a short summary about the existing interaction models that emphasize particularly psychological and behavioral aspects of this interaction. After a synopsis of the most important psychoneurobiological mechanisms of pain in the context of traumatization, we introduce the hypermnesia–hyperarousal model, which focuses on two psychoneurobiological aspects of the physiology of learning. This hypothesis provides an answer to the hitherto open question about the origin of pain persistence and pain sensitization following a traumatic event and also provides a straightforward explanatory model for educational purposes. Keywords: posttraumatic stress disorder, chronic pain, hypermnesia, hypersensitivity, traumatization

  16. Protection against cognitive deficits and markers of neurodegeneration by long-term oral administration of melatonin in a transgenic model of Alzheimer disease.

    Science.gov (United States)

    Olcese, James M; Cao, Chuanhai; Mori, Takashi; Mamcarz, Malgorzata B; Maxwell, Anne; Runfeldt, Melissa J; Wang, Li; Zhang, Chi; Lin, Xiaoyang; Zhang, Guixin; Arendash, Gary W

    2009-08-01

    The neurohormone melatonin has been reported to exert anti-beta-amyloid aggregation, antioxidant, and anti-inflammatory actions in various in vitro and animal models. To comprehensively determine the potential for long-term melatonin treatment to protect Alzheimer's transgenic mice against cognitive impairment and development of beta-amyloid (Abeta) neuropathology, we administered melatonin (100 mg/L drinking water) to APP + PS1 double transgenic (Tg) mice from 2-2.5 months of age to their killing at age 7.5 months. A comprehensive behavioral battery administered during the final 6 weeks of treatment revealed that Tg mice given melatonin were protected from cognitive impairment in a variety of tasks of working memory, spatial reference learning/memory, and basic mnemonic function; Tg control mice remained impaired in all of these cognitive tasks/domains. Immunoreactive Abeta deposition was significantly reduced in hippocampus (43%) and entorhinal cortex (37%) of melatonin-treated Tg mice. Although soluble and oligomeric forms of Abeta1-40 and 1-42 were unchanged in the hippocampus and cortex of the same melatonin-treated Tg mice, their plasma Abeta levels were elevated. These Abeta results, together with our concurrent demonstration that melatonin suppresses Abeta aggregation in brain homogenates, are consistent with a melatonin-facilitated removal of Abeta from the brain. Inflammatory cytokines such as tumor necrosis factor (TNF)-alpha were decreased in hippocampus (but not plasma) of Tg+ melatonin mice. Finally, the cortical mRNA expression of three antioxidant enzymes (SOD-1, glutathione peroxidase, and catalase) was significantly reduced to non-Tg levels by long-term melatonin treatment in Tg mice. Thus, melatonin's cognitive benefits could involve its anti-Abeta aggregation, anti-inflammatory, and/or antioxidant properties. Our findings provide support for long-term melatonin therapy as a primary or complementary strategy for abating the progression of

  17. Hypersensitivity of the hippocampal CA3 region to stress-induced neurodegeneration and amyloidogenesis in a rat model of surgical menopause.

    Science.gov (United States)

    Zhang, Quan-Guang; Wang, Rui-Min; Scott, Erin; Han, Dong; Dong, Yan; Tu, Jing-Yi; Yang, Fang; Reddy Sareddy, Gangadhara; Vadlamudi, Ratna K; Brann, Darrell W

    2013-05-01

    Females who enter menopause prematurely via bilateral ovariectomy (surgical menopause) have a significantly increased risk for cognitive decline and dementia. To help elucidate the mechanisms underlying this phenomenon, we used an animal model of surgical menopause, long-term (10-week) bilateral ovariectomy in female rats. Herein, we demonstrate that long-term oestrogen deprivation dramatically increases sensitivity of the normally resistant hippocampal CA3 region to ischaemic stress, an effect that was gender-specific, as it was not observed in long-term orchiectomized males. Furthermore, the enhanced damage to the CA3 region correlated with a worse cognitive outcome after ischaemic stress. Long-term ovariectomized rats also displayed a robust hyperinduction of Alzheimer's disease-related proteins in the CA3 region and a switch in amyloid precursor protein processing from non-amyloidogenic to amyloidogenic following ischaemic stress CA3 hypersensitivity also extended to an Alzheimer's disease-relevant insult, as the CA3 region of long-term ovariectomized rats was profoundly hypersensitive to the neurotoxic effects of amyloid-β1-42, the most amyloidogenic form of the amyloid-β peptide. Additional studies revealed that CA3 region hypersensitivity, Alzheimer's disease-related protein induction, and amyloidogenesis are mediated by a NADPH oxidase/superoxide/c-Jun N-terminal kinase/c-Jun signalling pathway, involving both transcriptional and post-translational mechanisms. In addition, while 17β-oestradiol replacement at the end of the long-term oestrogen deprivation period could not prevent CA3 hypersensitivity and amyloidogenesis, if 17β-oestradiol was initiated at the time of ovariectomy and maintained throughout the 10-week oestrogen deprivation period, it completely prevented these events, providing support for the 'critical window' hypothesis for oestrogen replacement therapy benefit. Collectively, these findings may help explain the increased risk of

  18. A novel model of chronic wounds: importance of redox imbalance and biofilm-forming bacteria for establishment of chronicity.

    Directory of Open Access Journals (Sweden)

    Sandeep Dhall

    Full Text Available Chronic wounds have a large impact on health, affecting ∼6.5 M people and costing ∼$25B/year in the US alone. We previously discovered that a genetically modified mouse model displays impaired healing similar to problematic wounds in humans and that sometimes the wounds become chronic. Here we show how and why these impaired wounds become chronic, describe a way whereby we can drive impaired wounds to chronicity at will and propose that the same processes are involved in chronic wound development in humans. We hypothesize that exacerbated levels of oxidative stress are critical for initiation of chronicity. We show that, very early after injury, wounds with impaired healing contain elevated levels of reactive oxygen and nitrogen species and, much like in humans, these levels increase with age. Moreover, the activity of anti-oxidant enzymes is not elevated, leading to buildup of oxidative stress in the wound environment. To induce chronicity, we exacerbated the redox imbalance by further inhibiting the antioxidant enzymes and by infecting the wounds with biofilm-forming bacteria isolated from the chronic wounds that developed naturally in these mice. These wounds do not re-epithelialize, the granulation tissue lacks vascularization and interstitial collagen fibers, they contain an antibiotic-resistant mixed bioflora with biofilm-forming capacity, and they stay open for several weeks. These findings are highly significant because they show for the first time that chronic wounds can be generated in an animal model effectively and consistently. The availability of such a model will significantly propel the field forward because it can be used to develop strategies to regain redox balance that may result in inhibition of biofilm formation and result in restoration of healthy wound tissue. Furthermore, the model can lead to the understanding of other fundamental mechanisms of chronic wound development that can potentially lead to novel therapies.

  19. Vascular Changes and Neurodegeneration in the Early Stages of Diabetic Retinopathy

    DEFF Research Database (Denmark)

    Jonsson, Karoline Boegeberg; Frydkjaer-Olsen, Ulrik; Grauslund, Jakob

    2016-01-01

    INTRODUCTION: Neurodegeneration is an early component of diabetic retinopathy (DR). It is unclear whether neurodegeneration is an independent factor or a consequence of damaged retinal vasculature. The aims of this study were to review the literature concerning neurodegeneration in diabetic...

  20. Berberine and neurodegeneration: A review of literature.

    Science.gov (United States)

    Ahmed, Touqeer; Gilani, Anwar-Ul-Hassan; Abdollahi, Mohammad; Daglia, Maria; Nabavi, Seyed Fazel; Nabavi, Seyed Mohammad

    2015-10-01

    The excessive production of reactive oxygen species in nervous tissues is considered one of the major risk factors of neurodegenerative diseases. During the last two decades, much attention has been paid to the antioxidant and anti-inflammatory activity of natural products and compounds isolated from natural products which are often characterized by high efficacy and low adverse effects. Berberine is an isoquinoline alkaloid, widely present in different medicinal herbs, especially in the genus Berberis. It is mainly used as antidiarrhoeal, antibacterial, antifungal, and antiprotozoal agent. However, current research has focused on its beneficial role in neurodegenerative diseases, mainly due to its powerful antioxidant effect. The therapeutic potential of Berberine in different neurodegenerative diseases such as Alzheimer, Parkinson and Huntington disease has been brought to evidence by numerous studies. However, a limited number of reviews focus on the beneficial role of Berberine against neurodegeneration. The main objective of this review is to discuss the role of oxidative stress in neurodegeneration and the potential role of antioxidant compounds, in particular Berberine which is analyzed in its chemical structure, source, bioavailability, therapeutic potential, with special attention to its mechanism of action at a molecular level.

  1. Neurological Disorders in a Murine Model of Chronic Renal Failure

    Directory of Open Access Journals (Sweden)

    Jean-Marc Chillon

    2014-01-01

    Full Text Available Cardiovascular disease is highly prevalent in patients with chronic renal failure (CRF. However, data on the impact of CRF on the cerebral circulatory system are scarce—despite the fact that stroke is the third most common cause of cardiovascular death in people with CRF. In the present study, we examined the impact of CRF on behavior (anxiety, recognition and ischemic stroke severity in a well-defined murine model of CRF. We did not observe any significant increases between CRF mice and non-CRF mice in terms of anxiety. In contrast, CRF mice showed lower levels of anxiety in some tests. Recognition was not impaired (vs. controls after 6 weeks of CRF but was impaired after 10 weeks of CRF. Chronic renal failure enhances the severity of ischemic stroke, as evaluated by the infarct volume size in CRF mice after 34 weeks of CRF. Furthermore, neurological test results in non-CRF mice tended to improve in the days following ischemic stroke, whereas the results in CRF mice tended to worsen. In conclusion, we showed that a murine model of CRF is suitable for evaluating uremic toxicity and the associated neurological disorders. Our data confirm the role of uremic toxicity in the genesis of neurological abnormalities (other than anxiety.

  2. p53 prevents neurodegeneration by regulating synaptic genes.

    Science.gov (United States)

    Merlo, Paola; Frost, Bess; Peng, Shouyong; Yang, Yawei J; Park, Peter J; Feany, Mel

    2014-12-16

    DNA damage has been implicated in neurodegenerative disorders, including Alzheimer's disease and other tauopathies, but the consequences of genotoxic stress to postmitotic neurons are poorly understood. Here we demonstrate that p53, a key mediator of the DNA damage response, plays a neuroprotective role in a Drosophila model of tauopathy. Further, through a whole-genome ChIP-chip analysis, we identify genes controlled by p53 in postmitotic neurons. We genetically validate a specific pathway, synaptic function, in p53-mediated neuroprotection. We then demonstrate that the control of synaptic genes by p53 is conserved in mammals. Collectively, our results implicate synaptic function as a central target in p53-dependent protection from neurodegeneration.

  3. B cells and antibodies in progressive multiple sclerosis: Contribution to neurodegeneration and progression.

    Science.gov (United States)

    Fraussen, Judith; de Bock, Laura; Somers, Veerle

    2016-09-01

    Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination, axonal degeneration and gliosis. The progressive form of MS is an important research topic as not much is known about its underlying mechanisms and no therapy is available. Although progressive MS is traditionally considered to be driven by neurodegeneration, compartmentalized CNS inflammation is currently accepted as one of the driving processes behind neurodegeneration and progression. In this review, the involvement of B cells and antibodies in progressive MS is discussed. The identification of meningeal ectopic B cell follicles in secondary progressive MS (SPMS) patients and the successful use of B cell-depleting therapy in primary progressive MS (PPMS) patients have underlined the importance of B cells in progressive MS. Proof is also available for the role of antibodies in neurodegeneration and progression in MS. Here, oligoclonal immunoglobulin M (IgM) production and autoreactive antibodies are described, with a focus on antibodies directed against sperm-associated antigen 16 (SPAG16). Further research into the role of B cells and autoantibodies in MS progression can lead to novel prognostic and theranostic opportunities.

  4. Home-based chronic care. An expanded integrative model for home health professionals.

    Science.gov (United States)

    Suter, Paula; Hennessey, Beth; Harrison, Gregory; Fagan, Martha; Norman, Barbara; Suter, W Newton

    2008-04-01

    The Chronic Care Model (CCM) developed by is an influential and accepted guide for the care of patients with chronic disease. Wagner acknowledges a current healthcare focus on acute care needs that often circumvents chronic care coordination. He identifies the need for a "division of labor" to assist the primary care physician with this neglected function. This article posits that the role of chronic care coordination assistance and disease management fits within the purview of home healthcare and should be central to home health chronic care delivery. An expanded Home-Based Chronic Care Model (HBCCM) is described that builds on Wagner's model and integrates salient theories from fields beyond medicine. The expanded model maximizes the potential for disease self-management success and is intended to provide a foundation for home health's integral role in chronic disease management.

  5. On the global dynamics of a chronic myelogenous leukemia model

    Science.gov (United States)

    Krishchenko, Alexander P.; Starkov, Konstantin E.

    2016-04-01

    In this paper we analyze some features of global dynamics of a three-dimensional chronic myelogenous leukemia (CML) model with the help of the stability analysis and the localization method of compact invariant sets. The behavior of CML model is defined by concentrations of three cellpopulations circulating in the blood: naive T cells, effector T cells specific to CML and CML cancer cells. We prove that the dynamics of the CML system around the tumor-free equilibrium point is unstable. Further, we compute ultimate upper bounds for all three cell populations and provide the existence conditions of the positively invariant polytope. One ultimate lower bound is obtained as well. Moreover, we describe the iterative localization procedure for refining localization bounds; this procedure is based on cyclic using of localizing functions. Applying this procedure we obtain conditions under which the internal tumor equilibrium point is globally asymptotically stable. Our theoretical analyses are supplied by results of the numerical simulation.

  6. Loss of tau rescues inflammation-mediated neurodegeneration

    Directory of Open Access Journals (Sweden)

    Nicole eMaphis

    2015-06-01

    Full Text Available Neuroinflammation is one of the neuropathological hallmarks of Alzheimer’s disease (AD and related tauopathies. Activated microglia spatially coexist with microtubule-associated protein tau (Mapt or tau-burdened neurons in the brains of human AD and non-AD tauopathies. Numerous studies have suggested that neuroinflammation precedes tau pathology and that induction or blockage of neuroinflammation via lipopolysaccharide (LPS or anti-inflammatory compounds (such as FK506 accelerate or block tau pathology, respectively in several animal models of tauopathy. We have previously demonstrated that microglia-mediated neuroinflammation via deficiency of the microglia-specific chemokine (fractalkine receptor, CX3CR1, promotes tau pathology and neurodegeneration in a mouse model of LPS-induced systemic inflammation. Here, we demonstrate that tau mediates the neurotoxic effects of LPS in Cx3cr1-/- mice. First, Mapt+/+ neurons displayed elevated levels of Annexin V (A5 and TUNEL (markers of neurodegeneration when co-cultured with LPS-treated Cx3cr1-/-microglia, which is rescued in Mapt-/- neurons. Second, a neuronal population positive for phospho-S199 (AT8 tau in the dentate gyrus is also positive for activated or cleaved caspase (CC3 in the LPS-treated Cx3cr1-/- mice. Third, genetic deficiency for tau in Cx3cr1-/- mice resulted in reduced microglial activation, altered expression of inflammatory genes and a significant reduction in the number of neurons positive for CC3 compared to Cx3cr1-/- mice. Finally, Cx3cr1-/- mice exposed to LPS displayed a lack of inhibition in an open field exploratory behavioral test, which is rescued by tau deficiency. Taken together, our results suggest that pathological alterations in tau mediate inflammation-induced neurotoxicity and that deficiency of Mapt is neuroprotective. Thus, therapeutic approaches towards either reducing tau levels or blocking neuroinflammatory pathways may serve as a potential strategy in treating

  7. Rat models of asthma and chronic obstructive lung disease.

    Science.gov (United States)

    Martin, James G; Tamaoka, Meiyo

    2006-01-01

    The rat has been extensively used to model asthma and somewhat less extensively to model chronic obstructive pulmonary disease (COPD). The features of asthma that have been successfully modeled include allergen-induced airway constriction, eosinophilic inflammation and allergen-induced airway hyperresponsiveness. T-cell involvement has been directly demonstrated using adoptive transfer techniques. Both CD4+ and CD8+ T cells are activated in response to allergen challenge in the sensitized rat and express Thelper2 cytokines (IL-4, IL-5 and IL-13). Repeated allergen exposure causes airway remodeling. Dry gas hyperpnea challenge also evokes increases in lung resistance, allowing exercise-induced asthma to be modeled. COPD is modeled using elastase-induced parenchymal injury to mimic emphysema. Cigarette smoke-induced airspace enlargement occurs but requires months of cigarette exposure. Inflammation and fibrosis of peripheral airways is an important aspect of COPD that is less well modeled. Novel approaches to the treatment of COPD have been reported including treatments aimed at parenchymal regeneration.

  8. IL-17 is not essential for inflammation and chronic pelvic pain development in an experimental model of chronic prostatitis/chronic pelvic pain syndrome.

    Science.gov (United States)

    Motrich, Ruben D; Breser, María L; Sánchez, Leonardo R; Godoy, Gloria J; Prinz, Immo; Rivero, Virginia E

    2016-03-01

    Pain and inflammation in the absence of infection are hallmarks in chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) patients. The etiology of CP/CPPS is unclear, and autoimmunity has been proposed as a cause. Experimental autoimmune prostatitis (EAP) models have long been used for studying CP/CPPS. Herein, we studied prostate inflammation induction and chronic pelvic pain development in EAP using IL-12p40-KO, IL-4-KO, IL-17-KO, and wild-type (C57BL/6) mice. Prostate antigen (PAg) immunization in C57BL/6 mice induced specific Th1 and Th17 immune responses and severe prostate inflammation and cell infiltration, mainly composed of CD4 T cells and macrophages. Moreover, chronic pelvic pain was evidenced by increased allodynia responses. In immunized IL-17-KO mice, the presence of a prominent PAg-specific Th1 immune response caused similar prostate inflammation and chronic pelvic pain. Furthermore, markedly high PAg-specific Th1 immune responses, exacerbated prostate inflammation, and chronic pelvic pain were detected in immunized IL-4-KO mice. Conversely, immunized IL-12p40-KO mice developed PAg-specific Th2 immune responses, characterized by high IL-4 secretion and neither infiltration nor damage in the prostate. As observed in wild-type control animals, IL12p40-KO mice did not evidence tactile allodynia responses. Our results suggest that, as in patients, chronic pelvic pain is a consequence of prostate inflammation. After PAg immunization, a Th1-associated immune response develops and induces prostate inflammation and chronic pelvic pain. The absence of Th1 or Th2 cytokines, respectively, diminishes or enhances EAP susceptibility. In addition, IL-17 showed not to be essential for pathology induction and chronic pelvic pain development.

  9. Salt-Induced Changes in Cardiac Phosphoproteome in a Rat Model of Chronic Renal Failure

    OpenAIRE

    Zhengxiu Su; Hongguo Zhu; Menghuan Zhang; Liangliang Wang; Hanchang He; Shaoling Jiang; Fan Fan Hou; Aiqing Li

    2014-01-01

    Heart damage is widely present in patients with chronic kidney disease. Salt diet is the most important environmental factor affecting development of chronic renal failure and cardiovascular diseases. The proteins involved in chronic kidney disease -induced heart damage, especially their posttranslational modifications, remain largely unknown to date. Sprague-Dawley rats underwent 5/6 nephrectomy (chronic renal failure model) or sham operation were treated for 2 weeks with a normal-(0.4% NaCl...

  10. An optimised mouse model of chronic pancreatitis with a combination of ethanol and cerulein

    OpenAIRE

    Ahmadi, Abbas; Nikkhoo, Bahram; Mokarizadeh, Aram; Rahmani, Mohammad-Reza; Fakhari, Shohreh; Mohammadi, Mehdi; Jalili, Ali

    2016-01-01

    Introduction Chronic pancreatitis (CP) is an intractable and multi-factorial disorder. Developing appropriate animal models is an essential step in pancreatitis research, and the best ones are those which mimic the human disorder both aetiologically and pathophysiologically. The current study presents an optimised protocol for creating a murine model of CP, which mimics the initial steps of chronic pancreatitis in alcohol chronic pancreatitis and compares it with two other mouse models treate...

  11. The healthy learner model for student chronic condition management--part I.

    Science.gov (United States)

    Erickson, Cecelia DuPlessis; Splett, Patricia L; Mullett, Sara Stoltzfus; Heiman, Mary Bielski

    2006-12-01

    A significant number of children have chronic health conditions that interfere with normal activities, including school attendance and active participation in the learning process. Management of students' chronic conditions is complex and requires an integrated system. Models to improve chronic disease management have been developed for the medical system and public health. Programs that address specific chronic disease management or coordinate school health services have been implemented in schools. Lacking is a comprehensive, integrated model that links schools, students, parents, health care, and other community providers. The Healthy Learner Model for chronic condition management identifies seven elements for creating, implementing, and sustaining an efficient and effective, comprehensive community-based system for improving the management of chronic conditions for school children. It has provided the framework for successful chronic condition management in an urban school district and is proposed for replication in other districts and communities.

  12. S-nitrosation of proteins relevant to Alzheimer's disease during early stages of neurodegeneration.

    Science.gov (United States)

    Seneviratne, Uthpala; Nott, Alexi; Bhat, Vadiraja B; Ravindra, Kodihalli C; Wishnok, John S; Tsai, Li-Huei; Tannenbaum, Steven R

    2016-04-12

    Protein S-nitrosation (SNO-protein), the nitric oxide-mediated posttranslational modification of cysteine thiols, is an important regulatory mechanism of protein function in both physiological and pathological pathways. A key first step toward elucidating the mechanism by which S-nitrosation modulates a protein's function is identification of the targeted cysteine residues. Here, we present a strategy for the simultaneous identification of SNO-cysteine sites and their cognate proteins to profile the brain of the CK-p25-inducible mouse model of Alzheimer's disease-like neurodegeneration. The approach-SNOTRAP (SNO trapping by triaryl phosphine)-is a direct tagging strategy that uses phosphine-based chemical probes, allowing enrichment of SNO-peptides and their identification by liquid chromatography tandem mass spectrometry. SNOTRAP identified 313 endogenous SNO-sites in 251 proteins in the mouse brain, of which 135 SNO-proteins were detected only during neurodegeneration. S-nitrosation in the brain shows regional differences and becomes elevated during early stages of neurodegeneration in the CK-p25 mouse. The SNO-proteome during early neurodegeneration identified increased S-nitrosation of proteins important for synapse function, metabolism, and Alzheimer's disease pathology. In the latter case, proteins related to amyloid precursor protein processing and secretion are S-nitrosated, correlating with increased amyloid formation. Sequence analysis of SNO-cysteine sites identified potential linear motifs that are altered under pathological conditions. Collectively, SNOTRAP is a direct tagging tool for global elucidation of the SNO-proteome, providing functional insights of endogenous SNO proteins in the brain and its dysregulation during neurodegeneration.

  13. Myeloperoxidase: Bridging the gap in neurodegeneration.

    Science.gov (United States)

    Ray, R S; Katyal, Anju

    2016-09-01

    Neurodegenerative conditions present a group of complex disease pathologies mostly due to unknown aetiology resulting in neuronal death and permanent neurological disability. Any undesirable stress to the brain, disrupts homeostatic balance, through a remarkable convergence of pathophysiological changes and immune dysregulation. The crosstalk between inflammatory and oxidative mechanisms results in the release of neurotoxic mediators apparently spearheaded by myeloperoxidase derived from activated microglia, astrocytes, neurons as well as peripheral inflammatory cells. These isolated entities combinedly have the potential to flare up and contribute significantly to neuropathology and disease progression. Recent, clinicopathological evidence support the association of myeloperoxidase and its cytotoxic product, hypochlorous acid in a plethora of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, Stroke, Epilepsy etc. But the biochemical and mechanistic insights into myeloperoxidase mediated neuroinflammation and neuronal death is still an uncharted territory. The current review outlines the emerging recognition of myeloperoxidase in neurodegeneration, which may offer novel therapeutic and diagnostic targets for neurodegenerative disorders.

  14. Biology and genetics of prions causing neurodegeneration.

    Science.gov (United States)

    Prusiner, Stanley B

    2013-01-01

    Prions are proteins that acquire alternative conformations that become self-propagating. Transformation of proteins into prions is generally accompanied by an increase in β-sheet structure and a propensity to aggregate into oligomers. Some prions are beneficial and perform cellular functions, whereas others cause neurodegeneration. In mammals, more than a dozen proteins that become prions have been identified, and a similar number has been found in fungi. In both mammals and fungi, variations in the prion conformation encipher the biological properties of distinct prion strains. Increasing evidence argues that prions cause many neurodegenerative diseases (NDs), including Alzheimer's, Parkinson's, Creutzfeldt-Jakob, and Lou Gehrig's diseases, as well as the tauopathies. The majority of NDs are sporadic, and 10% to 20% are inherited. The late onset of heritable NDs, like their sporadic counterparts, may reflect the stochastic nature of prion formation; the pathogenesis of such illnesses seems to require prion accumulation to exceed some critical threshold before neurological dysfunction manifests.

  15. Toll-like receptors in neurodegeneration

    DEFF Research Database (Denmark)

    Owens, Trevor

    2009-01-01

    Innate pattern recognition receptors are implicated in first-line defense against pathogens but also participate in maintenance of tissue homeostasis and response to injury. This chapter reviews the role of Toll-like receptors (TLRs) in neuronal and glial responses that are associated with neurod......Innate pattern recognition receptors are implicated in first-line defense against pathogens but also participate in maintenance of tissue homeostasis and response to injury. This chapter reviews the role of Toll-like receptors (TLRs) in neuronal and glial responses that are associated...... with neurodegeneration. Accompanying roles for infection and inflammation, involvement in clinical neurodegenerative disorders, and heterogeneity of glial response are discussed. A "strength of signal" hypothesis is advanced in an attempt to reconcile evolutionarily selected and therefore likely beneficial effects...

  16. Somatic mutations in aging, cancer and neurodegeneration.

    Science.gov (United States)

    Kennedy, Scott R; Loeb, Lawrence A; Herr, Alan J

    2012-04-01

    The somatic mutation theory of aging posits that the accumulation of mutations in the genetic material of somatic cells as a function of time results in a decrease in cellular function. In particular, the accumulation of random mutations may inactivate genes that are important for the functioning of the somatic cells of various organ systems of the adult, result in a decrease in organ function. When the organ function decreases below a critical level, death occurs. A significant amount of research has shown that somatic mutations play an important role in aging and a number of age related pathologies. In this review, we explore evidence for increases in somatic nuclear mutation burden with age and the consequences for aging, cancer, and neurodegeneration. We then review evidence for increases in mitochondrial mutation burden and the consequences for dysfunction in the disease processes.

  17. Adapting chronic care models for diabetes care delivery inlow-and-middle-income countries: A review

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    A contextual review of models for chronic care was doneto develop a context-adapted chronic care model-basedservice delivery model for chronic conditions includingdiabetes. The Philippines was used as the setting ofa low-to-middle-income country. A context-basednarrative review of existing models for chronic carewas conducted. A situational analysis was done at thegrassroots level, involving the leaders and members ofthe community, the patients, the local health system andthe healthcare providers. A second analysis making useof certain organizational theories was done to explore onimproving feasibility and acceptability of organizing carefor chronic conditions. The analyses indicated that carefor chronic conditions may be introduced, consideringthe needs of people with diabetes in particular andthe community in general as recipients of care, andthe issues and factors that may affect the healthcareworkers and the health system as providers of thiscare. The context-adapted chronic care model-basedservice delivery model was constructed accordingly.Key features are incorporation of chronic care in thehealth system's services; assimilation of chronic caredelivery with the other responsibilities of the healthcareworkers but with redistribution of certain tasks; andensuring that the recipients of care experience thewhole spectrum of basic chronic care that includes educationand promotion in the general population, riskidentification, screening, counseling including self-caredevelopment, and clinical management of the chroniccondition and any co-morbidities, regardless of level ofcontrol of the condition. This way, low-to-middle incomecountries can introduce and improve care for chronicconditions without entailing much additional demand ontheir limited resources.

  18. Interconnection between brain and retinal neurodegenerations.

    Science.gov (United States)

    Jindal, Vishal

    2015-01-01

    The eye is a special sensory organ, which is basically an extension of the brain. Both are derived from neural tube and consist of neurons. Therefore, diseases of both the brain and eye should have some similarity. Neurodegenerative disorders like Alzheimer's disease (AD) is the major cause of dementia in the world. Amyloid deposition in the cerebral cortex and hippocampal region is the basic pathology in AD. But along with it, there are various changes that take place in the eye, i.e., abnormal pupillary reaction, decreased vision, decreased contrast sensitivity, visual field changes, loss of retinal ganglionic cells and retinal fiber layer, peripapillary atrophy, increased cup-disk ratio, retinal thinning, tortuosity of blood vessels, and deposition of Aβ-like substance in the retina. And these changes are present in the early part of the disease when only mild cognitive impairment is there. As the brain is covered by a hard bony skull which makes it difficult to directly visualize the changes occurring in the brain at molecular levels, finer details of disease progression are not available with us. But the eye is the window of the brain; with advanced modern techniques, we can directly visualize the changes in the retina at a very fine level. Therefore, by depicting neurodegenerative changes in the eye, we can diagnose and manage AD at very early stages. Along with it, retinal neurodegenerations like glaucoma and age-related macular degeneration (ARMD) are the major cause of loss of vision, and still, there are no effective treatment modalities for these blinding conditions. So if we can understand its pathogenesis and progression by correlating with brain neurodegenerations, we can come up with a better therapy for glaucoma and ARMD.

  19. Rapamycin is neuroprotective in a rat chronic hypertensive glaucoma model.

    Directory of Open Access Journals (Sweden)

    Wenru Su

    Full Text Available Glaucoma is a leading cause of irreversible blindness. Injury of retinal ganglion cells (RGCs accounts for visual impairment of glaucoma. Here, we report rapamycin protects RGCs from death in experimental glaucoma model and the underlying mechanisms. Our results showed that treatment with rapamycin dramatically promote RGCs survival in a rat chronic ocular hypertension model. This protective action appears to be attributable to inhibition of neurotoxic mediators release and/or direct suppression of RGC apoptosis. In support of this mechanism, in vitro, rapamycin significantly inhibits the production of NO, TNF-α in BV2 microglials by modulating NF-κB signaling. In experimental animals, treatment with rapamycin also dramatically inhibited the activation of microglials. In primary RGCs, rapamycin was capable of direct suppression the apoptosis of primary RGCs induced by glutamate. Mechanistically, rapamycin-mediated suppression of RGCs apoptosis is by sparing phosphorylation of Akt at a site critical for maintenance of its survival-promoting activity in cell and animal model. These results demonstrate that rapamycin is neuroprotective in experimental glaucoma, possibly via decreasing neurotoxic releasing and suppressing directly apoptosis of RGCs.

  20. Nitric oxide synthase inhibitor, aminoguanidine reduces intracerebroventricular colchicine induced neurodegeneration, memory impairments and changes of systemic immune responses in rats.

    Science.gov (United States)

    Sil, Susmita; Ghosh, Tusharkanti; Ghosh, Rupsa; Gupta, Pritha

    2017-02-15

    Intracerebroventricular (i.c.v.) injection of colchicine induces neurodegeneration, memory impairments and changes of some systemic immune responses in rats. Though the role of cox 2 in these colchicine induced changes have been evaluated, the influence of nitric oxide synthase (NOS) remains to be studied. The present study was designed to assess the role of NOS on the i.c.v. colchicine induced neurodegeneration, memory impairments and changes of some systemic immune responses by inhibiting its activity with aminoguanidine. In the present study the impairments of working and reference memories, neurodegeneration (chromatolysis and plaque formation) and changes of neuroinflammatory markers in the hippocampus (increased TNF α, IL 1β, ROS and nitrite) along with changes of serum inflammatory markers (TNF α, IL 1β, ROS and nitrite) and alteration of systemic immune responses (higher phagocytic activity of blood WBC and splenic PMN, higher cytotoxicity and lower leukocyte adhesion inhibition index of splenic MNC) were measured in the intracerebroventricular colchicine injected rats (ICIR). Administration of aminoguanidine (p.o. 30/50mg/kg body weight) to ICIR resulted in recovery of neuroinflammation and partial prevention of neurodegeneration which could be corroborated with the partial recovery of memory impairments in this model. The recovery of serum inflammatory markers and the systemic immune responses in ICIR was also observed after administration of aminoguanidine. Therefore, the present study shows that aminoguanidine can protect the colchicine induced neurodegeneration, memory impairments, and changes of systemic immune systemic responses in ICIR by inhibiting the iNOS.

  1. Chronic GluN2B antagonism disrupts behavior in wild-type mice without protecting against synapse loss or memory impairment in Alzheimer's disease mouse models.

    Science.gov (United States)

    Hanson, Jesse E; Meilandt, William J; Gogineni, Alvin; Reynen, Paul; Herrington, James; Weimer, Robby M; Scearce-Levie, Kimberly; Zhou, Qiang

    2014-06-11

    Extensive evidence implicates GluN2B-containing NMDA receptors (GluN2B-NMDARs) in excitotoxic-insult-induced neurodegeneration and amyloid β (Aβ)-induced synaptic dysfunction. Therefore, inhibiting GluN2B-NMDARs would appear to be a potential therapeutic strategy to provide neuroprotection and improve cognitive function in Alzheimer's disease (AD). However, there are no reports of long-term in vivo treatment of AD mouse models with GluN2B antagonists. We used piperidine18 (Pip18), a potent and selective GluN2B-NMDAR antagonist with favorable pharmacokinetic properties, for long-term dosing in AD mouse models. Reduced freezing behavior in Tg2576 mice during fear conditioning was partially reversed after subchronic (17 d) Pip18 treatment. However, analysis of freezing behavior in different contexts indicated that this increased freezing likely involves elevated anxiety or excessive memory generalization in both nontransgenic (NTG) and Tg2576 mice. In PS2APP mice chronically fed with medicated food containing Pip18 for 4 months, spatial learning and memory deficits were not rescued, plaque-associated spine loss was not affected, and synaptic function was not altered. At the same time, altered open field activity consistent with increased anxiety and degraded performance in an active avoidance task were observed in NTG after chronic treatment. These results indicate that long-term treatment with a GluN2B-NMDAR antagonist does not provide a disease-modifying benefit and could cause cognitive liabilities rather than symptomatic benefit in AD mouse models. Therefore, these results challenge the expectation of the therapeutic potential for GluN2B-NMDAR antagonists in AD.

  2. Managing painful chronic wounds: the Wound Pain Management Model

    DEFF Research Database (Denmark)

    Price, Patricia; Fogh, Karsten; Glynn, Chris;

    2007-01-01

    document persistent wound pain and not to develop a treatment and monitoring strategy to improve the lives of persons with chronic wounds. Unless wound pain is optimally managed, patient suffering and costs to health care systems will increase. Udgivelsesdato: 2007-Apr......Chronic wound pain is not well understood and the literature is limited. Six of 10 patients venous leg ulcer experience pain with their ulcer, and similar trends are observed for other chronic wounds. Chronic wound pain can lead to depression and the feeling of constant tiredness. Pain related...... to the wound should be handled as one of the main priorities in chronic wound management together with addressing the cause. Management of pain in chronic wounds depends on proper assessment, reporting and documenting patient experiences of pain. Assessment should be based on six critical dimensions...

  3. Automated EEG monitoring in defining a chronic epilepsy model.

    Science.gov (United States)

    Mascott, C R; Gotman, J; Beaudet, A

    1994-01-01

    There has been a recent surge of interest in chronic animal models of epilepsy. Proper assessment of these models requires documentation of spontaneous seizures by EEG, observation, or both in each individual animal to confirm the presumed epileptic condition. We used the same automatic seizure detection system as that currently used for patients in our institution and many others. Electrodes were implanted in 43 rats before intraamygdalar administration of kainic acid (KA). Animals were monitored intermittently for 3 months. Nine of the rats were protected by anticonvulsants [pentobarbital (PB) and diazepam (DZP)] at the time of KA injection. Between 1 and 3 months after KA injection, spontaneous seizures were detected in 20 of the 34 unprotected animals (59%). Surprisingly, spontaneous seizures were also detected during the same period in 2 of the 9 protected animals that were intended to serve as nonepileptic controls. Although the absence of confirmed spontaneous seizures in the remaining animals cannot exclude their occurrence, it indicates that, if present, they are at least rare. On the other hand, definitive proof of epilepsy is invaluable in the attempt to interpret pathologic data from experimental brains.

  4. 5-lipoxygenase expression in a brain damage model induced by chronic oral administration of aluminum

    Institute of Scientific and Technical Information of China (English)

    Yongquan Pan; Peng Zhang; Junqing Yang; Qiang Su

    2010-01-01

    A preliminary study has found that the 5-lipoxygenase inhibitor, caffeic acid, has a marked protective effect on acute brain injury induced by intracerebroventricular microinjection of aluminum.In this experiment, chronic brain injury and neuronal degeneration model was established in rats by chronic oral administration of aluminum, and then intervened using caffeic acid. Results showed that caffeic acid can downregulate chronic aluminum overload-induced 5-lipoxygenase mRNA and protein expression, and repair the aluminum overload-induced hippocampal neuronal damage andspatial orientation impairment. It is suggested that direct intervention of 5-lipoxygenase expression has a neuroprotective role in the degeneration induced by chronic aluminum overload brain injury model.

  5. Role of neuroinflammation in neurodegeneration: new insights.

    Science.gov (United States)

    McManus, Róisín M; Heneka, Michael T

    2017-03-04

    Previously, the contribution of peripheral infection to cognitive decline was largely overlooked however, the past 15 years have established a key role for infectious pathogens in the progression of age-related neurodegeneration. It is now accepted that the immune privilege of the brain is not absolute, and that cells of the central nervous system are sensitive to both the inflammatory events occurring in the periphery and to the infiltration of peripheral immune cells. This is particularly relevant for the progression of Alzheimer's disease, in which it has been demonstrated that patients are more vulnerable to infection-related cognitive changes. This can occur from typical infectious challenges such as respiratory tract infections, although a number of specific viral, bacterial, and fungal pathogens have also been associated with the development of the disease. To date, it is not clear whether these microorganisms are directly related to Alzheimer's disease progression or if they are opportune pathogens that easily colonize those with dementia and exacerbate the ongoing inflammation observed in these individuals. This review will discuss the impact of each of these challenges, and examine the changes known to occur with age in the peripheral immune system, which may contribute to the age-related vulnerability to infection-induced cognitive decline.

  6. Oligodendroglia and neurotrophic factors in neurodegeneration

    Institute of Scientific and Technical Information of China (English)

    Andrew N.Bankston; Mariana D.Mandler; Yue Feng

    2013-01-01

    Myelination by oligodendroglial cells (OLs) enables the propagation of action potentials along neuronal axons,which is essential for rapid information flow in the central nervous system.Besides saltatory conduction,the myelin sheath also protects axons against inflammatory and oxidative insults.Loss of myelin results in axonal damage and ultimately neuronal loss in demyelinating disorders.However,accumulating evidence indicates that OLs also provide support to neurons via mechanisms beyond the insulating function of myelin.More importantly,an increasing volume of reports indicates defects of OLs in numerous neurodegenerative diseases,sometimes even preceding neuronal loss in pre-symptomatic episodes,suggesting that OL pathology may be an important mechanism contributing to the initiation and/or progression of neurodegeneration.This review focuses on the emerging picture of neuronal support by OLs in the pathogenesis of neurodegenerative disorders through diverse molecular and cellular mechanisms,including direct neuron-myelin interaction,metabolic support by OLs,and neurotrophic factors produced by and/or acting on OLs.

  7. Post-translational modifications in neurodegeneration

    Directory of Open Access Journals (Sweden)

    Federico Benetti

    2015-12-01

    Full Text Available Post-translational modifications increase proteome functionality for managing all aspects of normal cell biology. They are based on the covalent attachment of functional groups, leading to phosphorylation, acetylation, glycosylation, acylation, ubiquitination, SUMOylation and oxidation of protein targets. Post-translational modifications occur at any step of protein life cycle, modulating in time and space protein folding, subcellular localization and activity. Aberrant post-translational modifications of one or more culprit proteins may lead to neurodegeneration, as shown in paradigmatic neurological disorders such as Alzheimer’s, Parkinson’s and prion diseases. In this review, we report the most important post-translational modifications found in neurodegenerative disorders, illustrating the pathophysiological mechanisms in which they are involved. This work highlights the lack of a global framework of post-translational modifications in terms of complexity and regulation. Therefore, in the next future many efforts are required to describe the interplay existing between post-translational modifications and their combinatorial patterns on protein targets.

  8. Kainic Acid-Induced Excitotoxicity Experimental Model: Protective Merits of Natural Products and Plant Extracts

    Directory of Open Access Journals (Sweden)

    Nur Shafika Mohd Sairazi

    2015-01-01

    Full Text Available Excitotoxicity is well recognized as a major pathological process of neuronal death in neurodegenerative diseases involving the central nervous system (CNS. In the animal models of neurodegeneration, excitotoxicity is commonly induced experimentally by chemical convulsants, particularly kainic acid (KA. KA-induced excitotoxicity in rodent models has been shown to result in seizures, behavioral changes, oxidative stress, glial activation, inflammatory mediator production, endoplasmic reticulum stress, mitochondrial dysfunction, and selective neurodegeneration in the brain upon KA administration. Recently, there is an emerging trend to search for natural sources to combat against excitotoxicity-associated neurodegenerative diseases. Natural products and plant extracts had attracted a considerable amount of attention because of their reported beneficial effects on the CNS, particularly their neuroprotective effect against excitotoxicity. They provide significant reduction and/or protection against the development and progression of acute and chronic neurodegeneration. This indicates that natural products and plants extracts may be useful in protecting against excitotoxicity-associated neurodegeneration. Thus, targeting of multiple pathways simultaneously may be the strategy to maximize the neuroprotection effect. This review summarizes the mechanisms involved in KA-induced excitotoxicity and attempts to collate the various researches related to the protective effect of natural products and plant extracts in the KA model of neurodegeneration.

  9. Mathematical modeling of genesis and treatment of chronic myeloid leukemia.

    Science.gov (United States)

    Horn, Matthias; Loeffler, Markus; Roeder, Ingo

    2008-01-01

    Chronic myeloid leukemia (CML) is a clonal hematopoietic disorder induced by translocation of chromosomes 9 and 22, resulting in an overproduction of myeloid blood cells. CML-specific characteristics include a latency time of several years, a period of coexistence of malignant and normal cells and an eventual dominance of the malignant clone. Different drug therapies are available, most notably imatinib, which inhibits the oncogenic BCR-ABL1 tyrosine kinase. Although the chromosomal aberration causing CML is well known, the resulting dynamic effects on the system behavior are not sufficiently understood yet. Here, we apply an already established mathematical model of hematopoietic stem cell organization. Based on parameter estimates for normal hematopoiesis, we systematically explore the changes in these parameters necessary to reproduce CML-specific characteristics regarding emergence and course of disease as well as a variety of qualitative and quantitative clinical data on CML treatment. Our results indicate that 1 or more of the following mechanisms are compatible with the induction of a dominant clone in the proposed model: a retarded differentiation process, a reduced turnover time or a defective cell-microenvironment interaction of the neoplastic cells. However, in order to explain the massive overproduction of malignant cells, an unregulated and abnormal activation of leukemia stem cells into cycle has to be assumed additionally. Based on our simulation results we conclude that CML dynamics can most appropriately be explained by a modulation of the cell-microenvironment interactions of leukemia stem cells, including both the process of stem cell silencing and activation into cycle.

  10. Pediatric Fear-Avoidance Model of Chronic Pain: Foundation, Application and Future Directions

    Directory of Open Access Journals (Sweden)

    Gordon JG Asmundson

    2012-01-01

    Full Text Available The fear-avoidance model of chronic musculoskeletal pain has become an increasingly popular conceptualization of the processes and mechanisms through which acute pain can become chronic. Despite rapidly growing interest and research regarding the influence of fear-avoidance constructs on pain-related disability in children and adolescents, there have been no amendments to the model to account for unique aspects of pediatric chronic pain. A comprehensive understanding of the role of fear-avoidance in pediatric chronic pain necessitates understanding of both child/adolescent and parent factors implicated in its development and maintenance. The primary purpose of the present article is to propose an empirically-based pediatric fear-avoidance model of chronic pain that accounts for both child/adolescent and parent factors as well as their potential interactive effects. To accomplish this goal, the present article will define important fear-avoidance constructs, provide a summary of the general fear-avoidance model and review the growing empirical literature regarding the role of fear-avoidance constructs in pediatric chronic pain. Assessment and treatment options for children with chronic pain will also be described in the context of the proposed pediatric fear-avoidance model of chronic pain. Finally, avenues for future investigation will be proposed.

  11. In vivo protection against NMDA-induced neurodegeneration by MK-801 and nimodipine : Combined therapy and temporal course of protection

    NARCIS (Netherlands)

    Stuiver, BT; Douma, BRK; Bakker, R; Nyakas, C; Luiten, PGM

    1996-01-01

    Neuroprotection against excitotoxicity by a combined therapy with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and the L-type Ca2+ channel blocker nimodipine was examined using an in vivo rat model of NMDA-induced neurodegeneration. Attention was focused on the neuroprotective potentia

  12. NP031112, a thiadiazolidinone compound, prevents inflammation and neurodegeneration under excitotoxic conditions: potential therapeutic role in brain disorders.

    Science.gov (United States)

    Luna-Medina, Rosario; Cortes-Canteli, Marta; Sanchez-Galiano, Susana; Morales-Garcia, Jose A; Martinez, Ana; Santos, Angel; Perez-Castillo, Ana

    2007-05-23

    Inflammation and neurodegeneration coexist in many acute damage and chronic CNS disorders (e.g., stroke, Alzheimer's disease, Parkinson's disease). A well characterized animal model of brain damage involves administration of kainic acid, which causes limbic seizure activity and subsequent neuronal death, especially in the CA1 and CA3 pyramidal cells and interneurons in the hilus of the hippocampus. Our previous work demonstrated a potent anti-inflammatory and neuroprotective effect of two thiadiazolidinones compounds, NP00111 (2,4-dibenzyl-[1,2,4]thiadiazolidine-3,5-dione) and NP01138 (2-ethyl-4-phenyl-[1,2,4]thiadiazolidine-3,5-dione), in primary cultures of cortical neurons, astrocytes, and microglia. Here, we show that injection of NP031112, a more potent thiadiazolidinone derivative, into the rat hippocampus dramatically reduces kainic acid-induced inflammation, as measured by edema formation using T2-weighted magnetic resonance imaging and glial activation and has a neuroprotective effect in the damaged areas of the hippocampus. Last, NP031112-induced neuroprotection, both in vitro and in vivo, was substantially attenuated by cotreatment with GW9662 (2-chloro-5-nitrobenzanilide), a known antagonist of the nuclear receptor peroxisome proliferator-activated receptor gamma, suggesting that the effects of NP031112 can be mediated through activation of this receptor. As such, these findings identify NP031112 as a potential therapeutic agent for the treatment of neurodegenerative disorders.

  13. Interactions between Calcium and Alpha-Synuclein in Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Alex Rcom-H'cheo-Gauthier

    2014-08-01

    Full Text Available In Parkinson’s disease and some atypical Parkinson’s syndromes, aggregation of the α-synuclein protein (α-syn has been linked to neurodegeneration. Many triggers for pathological α-syn aggregation have been identified, including port-translational modifications, oxidative stress and raised metal ions, such as Ca2+. Recently, it has been found using cell culture models that transient increases of intracellular Ca2+ induce cytoplasmic α-syn aggregates. Ca2+-dependent α-syn aggregation could be blocked by the Ca2+ buffering agent, BAPTA-AM, or by the Ca2+ channel blocker, Trimethadione. Furthermore, a greater proportion of cells positive for aggregates occurred when both raised Ca2+ and oxidative stress were combined, indicating that Ca2+ and oxidative stress cooperatively promote α-syn aggregation. Current on-going work using a unilateral mouse lesion model of Parkinson’s disease shows a greater proportion of calbindin-positive neurons survive the lesion, with intracellular α-syn aggregates almost exclusively occurring in calbindin-negative neurons. These and other recent findings are reviewed in the context of neurodegenerative pathologies and suggest an association between raised Ca2+, α-syn aggregation and neurotoxicity.

  14. Molecular pathways underpinning ethanol-induced neurodegeneration

    Directory of Open Access Journals (Sweden)

    Dan eGoldowitz*

    2014-07-01

    -induced neurodegeneration.

  15. Evaluation of chronic immune system stimulation models in growing pigs.

    Science.gov (United States)

    Rakhshandeh, A; de Lange, C F M

    2012-02-01

    substantial reductions in feed intake and ADG, whereas MYCO did not induce effective ISS. In EXP II, ISS increased relative organ weights, eye temperature, white blood cell count and plasma acute-phase proteins (P < 0.05), confirming that repeated injection with increasing amounts of LPS induced chronic and relatively mild ISS. Repeated injection with increasing amounts of LPS is a suitable model for studying nutrient metabolism and evaluating the efficacy of nutritional intervention during chronic ISS in growing pigs.

  16. Using protein misfolding cyclic amplification generates a highly neurotoxic PrP dimer causing neurodegeneration.

    Science.gov (United States)

    Yang, XiuJin; Yang, LiFeng; Zhou, XiangMei; Khan, Sher Hayat; Wang, HuiNuan; Yin, XiaoMin; Yuan, Zhen; Song, ZhiQi; Wu, WenYu; Zhao, DeMing

    2013-11-01

    Under the "protein-only" hypothesis, prion-based diseases are proposed to result from an infectious agent that is an abnormal isoform of the prion protein in the scrapie form, PrP(Sc). However, since PrP(Sc) is highly insoluble and easily aggregates in vivo, this view appears to be overly simplistic, implying that the presence of PrP(Sc) may indirectly cause neurodegeneration through its intermediate soluble form. We generated a neurotoxic PrP dimer with partial pathogenic characteristics of PrP(Sc) by protein misfolding cyclic amplification in the presence of 1-palmitoyl-2-oleoylphosphatidylglycerol consisting of recombinant hamster PrP (23-231). After intracerebral injection of the PrP dimer, wild-type hamsters developed signs of neurodegeneration. Clinical symptoms, necropsy findings, and histopathological changes were very similar to those of transmissible spongiform encephalopathies. Additional investigation showed that the toxicity is primarily related to cellular apoptosis. All results suggested that we generated a new neurotoxic form of PrP, PrP dimer, which can cause neurodegeneration. Thus, our study introduces a useful model for investigating PrP-linked neurodegenerative mechanisms.

  17. Calcium influx and calpain activation mediate preclinical retinal neurodegeneration in autoimmune optic neuritis.

    Science.gov (United States)

    Hoffmann, Dorit B; Williams, Sarah K; Bojcevski, Jovana; Müller, Andreas; Stadelmann, Christine; Naidoo, Vinogran; Bahr, Ben A; Diem, Ricarda; Fairless, Richard

    2013-08-01

    Optic neuritis is a common manifestation of multiple sclerosis, an inflammatory demyelinating disease of the CNS. Recently, the neurodegenerative component of multiple sclerosis has come under focus particularly because permanent disability in patients correlates well with neurodegeneration; and observations in both humans and multiple sclerosis animal models highlight neurodegeneration of retinal ganglion cells as an early event. After myelin oligodendrocyte glycoprotein immunization of Brown Norway rats, significant retinal ganglion cell loss precedes the onset of pathologically defined autoimmune optic neuritis. To study the role calcium and calpain activation may play in mediating early degeneration, manganese-enhanced magnetic resonance imaging was used to monitor preclinical calcium elevations in the retina and optic nerve of myelin oligodendrocyte glycoprotein-immunized Brown Norway rats. Calcium elevation correlated with an increase in calpain activation during the induction phase of optic neuritis, as revealed by increased calpain-specific cleavage of spectrin. The relevance of early calpain activation to neurodegeneration during disease induction was addressed by performing treatment studies with the calpain inhibitor calpeptin. Treatment not only reduced calpain activity but also protected retinal ganglion cells from preclinical degeneration. These data indicate that elevation of retinal calcium levels and calpain activation are early events in autoimmune optic neuritis, providing a potential therapeutic target for neuroprotection.

  18. Metal and Microelement Biomarkers of Neurodegeneration in Early Life Permethrin-Treated Rats

    Directory of Open Access Journals (Sweden)

    Cinzia Nasuti

    2016-01-01

    Full Text Available Hair is a non-invasive biological material useful in the biomonitoring of trace elements because it is a vehicle for substance excretion from the body, and it permits evaluating long-term metal exposure. Here, hair from an animal model of neurodegeneration, induced by early life permethrin treatment from the sixth to 21th day of life, has been analyzed with the aim to assess if metal and microelement content could be used as biomarkers. A hair trace element assay was performed by the ICP-MS technique in six- and 12-month-old rats. A significant increase of As, Mg, S and Zn was measured in the permethrin-treated group at 12 months compared to six months, while Si and Cu/Zn were decreased. K, Cu/Zn and S were increased in the treated group compared to age-matched controls at six and 12 months, respectively. Cr significantly decreased in the treated group at 12 months. PCA analysis showed both a best difference between treated and age-matched control groups at six months. The present findings support the evidence that the Cu/Zn ratio and K, measured at six months, are the best biomarkers for neurodegeneration. This study supports the use of hair analysis to identify biomarkers of neurodegeneration induced by early life permethrin pesticide exposure.

  19. Characterization of a new rat model for chronic inflammatory demyelinating polyneuropathies.

    Science.gov (United States)

    Brun, Susana; Beaino, Wissam; Kremer, Laurent; Taleb, Omar; Mensah-Nyagan, Ayikoe Guy; Lam, Chanh D; Greer, Judith M; de Seze, Jérôme; Trifilieff, Elisabeth

    2015-01-15

    Our objective was to develop a chronic model of EAN which could be used as a tool to test treatment strategies for CIDP. Lewis rats injected with S-palmitoylated P0(180-199) peptide developed a chronic, sometimes relapsing-remitting type of disease. Our model fulfills electrophysiological criteria of demyelination with axonal degeneration, confirmed by immunohistopathology. The late phase of the chronic disease was characterized by accumulation of IL-17(+) cells and macrophages in sciatic nerves and by high serum IL-17 levels. In conclusion, we have developed a reliable and reproducible animal model resembling CIDP that can now be used for translational drug studies.

  20. Neurodegeneration in ataxia-telangiectasia is caused by horror autotoxicus.

    Science.gov (United States)

    Kuljis, R O; Aguila, M C

    1999-05-01

    Ataxia-telangiectasia (A-T) is a pleiotropic, multi-system disorder with manifestations that include immune deficiency, sensitivity to ionizing radiation and neoplasms. Many of these manifestations are understood in principle since the identification in A-T patients of mutations in a gene encoding a protein kinase that plays a key role in signaling and repair of DNA damage. However, the cause of the neurodegeneration that afflicts patients with A-T for at least a decade before they succumb to overwhelming infections or malignancy remains mysterious. Based on our work in a mouse model of A-T and previous evidence of extra-neural autoimmune disorders in A-T, we postulate that the neurodegenerative process in A-T is not due to a function for A-T mutated (ATM) essential for the postnatal brain, but to an autoimmune process (hence 'horror autotoxicus', Paul Ehrlich's term for autoimmune disorder). This hypothetical mechanism may be analogous to that in the so-called 'paraneoplastic' neurodegenerative syndromes in patients with various malignancies. Thus, alterations in the balance between cellular and humoral immunity in A-T probably result in autoantibodies to cerebral epitopes shared with cells of the immune system. This hypothesis has important implications for the understanding and development of effective palliative and even preventative strategies for A-T, and probably for other so far relentlessly progressive neurodegenerative disorders.

  1. Cystathionine γ-lyase deficiency mediates neurodegeneration in Huntington's disease.

    Science.gov (United States)

    Paul, Bindu D; Sbodio, Juan I; Xu, Risheng; Vandiver, M Scott; Cha, Jiyoung Y; Snowman, Adele M; Snyder, Solomon H

    2014-05-01

    Huntington's disease is an autosomal dominant disease associated with a mutation in the gene encoding huntingtin (Htt) leading to expanded polyglutamine repeats of mutant Htt (mHtt) that elicit oxidative stress, neurotoxicity, and motor and behavioural changes. Huntington's disease is characterized by highly selective and profound damage to the corpus striatum, which regulates motor function. Striatal selectivity of Huntington's disease may reflect the striatally selective small G protein Rhes binding to mHtt and enhancing its neurotoxicity. Specific molecular mechanisms by which mHtt elicits neurodegeneration have been hard to determine. Here we show a major depletion of cystathionine γ-lyase (CSE), the biosynthetic enzyme for cysteine, in Huntington's disease tissues, which may mediate Huntington's disease pathophysiology. The defect occurs at the transcriptional level and seems to reflect influences of mHtt on specificity protein 1, a transcriptional activator for CSE. Consistent with the notion of loss of CSE as a pathogenic mechanism, supplementation with cysteine reverses abnormalities in cultures of Huntington's disease tissues and in intact mouse models of Huntington's disease, suggesting therapeutic potential.

  2. Molecular basis of neurodegeneration and neurodevelopmental defects in Menkes disease.

    Science.gov (United States)

    Zlatic, Stephanie; Comstra, Heather Skye; Gokhale, Avanti; Petris, Michael J; Faundez, Victor

    2015-09-01

    ATP7A mutations impair copper metabolism resulting in three distinct genetic disorders in humans. These diseases are characterized by neurological phenotypes ranging from intellectual disability to neurodegeneration. Severe ATP7A loss-of-function alleles trigger Menkes disease, a copper deficiency condition where systemic and neurodegenerative phenotypes dominate clinical outcomes. The pathogenesis of these manifestations has been attributed to the hypoactivity of a limited number of copper-dependent enzymes, a hypothesis that we refer as the oligoenzymatic pathogenic hypothesis. This hypothesis, which has dominated the field for 25 years, only explains some systemic Menkes phenotypes. However, we argue that this hypothesis does not fully account for the Menkes neurodegeneration or neurodevelopmental phenotypes. Here, we propose revisions of the oligoenzymatic hypothesis that could illuminate the pathogenesis of Menkes neurodegeneration and neurodevelopmental defects through unsuspected overlap with other neurological conditions including Parkinson's, intellectual disability, and schizophrenia.

  3. The relation between inflammation and neurodegeneration in multiple sclerosis brains

    DEFF Research Database (Denmark)

    Frischer, J.M.; Bramow, S.; Dal-Bianco, A.;

    2009-01-01

    Some recent studies suggest that in progressive multiple sclerosis, neurodegeneration may occur independently from inflammation. The aim of our study was to analyse the interdependence of inflammation, neurodegeneration and disease progression in various multiple sclerosis stages in relation...... to lesional activity and clinical course, with a particular focus on progressive multiple sclerosis. The study is based on detailed quantification of different inflammatory cells in relation to axonal injury in 67 multiple sclerosis autopsies from different disease stages and 28 controls without neurological...... and the extent of axonal injury, too, was comparable with that in age-matched controls. Ongoing neurodegeneration in these patients, which exceeded the extent found in normal controls, could be attributed to confounding pathologies such as Alzheimer's or vascular disease. Our study suggests a close association...

  4. Early reduction of microglia activation by irradiation in a model of chronic glaucoma.

    Directory of Open Access Journals (Sweden)

    Alejandra Bosco

    Full Text Available Glaucoma is a neurodegenerative disease that results in the progressive decline and ultimate death of retinal ganglion cells (RGCs. While multiple risk factors are associated with glaucoma, the mechanisms leading to onset and progression of the disease remain unknown. Molecular analysis in various glaucoma models has revealed involvement of non-neuronal cell populations, including astrocytes, Mueller glia and microglia, at early stages of glaucoma. High-dose irradiation was reported to have a significant long-term protective effect in the DBA/2J (D2 mouse model of glaucoma, although the cellular and molecular basis for this effect remains unclear. In particular, the acute effects of irradiation on specific cell populations, including non-neuronal cells, in the D2 retina and nerve have not been assessed. Here we report that irradiation induces transient reduction in proliferating microglia within the optic nerve head and glial lamina within the first week post-irradiation. This was accompanied by reduced microglial activation, with no effect on astrocyte gliosis in those regions. At later stages we confirm that early high-dose irradiation of the mouse head results in improvement of axonal structural integrity and anterograde transport function, without reduction of intraocular pressure. Thus reduced microglial activation induced by irradiation at early stages is associated with reduced optic nerve and retinal neurodegeneration in the D2 mouse model of glaucoma.

  5. The role of exercise-induced myokines in muscle homeostasis and the defense against chronic diseases

    DEFF Research Database (Denmark)

    Brandt, Claus; Pedersen, Bente K

    2010-01-01

    Chronic inflammation is involved in the pathogenesis of insulin resistance, atherosclerosis, neurodegeneration, and tumour growth. Regular exercise offers protection against type 2 diabetes, cardiovascular diseases, colon cancer, breast cancer, and dementia. Evidence suggests that the protective...

  6. STUDY ON INFLAMMATORY CELLS IN BALF OF SMOKE-INDUCED CHRONIC BRONCHITIS RAT MODEL

    Institute of Scientific and Technical Information of China (English)

    李庆云; 黄绍光; 吴华成; 程齐俭; 项轶; 万欢英

    2004-01-01

    Objective To establish a smoke-induced chronic bronchitis rat model and evaluate the pathological change semi-quantitatively, and study the characteristics of the inflammatory cells in the bronchoalveolar lavage fluid (BALF) in various stages. Methods Chronic bronchitis sequential rat model was established by passively inhaling smoke mixture. Experiments were performed in 30 young male Sprague-Dawley rats, which comprised 5 groups in random, i.e.,4 chronic bronchitis model groups and I control group. After stained with hematoxylin and eosin, the specimens were studied by semi-quantitative method to evaluate the morphologic changes in various stages. Meanwhile, the inflammatory cells of the BALF and the activity of myeloperoxidase ( MPO ) of lung tissue were analysed. Results During the process of the chronic bronchitis, the pathologic score was increasing as time went on, and the typical morphologic changes of chronic bronchitis emerged in the group 7 weeks. The total number of inflammatory cells in BALF was increasing as time went on, correlated with the pathologic scores ( P < 0. 01 ).And the percentage of lymphocyte increased as well as positively correlated with pathologic scores ( P < 0. 05 ),whereas that of macrophage decreased and negatively correlated with pathologic scores (P <0. 05). The MPO lever of lung tissue was correlated with the pathologic scores ( P < 0. 01 ). But the percentage of the neutrophil in the BALF was just in a high level during the first week, then it maintained relatively lower. Conclusion Smoke-induced chronic bronchitis is a slowly progressive inflammation process. The model we established is convenient and simple for the longitudinal study on the inflammatory process of chronic bronchitis and the therapy in the early stage. The semi-quantitative evaluation for the pathological change is with much more value. During the inflammatory sequential process of early stage of chronic bronchitis, the cellular characteristics are

  7. Clinical challenges of chronic wounds: searching for an optimal animal model to recapitulate their complexity

    Directory of Open Access Journals (Sweden)

    Robert Nunan

    2014-11-01

    Full Text Available The efficient healing of a skin wound is something that most of us take for granted but is essential for surviving day-to-day knocks and cuts, and is absolutely relied on clinically whenever a patient receives surgical intervention. However, the management of a chronic wound – defined as a barrier defect that has not healed in 3 months – has become a major therapeutic challenge throughout the Western world, and it is a problem that will only escalate with the increasing incidence of conditions that impede wound healing, such as diabetes, obesity and vascular disorders. Despite being clinically and molecularly heterogeneous, all chronic wounds are generally assigned to one of three major clinical categories: leg ulcers, diabetic foot ulcers or pressure ulcers. Although we have gleaned much knowledge about the fundamental cellular and molecular mechanisms that underpin healthy, acute wound healing from various animal models, we have learned much less about chronic wound repair pathology from these models. This might largely be because the animal models being used in this field of research have failed to recapitulate the clinical features of chronic wounds. In this Clinical Puzzle article, we discuss the clinical complexity of chronic wounds and describe the best currently available models for investigating chronic wound pathology. We also assess how such models could be optimised to become more useful tools for uncovering pathological mechanisms and potential therapeutic treatments.

  8. Clinical challenges of chronic wounds: searching for an optimal animal model to recapitulate their complexity.

    Science.gov (United States)

    Nunan, Robert; Harding, Keith G; Martin, Paul

    2014-11-01

    The efficient healing of a skin wound is something that most of us take for granted but is essential for surviving day-to-day knocks and cuts, and is absolutely relied on clinically whenever a patient receives surgical intervention. However, the management of a chronic wound - defined as a barrier defect that has not healed in 3 months - has become a major therapeutic challenge throughout the Western world, and it is a problem that will only escalate with the increasing incidence of conditions that impede wound healing, such as diabetes, obesity and vascular disorders. Despite being clinically and molecularly heterogeneous, all chronic wounds are generally assigned to one of three major clinical categories: leg ulcers, diabetic foot ulcers or pressure ulcers. Although we have gleaned much knowledge about the fundamental cellular and molecular mechanisms that underpin healthy, acute wound healing from various animal models, we have learned much less about chronic wound repair pathology from these models. This might largely be because the animal models being used in this field of research have failed to recapitulate the clinical features of chronic wounds. In this Clinical Puzzle article, we discuss the clinical complexity of chronic wounds and describe the best currently available models for investigating chronic wound pathology. We also assess how such models could be optimised to become more useful tools for uncovering pathological mechanisms and potential therapeutic treatments.

  9. A mouse model for pathogen-induced chronic inflammation at local and systemic sites.

    Science.gov (United States)

    Papadopoulos, George; Kramer, Carolyn D; Slocum, Connie S; Weinberg, Ellen O; Hua, Ning; Gudino, Cynthia V; Hamilton, James A; Genco, Caroline A

    2014-08-08

    Chronic inflammation is a major driver of pathological tissue damage and a unifying characteristic of many chronic diseases in humans including neoplastic, autoimmune, and chronic inflammatory diseases. Emerging evidence implicates pathogen-induced chronic inflammation in the development and progression of chronic diseases with a wide variety of clinical manifestations. Due to the complex and multifactorial etiology of chronic disease, designing experiments for proof of causality and the establishment of mechanistic links is nearly impossible in humans. An advantage of using animal models is that both genetic and environmental factors that may influence the course of a particular disease can be controlled. Thus, designing relevant animal models of infection represents a key step in identifying host and pathogen specific mechanisms that contribute to chronic inflammation. Here we describe a mouse model of pathogen-induced chronic inflammation at local and systemic sites following infection with the oral pathogen Porphyromonas gingivalis, a bacterium closely associated with human periodontal disease. Oral infection of specific-pathogen free mice induces a local inflammatory response resulting in destruction of tooth supporting alveolar bone, a hallmark of periodontal disease. In an established mouse model of atherosclerosis, infection with P. gingivalis accelerates inflammatory plaque deposition within the aortic sinus and innominate artery, accompanied by activation of the vascular endothelium, an increased immune cell infiltrate, and elevated expression of inflammatory mediators within lesions. We detail methodologies for the assessment of inflammation at local and systemic sites. The use of transgenic mice and defined bacterial mutants makes this model particularly suitable for identifying both host and microbial factors involved in the initiation, progression, and outcome of disease. Additionally, the model can be used to screen for novel therapeutic strategies

  10. Regulation of brain-derived neurotrophic factor (BDNF) in the chronic unpredictable stress rat model and the effects of chronic antidepressant treatment

    DEFF Research Database (Denmark)

    Larsen, Marianne H; Mikkelsen, Jens D; Hay-Schmidt, Anders;

    2010-01-01

    Chronic unpredictable stress (CUS) is a widely used animal model of depression. The present study was undertaken to investigate behavioral, physiological and molecular effects of CUS and/or chronic antidepressant treatment (venlafaxine or imipramine) in the same set of animals. Anhedonia, a core...

  11. Integrating the Chronic Care Model into a Novel Medical Student Course

    Science.gov (United States)

    Block, Robert C.; Tran, Bill; McIntosh, Scott

    2011-01-01

    Objective: To determine whether integration of the Chronic Care Model into undergraduate medical education is associated with anticipated use of the Model and whether student perceptions match actual integration of the Model into their community projects. Design: This was a cross-sectional study using qualitative and quantitative data. Setting: A…

  12. Changes in erectile organ structure and function in a rat model of chronic prostatitis/chronic pelvic pain syndrome.

    Science.gov (United States)

    Wang, X-J; Xia, L-L; Xu, T-Y; Zhang, X-H; Zhu, Z-W; Zhang, M-G; Liu, Y; Xu, C; Zhong, S; Shen, Z-J

    2016-04-01

    There is a growing recognition of the association between chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and erectile dysfunction (ED); however, most of the reports are based on questionnaires which cannot distinguish between organic and functional ED. The purpose of this study was to determine the exact relationship between CP/CPPS and ED, and to investigate the changes in erectile organ structure and function in a rat model of CP/CPPS. We established a rat model of experimental autoimmune prostatitis (EAP), which is a valid model for CP/CPPS. Erectile function in EAP and normal rats was comparable after cavernous nerve electrostimulation. The serum testosterone and oestradiol levels, ultrastructure of the corpus cavernosum and expression of endothelial nitric oxide synthase and neuronal nitric oxide synthase in the two groups were similar; however, there was a decrease in smooth muscle-to-collagen ratio and alpha-smooth muscle actin expression and an increase in transforming growth factor-beta 1 expression was observed in EAP rats. Thus, organic ED may not exist in EAP rats. We speculate that ED complained by patients with CP/CPPS may be psychological, which could be caused by impairment in the quality of life; however, further studies are needed to fully understand the potential mechanisms underlying the penile fibrosis in EAP rats.

  13. Histopathological Analogies in Chronic Pulmonary Lesions between Cattle and Humans: Basis for an Alternative Animal Model

    Science.gov (United States)

    Ramírez-Romero, Rafael; Nevárez-Garza, Alicia M.; Rodríguez-Tovar, Luis E.; Wong-González, Alfredo; Ledezma-Torres, Rogelio A.; Hernández-Vidal, Gustavo

    2012-01-01

    Most of the natural cases of pneumonia in feedlot cattle are characterized by a longer clinical course due to chronic lung lesions. Microscopically, these lesions include interstitial fibroplasia, bronchitis, bronchiectasis, bronchiolitis obliterans, and epithelial metaplasia of the airways. Herein, the aim was to review, under a medical perspective, the pathologic mechanisms operating in these chronic pneumonic lesions in calves. Based on the similarities of these changes to those reported in bronchiolitis obliterans/organising pneumonia (BO/OP) and chronic obstructive pulmonary disease (COPD) in human beings, calves are proposed as an alternative animal model. PMID:22629176

  14. Histopathological Analogies in Chronic Pulmonary Lesions between Cattle and Humans: Basis for an Alternative Animal Model

    Directory of Open Access Journals (Sweden)

    Rafael Ramírez-Romero

    2012-01-01

    Full Text Available Most of the natural cases of pneumonia in feedlot cattle are characterized by a longer clinical course due to chronic lung lesions. Microscopically, these lesions include interstitial fibroplasia, bronchitis, bronchiectasis, bronchiolitis obliterans, and epithelial metaplasia of the airways. Herein, the aim was to review, under a medical perspective, the pathologic mechanisms operating in these chronic pneumonic lesions in calves. Based on the similarities of these changes to those reported in bronchiolitis obliterans/organising pneumonia (BO/OP and chronic obstructive pulmonary disease (COPD in human beings, calves are proposed as an alternative animal model.

  15. L-tyrosine improves neuroendocrine function in a mouse model of chronic stress

    Institute of Scientific and Technical Information of China (English)

    Zhihua Wang; Jinghua Li; Zhiming Wang; Lingyan Xue; Yi Zhang; Yingjie Chen; Jun Su; Zhongming Li

    2012-01-01

    Adult BALB/c mice, individually housed, were stimulated with nine different stressors, arranged randomly, for 4 continuous weeks to generate an animal model of chronic stress. In chronically stressed mice, spontaneous locomotor activity was significantly decreased, escape latency in the Morris water maze test was prolonged, serum levels of total thyrotropin and total triiodothyronine were significantly decreased, and dopamine and norepinephrine content in the pallium, hippocampus and hypothalamus were significantly reduced. All of these changes were suppressed, to varying degrees, by L-tyrosine supplementation. These findings indicate that the neuroendocrine network plays an important role in chronic stress, and that L-tyrosine supplementation has therapeutic effects.

  16. Opiates May Have Neuroprotective Properties against Neurodegeneration and Premature Death

    OpenAIRE

    Alen J Salerian

    2015-01-01

    Endorphins and endorphin agonists play a crucial role in the neuromodulation of mood, anxiety, pain and addiction. Review of clinical studies seem to elucidate possible protective role of opiates against neurodegeneration and premature death. The historical, biological, experimental, clinical and neuroimaging data strongly support the potential properties of opiates as neuro protectors.

  17. Phosphatidylinositol transfer protein alpha and its role in neurodegeneration

    NARCIS (Netherlands)

    Bunte, H.

    2007-01-01

    Selective neuronal loss is a prominent feature in neurodegenerative disorders. Recently, a link between neurodegeneration and a deficiency in the protein phosphatidylinositol transfer protein alpha (PI-TPalpha) has been demonstrated. In this context it is of importance that fibroblasts overexpressin

  18. MicroRNAs and deregulated gene expression networks in neurodegeneration.

    Science.gov (United States)

    Sonntag, Kai-Christian

    2010-06-18

    Neurodegeneration is characterized by the progressive loss of neuronal cell types in the nervous system. Although the main cause of cell dysfunction and death in many neurodegenerative diseases is not known, there is increasing evidence that their demise is a result of a combination of genetic and environmental factors which affect key signaling pathways in cell function. This view is supported by recent observations that disease-compromised cells in late-stage neurodegeneration exhibit profound dysregulation of gene expression. MicroRNAs (miRNAs) introduce a novel concept of regulatory control over gene expression and there is increasing evidence that they play a profound role in neuronal cell identity as well as multiple aspects of disease pathogenesis. Here, we review the molecular properties of brain cells derived from patients with neurodegenerative diseases, and discuss how deregulated miRNA/mRNA expression networks could be a mechanism in neurodegeneration. In addition, we emphasize that the dysfunction of these regulatory networks might overlap between different cell systems and suggest that miRNA functions might be common between neurodegeneration and other disease entities.

  19. Delayed mGluR5 activation limits neuroinflammation and neurodegeneration after traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Byrnes Kimberly R

    2012-02-01

    Full Text Available Abstract Background Traumatic brain injury initiates biochemical processes that lead to secondary neurodegeneration. Imaging studies suggest that tissue loss may continue for months or years after traumatic brain injury in association with chronic microglial activation. Recently we found that metabotropic glutamate receptor 5 (mGluR5 activation by (RS-2-chloro-5-hydroxyphenylglycine (CHPG decreases microglial activation and release of associated pro-inflammatory factors in vitro, which is mediated in part through inhibition of reduced nicotinamide adenine dinucleotide phosphate (NADPH oxidase. Here we examined whether delayed CHPG administration reduces chronic neuroinflammation and associated neurodegeneration after experimental traumatic brain injury in mice. Methods One month after controlled cortical impact traumatic brain injury, C57Bl/6 mice were randomly assigned to treatment with single dose intracerebroventricular CHPG, vehicle or CHPG plus a selective mGluR5 antagonist, 3-((2-Methyl-4-thiazolylethynylpyridine. Lesion volume, white matter tract integrity and neurological recovery were assessed over the following three months. Results Traumatic brain injury resulted in mGluR5 expression in reactive microglia of the cortex and hippocampus at one month post-injury. Delayed CHPG treatment reduced expression of reactive microglia expressing NADPH oxidase subunits; decreased hippocampal neuronal loss; limited lesion progression, as measured by repeated T2-weighted magnetic resonance imaging (at one, two and three months and white matter loss, as measured by high field ex vivo diffusion tensor imaging at four months; and significantly improved motor and cognitive recovery in comparison to the other treatment groups. Conclusion Markedly delayed, single dose treatment with CHPG significantly improves functional recovery and limits lesion progression after experimental traumatic brain injury, likely in part through actions at mGluR5 receptors

  20. Cost-effectiveness models for chronic obstructive pulmonary disease : cross-model comparison of hypothetical treatment scenarios

    NARCIS (Netherlands)

    Hoogendoorn, Martine; Feenstra, Talitha L; Asukai, Yumi; Borg, Sixten; Hansen, Ryan N; Jansson, Sven-Arne; Samyshkin, Yevgeniy; Wacker, Margarethe; Briggs, Andrew H; Lloyd, Adam; Sullivan, Sean D; Rutten-van Mölken, Maureen P M H

    2014-01-01

    OBJECTIVES: To compare different chronic obstructive pulmonary disease (COPD) cost-effectiveness models with respect to structure and input parameters and to cross-validate the models by running the same hypothetical treatment scenarios. METHODS: COPD modeling groups simulated four hypothetical inte

  1. Electron Transport Disturbances and Neurodegeneration: From Albert Szent-Györgyi's Concept (Szeged) till Novel Approaches to Boost Mitochondrial Bioenergetics

    OpenAIRE

    Levente Szalárdy; Dénes Zádori; Péter Klivényi; József Toldi; László Vécsei

    2015-01-01

    Impaired function of certain mitochondrial respiratory complexes has long been linked to the pathogenesis of chronic neurodegenerative disorders such as Parkinson’s and Huntington’s diseases. Furthermore, genetic alterations of mitochondrial genome or nuclear genes encoding proteins playing essential roles in maintaining proper mitochondrial function can lead to the development of severe systemic diseases associated with neurodegeneration and vacuolar myelinopathy. At present, all of these di...

  2. Murine Model Imitating Chronic Wound Infections for Evaluation of Antimicrobial Photodynamic Therapy Efficacy

    Science.gov (United States)

    Fila, Grzegorz; Kasimova, Kamola; Arenas, Yaxal; Nakonieczna, Joanna; Grinholc, Mariusz; Bielawski, Krzysztof P.; Lilge, Lothar

    2016-01-01

    It is generally acknowledged that the age of antibiotics could come to an end, due to their widespread, and inappropriate use. Particularly for chronic wounds alternatives are being thought. Antimicrobial Photodynamic Therapy (APDT) is a potential candidate, and while approved for some indications, such as periodontitis, chronic sinusitis and other niche indications, its use in chronic wounds is not established. To further facilitate the development of APDT in chronic wounds we present an easy to use animal model exhibiting the key hallmarks of chronic wounds, based on full-thickness skin wounds paired with an optically transparent cover. The moisture-retaining wound exhibited rapid expansion of pathogen colonies up to 8 days while not jeopardizing the host survival. Use of two bioluminescent pathogens; methicillin resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa permits real time monitoring of the pathogens. The murine model was employed to evaluate the performance of four different photosensitizers as mediators in Photodynamic Therapy. While all four photosensitizers, Rose Bengal, porphyrin TMPyP, New Methylene Blue, and TLD1411 demonstrated good to excellent antimicrobial efficacy in planktonic solutions at 1 to 50 μM concentrations, whereas in in vivo the growth delay was limited with 24–48 h delay in pathogen expansion for MRSA, and we noticed longer growth suppression of P. aeruginosa with TLD1411 mediated Photodynamic Therapy. The murine model will enable developing new strategies for enhancement of APDT for chronic wound infections. PMID:27555843

  3. Stiripentol in acute/chronic efficacy tests in monkey model.

    Science.gov (United States)

    Lockard, J S; Levy, R H; Rhodes, P H; Moore, D F

    1985-01-01

    Acute and chronic efficacy tests of stiripentol (4,4-dimethyl-1-[3,4-(methylenedioxy)-phenyl]-1-penten-3-ol) were conducted in alumina-gel rhesus monkeys. In the acute study (n = 6), discrete serial seizures precipitated by 150 mg/kg of 4-deoxypyridoxine hydrochloride were challenged by intravenous administration of stiripentol and the data compared with those obtained with valproate similarly tested in other monkeys (reported here) and with those from four other standard anticonvulsants (phenytoin, carbamazepine, phenobarbital, and diazepam--data published previously). In the acute challenge (Study 1), stiripentol performed comparably to valproate by delaying the onset of seizures but not eliminating them as did the other four drugs. In two separate chronic studies (at different doses, n = 6 each), stiripentol was given every 4 h by gastric catheter for 4 weeks, preceded and followed by 4 weeks of baseline. In these studies, stiripentol significantly reduced EEG interictal spike rates at mean plasma concentrations from 20 to 27 micrograms/ml in Study 2 and 11 to 14 micrograms/ml in Study 3. From these results, and those evinced in other studies, it appears that stiripentol should be evaluated for absence epilepsy and possible synergistic effects in polytherapy.

  4. The woodchuck as an animal model for pathogenesis and therapy of chronic hepatitis B virus infection

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    This review describes the woodchuck and the woodchuck hepatitis virus (WHV) as an animal model for pathogenesis and therapy of chronic hepatitis B virus (HBV) infection and disease in humans. The establishment of woodchuck breeding colonies, and use of laboratory-reared woodchucks infected with defined WHV inocula, have enhanced our understanding of the virology and immunology of HBV infection and disease pathogenesis, including major sequelae like chronic hepatitis and hepatocellular carcinoma. The role of persistent WHV infection and of viral load on the natural history of infection and disease progression has been firmly established along the way. More recently, the model has shed new light on the role of host immune responses in these natural processes,and on how the immune system of the chronic carrier can be manipulated therapeutically to reduce or delay serious disease sequelae through induction of the recovery phenotype. The woodchuck is an outbred species and is not well defined immunologically due to a limitation of available host markers. However, the recent development of several key host response assays for woodchucks provides experimental opportunities for further mechanistic studies of outcome predictors in neonatal- and adult-acquired infections. Understanding the virological and immunological mechanisms responsible for resolution of self-limited infection, and for the onset and maintenance of chronic infection, will greatly facilitate the development of successful strategies for the therapeutic eradication of established chronic HBV infection. Likewise, the results of drug efficacy and toxicity studies in the chronic carrier woodchucks are predictive for responses of patients chronically infected with HBV. Therefore, chronic WHV carrier woodchucks provide a well-characterized mammalian model for preclinical evaluation of the safety and efficacy of drug candidates, experimental therapeutic vaccines, and immunomodulators for the treatment and

  5. Model Construction for the Intention to Use Telecare in Patients with Chronic Diseases

    Directory of Open Access Journals (Sweden)

    Jui-Chen Huang

    2013-01-01

    Full Text Available Objective. This study chose patients with chronic diseases as study subjects to investigate their intention to use telecare. Methods. A large medical institute in Taiwan was used as the sample unit. Patients older than 20 years, who had chronic diseases, were sampled by convenience sampling and surveyed with a structural questionnaire, and a total of 500 valid questionnaires were collected. Model construction was based on the Health Belief Model. The reliability and validity of the measurement model were tested using confirmatory factor analysis (CFA, and the causal model was explained by structural equation modeling (SEM. Results. The priority should be on promoting the perceived benefits of telecare, with a secondary focus on the external cues to action, such as promoting the influences of important people on the patients. Conclusion. The findings demonstrated that patients with chronic diseases use telecare differently from the general public. To promote the use and acceptance of telecare in patients with chronic diseases, technology developers should prioritize the promotion of the usefulness of telecare. In addition, policy makers can strengthen the marketing from media and medical personnel, in order to increase the acceptance of telecare by patients with chronic diseases.

  6. An integrated chronic disease management model: a diagonal approach to health system strengthening in South Africa.

    Science.gov (United States)

    Mahomed, Ozayr Haroon; Asmall, Shaidah; Freeman, Melvyn

    2014-11-01

    The integrated chronic disease management model provides a systematic framework for creating a fundamental change in the orientation of the health system. This model adopts a diagonal approach to health system strengthening by establishing a service-linked base to training, supervision, and the opportunity to try out, assess, and implement integrated interventions.

  7. Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites

    Science.gov (United States)

    Breda, Carlo; Sathyasaikumar, Korrapati V.; Sograte Idrissi, Shama; Notarangelo, Francesca M.; Estranero, Jasper G.; Moore, Gareth G. L.; Green, Edward W.; Kyriacou, Charalambos P.; Schwarcz, Robert; Giorgini, Flaviano

    2016-01-01

    Metabolites of the kynurenine pathway (KP) of tryptophan (TRP) degradation have been closely linked to the pathogenesis of several neurodegenerative disorders. Recent work has highlighted the therapeutic potential of inhibiting two critical regulatory enzymes in this pathway—kynurenine-3-monooxygenase (KMO) and tryptophan-2,3-dioxygenase (TDO). Much evidence indicates that the efficacy of KMO inhibition arises from normalizing an imbalance between neurotoxic [3-hydroxykynurenine (3-HK); quinolinic acid (QUIN)] and neuroprotective [kynurenic acid (KYNA)] KP metabolites. However, it is not clear if TDO inhibition is protective via a similar mechanism or if this is instead due to increased levels of TRP—the substrate of TDO. Here, we find that increased levels of KYNA relative to 3-HK are likely central to the protection conferred by TDO inhibition in a fruit fly model of Huntington’s disease and that TRP treatment strongly reduces neurodegeneration by shifting KP flux toward KYNA synthesis. In fly models of Alzheimer’s and Parkinson’s disease, we provide genetic evidence that inhibition of TDO or KMO improves locomotor performance and ameliorates shortened life span, as well as reducing neurodegeneration in Alzheimer's model flies. Critically, we find that treatment with a chemical TDO inhibitor is robustly protective in these models. Consequently, our work strongly supports targeting of the KP as a potential treatment strategy for several major neurodegenerative disorders and suggests that alterations in the levels of neuroactive KP metabolites could underlie several therapeutic benefits. PMID:27114543

  8. Prepubertal chronic stress and ketamine administration to rats as a neurodevelopmental model of schizophrenia symptomatology.

    Science.gov (United States)

    Ram, Edward; Raphaeli, Shani; Avital, Avi

    2013-11-01

    Increased vulnerability to psychiatric disorders, such as schizophrenia, has been associated with higher levels of stress. In the early development of the central nervous system, changes in function of glutamatergic N-Methyl-D-aspartate (NMDA) receptors can possibly result in the development of psychosis, cognitive impairment and emotional dysfunction in adulthood. Thus, in this study we examined the behavioural consequences of the exposure of male rats to chronic stress (postnatal days 30-60) and ketamine administration (postnatal days 41-45); both during a sensitive developmental time window. We found that the locomotor activity of both ketamine and ketamine+chronic stress groups was significantly higher compared with that of the control rats. In contrast, the locomotor activity of the chronic stress group was significantly lower compared with all other groups. Examining anhedonia in the sucrose preference test we found a significantly decreased sucrose intake in both ketamine+chronic stress and the chronic stress groups compared with the control rats. No significant differences were observed in sucrose intake between the control and the ketamine group. The object recognition test revealed that the attention to the novel object was significantly impaired in the ketamine+chronic stress group. Similarly, the ketamine+chronic stress group showed the poorest learning ability in the eight-arm radial maze, starting on the 8th day. Finally, throughout the different pre-pulse intensities, the ketamine+chronic stress group showed impaired PPI compared with all other groups. The results indicate that the combination of prepubertal onset of chronic stress and ketamine may serve as a valid novel animal model for schizophrenia-like symptoms.

  9. The Relevance of Value Net Integrator and Shared Infrastructure Business Models in Managing Chronic Conditions

    Directory of Open Access Journals (Sweden)

    Susan Lambert

    2005-11-01

    Full Text Available There is widespread support for chronic condition management (CCM programs that require a multi-disciplinary, care-team approach. Implementation of such programs represents a paradigm shift in primary care service delivery and has significant resource implications for the general practice. Integral to the widespread uptake of care-team based CCM is information collection, storage and dissemination amongst the care-team members. This paper looks to ebusiness models for assistance in understanding the requirements of general practitioners (GPs in providing multi-disciplinary team care to patients with chronic conditions. The role required of GPs in chronic condition management is compared to that of a value net integrator. The essential characteristics of value net integrators are identified and compared to those of GPs providing multi-disciplinary team care to patients with chronic conditions. It is further suggested that a shared infrastructure is required.

  10. Gene expression patterns in the hippocampus and amygdala of endogenous depression and chronic stress models.

    Science.gov (United States)

    Andrus, B M; Blizinsky, K; Vedell, P T; Dennis, K; Shukla, P K; Schaffer, D J; Radulovic, J; Churchill, G A; Redei, E E

    2012-01-01

    The etiology of depression is still poorly understood, but two major causative hypotheses have been put forth: the monoamine deficiency and the stress hypotheses of depression. We evaluate these hypotheses using animal models of endogenous depression and chronic stress. The endogenously depressed rat and its control strain were developed by bidirectional selective breeding from the Wistar-Kyoto (WKY) rat, an accepted model of major depressive disorder (MDD). The WKY More Immobile (WMI) substrain shows high immobility/despair-like behavior in the forced swim test (FST), while the control substrain, WKY Less Immobile (WLI), shows no depressive behavior in the FST. Chronic stress responses were investigated by using Brown Norway, Fischer 344, Lewis and WKY, genetically and behaviorally distinct strains of rats. Animals were either not stressed (NS) or exposed to chronic restraint stress (CRS). Genome-wide microarray analyses identified differentially expressed genes in hippocampi and amygdalae of the endogenous depression and the chronic stress models. No significant difference was observed in the expression of monoaminergic transmission-related genes in either model. Furthermore, very few genes showed overlapping changes in the WMI vs WLI and CRS vs NS comparisons, strongly suggesting divergence between endogenous depressive behavior- and chronic stress-related molecular mechanisms. Taken together, these results posit that although chronic stress may induce depressive behavior, its molecular underpinnings differ from those of endogenous depression in animals and possibly in humans, suggesting the need for different treatments. The identification of novel endogenous depression-related and chronic stress response genes suggests that unexplored molecular mechanisms could be targeted for the development of novel therapeutic agents.

  11. Effects of Modeling and Reinforcement on Adult Chronic Schizophrenics

    Science.gov (United States)

    Olson, R. Paul

    1971-01-01

    This study confirmed two general predictions: (1) the model contributes to new learning; and (2) neither the model nor reinforcement of the model adds significantly to motivation, beyond the effect that can be attributed to reinforcement of the subject himself. (Author/CG)

  12. Eugenia jambolana Lam. Increases lifespan and ameliorates experimentally induced neurodegeneration in C. elegans

    Directory of Open Access Journals (Sweden)

    Maria de Fátima Bezerra

    2014-09-01

    Full Text Available Summary. Type-2 diabetes mellitus (T2DM, dyslipidemia (DL and inflammation (IF are associated with reduced lifespan (LS and increased risk of neurodegenerative diseases (NDG. Dysregulation in insulin/insulin-like growth factor-1 (IGF-1 (IIS signaling, forkhead box O transcription factor (FOXO and Silent Information Regulators or Sirtuins (SIRT may be responsible. We investigated the effect of spray dried Jambolan (Eugenia jambolana Lam. fruit in Caenorhabditis elegans model for lifespan, amyloid b1-42 (Ab1-42 aggregation induced paralysis and MPP+ (1-methyl-4-phenylpyridinium induced neurodegeneration. Effect on modulating critical genes involved signaling pathways important in IIS, LS and NDG were also studied in C. elegans. Results show suggest statistically significant increase in lifespan (9-22.7% coupled with a delay in Ab1-42 induced paralysis (11.5% and MPP+ induced paralysis (38-43%. Gene expression studies indicated a significant upregulation in expression of  C. elegans homologs of foxo, sirt1, dopamine D1 receptor and suggested a non-FOXO mediated mechanism of action.Industrial relevance. Jambolan is a bioactive-rich tropical fruit with high colorant potential. Despite this fact, its perishability has hampered its market and industrial use beyond the countries where it is cultivated. Considering that drying is a popular technique able to extend fruits shelf life and concentrate their natural bioactive compounds, this research investigates the health relevance of spray dried jambolan. Here we addressed the potential of dried Jambolan fruit to extend lifespan and inhibit the progression of experimentally induced neurodegeneration using the C. elegans model. We demonstrated that this convenient fruit product was able to increase the lifespan of C. elegans. The jambolan extracts also influenced some critical genes of signaling pathways relevant to metabolic diseases, aging and neurodegeneration. Based on our results, some insight about

  13. Complement is dispensable for neurodegeneration in Niemann-Pick disease type C

    Directory of Open Access Journals (Sweden)

    Lopez Manuel E

    2012-09-01

    Full Text Available Abstract Background The immune system has been implicated in neurodegeneration during development and disease. In various studies, the absence of complement (that is, C1q deficiency impeded the elimination of apoptotic neurons, allowing survival. In the genetic lysosomal storage disease Niemann-Pick C (NPC, caused by loss of NPC1 function, the expression of complement system components, C1q especially, is elevated in degenerating brain regions of Npc1-/- mice. Here we test whether complement is mediating neurodegeneration in NPC disease. Findings In normal mature mice, C1q mRNA was found in neurons, particularly cerebellar Purkinje neurons (PNs. In Npc1-/- mice, C1q mRNA was additionally found in activated microglia, which accumulate during disease progression and PN loss. Interestingly, C1q was not enriched on or near degenerating neurons. Instead, C1q was concentrated in other brain regions, where it partially co-localized with a potential C1q inhibitor, chondroitin sulfate proteoglycan (CSPG. Genetic deletion of C1q, or of the downstream complement pathway component C3, did not significantly alter patterned neuron loss or disease progression. Deletion of other immune response factors, a Toll-like receptor, a matrix metalloprotease, or the apoptosis facilitator BIM, also failed to alter neuron loss. Conclusion We conclude that complement is not involved in the death and clearance of neurons in NPC disease. This study supports a view of neuroinflammation as a secondary response with non-causal relationship to neuron injury in the disease. This disease model may prove useful for understanding the conditions in which complement and immunity do contribute to neurodegeneration in other disorders.

  14. Neurodegeneration Alters Metabolic Profile and Sirt 1 Signaling in High-Fat-Induced Obese Mice.

    Science.gov (United States)

    Lima, Leandro Ceotto Freitas; Saliba, Soraya Wilke; Andrade, João Marcus Oliveira; Cunha, Maria Luisa; Cassini-Vieira, Puebla; Feltenberger, John David; Barcelos, Lucíola Silva; Guimarães, André Luiz Sena; de-Paula, Alfredo Mauricio Batista; de Oliveira, Antônio Carlos Pinheiro; Santos, Sérgio Henrique Sousa

    2016-05-16

    Different factors may contribute to the development of neurodegenerative diseases. Among them, metabolic syndrome (MS), which has reached epidemic proportions, has emerged as a potential element that may be involved in neurodegeneration. Furthermore, studies have shown the importance of the sirtuin family in neuronal survival and MS, which opens the possibility of new pharmacological targets. This study investigates the influence of sirtuin metabolic pathways by examining the functional capacities of glucose-induced obesity in an excitotoxic state induced by a quinolinic acid (QA) animal model. Mice were divided into two groups that received different diets for 8 weeks: one group received a regular diet, and the other group received a high-fat diet (HF) to induce MS. The animals were submitted to a stereotaxic surgery and subdivided into four groups: Standard (ST), Standard-QA (ST-QA), HF and HF-QA. The QA groups were given a 250 nL quinolinic acid injection in the right striatum and PBS was injected in the other groups. Obese mice presented with a weight gain of 40 % more than the ST group beyond acquiring an insulin resistance. QA induced motor impairment and neurodegeneration in both ST-QA and HF-QA, although no difference was observed between these groups. The HF-QA group showed a reduction in adiposity when compared with the groups that received PBS. Therefore, the HF-QA group demonstrated a commitment-dependent metabolic pathway. The results suggest that an obesogenic diet does not aggravate the neurodegeneration induced by QA. However, the excitotoxicity induced by QA promotes a sirtuin pathway impairment that contributes to metabolic changes.

  15. Exacerbation of CNS inflammation and neurodegeneration by systemic LPS treatment is independent of circulating IL-1 beta and IL-6

    LENUS (Irish Health Repository)

    Murray, Carol L

    2011-05-17

    Abstract Background Chronic neurodegeneration comprises an inflammatory response but its contribution to the progression of disease remains unclear. We have previously shown that microglial cells are primed by chronic neurodegeneration, induced by the ME7 strain of prion disease, to synthesize limited pro-inflammatory cytokines but to produce exaggerated responses to subsequent systemic inflammatory insults. The consequences of this primed response include exaggerated hypothermic and sickness behavioural responses, acute neuronal death and accelerated progression of disease. Here we investigated whether inhibition of systemic cytokine synthesis using the anti-inflammatory steroid dexamethasone-21-phosphate was sufficient to block any or all of these responses. Methods ME7 animals, at 18-19 weeks post-inoculation, were challenged with LPS (500 μg\\/kg) in the presence or absence of dexamethasone-21-phosphate (2 mg\\/kg) and effects on core-body temperature and systemic and CNS cytokine production and apoptosis were examined. Results LPS induced hypothermia and decreased exploratory activity. Dexamethasone-21-phosphate prevented this hypothermia, markedly suppressed systemic IL-1β and IL-6 secretion but did not prevent decreased exploration. Furthermore, robust transcription of cytokine mRNA occurred in the hippocampus of both ME7 and NBH (normal brain homogenate) control animals despite the effective blocking of systemic cytokine synthesis. Microglia primed by neurodegeneration were not blocked from the robust synthesis of IL-1β protein and endothelial COX-2 was also robustly synthesized. We injected biotinylated LPS at 100 μg\\/kg and even at this lower dose this could be detected in blood plasma. Apoptosis was acutely induced by LPS, despite the inhibition of the systemic cytokine response. Conclusions These data suggest that LPS can directly activate the brain endothelium even at relatively low doses, obviating the need for systemic cytokine stimulation to

  16. Chronic pain and PTSD: the Perpetual Avoidance Model and its treatment implications.

    Science.gov (United States)

    Liedl, Alexandra; Knaevelsrud, Christine

    2008-01-01

    Posttraumatic Stress Disorder (PTSD) and chronic pain are frequently seen in the aftermath of a traumatic experience. Torture survivors have an increased risk to suffer from these two disorders. Although many studies report high comorbidity,there is still insufficient knowledge on the mechanisms of the development and maintenance of PTSD and chronic pain. After providing an overview of the current literature concerning the comorbidity of these two disorders, we will present the "Perpetual Avoidance Model" (PAM). This model provides an explanation of the reciprocal maintenance of both disorders and offers treatment implications.

  17. Traumatic brain injury, neuroimaging, and neurodegeneration.

    Science.gov (United States)

    Bigler, Erin D

    2013-01-01

    Depending on severity, traumatic brain injury (TBI) induces immediate neuropathological effects that in the mildest form may be transient but as severity increases results in neural damage and degeneration. The first phase of neural degeneration is explainable by the primary acute and secondary neuropathological effects initiated by the injury; however, neuroimaging studies demonstrate a prolonged period of pathological changes that progressively occur even during the chronic phase. This review examines how neuroimaging may be used in TBI to understand (1) the dynamic changes that occur in brain development relevant to understanding the effects of TBI and how these relate to developmental stage when the brain is injured, (2) how TBI interferes with age-typical brain development and the effects of aging thereafter, and (3) how TBI results in greater frontotemporolimbic damage, results in cerebral atrophy, and is more disruptive to white matter neural connectivity. Neuroimaging quantification in TBI demonstrates degenerative effects from brain injury over time. An adverse synergistic influence of TBI with aging may predispose the brain injured individual for the development of neuropsychiatric and neurodegenerative disorders long after surviving the brain injury.

  18. Traumatic brain injury, neuroimaging, and neurodegeneration

    Directory of Open Access Journals (Sweden)

    Erin D. Bigler

    2013-08-01

    Full Text Available Depending on severity, traumatic brain injury (TBI induces immediate neuropathological effects that in the mildest form may be transient but as severity increases results in neural damage and degeneration. The first phase of neural degeneration is explainable by the primary acute and secondary neuropathological effects initiated by the injury; however, neuroimaging studies demonstrate a prolonged period of pathological changes that progressively occur even during the chronic phase. This review examines how neuroimaging may be used in TBI to understand (1 the dynamic changes that occur in brain development relevant to understanding the effects of TBI and how these relate to developmental stage when the brain is injured, (2 how TBI interferes with age-typical brain development and the effects of aging thereafter, and (3 how TBI results in greater frontotemporolimbic damage, results in cerebral atrophy, and is more disruptive to white matter neural connectivity. Neuroimaging quantification in TBI demonstrates degenerative effects from brain injury over time. An adverse synergistic influence of TBI with aging may predispose the brain injured individual for the development of neuropsychiatric and neurodegenerative disorders long after surviving the brain injury.

  19. Molecular bases of methamphetamine-induced neurodegeneration.

    Science.gov (United States)

    Cadet, Jean Lud; Krasnova, Irina N

    2009-01-01

    Methamphetamine (METH) is a highly addictive psychostimulant drug, whose abuse has reached epidemic proportions worldwide. The addiction to METH is a major public concern because its chronic abuse is associated with serious health complications including deficits in attention, memory, and executive functions in humans. These neuropsychiatric complications might, in part, be related to drug-induced neurotoxic effects, which include damage to dopaminergic and serotonergic terminals, neuronal apoptosis, as well as activated astroglial and microglial cells in the brain. Thus, the purpose of the present paper is to review cellular and molecular mechanisms that might be responsible for METH neurotoxicity. These include oxidative stress, activation of transcription factors, DNA damage, excitotoxicity, blood-brain barrier breakdown, microglial activation, and various apoptotic pathways. Several approaches that allow protection against METH-induced neurotoxic effects are also discussed. Better understanding of the cellular and molecular mechanisms involved in METH toxicity should help to generate modern therapeutic approaches to prevent or attenuate the long-term consequences of psychostimulant use disorders in humans.

  20. Endosome-lysosomes, ubiquitin and neurodegeneration.

    Science.gov (United States)

    Mayer, R J; Tipler, C; Arnold, J; Laszlo, L; Al-Khedhairy, A; Lowe, J; Landon, M

    1996-01-01

    Before the advent of ubiquitin immunochemistry and immunogold electron microscopy, there was no known intracellular molecular commonality between neurodegenerative diseases. The application of antibodies which primarily detect ubiquitin protein conjugates has shown that all of the human and animal idiopathic and transmissible chronic neurodegenerative diseases, (including Alzheimer's disease (AD), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease (CJD) and scrapie) are related by some form of intraneuronal inclusion which contains ubiquitin protein conjugates. In addition, disorders such as Alzheimer's disease, CJD and sheep scrapie, are characterised by deposits of amyloid, arising through incomplete breakdown of membrane proteins which may be associated with cytoskeletal reorganisation. Although our knowledge about these diseases is increasing, they remain largely untreatable. Recently, attention has focused on the mechanisms of production of different types of amyloid and the likely involvement within cells of the endosome-lysosome system, organelles which are immuno-positive for ubiquitin protein conjugates. These organelles may be 'bioreactor' sites for the unfolding and partial degradation of membrane proteins to generate the amyloid materials or their precursors which subsequently become expelled from the cell, or are released from dead cells, and accumulate as pathological entities. Such common features of the disease processes give new direction to therapeutic intervention.

  1. Evidence for early neurodegeneration in the cervical cord of patients with primary progressive multiple sclerosis.

    Science.gov (United States)

    Abdel-Aziz, Khaled; Schneider, Torben; Solanky, Bhavana S; Yiannakas, Marios C; Altmann, Dan R; Wheeler-Kingshott, Claudia A M; Peters, Amy L; Day, Brian L; Thompson, Alan J; Ciccarelli, Olga

    2015-06-01

    Spinal neurodegeneration is an important determinant of disability progression in patients with primary progressive multiple sclerosis. Advanced imaging techniques, such as single-voxel (1)H-magnetic resonance spectroscopy and q-space imaging, have increased pathological specificity for neurodegeneration, but are challenging to implement in the spinal cord and have yet to be applied in early primary progressive multiple sclerosis. By combining these imaging techniques with new clinical measures, which reflect spinal cord pathology more closely than conventional clinical tests, we explored the potential for spinal magnetic resonance spectroscopy and q-space imaging to detect early spinal neurodegeneration that may be responsible for clinical disability. Data from 21 patients with primary progressive multiple sclerosis within 6 years of disease onset, and 24 control subjects were analysed. Patients were clinically assessed on grip strength, vibration perception thresholds and postural stability, in addition to the Expanded Disability Status Scale, Nine Hole Peg Test, Timed 25-Foot Walk Test, Multiple Sclerosis Walking Scale-12, and Modified Ashworth Scale. All subjects underwent magnetic resonance spectroscopy and q-space imaging of the cervical cord and conventional brain and spinal magnetic resonance imaging at 3 T. Multivariate analyses and multiple regression models were used to assess the differences in imaging measures between groups and the relationship between magnetic resonance imaging measures and clinical scores, correcting for age, gender, spinal cord cross-sectional area, brain T2 lesion volume, and brain white matter and grey matter volume fractions. Although patients did not show significant cord atrophy when compared with healthy controls, they had significantly lower total N-acetyl-aspartate (mean 4.01 versus 5.31 mmol/l, P = 0.020) and glutamate-glutamine (mean 4.65 versus 5.93 mmol/l, P = 0.043) than controls. Patients showed an increase in q

  2. Partnerships to provide care and medicine for chronic diseases: a model for emerging markets.

    Science.gov (United States)

    Goroff, Michael; Reich, Michael R

    2010-12-01

    The challenge of expanding access to treatment and medicine for chronic diseases in emerging markets is both a public health imperative and a commercial opportunity. Cross-sector partnerships-involving a pharmaceutical manufacturer; a local health care provider; and other private, public, and nonprofit entities-could address this challenge. Such partnerships would provide integrated, comprehensive care and medicines for a specific chronic disease, with medicines directly supplied to the partnership at preferential prices by the manufacturer. The model discussed here requires additional specification, using real numbers and specific contexts, to assess its feasibility. Still, we believe that this model has the potential for public health and private business to cooperate in addressing the rising problem of chronic diseases in emerging markets.

  3. Adenosine A3 receptor activation is neuroprotective against retinal neurodegeneration.

    Science.gov (United States)

    Galvao, Joana; Elvas, Filipe; Martins, Tiago; Cordeiro, M Francesca; Ambrósio, António Francisco; Santiago, Ana Raquel

    2015-11-01

    Death of retinal neural cells, namely retinal ganglion cells (RGCs), is a characteristic of several retinal neurodegenerative diseases. Although the role of adenosine A3 receptor (A3R) in neuroprotection is controversial, A3R activation has been reported to afford protection against several brain insults, with few studies in the retina. In vitro models (retinal neural and organotypic cultures) and animal models [ischemia-reperfusion (I-R) and partial optic nerve transection (pONT)] were used to study the neuroprotective properties of A3R activation against retinal neurodegeneration. The A3R selective agonist (2-Cl-IB-MECA, 1 μM) prevented apoptosis (TUNEL(+)-cells) induced by kainate and cyclothiazide (KA + CTZ) in retinal neural cultures (86.5 ± 7.4 and 37.2 ± 6.1 TUNEL(+)-cells/field, in KA + CTZ and KA + CTZ + 2-Cl-IB-MECA, respectively). In retinal organotypic cultures, 2-Cl-IB-MECA attenuated NMDA-induced cell death, assessed by TUNEL (17.3 ± 2.3 and 8.3 ± 1.2 TUNEL(+)-cells/mm(2) in NMDA and NMDA+2-Cl-IB-MECA, respectively) and PI incorporation (ratio DIV4/DIV2 3.3 ± 0.3 and 1.3 ± 0.1 in NMDA and NMDA+2-Cl-IB-MECA, respectively) assays. Intravitreal 2-Cl-IB-MECA administration afforded protection against I-R injury decreasing the number of TUNEL(+) cells by 72%, and increased RGC survival by 57%. Also, intravitreal administration of 2-Cl-IB-MECA inhibited apoptosis (from 449.4 ± 37.8 to 207.6 ± 48.9 annexin-V(+)-cells) and RGC loss (from 1.2 ± 0.6 to 8.1 ± 1.7 cells/mm) induced by pONT. This study demonstrates that 2-Cl-IB-MECA is neuroprotective to the retina, both in vitro and in vivo. Activation of A3R may have great potential in the management of retinal neurodegenerative diseases characterized by RGC death, as glaucoma and diabetic retinopathy, and ischemic diseases.

  4. Moderate exercise prevents neurodegeneration in D-galactose-induced aging mice

    Institute of Scientific and Technical Information of China (English)

    Li Li; Meng Xu; Bo Shen; Man Li; Qian Gao; Shou-gang Wei

    2016-01-01

    D-galactose has been widely used in aging research because of its efifcacy in inducing senescence and accelerating aging in animal models. The present study investigated the beneifts of exercise for preventing neurodegeneration, such as synaptic plasticity, spatial learning and memory abilities, in mouse models of aging. D-galactose-induced aging mice were administered daily subcutaneous injections of D-ga-lactose at the base of the neck for 10 consecutive weeks. Then, the mice were subjected to exercise training by running on a treadmill for 6 days a week. Shortened escape latency in a Morris water maze test indicated that exercise improved learning and memory in aging mice. The ameliorative changes were likely induced by an upregulation of Bcl-2 and brain-derived neurotrophic factor, the repression of apop-tosis factors such as Fas and Bax, and an increase in the activity of glucose transporters-1 and 4. The data suggest moderate exercise may retard or inhibit neurodegeneration in D-galactose-induced aging mice.

  5. Astrocytic Pathological Calcium Homeostasis and Impaired Vesicle Trafficking in Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Nina Vardjan

    2017-02-01

    Full Text Available Although the central nervous system (CNS consists of highly heterogeneous populations of neurones and glial cells, clustered into diverse anatomical regions with specific functions, there are some conditions, including alertness, awareness and attention that require simultaneous, coordinated and spatially homogeneous activity within a large area of the brain. During such events, the brain, representing only about two percent of body mass, but consuming one fifth of body glucose at rest, needs additional energy to be produced. How simultaneous energy procurement in a relatively extended area of the brain takes place is poorly understood. This mechanism is likely to be impaired in neurodegeneration, for example in Alzheimer’s disease, the hallmark of which is brain hypometabolism. Astrocytes, the main neural cell type producing and storing glycogen, a form of energy in the brain, also hold the key to metabolic and homeostatic support in the central nervous system and are impaired in neurodegeneration, contributing to the slow decline of excitation-energy coupling in the brain. Many mechanisms are affected, including cell-to-cell signalling. An important question is how changes in cellular signalling, a process taking place in a rather short time domain, contribute to the neurodegeneration that develops over decades. In this review we focus initially on the slow dynamics of Alzheimer’s disease, and on the activity of locus coeruleus, a brainstem nucleus involved in arousal. Subsequently, we overview much faster processes of vesicle traffic and cytosolic calcium dynamics, both of which shape the signalling landscape of astrocyte-neurone communication in health and neurodegeneration.

  6. Molecular Basis of Neurodegeneration and Neurodevelopmental Defects in Menkes Disease

    OpenAIRE

    Zlatic, Stephanie; Comstra, Heather Skye; Gokhale, Avanti; Petris, Michael J.; Faundez, Victor

    2015-01-01

    ATP7A mutations impair copper metabolism resulting in three distinct genetic disorders in humans. These diseases are characterized by neurological phenotypes ranging from intellectual disability to neurodegeneration. Severe ATP7A loss-of function alleles trigger Menkes disease, a copper deficiency condition where systemic and neurodegenerative phenotypes dominate clinical outcomes. The pathogenesis of these manifestations has been attributed to hypoactivity of a limited number of copper-depen...

  7. Brain diabetic neurodegeneration segregates with low intrinsic aerobic capacity

    OpenAIRE

    Choi, Joungil; Chandrasekaran, Krish; Demarest, Tyler G.; Kristian, Tibor; Xu, Su; Vijaykumar, Kadambari; Dsouza, Kevin Geoffrey; Qi, Nathan R; Yarowsky, Paul J.; Gallipoli, Rao; Koch, Lauren G.; Fiskum, Gary M.; Steven L Britton; Russell, James W.

    2014-01-01

    Objectives Diabetes leads to cognitive impairment and is associated with age-related neurodegenerative diseases including Alzheimer's disease (AD). Thus, understanding diabetes-induced alterations in brain function is important for developing early interventions for neurodegeneration. Low-capacity runner (LCR) rats are obese and manifest metabolic risk factors resembling human “impaired glucose tolerance” or metabolic syndrome. We examined hippocampal function in aged LCR rats compared to the...

  8. Astrocytic Pathological Calcium Homeostasis and Impaired Vesicle Trafficking in Neurodegeneration

    Science.gov (United States)

    Vardjan, Nina; Verkhratsky, Alexej; Zorec, Robert

    2017-01-01

    Although the central nervous system (CNS) consists of highly heterogeneous populations of neurones and glial cells, clustered into diverse anatomical regions with specific functions, there are some conditions, including alertness, awareness and attention that require simultaneous, coordinated and spatially homogeneous activity within a large area of the brain. During such events, the brain, representing only about two percent of body mass, but consuming one fifth of body glucose at rest, needs additional energy to be produced. How simultaneous energy procurement in a relatively extended area of the brain takes place is poorly understood. This mechanism is likely to be impaired in neurodegeneration, for example in Alzheimer’s disease, the hallmark of which is brain hypometabolism. Astrocytes, the main neural cell type producing and storing glycogen, a form of energy in the brain, also hold the key to metabolic and homeostatic support in the central nervous system and are impaired in neurodegeneration, contributing to the slow decline of excitation-energy coupling in the brain. Many mechanisms are affected, including cell-to-cell signalling. An important question is how changes in cellular signalling, a process taking place in a rather short time domain, contribute to the neurodegeneration that develops over decades. In this review we focus initially on the slow dynamics of Alzheimer’s disease, and on the activity of locus coeruleus, a brainstem nucleus involved in arousal. Subsequently, we overview much faster processes of vesicle traffic and cytosolic calcium dynamics, both of which shape the signalling landscape of astrocyte-neurone communication in health and neurodegeneration. PMID:28208745

  9. Brief but chronic increase in allopregnanolone cause accelerated AD pathology differently in two mouse models.

    Science.gov (United States)

    Bengtsson, Sara K; Johansson, Maja; Backstrom, Torbjorn; Nitsch, Roger M; Wang, Mingde

    2013-01-01

    Previously, we have shown that chronic treatment with allopregnanolone (ALLO) for three months impaired learning function in the Swe/PS1 mouse model. ALLO is a neurosteroid, produced in the CNS and a GABAA receptor agonist. ALLO modulates the general inhibitory system in the CNS by enhancing the effect of GABA. Chronic treatment with other GABAA receptor active compounds, such as benzodiazepines, ethanol and medroxy-progesterone acetate has been associated to cognitive decline and/or increased risk for dementia. In this study, we sufficed with a treatment period of one month for the Swe/PS1 mouse, and included another Alzheimer's disease mouse model; the Swe/Arc model. We found that one month of chronic treatment with elevated ALLO levels within physiological range impaired learning and memory function in the Swe/Arc female and male mice. Male Swe/PS1 mice also showed marginally impaired function, while the female mice did not. Furthermore, the chronic ALLO treatment caused increased levels of soluble Aβ in the Swe/PS1 mouse model while the levels were unchanged in the Swe/Arc model. Therefore, both Swe/Arc and Swe/PS1 mice showed signs of accelerated disease progression. Still, further studies are required to determine the mechanisms behind the cognitive impairment and the increased Aβ-levels caused by mildly elevated ALLO-levels.

  10. Establishment of a chronic left ventricular aneurysm model in rabbit

    Institute of Scientific and Technical Information of China (English)

    Cang-Song XIAO; Chang-Qing GAO; Li-Bing LI; Yao WANG; Tao ZHAO; Wei-Hua YE; Chong-Lei REN; Zhi-Yong LIU; Yang WU

    2014-01-01

    Objectives To establish a cost-effective and reproducible procedure for induction of chronic left ventricular aneurysm (LVA) in rabbits. Methods Acute myocardial infarction (AMI) was induced in 35 rabbits via concomitant ligation of the left anterior descending (LAD) coronary artery and the circumflex (Cx) branch at the middle portion. Development of AMI was co n-firmed by ST segment elevation and akinesis of the occluded area. Echocardiography, pathological evaluation, and agar i n-tra-chamber casting were utilized to validate the formation of LVA four weeks after the surgery. Left ventricular end systolic pressure (LVESP) and diastolic pressure (LVEDP) were measured before, immediately after and four weeks after ligation. D i-mensions of the ventricular chamber, thickness of the interventricular septum (IVS) and the left ventricular posterior wall (LVPW) left ventricular end diastolic volume (LVEDV) and systolic volume (LVESV), and ejection fraction (EF) were recorded by echo-cardiography. Results Thirty one (88.6%) rabbits survived myocardial infarction and 26 of them developed aneurysm (83.9%). The mean area of aneurysm was 33.4% ± 2.4% of the left ventricle. LVEF markedly decreased after LVA formation, whereas LVEDV, LVESV and the thickness of IVS as well as the dimension of ventricular chamber from apex to mitral valve annulus significantly increased. LVESP immediately dropped after ligation and recovered to a small extent after LVA formation. LVEDP progressively increased after ligation till LVA formation. Areas in the left ventricle (LV) that underwent fibrosis included the apex, anterior wall and lateral wall but not IVS. Agar intra-chamber cast showed that the bulging of LV wall was prominent in the area of aneurysm. Conclusions Ligation of LAD and Cx at the middle portion could induce develo pment of LVA at a mean area ratio of 33.4%±2.4%which involves the apex, anterior wall and lateral wall of the LV.

  11. Consensus paper: pathological mechanisms underlying neurodegeneration in spinocerebellar ataxias.

    Science.gov (United States)

    Matilla-Dueñas, A; Ashizawa, T; Brice, A; Magri, S; McFarland, K N; Pandolfo, M; Pulst, S M; Riess, O; Rubinsztein, D C; Schmidt, J; Schmidt, T; Scoles, D R; Stevanin, G; Taroni, F; Underwood, B R; Sánchez, I

    2014-04-01

    Intensive scientific research devoted in the recent years to understand the molecular mechanisms or neurodegeneration in spinocerebellar ataxias (SCAs) are identifying new pathways and targets providing new insights and a better understanding of the molecular pathogenesis in these diseases. In this consensus manuscript, the authors discuss their current views on the identified molecular processes causing or modulating the neurodegenerative phenotype in spinocerebellar ataxias with the common opinion of translating the new knowledge acquired into candidate targets for therapy. The following topics are discussed: transcription dysregulation, protein aggregation, autophagy, ion channels, the role of mitochondria, RNA toxicity, modulators of neurodegeneration and current therapeutic approaches. Overall point of consensus includes the common vision of neurodegeneration in SCAs as a multifactorial, progressive and reversible process, at least in early stages. Specific points of consensus include the role of the dysregulation of protein folding, transcription, bioenergetics, calcium handling and eventual cell death with apoptotic features of neurons during SCA disease progression. Unresolved questions include how the dysregulation of these pathways triggers the onset of symptoms and mediates disease progression since this understanding may allow effective treatments of SCAs within the window of reversibility to prevent early neuronal damage. Common opinions also include the need for clinical detection of early neuronal dysfunction, for more basic research to decipher the early neurodegenerative process in SCAs in order to give rise to new concepts for treatment strategies and for the translation of the results to preclinical studies and, thereafter, in clinical practice.

  12. Tryptase - PAR2 axis in Experimental Autoimmune Prostatitis, a model for Chronic Pelvic Pain Syndrome

    Science.gov (United States)

    Roman, Kenny; Done, Joseph D.; Schaeffer, Anthony J.; Murphy, Stephen F.; Thumbikat, Praveen

    2014-01-01

    Chronic prostatitis/Chronic pelvic pain syndrome (CP/CPPS) affects up to 15% of the male population and is characterized by pelvic pain. Mast cells are implicated in the murine experimental autoimmune prostatitis (EAP) model as key to chronic pelvic pain development. The mast cell mediator tryptase-β and its cognate receptor protease-activated receptor 2 (PAR2) are involved in mediating pain in other visceral disease models. Prostatic secretions and urines from CP/CPPS patients were examined for the presence of mast cell degranulation products. Tryptase-β and PAR2 expression were examined in murine experimental autoimmune prostatitis (EAP). Pelvic pain and inflammation were assessed in the presence or absence of PAR2 expression and upon PAR2 neutralization. Tryptase-β and carboxypeptidase A3 were elevated in CP/CPPS compared to healthy volunteers. Tryptase-β was capable of inducing pelvic pain and was increased in EAP along with its receptor PAR2. PAR2 was required for the development of chronic pelvic pain in EAP. PAR2 signaling in dorsal root ganglia lead to ERK1/2 phosphorylation and calcium influx. PAR2 neutralization using antibodies attenuated chronic pelvic pain in EAP. The tryptase-PAR2 axis is an important mediator of pelvic pain in EAP and may play a role in the pathogenesis of CP/CPPS. PMID:24726923

  13. A neural model for chronic pain and pain relief by extracorporeal shock wave treatment.

    Science.gov (United States)

    Wess, Othmar J

    2008-12-01

    The paper develops a new theory of chronic pain and pain relief by extracorporeal shock wave treatment. Chronic pain without underlying anatomical disorder is looked at as a pathological control function of memory. Conditioned reflexes are considered to be engraved memory traces linking sensory input of afferent signals with motor response of efferent signals. This feature can be described by associative memory functions of the nervous system. Some conditioned reflexes may cause inappropriate or pathological reactions. Consequently, a circulus vitiosus of pain sensation and muscle and/or vessel contraction is generated when pain becomes chronic (pain spiral). The key feature is a dedicated engram responsible for a pathological (painful) reaction. The pain memory may be explained by the concept of a holographic memory model published by several authors. According to this model it is shown how nervous systems may generate and recall memory contents. The paper shows how extracorporeal shock wave treatment may reorganize pathologic memory traces, thus giving cause to real and permanent pain relief. In a generalized manner, the idea of associative memory functions may help in the understanding of conditioning as a learning process and explain extracorporeal shock wave application as an efficient treatment concept for chronic pain. This concept may open the door for new treatment approaches to chronic pain and several other disorders of the nervous system.

  14. Tryptase-PAR2 axis in experimental autoimmune prostatitis, a model for chronic pelvic pain syndrome.

    Science.gov (United States)

    Roman, Kenny; Done, Joseph D; Schaeffer, Anthony J; Murphy, Stephen F; Thumbikat, Praveen

    2014-07-01

    Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) affects up to 15% of the male population and is characterized by pelvic pain. Mast cells are implicated in the murine experimental autoimmune prostatitis (EAP) model as key to chronic pelvic pain development. The mast cell mediator tryptase-β and its cognate receptor protease-activated receptor 2 (PAR2) are involved in mediating pain in other visceral disease models. Prostatic secretions and urines from CP/CPPS patients were examined for the presence of mast cell degranulation products. Tryptase-β and PAR2 expression were examined in murine EAP. Pelvic pain and inflammation were assessed in the presence or absence of PAR2 expression and upon PAR2 neutralization. Tryptase-β and carboxypeptidase A3 were elevated in CP/CPPS compared to healthy volunteers. Tryptase-β was capable of inducing pelvic pain and was increased in EAP along with its receptor PAR2. PAR2 was required for the development of chronic pelvic pain in EAP. PAR2 signaling in dorsal root ganglia led to extracellular signal-regulated kinase (ERK)1/2 phosphorylation and calcium influx. PAR2 neutralization using antibodies attenuated chronic pelvic pain in EAP. The tryptase-PAR2 axis is an important mediator of pelvic pain in EAP and may play a role in the pathogenesis of CP/CPPS.

  15. Nitrosamine exposure exacerbates high fat diet-mediated type 2 diabetes mellitus, non-alcoholic steatohepatitis, and neurodegeneration with cognitive impairment

    Directory of Open Access Journals (Sweden)

    de la Monte Suzanne M

    2009-12-01

    Full Text Available Abstract Background The current epidemics of type 2 diabetes mellitus (T2DM, non-alcoholic steatohepatitis (NASH, and Alzheimer's disease (AD all represent insulin-resistance diseases. Previous studies linked insulin resistance diseases to high fat diets or exposure to streptozotocin, a nitrosamine-related compound that causes T2DM, NASH, and AD-type neurodegeneration. We hypothesize that low-level exposure to nitrosamines that are widely present in processed foods, amplifies the deleterious effects of high fat intake in promoting T2DM, NASH, and neurodegeneration. Methods Long Evans rat pups were treated with N-nitrosodiethylamine (NDEA by i.p. Injection, and upon weaning, they were fed with high fat (60%; HFD or low fat (5%; LFD chow for 6 weeks. Rats were evaluated for cognitive impairment, insulin resistance, and neurodegeneration using behavioral, biochemical, molecular, and histological methods. Results NDEA and HFD ± NDEA caused T2DM, NASH, deficits in spatial learning, and neurodegeneration with hepatic and brain insulin and/or IGF resistance, and reductions in tau and choline acetyltransferase levels in the temporal lobe. In addition, pro-ceramide genes, which promote insulin resistance, were increased in livers and brains of rats exposed to NDEA, HFD, or both. In nearly all assays, the adverse effects of HFD+NDEA were worse than either treatment alone. Conclusions Environmental and food contaminant exposures to low, sub-mutagenic levels of nitrosamines, together with chronic HFD feeding, function synergistically to promote major insulin resistance diseases including T2DM, NASH, and AD-type neurodegeneration. Steps to minimize human exposure to nitrosamines and consumption of high-fat content foods are needed to quell these costly and devastating epidemics.

  16. The microRNA miR-34 modulates ageing and neurodegeneration in Drosophila.

    Science.gov (United States)

    Liu, Nan; Landreh, Michael; Cao, Kajia; Abe, Masashi; Hendriks, Gert-Jan; Kennerdell, Jason R; Zhu, Yongqing; Wang, Li-San; Bonini, Nancy M

    2012-02-15

    Human neurodegenerative diseases have the temporal hallmark of afflicting the elderly population. Ageing is one of the most prominent factors to influence disease onset and progression, yet little is known about the molecular pathways that connect these processes. To understand this connection it is necessary to identify the pathways that functionally integrate ageing, chronic maintenance of the brain and modulation of neurodegenerative disease. MicroRNAs (miRNA) are emerging as critical factors in gene regulation during development; however, their role in adult-onset, age-associated processes is only beginning to be revealed. Here we report that the conserved miRNA miR-34 regulates age-associated events and long-term brain integrity in Drosophila, providing a molecular link between ageing and neurodegeneration. Fly mir-34 expression exhibits adult-onset, brain-enriched and age-modulated characteristics. Whereas mir-34 loss triggers a gene profile of accelerated brain ageing, late-onset brain degeneration and a catastrophic decline in survival, mir-34 upregulation extends median lifespan and mitigates neurodegeneration induced by human pathogenic polyglutamine disease protein. Some of the age-associated effects of miR-34 require adult-onset translational repression of Eip74EF, an essential ETS domain transcription factor involved in steroid hormone pathways. Our studies indicate that miRNA-dependent pathways may have an impact on adult-onset, age-associated events by silencing developmental genes that later have a deleterious influence on adult life cycle and disease, and highlight fly miR-34 as a key miRNA with a role in this process.

  17. Developing an active implementation model for a chronic disease management program

    Directory of Open Access Journals (Sweden)

    Margrethe Smidth

    2013-06-01

    Full Text Available Background: Introduction and diffusion of new disease management programs in healthcare is usually slow, but active theory-driven implementation seems to outperform other implementation strategies. However, we have only scarce evidence on the feasibility and real effect of such strategies in complex primary care settings where municipalities, general practitioners and hospitals should work together. The Central Denmark Region recently implemented a disease management program for chronic obstructive pulmonary disease (COPD which presented an opportunity to test an active implementation model against the usual implementation model. The aim of the present paper is to describe the development of an active implementation model using the Medical Research Council’s model for complex interventions and the Chronic Care Model.Methods: We used the Medical Research Council’s five-stage model for developing complex interventions to design an implementation model for a disease management program for COPD. First, literature on implementing change in general practice was scrutinised and empirical knowledge was assessed for suitability. In phase I, the intervention was developed; and in phases II and III, it was tested in a block- and cluster-randomised study. In phase IV, we evaluated the feasibility for others to use our active implementation model.Results: The Chronic Care Model was identified as a model for designing efficient implementation elements. These elements were combined into a multifaceted intervention, and a timeline for the trial in a randomised study was decided upon in accordance with the five stages in the Medical Research Council’s model; this was captured in a PaTPlot, which allowed us to focus on the structure and the timing of the intervention. The implementation strategies identified as efficient were use of the Breakthrough Series, academic detailing, provision of patient material and meetings between providers. The active

  18. Developing an active implementation model for a chronic disease management program

    Directory of Open Access Journals (Sweden)

    Margrethe Smidth

    2013-06-01

    Full Text Available Background: Introduction and diffusion of new disease management programs in healthcare is usually slow, but active theory-driven implementation seems to outperform other implementation strategies. However, we have only scarce evidence on the feasibility and real effect of such strategies in complex primary care settings where municipalities, general practitioners and hospitals should work together. The Central Denmark Region recently implemented a disease management program for chronic obstructive pulmonary disease (COPD which presented an opportunity to test an active implementation model against the usual implementation model. The aim of the present paper is to describe the development of an active implementation model using the Medical Research Council’s model for complex interventions and the Chronic Care Model.Methods: We used the Medical Research Council’s five-stage model for developing complex interventions to design an implementation model for a disease management program for COPD. First, literature on implementing change in general practice was scrutinised and empirical knowledge was assessed for suitability. In phase I, the intervention was developed; and in phases II and III, it was tested in a block- and cluster-randomised study. In phase IV, we evaluated the feasibility for others to use our active implementation model. Results: The Chronic Care Model was identified as a model for designing efficient implementation elements. These elements were combined into a multifaceted intervention, and a timeline for the trial in a randomised study was decided upon in accordance with the five stages in the Medical Research Council’s model; this was captured in a PaTPlot, which allowed us to focus on the structure and the timing of the intervention. The implementation strategies identified as efficient were use of the Breakthrough Series, academic detailing, provision of patient material and meetings between providers. The active

  19. A comprehensive examination of the model underlying acceptance and commitment therapy for chronic pain.

    Science.gov (United States)

    Vowles, Kevin E; Sowden, Gail; Ashworth, Julie

    2014-05-01

    The therapeutic model underlying Acceptance and Commitment Therapy (ACT) is reasonably well-established as it applies to chronic pain. Several studies have examined measures of single ACT processes, or subsets of processes, and have almost uniformly indicated reliable relations with patient functioning. To date, however, no study has performed a comprehensive examination of the entire ACT model, including all of its component processes, as it relates to functioning. The present study performed this examination in 274 individuals with chronic pain presenting for an assessment appointment. Participants completed a battery of self-report questionnaires, assessing multiple aspects of the ACT model, as well as pain intensity, disability, and emotional distress. Initial exploratory factor analyses examined measures of the ACT model and measures of patient functioning separately with each analysis identifying three factors. Next, the fit of a model including ACT processes on the one hand and patient functioning on the other was examined using Structural Equation Modeling. Overall model fit was acceptable and indicated moderate correlations among the ACT processes themselves, as well as significant relations with pain intensity, emotional distress, and disability. These analyses build on the existing literature by providing, to our knowledge, the most comprehensive evaluation of the ACT theoretical model in chronic pain to date.

  20. Modeling hematopoietic system response caused by chronic exposure to ionizing radiation.

    Science.gov (United States)

    Akushevich, Igor V; Veremeyeva, Galina A; Dimov, Georgy P; Ukraintseva, Svetlana V; Arbeev, Konstantin G; Akleyev, Alexander V; Yashin, Anatoly I

    2011-05-01

    A new model of the hematopoietic system response in humans chronically exposed to ionizing radiation describes the dynamics of the hematopoietic stem cell compartment as well as the dynamics of each of the four blood cell types (lymphocytes, neutrophiles, erythrocytes, and platelets). The required model parameters were estimated based on available results of human and experimental animal studies. They include the steady-state number of hematopoietic stem cells and peripheral blood cell lines in an unexposed organism, amplification parameters for each blood line, parameters describing proliferation and apoptosis, parameters of feedback functions regulating the steady-state numbers, and characteristics of radiosensitivity related to cell death and non-lethal cell damage. The model predictions were tested using data on hematological measurements (e.g., blood counts) performed in 1950-1956 in the Techa River residents chronically exposed to ionizing radiation since 1949. The suggested model of hematopoiesis is capable of describing experimental findings in the Techa River Cohort, including: (1) slopes of the dose-effect curves reflecting the inhibition of hematopoiesis due to chronic ionizing radiation, (2) delay in effect of chronic exposure and accumulated character of the effect, and (3) dose-rate patterns for different cytopenic states (e.g., leukopenia, thrombocytopenia).

  1. Multidisciplinary Rehabilitation Treatment of Patients With Chronic Low Back Pain: A Prognostic Model for Its Outcome

    NARCIS (Netherlands)

    Hulst, van der Marije; Vollenbroek-Hutten, Miriam M.R.; Groothuis-Oudshoorn, Karin G.M.; Hermens, Hermie J.

    2008-01-01

    Objectives: (1) To determine if treatment outcome in chronic low back pain can be predicted by a predefined multivariate prognostic model based on consistent predictors from the literature and (2) to explore the value of potentially prognostic factors further. Methods: Data were derived from a rand

  2. Can the common-sense model predict adherence in chronically ill patients? A meta-analysis

    NARCIS (Netherlands)

    K. Brandes; B. Mullan

    2013-01-01

    The aim of this meta-analysis was to explore whether mental representations, derived from the common-sense model of illness representations (CSM), were able to predict adherence in chronically ill patients. Electronic databases were searched for studies that used the CSM and measured adherence behav

  3. Remote patient management: technology-enabled innovation and evolving business models for chronic disease care.

    Science.gov (United States)

    Coye, Molly Joel; Haselkorn, Ateret; DeMello, Steven

    2009-01-01

    Remote patient management (RPM) is a transformative technology that improves chronic care management while reducing net spending for chronic disease. Broadly deployed within the Veterans Health Administration and in many small trials elsewhere, RPM has been shown to support patient self-management, shift responsibilities to non-clinical providers, and reduce the use of emergency department and hospital services. Because transformative technologies offer major opportunities to advance national goals of improved quality and efficiency in health care, it is important to understand their evolution, the experiences of early adopters, and the business models that may support their deployment.

  4. Protective Action of Acupuncture and Moxibustion on Gastric Mucosa in Model Rats with Chronic Atrophic Gastritis

    Institute of Scientific and Technical Information of China (English)

    高希言; 饶红; 王燕; 孟丹; 魏玉龙

    2005-01-01

    Objective: To probe the mechanism of acupuncture and moxibustion in atrophic gastritis so as to provide a basis for clinical treatment. Method: Observe the effects of acupuncture and moxibustion at the points of Zusanli, Zhongwan and Tianshu on gastric mucosa in model rats with chronic atrophic gastritis. Results:Acupuncture and moxibustion can increase the contents of PGE2α, PGF2α and cAMP, and decrease the content of cGMP in the tissue of gastric mucosa. Conclusion: Acupuncture and moxibustion shows cytoprotection on gastric mucosa, so it is an effective method for treating chronic atrophic gastritis.

  5. Salt-induced changes in cardiac phosphoproteome in a rat model of chronic renal failure.

    Directory of Open Access Journals (Sweden)

    Zhengxiu Su

    Full Text Available Heart damage is widely present in patients with chronic kidney disease. Salt diet is the most important environmental factor affecting development of chronic renal failure and cardiovascular diseases. The proteins involved in chronic kidney disease -induced heart damage, especially their posttranslational modifications, remain largely unknown to date. Sprague-Dawley rats underwent 5/6 nephrectomy (chronic renal failure model or sham operation were treated for 2 weeks with a normal-(0.4% NaCl, or high-salt (4% NaCl diet. We employed TiO2 enrichment, iTRAQ labeling and liquid-chromatography tandem mass spectrometry strategy for phosphoproteomic profiling of left ventricular free walls in these animals. A total of 1724 unique phosphopeptides representing 2551 non-redundant phosphorylation sites corresponding to 763 phosphoproteins were identified. During normal salt feeding, 89 (54% phosphopeptides upregulated and 76 (46% phosphopeptides downregulated in chronic renal failure rats relative to sham rats. In chronic renal failure rats, high salt intake induced upregulation of 84 (49% phosphopeptides and downregulation of 88 (51% phosphopeptides. Database searches revealed that most of the identified phospholproteins were important signaling molecules such as protein kinases, receptors and phosphatases. These phospholproteins were involved in energy metabolism, cell communication, cell differentiation, cell death and other biological processes. The Search Tool for the Retrieval of Interacting Genes analysis revealed functional links among 15 significantly regulated phosphoproteins in chronic renal failure rats compared to sham group, and 23 altered phosphoproteins induced by high salt intake. The altered phosphorylation levels of two proteins involved in heart damage, lamin A and phospholamban were validated. Expression of the downstream genes of these two proteins, desmin and SERCA2a, were also analyzed.

  6. Salt-induced changes in cardiac phosphoproteome in a rat model of chronic renal failure.

    Science.gov (United States)

    Su, Zhengxiu; Zhu, Hongguo; Zhang, Menghuan; Wang, Liangliang; He, Hanchang; Jiang, Shaoling; Hou, Fan Fan; Li, Aiqing

    2014-01-01

    Heart damage is widely present in patients with chronic kidney disease. Salt diet is the most important environmental factor affecting development of chronic renal failure and cardiovascular diseases. The proteins involved in chronic kidney disease -induced heart damage, especially their posttranslational modifications, remain largely unknown to date. Sprague-Dawley rats underwent 5/6 nephrectomy (chronic renal failure model) or sham operation were treated for 2 weeks with a normal-(0.4% NaCl), or high-salt (4% NaCl) diet. We employed TiO2 enrichment, iTRAQ labeling and liquid-chromatography tandem mass spectrometry strategy for phosphoproteomic profiling of left ventricular free walls in these animals. A total of 1724 unique phosphopeptides representing 2551 non-redundant phosphorylation sites corresponding to 763 phosphoproteins were identified. During normal salt feeding, 89 (54%) phosphopeptides upregulated and 76 (46%) phosphopeptides downregulated in chronic renal failure rats relative to sham rats. In chronic renal failure rats, high salt intake induced upregulation of 84 (49%) phosphopeptides and downregulation of 88 (51%) phosphopeptides. Database searches revealed that most of the identified phospholproteins were important signaling molecules such as protein kinases, receptors and phosphatases. These phospholproteins were involved in energy metabolism, cell communication, cell differentiation, cell death and other biological processes. The Search Tool for the Retrieval of Interacting Genes analysis revealed functional links among 15 significantly regulated phosphoproteins in chronic renal failure rats compared to sham group, and 23 altered phosphoproteins induced by high salt intake. The altered phosphorylation levels of two proteins involved in heart damage, lamin A and phospholamban were validated. Expression of the downstream genes of these two proteins, desmin and SERCA2a, were also analyzed.

  7. Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease

    Science.gov (United States)

    Martin, Ian; Kim, Jungwoo Wren; Lee, Byoung Dae; Kang, Ho Chul; Xu, Jin-Chong; Jia, Hao; Stankowski, Jeannette; Kim, Min-Sik; Zhong, Jun; Kumar, Manoj; Andrabi, Shaida A.; Xiong, Yulan; Dickson, Dennis W.; Wszolek, Zbigniew K.; Pandey, Akhilesh; Dawson, Ted M.; Dawson, Valina L.

    2014-01-01

    Summary Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial and sporadic Parkinson's disease (PD). Elevated LRRK2 kinase activity and neurodegeneration are linked, but the phosphosubstrate that connects LRRK2 kinase activity to neurodegeneration is not known. Here, we show that ribosomal protein s15 is a key pathogenic LRRK2 substrate in Drosophila and human neuron PD models. Phospho-deficient s15 carrying a threonine 136 to alanine substitution rescues dopamine neuron degeneration and age-related locomotor deficits in G2019S LRRK2 transgenic Drosophila and substantially reduces G2019S LRRK2-mediated neurite loss and cell death in human dopamine and cortical neurons. Remarkably, pathogenic LRRK2 stimulates both cap-dependent and cap-independent mRNA translation, and induces a bulk increase in protein synthesis in Drosophila, which can be prevented by phospho-deficient T136A s15. These results reveal a novel mechanism of PD pathogenesis linked to elevated LRRK2 kinase activity and aberrant protein synthesis in vivo. PMID:24725412

  8. A functional misexpression screen uncovers a role for enabled in progressive neurodegeneration.

    Directory of Open Access Journals (Sweden)

    Carolina Rezával

    Full Text Available Drosophila is a well-established model to study the molecular basis of neurodegenerative diseases. We carried out a misexpression screen to identify genes involved in neurodegeneration examining locomotor behavior in young and aged flies. We hypothesized that a progressive loss of rhythmic activity could reveal novel genes involved in neurodegenerative mechanisms. One of the interesting candidates showing progressive arrhythmicity has reduced enabled (ena levels. ena down-regulation gave rise to progressive vacuolization in specific regions of the adult brain. Abnormal staining of pre-synaptic markers such as cystein string protein (CSP suggest that axonal transport could underlie the neurodegeneration observed in the mutant. Reduced ena levels correlated with increased apoptosis, which could be rescued in the presence of p35, a general Caspase inhibitor. Thus, this mutant recapitulates two important features of human neurodegenerative diseases, i.e., vulnerability of certain neuronal populations and progressive degeneration, offering a unique scenario in which to unravel the specific mechanisms in an easily tractable organism.

  9. [Pentylenetetrazole kindling in rats: whether neurodegeneration is associated with manifestations of seizure activity?].

    Science.gov (United States)

    Pavlova, T V; Iakovleva, A A; Stepanichev, M Iu; Guliaeva, N V

    2005-07-01

    Structural changes in neurons and oxidative stress in hippocampus were studied in rats "tolerant" (TR) and susceptible (SR) to tonic and clonic seizures in pentylenetetrazole (PTZ) kindling. The number of normal neurons was significantly decreased in CA1 subfield of TR hippocampus after 11 injections of PTZ, while in SR neuronal cell loss was evident in CA1 and fascia dentata. In both groups, neuronal cell loss was accompanied by increase in damaged neuron number in CA4 subfield. After 21 injections of PTZ, the decrease in normal neuron number was revealed in CA1 subfield of both TR and SR, while the number of damaged neurons was above the control level in hippocampal subfields CA1 and CA4 in TR only. Glutathione level was decreased in hippocampus of both TR and SR as compared with control rats. Thus, rats tolerant to PTZ-induced convulsions demonstrated oxidative stress and neurodegeneration in hippocampus. The results suggest that, in PTZ kindling model, oxidative damage of neurons resulting in neurodegeneration in hippocampus is not directly related to the convulsive activity.

  10. The P66Shc/Mitochondrial Permeability Transition Pore Pathway Determines Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Costanza Savino

    2013-01-01

    Full Text Available Mitochondrial-mediated oxidative stress and apoptosis play a crucial role in neurodegenerative disease and aging. Both mitochondrial permeability transition (PT and swelling of mitochondria have been involved in neurodegeneration. Indeed, knockout mice for cyclophilin-D (Cyc-D, a key regulatory component of the PT pore (PTP that triggers mitochondrial swelling, resulted to be protected in preclinical models of multiple sclerosis (MS, Parkinson’s disease (PD, and amyotrophic lateral sclerosis (ALS. However, how neuronal stress is transduced into mitochondrial oxidative stress and swelling is unclear. Recently, the aging determinant p66Shc that generates H2O2 reacting with cytochrome c and induces oxidation of PTP and mitochondrial swelling was found to be involved in MS and ALS. To investigate the role of p66Shc/PTP pathway in neurodegeneration, we performed experimental autoimmune encephalomyelitis (EAE experiments in p66Shc knockout mice (p66Shc−/−, knock out mice for cyclophilin-D (Cyc-D−/−, and p66Shc Cyc-D double knock out (p66Shc/Cyc-D−/− mice. Results confirm that deletion of p66Shc protects from EAE without affecting immune response, whereas it is not epistatic to the Cyc-D mutation. These findings demonstrate that p66Shc contributes to EAE induced neuronal damage most likely through the opening of PTP suggesting that p66Shc/PTP pathway transduces neurodegenerative stresses.

  11. Prediction of chronic damage in systemic lupus erythematosus by using machine-learning models

    Science.gov (United States)

    Perricone, Carlo; Galvan, Giulio; Morelli, Francesco; Vicente, Luis Nunes; Leccese, Ilaria; Massaro, Laura; Cipriano, Enrica; Spinelli, Francesca Romana; Alessandri, Cristiano; Valesini, Guido; Conti, Fabrizio

    2017-01-01

    Objective The increased survival in Systemic Lupus Erythematosus (SLE) patients implies the development of chronic damage, occurring in up to 50% of cases. Its prevention is a major goal in the SLE management. We aimed at predicting chronic damage in a large monocentric SLE cohort by using neural networks. Methods We enrolled 413 SLE patients (M/F 30/383; mean age ± SD 46.3±11.9 years; mean disease duration ± SD 174.6 ± 112.1 months). Chronic damage was assessed by the SLICC/ACR Damage Index (SDI). We applied Recurrent Neural Networks (RNNs) as a machine-learning model to predict the risk of chronic damage. The clinical data sequences registered for each patient during the follow-up were used for building and testing the RNNs. Results At the first visit in the Lupus Clinic, 35.8% of patients had an SDI≥1. For the RNN model, two groups of patients were analyzed: patients with SDI = 0 at the baseline, developing damage during the follow-up (N = 38), and patients without damage (SDI = 0). We created a mathematical model with an AUC value of 0.77, able to predict damage development. A threshold value of 0.35 (sensitivity 0.74, specificity 0.76) seemed able to identify patients at risk to develop damage. Conclusion We applied RNNs to identify a prediction model for SLE chronic damage. The use of the longitudinal data from the Sapienza Lupus Cohort, including laboratory and clinical items, resulted able to construct a mathematical model, potentially identifying patients at risk to develop damage. PMID:28329014

  12. Effect of Electro-acupuncture on Rat Joint Patho-morphology of Chronic Adjuvant Arthritis Model

    Institute of Scientific and Technical Information of China (English)

    张幼美; 胡玲; 唐纯志; 曹伟

    2003-01-01

    Objective:To study the effect of electro-acupuncture (EA) on pathomorphological changes of joints in rat model of chronic adjuvant arthritis. Methods: The rat chronic adjuvant arthritis model was established by subcutaneous injection of 0.1 ml of complete Freund's adjuvant to the left hind sole. Forty Wistar rats were randomly divided into the model group, the low frequency (2 Hz) EA group, the high frequency EA (100 Hz) group and the body acupuncture group. After being modeled except the model group, the other three groups were treated with EA or body acupuncture in Yanglingquan points (bilateral) for 3 weeks, the left ankle joints and metatarsal joints of rats were taken for pathological examination by fixing with 10% formalin and embedding in paraffin, sectioning and staining with HE. Results: Obvious inflammatory cell infiltration, loosened synovial tissue, damage of articular cartilage and proliferation of synovial cells and granulation tissue were observed in the sections of joints in model rats. These pathological changes were significantly improved after treatment, and the effect in the high frequency EA group were significantly superior to that in the low frequency EA and body acupuncture group. Conclusion: High frequency EA could significantly improve the pathomorphological changes of joints in chronic adjuvant arthritis rat models.

  13. Effect of Electro—acupuncture on Rat Joint Pathomorphology of Chronic Adjuvant Arthritis Model

    Institute of Scientific and Technical Information of China (English)

    ZHANGYou-mei; HULing; 等

    2003-01-01

    Objective:To study the effect of electro-acupuncture(EA) on pathomorphological changes of joints in rat model of chronic adjuvant arthritis.Methods:The rat chronic adjuvant arthritis model was established by subcutaneous injection of 0.1 ml of complete Freunds adjuvant to the left hind sole.Forty Wistar rats were randomly divided into the model group,the low frequency(2Hz) EA group,the high frequency EA(100Hz)group and the body acupuncture group.After being modeled except the model group,the other three groups were treated with EA or body acupuncture in Yanglingquan points(bilater-al)for 3weeks,the left ankle joints and metatarsal joints of rats were taken for pathological examination by fixing with 10% formalin and embedding in paraffin,sectioning and staining with HE.Results:Obvious inflammatory cell infiltration,loosened synovial tissue,damage of articular cartilage and proliferation of synovial cells and granulation tissue were observed in the sections of joints in model rats.These pathologi-cal changes were significantly improved after treatment,and the effect in the high frequency EA group were significantly superior to that in the low frequency EA and body acupuncture group.Conclusion:High frequency EA could significantly improve the pathomorphological changes of joints in chronic adjuvant ar-thritis rat models.

  14. Accuracy of a predictive model for severe hepatic fibrosis or cirrhosis in chronic hepatitis C

    Institute of Scientific and Technical Information of China (English)

    Agostino Colli; Alice Colucci; Silvia Paggi; Mirella Fraquelli; Sara Massironi; Marco Andreoletti; Vittorio Michela; Dario Conte

    2005-01-01

    AIM: To assess the accuracy of a model in diagnosing severe fibrosis/cirrhosis in chronic hepatitis C virus (HCV)infection.METHODS: The model, based on the sequential combination of the Bonacini score (BS: ALT/AST ratio,platelet count and INR) and ultrasonography liver surface characteristics, was applied to 176 patients with chronic HCV infection. Assuming a pre-test probability of 35%,the model defined four levels of post-test probability of severe fibrosis/cirrhosis: 90% (almost absolute).The predicted probabilities were compared with the observed patients' distribution according to the histology (METAVIR).RESULTS: Severe fibrosis/cirrhosis was found in 67 patients (38%). The model discriminated patients in three comparable groups: 34% with a very high (>90%)or low (75%) or low (<10%) probability of cirrhosis, leaving only 33% of the patients still requiring liver biopsy.

  15. The chronic mild stress (CMS) model of depression: History, evaluation and usage.

    Science.gov (United States)

    Willner, Paul

    2017-02-01

    Now 30 years old, the chronic mild stress (CMS) model of depression has been used in >1300 published studies, with a year-on-year increase rising to >200 papers in 2015. Data from a survey of users show that while a variety of names are in use (chronic mild/unpredictable/varied stress), these describe essentially the same procedure. This paper provides an update on the validity and reliability of the CMS model, and reviews recent data on the neurobiological basis of CMS effects and the mechanisms of antidepressant action: the volume of this research may be unique in providing a comprehensive account of antidepressant action within a single model. Also discussed is the use of CMS in drug discovery, with particular reference to hippocampal and extra-hippocampal targets. The high translational potential of the CMS model means that the neurobiological mechanisms described may be of particular relevance to human depression and mechanisms of clinical antidepressant action.

  16. Use of small intestine submucosa in a rat model of acute and chronic rotator cuff tear.

    Science.gov (United States)

    Perry, Stephanie M; Gupta, Rishi R; Van Kleunen, Jonathan; Ramsey, Matthew L; Soslowsky, Louis J; Glaser, David L

    2007-01-01

    Augmentation materials for rotator cuff tears, such as small intestine submucosa (SIS), have been used with the goal of improving outcome. Knowledge is limited on the use of SIS in animal models of acute and chronic rotator cuff tears. We hypothesized that the use of SIS in the surgical management of full thickness supraspinatus tears would improve histologic and biomechanical properties. Results show temporal improvements in several histologic parameters. Both acute and chronic injuries repaired with SIS have similar and increased mechanical properties respectively, compared to those repaired without SIS. In general, acute repairs with SIS were comparable to acute repairs without SIS. In chronic repairs, the use of SIS significantly reduced the cross sectional area of the healing tendon and increased the modulus. These results provide information on the use of SIS for rotator cuff repairs.

  17. Different microRNA profiles in chronic epilepsy versus acute seizure mouse models.

    Science.gov (United States)

    Kretschmann, Anita; Danis, Benedicte; Andonovic, Lidija; Abnaof, Khalid; van Rikxoort, Marijke; Siegel, Franziska; Mazzuferi, Manuela; Godard, Patrice; Hanon, Etienne; Fröhlich, Holger; Kaminski, Rafal M; Foerch, Patrik; Pfeifer, Alexander

    2015-02-01

    Epilepsy affects around 50 million people worldwide, and in about 65% of patients, the etiology of disease is unknown. MicroRNAs are small non-coding RNAs that have been suggested to play a role in the pathophysiology of epilepsy. Here, we compared microRNA expression patterns in the hippocampus using two chronic models of epilepsy characterised by recurrent spontaneous seizures (pilocarpine and self-sustained status epilepticus (SSSE)) and an acute 6-Hz seizure model. The vast majority of microRNAs deregulated in the acute model exhibited increased expression with 146 microRNAs up-regulated within 6 h after a single seizure. In contrast, in the chronic models, the number of up-regulated microRNAs was similar to the number of down-regulated microRNAs. Three microRNAs-miR-142-5p, miR-331-3p and miR-30a-5p-were commonly deregulated in all three models. However, there is a clear overlap of differentially expressed microRNAs within the chronic models with 36 and 15 microRNAs co-regulated at 24 h and at 28 days following status epilepticus, respectively. Pathway analysis revealed that the altered microRNAs are associated with inflammation, innate immunity and cell cycle regulation. Taken together, the identified microRNAs and the pathways they modulate might represent candidates for novel molecular approaches for the treatment of patients with epilepsy.

  18. Prognostic factors for chronic severe hepatitis and construction of a prognostic model

    Institute of Scientific and Technical Information of China (English)

    Qian Li; Gui-Yu Yuan; Ke-Cheng Tang; Guo-Wang Liu; Rui Wang; Wu-Kui Cao

    2008-01-01

    BACKGROUND:Chronic severe hepatitis is a serious illness with a high mortality rate. Discussion of prognostic judgment criteria for chronic severe hepatitis is of great value in clinical guidance. This study was designed to investigate the clinical and laboratory indices affecting the prognosis of chronic severe hepatitis and construct a prognostic model. METHODS: The clinical and laboratory indices of 213 patients with chronic severe hepatitis within 24 hours after diagnosis were analyzed retrospectively. Death or survival was limited to within 3 months after diagnosis. RESULTS: The mortality of all patients was 47.42%. Compared with the survival group, the age, basis of hepatocirrhosis, infection, degree of hepatic encephalopathy (HE) and the levels of total bilirubin (TBil), total cholesterol (CHO), cholinesterase (CHE), blood urea nitrogen (BUN), blood creatinine (Cr), blood sodium ion (Na), peripheral blood leukocytes (WBC), alpha-fetoprotein (AFP), international normalized ratio (INR) of blood coagulation and prothrombin time (PT) were signiifcantly different in the group who died, but the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB) and hemoglobin (HGB) were not different between the two groups. At the same time, a regression model, Logit (P)=1.573×Age+1.338× HE-1.608×CHO+0.011×Cr-0.109×Na+1.298×INR+11.057, was constructed by logistic regression analysis and the prognostic value of the model was higher than that of the MELD score. CONCLUSIONS:Multivariate analysis excels univariate anlysis in the prognosis of chronic severe hepatitis, and the regression model is of signiifcant value in the prognosis of this disease.

  19. Neuroprotective Effect of Fisetin Against Amyloid-Beta-Induced Cognitive/Synaptic Dysfunction, Neuroinflammation, and Neurodegeneration in Adult Mice.

    Science.gov (United States)

    Ahmad, Ashfaq; Ali, Tahir; Park, Hyun Young; Badshah, Haroon; Rehman, Shafiq Ur; Kim, Myeong Ok

    2017-04-01

    Alzheimer's disease (AD) is a devastating and progressive neurodegenerative disease and is characterized pathologically by the accumulation of amyloid beta (Aβ) and the hyperphosphorylation of tau proteins in the brain. The deposition of Aβ aggregates triggers synaptic dysfunction, hyperphosphorylation of tau, and neurodegeneration, which lead to cognitive disorders. Here, we investigated the neuroprotective effect of fisetin in the Aβ1-42 mouse model of AD. Single intracerebroventricular injections of Aβ1-42 (3 μl/5 min/mouse) markedly induced memory/synaptic deficits, neuroinflammation, and neurodegeneration. Intraperitoneal injections of fisetin at a dose of 20 mg/kg/day for 2 weeks starting 24 h after Aβ1-42 injection significantly decreased the Aβ1-42-induced accumulation of Aβ, BACE-1 expression, and hyperphosphorylation of tau protein at serine 413. Fisetin treatment also markedly reversed Aβ1-42-induced synaptic dysfunction by increasing the levels of both presynaptic (SYN and SNAP-25) and postsynaptic proteins (PSD-95, SNAP-23, p-GluR1 (Ser 845), p-CREB (Ser 133) and p-CAMKII (Thr 286) and ultimately improved mouse memory, as observed in the Morris water maze test. Fisetin significantly activated p-PI3K, p-Akt (Ser 473), and p-GSK3β (Ser 9) expression in Aβ1-42-treated mice. Moreover, fisetin prevented neuroinflammation by suppressing various activated neuroinflammatory mediators and gliosis; it also suppressed the apoptotic neurodegeneration triggered by Aβ1-42 injections in the mouse hippocampus. Fluorojade-B and immunohistochemical staining for caspase-3 revealed that fisetin prevented neurodegeneration in Aβ1-42-treated mice. Our results suggest that fisetin has a potent neuroprotective effect against Aβ1-42-induced neurotoxicity. These results demonstrate that polyphenolic flavonoids such as fisetin could be a beneficial, effective and safe neuroprotective agent for preventing neurological disorders such as AD.

  20. In vitro detection of oxygen and glucose deprivation-induced neurodegeneration and pharmacological neuroprotection based on hippocampal stratum pyramidale width.

    Science.gov (United States)

    Öz, Pınar; Saybaşılı, Hale

    2017-01-01

    Ischemia is one of the most prominent risk factors of neurodegenerative diseases such as Alzheimer's disease. The effects of oxygen and glucose depletion in hippocampal tissue due to ischemia can be mimicked in vitro using the oxygen and glucose deprivation (OGD) model. In this study, we applied OGD on acute rat hippocampal slices in order to design an elementary yet quantitative histological technique that compares the neuroprotective effects of (l)-carnitine to known neuroprotectors, such as the N-methyl-d-aspartate (NMDA) receptor antagonist memantine and the gamma-aminobutyric acid (GABA)-B receptor agonist baclofen. The level of neurodegeneration and the efficiency of pharmacological applications were estimated via stratum pyramidale width measurements in CA1 and CA3 regions of Nissl-stained 200-μm thick hippocampal slices. We demonstrated that (l)-carnitine is an effective pharmacological target against the neurodegeneration induced by in vitro ischemia in a narrow range of concentrations. Even though the effect of chemical neuroprotection was significant, full recovery was not achieved in the dose interval of 5-100μM. In addition to chemical applications, hypothermia was used as a physical neuroprotection against ischemia-related neurodegeneration. Our results showed that incubation of slices for 60min at 4°C provided the same level of neuroprotection as the most effective doses of memantine, baclofen, and (l)-carnitine.

  1. A novel inexpensive murine model of oral chronic digitalization.

    Science.gov (United States)

    Helber, Izo; Kanashiro, Rosemeire M; Alarcon, Ernesto A; Antonio, Ednei L; Tucci, Paulo J F

    2004-01-01

    A novel inexpensive murine model of oral administration of digitoxin (100 micro g/kg per day) added to routine chow is described. Serum digitoxin levels achieved after oral (n = 5; 116 +/- 14 ng/mL) and subcutaneous (n = 5; 124 +/- 11 ng/mL) administration were similar. A significant increase in the maximal left ventricular pressure rise of treated (n = 9) compared with control (n = 6) rats (dP/dt: 8956 +/- 233 vs 7980 +/- 234 mmHg/s, respectively; P = 0.01) characterized the positive inotropic action of digitoxin. In addition, no differences were observed in treated compared with control rats with regard to the electrocardiogram and systolic and diastolic left ventricular pressures.

  2. Adjustment and Characterization of an Original Model of Chronic Ischemic Heart Failure in Pig

    Directory of Open Access Journals (Sweden)

    Laurent Barandon

    2010-01-01

    Full Text Available We present and characterize an original experimental model to create a chronic ischemic heart failure in pig. Two ameroid constrictors were placed around the LAD and the circumflex artery. Two months after surgery, pigs presented a poor LV function associated with a severe mitral valve insufficiency. Echocardiography analysis showed substantial anomalies in radial and circumferential deformations, both on the anterior and lateral surface of the heart. These anomalies in function were coupled with anomalies of perfusion observed in echocardiography after injection of contrast medium. No demonstration of myocardial infarction was observed with histological analysis. Our findings suggest that we were able to create and to stabilize a chronic ischemic heart failure model in the pig. This model represents a useful tool for the development of new medical or surgical treatment in this field.

  3. Combined Population Dynamics and Entropy Modelling Supports Patient Stratification in Chronic Myeloid Leukemia

    Science.gov (United States)

    Brehme, Marc; Koschmieder, Steffen; Montazeri, Maryam; Copland, Mhairi; Oehler, Vivian G.; Radich, Jerald P.; Brümmendorf, Tim H.; Schuppert, Andreas

    2016-04-01

    Modelling the parameters of multistep carcinogenesis is key for a better understanding of cancer progression, biomarker identification and the design of individualized therapies. Using chronic myeloid leukemia (CML) as a paradigm for hierarchical disease evolution we show that combined population dynamic modelling and CML patient biopsy genomic analysis enables patient stratification at unprecedented resolution. Linking CD34+ similarity as a disease progression marker to patient-derived gene expression entropy separated established CML progression stages and uncovered additional heterogeneity within disease stages. Importantly, our patient data informed model enables quantitative approximation of individual patients’ disease history within chronic phase (CP) and significantly separates “early” from “late” CP. Our findings provide a novel rationale for personalized and genome-informed disease progression risk assessment that is independent and complementary to conventional measures of CML disease burden and prognosis.

  4. Can the common-sense model predict adherence in chronically ill patients? A meta-analysis.

    Science.gov (United States)

    Brandes, Kim; Mullan, Barbara

    2014-01-01

    The aim of this meta-analysis was to explore whether mental representations, derived from the common-sense model of illness representations (CSM), were able to predict adherence in chronically ill patients. Electronic databases were searched for studies that used the CSM and measured adherence behaviour in chronically ill patients. Correlations from the included articles were meta-analysed using a random-size effect model. A moderation analysis was conducted for the type of adherence behaviour. The effect sizes for the different mental representations and adherence constructs ranged from -0.02 to 0.12. Further analyses showed that the relationship between the mental representations and adherence did not differ by the type of adherence behaviour. The low-effect sizes indicate that the relationships between the different mental representations of the CSM and adherence are very weak. Therefore, the CSM may not be the most appropriate model to use in predictive studies of adherence.

  5. Individualizing Opioid Use Disorder (OUD Treatment: Time to Fully Embrace a Chronic Disease Model

    Directory of Open Access Journals (Sweden)

    Richard Gustin

    2015-02-01

    Full Text Available The current opioid epidemic in the United States is changing our perceptions of the face of addiction. Opioid Use Disorder (OUD has become pervasive and is affecting all ethnicities, races, socioeconomic classes, the young and the old. In 2015, 46 people will lose their life each day to a chronic brain disease that is going unnoticed and undertreated. Over the last five decades, numerous scientific and clinical breakthroughs have allowed for a better understanding of the mechanisms underlying addiction, and the development of medications that can help support a patient’s long-term recovery. All of those that have contributed to these advancements have aided in redefining addiction as a primary, chronic disease of the brain reward, motivation, memory and related circuitry; however, our treatment strategies have not necessarily advanced to the same extent as our current understanding of the disease. This commentary will explore how personal philosophies can bias treatments strategies and definitions of treatment success, and prevent adoption of chronic disease treatment models that would significantly improve the quality of life of those suffering with OUD. This is a challenge to consider how our views and stigma can impact a patient’s recovery. We are currently losing a battle with a disease that is taking the lives of 46 individuals daily; it is time to fully embrace a chronic disease model which comprises an integrated pharmacopsychosocial approach for treating the biopsychosocial disorder that is addiction to reverse these trends.

  6. Enzymology of Pyrimidine Metabolism and Neurodegeneration.

    Science.gov (United States)

    Vincenzetti, Silvia; Polzonetti, Valeria; Micozzi, Daniela; Pucciarelli, Stefania

    2016-01-01

    It is well known that disorders of pyrimidine pathways may lead to neurological, hematological, immunological diseases, renal impairments, and association with malignancies. Nucleotide homeostasis depends on the three stages of pyrimidine metabolism: de novo synthesis, catabolism and recycling of these metabolites. Cytidine and uridine, in addition to be used as substrates for pyrimidine nucleotide salvaging, also act as the precursors of cytidine triphosphate used in the biosynthetic pathway of both brain's phosphatidylcholine and phosphatidylethanolamine via the Kennedy cycle. The synthesis in the brain of phosphatidylcholine and other membrane phosphatides can utilize, in addition to glucose, three compounds present in the blood stream: choline, uridine, and a polyunsaturated fatty acids like docosahexaenoic acid. Some authors, using rat models, found that oral administration of two phospholipid precursors such as uridine and omega-3 fatty acids, along with choline from the diet, can increase the amount of synaptic membrane generated by surviving striatal neurons in rats with induced Parkinson's disease. Other authors found that in hypertensive rat fed with uridine and choline, cognitive deficit resulted improved. Uridine has also been recently considered as a neuroactive molecule, because of its involvement in important neurological functions by improving memory, sleep disorders, anti-epileptic effects, as well as neuronal plasticity. Cytidine and uridine are uptaken by the brain via specific receptors and successively salvaged to the corresponding nucleotides. The present review is devoted to the enzymology of pyrimidine pathways whose importance has attracted the attention of several researchers investigating on the mechanisms underlying the physiopathology of brain.

  7. Mechanism of Oxidative Stress in Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Sonia Gandhi

    2012-01-01

    Full Text Available Biological tissues require oxygen to meet their energetic demands. However, the consumption of oxygen also results in the generation of free radicals that may have damaging effects on cells. The brain is particularly vulnerable to the effects of reactive oxygen species due to its high demand for oxygen, and its abundance of highly peroxidisable substrates. Oxidative stress is caused by an imbalance in the redox state of the cell, either by overproduction of reactive oxygen species, or by dysfunction of the antioxidant systems. Oxidative stress has been detected in a range of neurodegenerative disease, and emerging evidence from in vitro and in vivo disease models suggests that oxidative stress may play a role in disease pathogenesis. However, the promise of antioxidants as novel therapies for neurodegenerative diseases has not been borne out in clinical studies. In this review, we critically assess the hypothesis that oxidative stress is a crucial player in common neurodegenerative disease and discuss the source of free radicals in such diseases. Furthermore, we examine the issues surrounding the failure to translate this hypothesis into an effective clinical treatment.

  8. Phage therapy of staphylococcal chronic osteomyelitis in experimental animal model

    Directory of Open Access Journals (Sweden)

    Chandan Kishor

    2016-01-01

    Full Text Available Background & objectives: Methicillin resistant Staphylococcus aureus (MRSA are the commonest cause of osteomyelitis. The aim of this study was to evaluate the role of an alternative therapy i.e. application of S. aureus specific bacteriophages in cases of osteomyelitis caused by MRSA in animal model. Methods: Twenty two rabbits were included in this study. The first two rabbits were used to test the safety of phage cocktail while the remaining 20 rabbits were divided into three groups; group A (n=4 to assess the establishment of osteomyelitis; group B (n=4 osteomyelitis developed but therapy started only after six weeks; and group C (n=12 osteomyelitis developed and therapy started after three weeks. Groups B and C rabbits were treated with four doses of cocktail of seven virulent bacteriophages at the interval of 48 h. Comparison between three groups was made on the basis of observation of clinical, radiological, microbiological, and histopathological examinations. Results: Experimental group rabbits recovered from the illness in the subsequent two weeks of the therapy. Appetite and activity of the rabbits improved, local oedema, erythema and induration subsided. There were minimal changes associated with osteomyelitis in X-ray and histopathology also showed no signs of infection with new bone formation. Control B group rabbits also recovered well from the infection. Interpretation & conclusions: The present study shows a potential of phage therapy to treat difficult infections caused by multidrug resistant bacteria.

  9. Treatment of severe chronic hypotonic hyponatremia: a new treatment model

    Directory of Open Access Journals (Sweden)

    Antonio Burgio

    2013-03-01

    Full Text Available Recommended treatment of severe hypotonic hyponatremia is based on the infusion of 3% sodium chloride solution, with a daily correction rate below 10 mEq/L of sodium concentration, according to the Adrogué and Madias formula that includes the current desired change in sodium concentrations. However, such treatment needs close monitoring of the rate of infusion and does not take into account the body weight or age of the patient. This may result in hypercorrection and neurological damage. We made an inverse calculation using the same algorithms of the Adrogué and Madias formula to estimate the number of vials of sodium chloride needed to reach a correction rate of the serum sodium concentration below 0.4 mEq/h, taking into account the body weight and age of the patient. Three tables have been produced, each containing the number of vials to be infused, according to the patient’s age and body weight, the serum sodium concentration, and the rate of correction over 24 h to avoid the risk of brain damage. We propose a new practical model to calculate the need of sodium chloride infusate to safely correct the hyponatremia. The tables make treatment easier to manage in daily clinical practice in a wide range of patient ages and body weights.

  10. Stability Analysis of a Simplified Yet Complete Model for Chronic Myelegenous Leukemia

    CERN Document Server

    Jauffret, Marie Doumic; Perthame, Benoît

    2009-01-01

    We analyze the asymptotic behavior of a partial differential equation (PDE) model for hematopoiesis. This PDE model is derived from the original agent-based model formulated by (Roeder et al., Nat. Med., 2006), and it describes the progression of blood cell development from the stem cell to the terminally differentiated state. To conduct our analysis, we start with the PDE model of (Kim et al, JTB, 2007), which coincides very well with the simulation results obtained by Roeder et al. We simplify the PDE model to make it amenable to analysis and justify our approximations using numerical simulations. An analysis of the simplified PDE model proves to exhibit very similar properties to those of the original agent-based model, even if for slightly different parameters. Hence, the simplified model is of value in understanding the dynamics of hematopoiesis and of chronic myelogenous leukemia, and it presents the advantage of having fewer parameters, which makes comparison with both experimental data and alternative...

  11. Describing and analysing primary health care system support for chronic illness care in Indigenous communities in Australia's Northern Territory – use of the Chronic Care Model

    Directory of Open Access Journals (Sweden)

    Stewart Allison

    2008-05-01

    Full Text Available Abstract Background Indigenous Australians experience disproportionately high prevalence of, and morbidity and mortality from chronic illness such as diabetes, renal disease and cardiovascular disease. Improving the understanding of how Indigenous primary care systems are organised to deliver chronic illness care will inform efforts to improve the quality of care for Indigenous people. Methods This cross-sectional study was conducted in 12 Indigenous communities in Australia's Northern Territory. Using the Chronic Care Model as a framework, we carried out a mail-out survey to collect information on material, financial and human resources relating to chronic illness care in participating health centres. Follow up face-to-face interviews with health centre staff were conducted to identify successes and difficulties in the systems in relation to providing chronic illness care to community members. Results Participating health centres had distinct areas of strength and weakness in each component of systems: 1 organisational influence – strengthened by inclusion of chronic illness goals in business plans, appointment of designated chronic disease coordinators and introduction of external clinical audits, but weakened by lack of training in disease prevention and health promotion and limited access to Medicare funding; 2 community linkages – facilitated by working together with community organisations (e.g. local stores and running community-based programs (e.g. "health week", but detracted by a shortage of staff especially of Aboriginal health workers working in the community; 3 self management – promoted through patient education and goal setting with clients, but impeded by limited focus on family and community-based activities due to understaffing; 4 decision support – facilitated by distribution of clinical guidelines and their integration with daily care, but limited by inadequate access to and support from specialists; 5 delivery system

  12. The phenomenological-existential comprehension of chronic pain: going beyond the standing healthcare models.

    Science.gov (United States)

    Lima, Daniela Dantas; Alves, Vera Lucia Pereira; Turato, Egberto Ribeiro

    2014-01-10

    A distinguishing characteristic of the biomedical model is its compartmentalized view of man. This way of seeing human beings has its origin in Greek thought; it was stated by Descartes and to this day it still considers humans as beings composed of distinct entities combined into a certain form. Because of this observation, one began to believe that the focus of a health treatment could be exclusively on the affected area of the body, without the need to pay attention to patient's subjectivity. By seeing pain as a merely sensory response, this model was not capable of encompassing chronic pain, since the latter is a complex process that can occur independently of tissue damage. As of the second half of the twentieth century, when it became impossible to deny the relationship between psyche and soma, the current understanding of chronic pain emerges: that of chronic pain as an individual experience, the result of a sum of physical, psychological, and social factors that, for this reason, cannot be approached separately from the individual who expresses pain. This understanding has allowed a significant improvement in perspective, emphasizing the characteristic of pain as an individual experience. However, the understanding of chronic pain as a sum of factors corresponds to the current way of seeing the process of falling ill, for its conception holds a Cartesian duality and the positivist premise of a single reality. For phenomenology, on the other hand, the individual in his/her unity is more than a simple sum of parts. Phenomenology sees a human being as an intending entity, in which body, mind, and the world are intertwined and constitute each other mutually, thus establishing the human being's integral functioning. Therefore, a real understanding of the chronic pain process would only be possible from a phenomenological point of view at the experience lived by the individual who expresses and communicates pain.

  13. Chronic Toxoplasmosis Modulates the Induction of Contact Hypersensitivity by TNCB in Mouse Model.

    Science.gov (United States)

    Yang, Zhaoshou; Ahn, Hye-Jin; Nam, Ho-Woo

    2015-12-01

    Mouse models of chronic toxoplasmosis and atopic dermatitis (AD) were combined to clarify the effect of opportunistic Toxoplasma gondii infection on the development of AD. AD was induced as a chronic contact hypersensitivity (CHS) with repeated challenge of 2,4,6-trinitro-1-chlorobenzene (TNCB) on the dorsal skin of mice. TNCB induced skin thickness increases in both normal and toxoplasmic mice. The changing patterns were different from the sigmoidal which saturated at 20 days in normal mice to the convex saturated at 12 days in toxoplasmic mice with the crossing at 18 days. Compared to normal mice, toxoplasmic mice presented CHS more severely in earlier times and then moderately in later times. These data suggest that host immune modification by T. gondii infection enhances CHS in early times of atopic stimulation but soothes the reaction of CHS in later times in mouse model.

  14. A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis

    Science.gov (United States)

    Fransén-Pettersson, Nina; Duarte, Nadia; Nilsson, Julia; Lundholm, Marie; Mayans, Sofia; Larefalk, Åsa; Hannibal, Tine D.; Hansen, Lisbeth; Schmidt-Christensen, Anja; Ivars, Fredrik; Cardell, Susanna; Palmqvist, Richard; Rozell, Björn

    2016-01-01

    Here we characterize a new animal model that spontaneously develops chronic inflammation and fibrosis in multiple organs, the non-obese diabetic inflammation and fibrosis (N-IF) mouse. In the liver, the N-IF mouse displays inflammation and fibrosis particularly evident around portal tracts and central veins and accompanied with evidence of abnormal intrahepatic bile ducts. The extensive cellular infiltration consists mainly of macrophages, granulocytes, particularly eosinophils, and mast cells. This inflammatory syndrome is mediated by a transgenic population of natural killer T cells (NKT) induced in an immunodeficient NOD genetic background. The disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can inhibit the disease phenotype. Because of the fibrotic component, early on-set, spontaneous nature and reproducibility, this novel mouse model provides a unique tool to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into fibrosis and to evaluate intervention protocols for treating conditions of fibrotic disorders. PMID:27441847

  15. Multiple sclerosis and fatigue: A review on the contribution of inflammation and immune-mediated neurodegeneration.

    Science.gov (United States)

    Patejdl, Robert; Penner, Iris K; Noack, Thomas K; Zettl, Uwe K

    2016-03-01

    Multiple sclerosis (MS) is an immune mediated disease of the central nervous system (CNS) and the leading cause of non-traumatic disability among young and middle-aged adults in the western world. One of its most prevalent and debilitating symptoms is fatigue. Despite the general acceptance of the idea of an immune pathogenesis of MS itself, the role of autoimmunity in the course of MS-fatigue is a matter of debate. Both immune-related processes (acute inflammation, chronic inflammation, immune-mediated neurodegeneration, immune-mediated alterations of endocrine functions related to fatigue) and presumably non-immune-mediated disturbances and factors (sleep disturbances, depression, cognitive alterations, chronic infections, adverse effects of medications) contribute to the clinical picture. Data from in vitro and animal experiments has provided evidence for a role of cytokines as IL-1 and TNF-alpha. This association could not be verified directly in blood samples from humans whereas whole blood stimulation protocols gave some indirect evidence for a role of cytokines in MS-fatigue. MRI being able to detect acute and chronic immune mediated damage to the CNS could depict that global atrophy of gray or white matter does not correlate with fatigue. Rather, distinctive clusters of lesions and atrophy at different locations, mostly bifrontal or in subcortical structures, correlate specifically with fatigue. Regardless of the difficulties in pinpointing the immunogenesis of MS-fatigue, an important role of autoimmunity is strongly supported by an indirect route: A growing amount of data shows that the highly effective immunotherapeutics which have been introduced to MS-treatment over the last years effectively and sustainably stabilize and ameliorate fatigue in parallel to their dampening effects on the neuroinflammatory process. This review summarizes the existing data on the relation between inflammation, patterns of CNS-lesions and the effects of immunotherapeutics

  16. The Model of Quality of Life Improvement for Chronic Patients in Community by Using Social Support

    Directory of Open Access Journals (Sweden)

    Amorn Suwannimitr

    2010-01-01

    Full Text Available Problem statement: Caring for a chronically ill-patients is a complex process which require the cooperation and social support to manage a chronic disease. It need an interaction of a large number of actors or collaborations from health care personnel of different organizations. Questions were raised to develop an appropriate intervention and the model of QOL improvement for chronic-patients in the community. Approach: To (1 develop the Quality Of Life (QOL improvement for chronic illness patients in community by using social support program (2 evaluate the effects of the program on perception of illness, severity of illness, benefits and barriers of health promotion, health behaviors, Quality Of Life (QOL and stress level. Participatory Action Research (PAR was used. It was consisted of two phrases. The participants in first phase including with nurses, nutritionist, patients, caregivers, Village Health Volunteers (VHVs and research team. The second phrase was to implement the interventions and evaluation. A total of 10 VHVs and 50 participants who met the inclusion criteria. The intervention composed of 2 main programs; (1The VHVs were trained for 1 month as a comprehensive program to be a healthcare team collaboration. (2The chronically ill-patients received main interventions including self-care education, apply Thai traditional medicine and home visits. Descriptive statistics and t-test were use to evaluate the pre-post intervention. Results: The majority of the participants were female (n = 38,76%, with the mean age of 66.68 years (SD = 17.20, 85% caring by their children and 42.5% by their relatives. Most participants came from low income family (40%. The post test score on each item showed that after intervention, changed scores on all five items (before-after, how ever the changes were statistically significantly (0.05. Conclusion: The findings suggested the set of interventions were effective to improve QOL of chronic patients and it

  17. Biliopancreatic duct injection of ethanol as an experimental model of acute and chronic pancreatitis in rats.

    Science.gov (United States)

    Unal, Ethem; Atalay, Suleyman; Tolan, Huseyin Kerem; Yuksekdag, Sema; Yucel, Metin; Acar, Aylin; Basak, Fatih; Gunes, Pembegul; Bas, Gurhan

    2015-01-01

    In the present study, we described an easily reproducable experimental pancreatits model induced by biliopancreatic duct injection of ethyl alcohol. Seventy Wistar albino rats were divided equally into seven groups randomly: the control group (group 1), acute pancreatitis groups; induced by 20% ethanol (group 2), 48% ethanol (group 3), 80% ethanol (group 4), chronic pancreatitis groups; induced by 20% ethanol (group 5), 48% ethanol (group 6) and by 80% ethanol (group 7). Acute pancreatitis groups were sacrified on postoperative day 3, while the control group and chronic pancreatitis groups were killed on postoperative day 7. Histopathologic evaluation was done, and P acute pancreatitis (100%). Inflammatory infiltration of neutrophils and mononuclear cells, interstitial edema, and focal necrotic areas were seen in the pancreatic tissues. Similarly, all rats in group 6 developed chronic pancreatitis (100%). Interstitial fibrosis, lymphotic infiltration, ductal dilatation, acinar cell atrophy, periductal hyperplasia were seen in the pancreatic tissues. Mortality was seen only in group 7. The biliopancreatic ductal injection of 48% ethanol induced acute and chronic pancreatitis has 100% success rate.

  18. Effect of Chronic Uremia on the Cell Surface Expression of B7 Family Costimulatory Molecules in an HLA-A2 Transgenic Mouse Model of Chronic Kidney Disease.

    Science.gov (United States)

    Makidon, Paul E; Smith, Douglas M; Groom Ii, Jeffery V; Cao, Zhengyi; Landers, Jeffery J; Baker, James R

    2015-08-01

    Uremia due to chronic kidney disease (CKD) in humans is associated with immune dysfunction, increased susceptibility to infections, immune-activation-associated inflammation, and poor responses to vaccines. The pathophysiologic basis of these immune defects is hypothesized to be associated with a wide range of immunologic abnormalities, including an inability to sufficiently express the B7 family (B7-1, CD80; B7-2, CD86) of T-cell costimulatory molecules. However, testing the hypothesis that a state of chronic uremia contributes to attenuated expression of CD80 or CD86 has been difficult because few animal models faithfully recapitulate the immune defects observed in human CKD patients. We used a humanized mouse in a model of surgically induced renal failure and secondary chronic uremia to evaluate the effect of uremia on the expression of these markers. In a manner that resembles the changes observed in CKD patients, surgically induced CKD in mice resulted in decreased costimulatory CD86 expression compared with that in sham-operated controls. Immunodeficiency was functionally demonstrated in this mouse model by documenting an attenuated immune response to a cholera-toxin-based hepatitis B vaccine. This model will be useful for investigating the mechanisms involved in chronic uremia-associated immunodeficiency, poor response to vaccination, and problems associated with immunization of CKD patients.

  19. Resveratrol Treatment after Status Epilepticus Restrains Neurodegeneration and Abnormal Neurogenesis with Suppression of Oxidative Stress and Inflammation.

    Science.gov (United States)

    Mishra, Vikas; Shuai, Bing; Kodali, Maheedhar; Shetty, Geetha A; Hattiangady, Bharathi; Rao, Xiaolan; Shetty, Ashok K

    2015-12-07

    Antiepileptic drug therapy, though beneficial for restraining seizures, cannot thwart status epilepticus (SE) induced neurodegeneration or down-stream detrimental changes. We investigated the efficacy of resveratrol (RESV) for preventing SE-induced neurodegeneration, abnormal neurogenesis, oxidative stress and inflammation in the hippocampus. We induced SE in young rats and treated with either vehicle or RESV, commencing an hour after SE induction and continuing every hour for three-hours on SE day and twice daily thereafter for 3 days. Seizures were terminated in both groups two-hours after SE with a diazepam injection. In contrast to the vehicle-treated group, the hippocampus of animals receiving RESV during and after SE presented no loss of glutamatergic neurons in hippocampal cell layers, diminished loss of inhibitory interneurons expressing parvalbumin, somatostatin and neuropeptide Y in the dentate gyrus, reduced aberrant neurogenesis with preservation of reelin + interneurons, lowered concentration of oxidative stress byproduct malondialdehyde and pro-inflammatory cytokine tumor necrosis factor-alpha, normalized expression of oxidative stress responsive genes and diminished numbers of activated microglia. Thus, 4 days of RESV treatment after SE is efficacious for thwarting glutamatergic neuron degeneration, alleviating interneuron loss and abnormal neurogenesis, and suppressing oxidative stress and inflammation. These results have implications for restraining SE-induced chronic temporal lobe epilepsy.

  20. Prediction models of hepatocellular carcinoma development in chronic hepatitis B patients

    Science.gov (United States)

    Lee, Hye Won; Ahn, Sang Hoon

    2016-01-01

    Chronic hepatitis B virus (HBV) infection is a major cause of cirrhosis and hepatocellular carcinoma (HCC). Applying the same strategies for antiviral therapy and HCC surveillance to all chronic hepatitis B (CHB) patients would be a burden worldwide. To properly manage CHB patients, it is necessary to identify and classify the risk for HCC development in such patients. Several HCC risk scores based on risk factors such as cirrhosis, age, male gender, and high viral load have been used, and have negative predictive values of ≥ 95%. Most of these have been derived from, and internally validated in, treatment-naïve Asian CHB patients. Herein, we summarized various HCC prediction models, including IPM (Individual Prediction Model), CU-HCC (Chinese University-HCC), GAG-HCC (Guide with Age, Gender, HBV DNA, Core Promoter Mutations and Cirrhosis-HCC), NGM-HCC (Nomogram-HCC), REACH-B (Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B), and Page-B score. To develop a noninvasive test of liver fibrosis, we also introduced a new scoring system that uses liver stiffness values from transient elastography, including an LSM (Liver Stiffness Measurement)-based model, LSM-HCC, and mREACH-B (modified REACH-B). PMID:27729738

  1. Physical Exercise Restores the Generation of Newborn Neurons in an Animal Model of Chronic Epilepsy

    Science.gov (United States)

    Mendonça, Fabricio N.; Santos, Luiz E. C.; Rodrigues, Antônio M.; Gomes da Silva, Sérgio; Arida, Ricardo M.; da Silveira, Gilcélio A.; Scorza, Fulvio A.; Almeida, Antônio-Carlos G.

    2017-01-01

    Neurogenesis impairment is associated with the chronic phase of the epilepsy in humans and also observed in animal models. Recent studies with animal models have shown that physical exercise is capable of improving neurogenesis in adult subjects, alleviating cognitive impairment and depression. Here, we show that there is a reduction in the generation of newborn granule cells in the dentate gyrus of adult rats subjected to a chronic model of epilepsy during the postnatal period of brain development. We also show that the physical exercise was capable to restore the number of newborn granule cells in this animals to the level observed in the control group. Notably, a larger number of newborn granule cells exhibiting morphological characteristics indicative of correct targeting into the hippocampal circuitry and the absence of basal dendrite projections was also observed in the epileptic animals subjected to physical exercise compared to the epileptic animals. The results described here could represent a positive interference of the physical exercise on the neurogenesis process in subjects with chronic epilepsy. The results may also help to reinterpret the benefits of the physical exercise in alleviating symptoms of depression and cognitive dysfunction. PMID:28298884

  2. Neuronal changes after chronic high blood pressure in animal models and its implication for vascular dementia.

    Science.gov (United States)

    Flores, Gonzalo; Flores-Gómez, Gabriel D; de Jesús Gomez-Villalobos, Ma

    2016-05-01

    Vascular dementia is a devastating disorder not only for the patient, but also for the family because this neurocognitive disorder breaks the patient's independence, and leads to family care of the patient with a high cost for the family. This complex disorder alters memory, learning, judgment, emotional control and social behavior and affects 4% of the elderly world population. The high blood pressure or arterial hypertension is a major risk factor for cerebrovascular disease, which in most cases leads to vascular dementia. Interestingly, this neurocognitive disorder starts after long lasting hypertension, which is associated with reduced cerebral blood flow or hypoperfusion, and complete or incomplete ischemia with cortical thickness. Animal models have been generated to elucidate the pathophysiology of this disorder. It is known that dendritic complexity determines the receptive synaptic contacts, and the loss of dendritic spine and arbor stability are strongly associated with dementia in humans. This review evaluates relevant data of human and animal models that have investigated the link between long-lasting arterial hypertension and neural morphological changes in the context of vascular dementia. We examined the effect of chronic arterial hypertension and aged in vascular dementia. Neural dendritic morphology in the prefrontal cortex and the dorsal hippocampus and nucleus accumbens after chronic hypertension was diskussed in the animal models of hypertension. Chronic hypertension reduced the dendritic length and spine density in aged rats.

  3. A microsimulation model for the development and progression of chronic obstructive pulmonary disease.

    Science.gov (United States)

    Tan, Emma; Boessen, Ruud; Fishwick, David; Klein Entink, Rinke; Meijster, Tim; Pronk, Anjoeka; van Duuren-Stuurman, Birgit; Warren, Nick

    2015-12-01

    Chronic obstructive pulmonary disease (COPD) is a chronic lung disease that is thought to affect over one million people in Great Britain. The main factor contributing to the development of COPD is tobacco smoke. This paper presents a microsimulation model for the development of COPD, incorporating population dynamics and trends in smoking. The model simulates a population longitudinally throughout their lifetimes, providing projections of future COPD prevalence and evaluation of the effects of changes in risk factor prevalence such as smoking. Sensitivity analysis provides information on the most influential model parameters. The model-predicted prevalence of COPD in 2040 was 17% in males over the age of 35 years (13% amongst non-smokers and 22% amongst smokers), and a modest decline over the next 25 years due to recent trends in smoking rates. The simulation model provides us with valuable information on current and future trends in COPD in Great Britain. It was developed primarily to enable easy extension to evaluate the effects of occupational and environmental exposures on lung function and the prevalence of COPD and to allow evaluation of interventions, such as introducing health surveillance or policy changes. As longitudinal studies for investigating COPD are difficult due to the lengthy follow-up time required and the potentially large number of drop-outs, we anticipate that the model will provide a valuable tool for health impact assessment. An extended model for occupational exposures is under development and will be presented in a subsequent paper.

  4. A ketogenic diet delays weight loss and does not impair working memory or motor function in the R6/2 1J mouse model of Huntington’s disease

    OpenAIRE

    Ruskin, David N.; Ross, Jessica L.; Kawamura, Masahito; Ruiz, Tiffany L.; Geiger, Jonathan D.; Masino, Susan A.

    2011-01-01

    Ketogenic diets are high in fat and low in carbohydrates, and have long been used as an anticonvulsant therapy for drug-intractable and pediatric epilepsy. Additionally, ketogenic diets have been shown to provide neuroprotective effects against acute and chronic brain injury, including beneficial effects in various rodent models of neurodegeneration. Huntington’s disease is a progressive neurodegenerative disease characterized by neurological, behavioral and metabolic dysfunction, and ketogen...

  5. An animal model of schizophrenia based on chronic LSD administration: old idea, new results.

    Science.gov (United States)

    Marona-Lewicka, Danuta; Nichols, Charles D; Nichols, David E

    2011-09-01

    Many people who take LSD experience a second temporal phase of LSD intoxication that is qualitatively different, and was described by Daniel Freedman as "clearly a paranoid state." We have previously shown that the discriminative stimulus effects of LSD in rats also occur in two temporal phases, with initial effects mediated by activation of 5-HT(2A) receptors (LSD30), and the later temporal phase mediated by dopamine D2-like receptors (LSD90). Surprisingly, we have now found that non-competitive NMDA antagonists produced full substitution in LSD90 rats, but only in older animals, whereas in LSD30, or in younger animals, these drugs did not mimic LSD. Chronic administration of low doses of LSD (>3 months, 0.16 mg/kg every other day) induces a behavioral state characterized by hyperactivity and hyperirritability, increased locomotor activity, anhedonia, and impairment in social interaction that persists at the same magnitude for at least three months after cessation of LSD treatment. These behaviors, which closely resemble those associated with psychosis in humans, are not induced by withdrawal from LSD; rather, they are the result of neuroadaptive changes occurring in the brain during the chronic administration of LSD. These persistent behaviors are transiently reversed by haloperidol and olanzapine, but are insensitive to MDL-100907. Gene expression analysis data show that chronic LSD treatment produced significant changes in multiple neurotransmitter system-related genes, including those for serotonin and dopamine. Thus, we propose that chronic treatment of rats with low doses of LSD can serve as a new animal model of psychosis that may mimic the development and progression of schizophrenia, as well as model the established disease better than current acute drug administration models utilizing amphetamine or NMDA antagonists such as PCP.

  6. Local NMDA receptor blockade attenuates chronic tinnitus and associated brain activity in an animal model.

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    Thomas J Brozoski

    Full Text Available Chronic tinnitus has no broadly effective treatment. Identification of specific markers for tinnitus should facilitate the development of effective therapeutics. Recently it was shown that glutamatergic blockade in the cerebellar paraflocculus, using an antagonist cocktail was successful in reducing chronic tinnitus. The present experiment examined the effect of selective N-methyl d-aspartate (NMDA receptor blockade on tinnitus and associated spontaneous brain activity in a rat model. The NMDA antagonist, D(--2-amino-5-phosphonopentanoic acid (D-AP5 (0.5 mM, was continuously infused for 2 weeks directly to the ipsilateral paraflocculus of rats with tinnitus induced months prior by unilateral noise exposure. Treated rats were compared to untreated normal controls without tinnitus, and to untreated positive controls with tinnitus. D-AP5 significantly decreased tinnitus within three days of beginning treatment, and continued to significantly reduce tinnitus throughout the course of treatment and for 23 days thereafter, at which time testing was halted. At the conclusion of psychophysical testing, neural activity was assessed using manganese enhanced magnetic resonance imaging (MEMRI. In agreement with previous research, untreated animals with chronic tinnitus showed significantly elevated bilateral activity in their paraflocculus and brainstem cochlear nuclei, but not in mid or forebrain structures. In contrast, D-AP5-treated-tinnitus animals showed significantly less bilateral parafloccular and dorsal cochlear nucleus activity, as well as significantly less contralateral ventral cochlear nucleus activity. It was concluded that NMDA-mediated glutamatergic transmission in the paraflocculus appears to be a necessary component of chronic noise-induced tinnitus in a rat model. Additionally, it was confirmed that in this model, elevated spontaneous activity in the cerebellar paraflocculus and auditory brainstem is associated with tinnitus.

  7. Application of transtheoretical model to assess the compliance of chronic periodontitis patients to periodontal therapy

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    Shilpa Emani

    2016-01-01

    Full Text Available Background: The present cross-sectional survey study was conducted to assess whether the transtheoretical model for oral hygiene behavior was interrelated in theoretically consistent directions in chronic periodontitis patients and its applicability to assess the compliance of the chronic periodontitis patients to the treatment suggested. Materials and Methods: A total of 150 chronic periodontitis patients were selected for the proposed study. The selected patients were given four questionnaires that were constructed based on transtheoretical model (TTM, and the patients were divided subsequently into five different groups (precontemplation, contemplation, preparation, action, and maintenance groups based on their answers to the questionnaires. Then, each patient was given four appointments for their periodontal treatment spaced with a time gap of 10 days. The patients visit for each appointments scheduled to them was documented. The results obtained were assessed using TTM. Results: Higher mean pro scores of decisional balance, self-efficacy, and process of change scores was recorded in maintenance group followed by action group, preparation group, contemplation group, and precontemplation group, respectively, whereas higher mean cons score was recorded in precontemplation group followed by contemplation group, preparation group, action group, and maintenance group, respectively. The difference scores of TTM constructs were statistically highly significant between all the five groups. Furthermore, the number of appointment attended in were significantly more than maintenance group followed by action group, preparation group, contemplation group, and precontemplation group. Conclusion: Within the limitations of this study, it can be concluded that transtheoretical model can be successfully applied to chronic periodontitis patients to assess their compliance to the suggested periodontal treatment.

  8. Hypericum perforatum treatment: effect on behaviour and neurogenesis in a chronic stress model in mice

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    Cuzzocrea Salvatore

    2011-01-01

    Full Text Available Abstract Background Extracts of Hypericum perforatum (St. John's wort have been traditionally recommended for a wide range of medical conditions, in particular mild-to-moderate depression. The present study was designed to investigate the effect of Hypericum perforatum treatment in a mouse model of anxiety/depressive-like behavior, induced by chronic corticosterone administration. Methods CD1 mice were submitted to 7 weeks corticosterone administration and then behavioral tests as Open Field (OF, Novelty-Suppressed Feeding (NSF, Forced Swim Test (FST were performed. Cell proliferation in hippocampal dentate gyrus (DG was investigated by both 5-bromo-2'-deoxyuridine (BrdU and doublecortin (DCX immunohistochemistry techniques and stereological procedure was used to quantify labeled cells. Golgi-impregnation method was used to evaluate changes in dendritic spines in DG. Hypericum perforatum (30 mg/Kg has been administered for 3 weeks and then neural development in the adult hippocampus and behavioral changes have been examined. Results The anxiety/depressive-like state due to chronic corticosterone treatment was reversed by exogenous administration of Hypericum perforatum; the proliferation of progenitor cells in mice hippocampus was significantly reduced under chronic corticosterone treatment, whereas a long term treatment with Hypericum perforatum prevented the corticosterone-induced decrease in hippocampal cell proliferation. Corticosterone-treated mice exhibited a reduced spine density that was ameliorated by Hypericum perforatum administration. Conclusion These results provide evidence of morphological adaptations occurring in mature hippocampal neurons that might underlie resilient responses to chronic stress and contribute to the therapeutic effects of chronic Hypericum perforatum treatment.

  9. Nutrient excess and altered mitochondrial proteome and function contribute to neurodegeneration in diabetes.

    Science.gov (United States)

    Chowdhury, Subir K Roy; Dobrowsky, Rick T; Fernyhough, Paul

    2011-11-01

    Diabetic neuropathy is a major complication of diabetes that results in the progressive deterioration of the sensory nervous system. Mitochondrial dysfunction has been proposed to play an important role in the pathogenesis of the neurodegeneration observed in diabetic neuropathy. Our recent work has shown that mitochondrial dysfunction occurs in dorsal root ganglia (DRG) sensory neurons in streptozotocin (STZ) induced diabetic rodents. In neurons, the nutrient excess associated with prolonged diabetes may trigger a switching off of AMP kinase (AMPK) and/or silent information regulator T1 (SIRT1) signaling leading to impaired peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1α) expression/activity and diminished mitochondrial activity. This review briefly summarizes the alterations of mitochondrial function and proteome in sensory neurons of STZ-diabetic rodents. We also discuss the possible involvement of AMPK/SIRT/PGC-1α pathway in other diabetic models and different tissues affected by diabetes.

  10. Regulation of brain-derived neurotrophic factor (BDNF) in the chronic unpredictable stress rat model and the effects of chronic antidepressant treatment.

    Science.gov (United States)

    Larsen, Marianne H; Mikkelsen, Jens D; Hay-Schmidt, Anders; Sandi, Carmen

    2010-10-01

    Chronic unpredictable stress (CUS) is a widely used animal model of depression. The present study was undertaken to investigate behavioral, physiological and molecular effects of CUS and/or chronic antidepressant treatment (venlafaxine or imipramine) in the same set of animals. Anhedonia, a core symptom of depression, was assessed by measuring consumption of a palatable solution. Exposure to CUS reduced intake of a palatable solution and this effect was prevented by chronic antidepressant treatment. Moreover, chronic antidepressant treatment decreased depressive-like behavior in a modified forced swim test in stressed rats. Present evidence suggests a role for brain-derived neurotrophic factor (BDNF) in depression. BDNF mRNA levels in the ventral and dorsal hippocampus were assessed by in situ hybridization. Exposure to CUS was not correlated with a decrease but rather with an increase in BDNF mRNA expression in both the dentate gyrus of the dorsal hippocampus and the CA3 region of the ventral hippocampus indicating that there is no simple link between depression-like behaviors per se and brain BDNF levels in rats. However, a significant increase in BDNF mRNA levels in the dentate gyrus of the dorsal hippocampus correlated with chronic antidepressant treatment emphasizing a role for BDNF in the mechanisms underlying antidepressant activity.

  11. Development of Toxicological Risk Assessment Models for Acute and Chronic Exposure to Pollutants

    Directory of Open Access Journals (Sweden)

    Elke S. Reichwaldt

    2016-08-01

    Full Text Available Alert level frameworks advise agencies on a sequence of monitoring and management actions, and are implemented so as to reduce the risk of the public coming into contact with hazardous substances. Their effectiveness relies on the detection of the hazard, but with many systems not receiving any regular monitoring, pollution events often go undetected. We developed toxicological risk assessment models for acute and chronic exposure to pollutants that incorporate the probabilities that the public will come into contact with undetected pollution events, to identify the level of risk a system poses in regards to the pollutant. As a proof of concept, we successfully demonstrated that the models could be applied to determine probabilities of acute and chronic illness types related to recreational activities in waterbodies containing cyanotoxins. Using the acute model, we identified lakes that present a ‘high’ risk to develop Day Away From Work illness, and lakes that present a ‘low’ or ‘medium’ risk to develop First Aid Cases when used for swimming. The developed risk models succeeded in categorising lakes according to their risk level to the public in an objective way. Modelling by how much the probability of public exposure has to decrease to lower the risks to acceptable levels will enable authorities to identify suitable control measures and monitoring strategies. We suggest broadening the application of these models to other contaminants.

  12. Modeling chronic dietary cadmium bioaccumulation and toxicity from periphyton to Hyalella azteca.

    Science.gov (United States)

    Golding, Lisa A; Borgmann, Uwe; Dixon, D George

    2011-07-01

    A chronic (28-d) Cd saturation bioaccumulation model was developed to quantify the Cd contribution from a natural periphyton diet to Cd in the freshwater amphipod Hyalella azteca. Bioaccumulation was then linked to chronic toxic effects. Juvenile H. azteca were exposed to treatments of Cd in water (3.13-100 nmol/L nominal) and food (389-26,300 nmol/g ash-free dry mass). Cadmium bioaccumulation, survival, and growth were recorded. Dietary Cd was estimated to contribute 21 to 31, 59 to 94, and 40 to 55% to bioaccumulated Cd in H. azteca exposed to treatments of Cd primarily in water, food, and food + water, respectively. Survival as a function of Cd lethal body concentration (679 nmol/g; 95% confidence limits, 617-747) was the most robust endpoint. Body concentration integrated all exposure routes. Based on the lethal body concentration, dietary Cd was predicted to contribute markedly (26-90%) to Cd in H. azteca. Cadmium concentration and food nutritional quality (biomass, chlorophyll a, total lipid, fatty acids, total protein) had no effect on H. azteca nutritional quality (total lipid, fatty acids, total protein) but did influence H. azteca dry weight. This research highlighted the importance of including a dietary component when modeling chronic effects of Cd and when refining endpoints for use in ecological risk assessment and water quality guidelines.

  13. Chronic behavioral and cognitive deficits in a rat survival model of paraoxon toxicity.

    Science.gov (United States)

    Deshpande, Laxmikant S; Phillips, Kristin; Huang, Beverly; DeLorenzo, Robert J

    2014-09-01

    Organophosphate (OP) compounds, including paraoxon (POX), are similar to nerve agents such as sarin. There is a growing concern that OP agents could be weaponized to cause mass civilian causalities. We have developed a rodent survival model of POX toxicity that is being used to evaluate chronic morbidity and to screen for medical countermeasures against severe OP exposure. It is well known that the survivors of nerve gas and chronic OP exposure exhibit neurobehavioral deficits such as mood changes, depression, and memory impairments. In this study we investigated whether animals surviving severe POX exposure exhibited long-term neurological impairments. POX exposure produced overt signs of cholinergic toxicity. Rats were rescued using an optimized atropine, 2-PAM and diazepam therapy. Surviving rats were studied using established behavioral assays for identifying symptoms of depression and memory impairment 3-months after POX exposure. In the forced swim test, POX rats exhibited increased immobility time indicative of a despair-like state. In the sucrose preference test, POX rats consumed significantly less sucrose water indicating anhedonia-like condition. POX rats also displayed increased anxiety as characterized by significantly lower performance in the open arm of the elevated plus maze. Further, when tested with a novel object recognition paradigm, POX rats exhibited a negative discrimination ratio indicative of impaired recognition memory. The results indicate that this model of survival from severe POX exposure can be employed to study some of the molecular bases for OP-induced chronic behavioral and cognitive comorbidities and develop therapies for their treatment.

  14. Aligning health information technologies with effective service delivery models to improve chronic disease care

    Science.gov (United States)

    Bauer, Amy M.; Thielke, Stephen M.; Katon, Wayne; Unützer, Jürgen; Areán, Patricia

    2014-01-01

    Objective Healthcare reforms in the United States, including the Affordable Care and HITECH Acts, and the NCQA criteria for the Patient Centered Medical Home have promoted health information technology (HIT) and the integration of general medical and mental health services. These developments, which aim to improve chronic disease care have largely occurred in parallel, with little attention to the need for coordination. In this article, the fundamental connections between HIT and improvements in chronic disease management are explored. We use the evidence-based collaborative care model as an example, with attention to health literacy improvement for supporting patient engagement in care. Method A review of the literature was conducted to identify how HIT and collaborative care, an evidence-based model of chronic disease care, support each other. Results Five key principles of effective collaborative care are outlined: care is patient-centered, evidence-based, measurement-based, population-based, and accountable. The potential role of HIT in implementing each principle is discussed. Key features of the mobile health paradigm are described, including how they can extend evidence-based treatment beyond traditional clinical settings. Conclusion HIT, and particularly mobile health, can enhance collaborative care interventions, and thus improve the health of individuals and populations when deployed in integrated delivery systems. PMID:24963895

  15. Mild systemic thermal therapy ameliorates renal dysfunction in a rodent model of chronic kidney disease.

    Science.gov (United States)

    Iwashita, Yoshihiro; Kuwabara, Takashige; Hayata, Manabu; Kakizoe, Yutaka; Izumi, Yuichiro; Iiyama, Junichi; Kitamura, Kenichiro; Mukoyama, Masashi

    2016-06-01

    Thermal therapy has become a nonpharmacological therapy in clinical settings, especially for cardiovascular diseases. However, the practical role of thermal therapy on chronic kidney disease remains elusive. We performed the present study to investigate whether a modified thermal protocol, repeated mild thermal stimulation (MTS), could affect renal damages in chronic kidney disease using a mouse renal ablation model. Mice were subjected to MTS or room temperature (RT) treatment once daily for 4 wk after subtotal nephrectomy (Nx) or sham operation (Sh). We revealed that MTS alleviated renal impairment as indicated by serum creatinine and albuminuria in Nx groups. In addition, the Nx + MTS group showed attenuated tubular histological changes and reduced urinary neutrophil gelatinase-associated lipocalin excretion approximately by half compared with the Nx + RT group. Increased apoptotic signaling, such as TUNEL-positive cell count and cleavage of caspase 3, as well as enhanced oxidative stress were significantly reduced in the Nx + MTS group compared with the Nx + RT group. These changes were accompanied with the restoration of kidney Mn-SOD levels by MTS. Heat shock protein 27, a key molecular chaperone, was phosphorylated by MTS only in Nx kidneys rather than in Sh kidneys. MTS also tended to increase the phosphorylation of p38 MAPK and Akt in Nx kidneys, possibly associated with the activation of heat shock protein 27. Taken together, these results suggest that modified MTS can protect against renal injury in a rodent model of chronic kidney disease.

  16. Attachment in medical care: A review of the interpersonal model in chronic disease management.

    Science.gov (United States)

    Jimenez, Xavier F

    2017-03-01

    Objective Patient-physician interaction is continually examined in an era prioritizing patient-centered approaches, yet elaboration beyond aspects of communication and empathy is lacking. Major chronic conditions would benefit tremendously from understanding interpersonal aspects of patient-physician encounters. This review intends to provide a concise introduction to the interpersonal model of attachment theory and how it informs both the patient-physician interaction and medical outcomes in chronic care. Methods A narrative review of the theoretical, neurobiological, epidemiological, investigational, and clinical literature on attachment theory and its impact on medical outcomes was conducted, utilizing a variety of key words as searched on PubMed database. Studies and reviews included were of a variety of sources, including textbooks and peer-reviewed journals. Reports in languages other than English were excluded. Results Measurable, discrete attachment styles and behavioral patterns correlate with poor medical outcomes, including nonadherence in insecure dismissing attachment and care overutilization in insecure preoccupied attachment. Furthermore, insecure dismissing attachment is associated with significant mortality. These variables can be easily assessed, and their effects are reversible, as evidenced by collaborative care outcome data. Discussion Attachment theory is useful a model with application in clinical and investigational aspects of chronic illness care. Implications and guidelines are explored.

  17. Therapeutic activity of two xanthones in a xenograft murine model of human chronic lymphocytic leukemia

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    Berthou Christian

    2010-12-01

    Full Text Available Abstract Background We previously reported that allanxanthone C and macluraxanthone, two xanthones purified from Guttiferae trees, display in vitro antiproliferative and proapoptotic activities in leukemic cells from chronic lymphocytic leukemia (CLL and leukemia B cell lines. Results Here, we investigated the in vivo therapeutic effects of the two xanthones in a xenograft murine model of human CLL, developed by engrafting CD5-transfected chronic leukemia B cells into SCID mice. Treatment of the animals with five daily injections of either allanxanthone C or macluraxanthone resulted in a significant prolongation of their survival as compared to control animals injected with the solvent alone (p = 0.0006 and p = 0.0141, respectively. The same treatment of mice which were not xenografted induced no mortality. Conclusion These data show for the first time the in vivo antileukemic activities of two plant-derived xanthones, and confirm their potential interest for CLL therapy.

  18. C. elegans and mutants with chronic nicotine exposure as a novel model of cancer phenotype.

    Science.gov (United States)

    Kanteti, Rajani; Dhanasingh, Immanuel; El-Hashani, Essam; Riehm, Jacob J; Stricker, Thomas; Nagy, Stanislav; Zaborin, Alexander; Zaborina, Olga; Biron, David; Alverdy, John C; Im, Hae Kyung; Siddiqui, Shahid; Padilla, Pamela A; Salgia, Ravi

    2016-01-01

    We previously investigated MET and its oncogenic mutants relevant to lung cancer in C. elegans. The inactive orthlogues of the receptor tyrosine kinase Eph and MET, namely vab-1 and RB2088 respectively, the temperature sensitive constitutively active form of KRAS, SD551 (let-60; GA89) and the inactive c-CBL equivalent mutants in sli-1 (PS2728, PS1258, and MT13032) when subjected to chronic exposure of nicotine resulted in a significant loss in egg-laying capacity and fertility. While the vab-1 mutant revealed increased circular motion in response to nicotine, the other mutant strains failed to show any effect. Overall locomotion speed increased with increasing nicotine concentration in all tested mutant strains except in the vab-1 mutants. Moreover, chronic nicotine exposure, in general, upregulated kinases and phosphatases. Taken together, these studies provide evidence in support of C. elegans as initial in vivo model to study nicotine and its effects on oncogenic mutations identified in humans.

  19. [The medical perspective towards chronic pain: biomedical model and clinical practice].

    Science.gov (United States)

    Lima, Mônica Angelim Gomes de; Trad, Leny A Bomfim

    2007-11-01

    This study aimed to shed light on the meanings ascribed to chronic pain in medical discourse and clinical practice in two Pain Clinics located in University hospitals in Salvador (Bahia) and São Paulo, Brazil. An ethnographic approach used participant observation and semi-structuralized interviews with attending and managing physicians. Data analysis drew on the clinical models developed by Byron Good and the medical rationalities project formulated by Madel Luz. The meanings emerging from the study were the recognition of chronic pain by biomedicine as a disease rather than a symptom, its invisibility to physicians, and its non-communicability and inevitability. The informants suggested the need for valorization of the human encounter in the clinic, exercise of understanding as opposed to suspicion, and negotiation of sustainable therapeutic projects.

  20. Therapeutic strategies in an animal model of neurodegeneration

    NARCIS (Netherlands)

    Borre, Y.E.

    2013-01-01

    Neurodegenerative diseases have complex and multifactorial etiologies, creating an enormous burden on society without an effective treatment. This thesis utilized olfactory bulbectomized rats to investigate therapeutic approaches to neurodegenerative disorders. Removal of the olfactory bulbs, leads

  1. S100b Counteracts Neurodegeneration of Rat Cholinergic Neurons in Brain Slices after Oxygen-Glucose Deprivation

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    Daniela Serbinek

    2010-01-01

    Full Text Available Alzheimer's disease is a severe chronic neurodegenerative disorder characterized by beta-amyloid plaques, tau pathology, cerebrovascular damage, inflammation, reactive gliosis, and cell death of cholinergic neurons. The aim of the present study is to test whether the glia-derived molecule S100b can counteract neurodegeneration of cholinergic neurons after oxygen-glucose deprivation (OGD in organotypic brain slices of basal nucleus of Meynert. Our data showed that 3 days of OGD induced a marked decrease of cholinergic neurons (60% of control, which could be counteracted by 50 μg/mL recombinant S100b. The effect was dose and time dependent. Application of nerve growth factor or fibroblast growth factor-2 was less protective. C-fos-like immunoreactivity was enhanced 3 hours after OGD indicating metabolic stress. We conclude that S100b is a potent neuroprotective factor for cholinergic neurons during ischemic events.

  2. Experimental chronic hepatitis B infection of neonatal tree shrews (Tupaia belangeri chinensis: A model to study molecular causes for susceptibility and disease progression to chronic hepatitis in humans

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    Wang Qi

    2012-08-01

    Full Text Available Abstract Background Hepatitis B virus (HBV infection continues to be an escalating global health problem. Feasible and effective animal models for HBV infection are the prerequisite for developing novel therapies for this disease. The tree shrew (Tupaia is a small animal species evolutionary closely related to humans, and thus is permissive to certain human viral pathogens. Whether tree shrews could be chronically infected with HBV in vivo has been controversial for decades. Most published research has been reported on adult tree shrews, and only small numbers of HBV infected newborn tree shrews had been observed over short time periods. We investigated susceptibility of newborn tree shrews to experimental HBV infection as well as viral clearance over a protracted time period. Results Forty-six newborn tree shrews were inoculated with the sera from HBV-infected patients or tree shrews. Serum and liver samples of the inoculated animals were periodically collected and analyzed using fluorescence quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, Southern blot, and immunohistochemistry. Six tree shrews were confirmed and four were suspected as chronically HBV-infected for more than 48 (up to 228 weeks after inoculation, including three that had been inoculated with serum from a confirmed HBV-infected tree shrew. Conclusions Outbred neonatal tree shrews can be long-term chronically infected with HBV at a frequency comparable to humans. The model resembles human disease where also a smaller proportion of infected individuals develop chronic HBV related disease. This model might enable genetic and immunologic investigations which would allow determination of underlying molecular causes favoring susceptibility for chronic HBV infection and disease establishment vs. viral clearance.

  3. Renal Impairment with Sublethal Tubular Cell Injury in a Chronic Liver Disease Mouse Model.

    Science.gov (United States)

    Ishida, Tokiko; Kotani, Hirokazu; Miyao, Masashi; Kawai, Chihiro; Jemail, Leila; Abiru, Hitoshi; Tamaki, Keiji

    2016-01-01

    The pathogenesis of renal impairment in chronic liver diseases (CLDs) has been primarily studied in the advanced stages of hepatic injury. Meanwhile, the pathology of renal impairment in the early phase of CLDs is poorly understood, and animal models to elucidate its mechanisms are needed. Thus, we investigated whether an existing mouse model of CLD induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) shows renal impairment in the early phase. Renal injury markers, renal histology (including immunohistochemistry for tubular injury markers and transmission electron microscopy), autophagy, and oxidative stress were studied longitudinally in DDC- and standard diet-fed BALB/c mice. Slight but significant renal dysfunction was evident in DDC-fed mice from the early phase. Meanwhile, histological examinations of the kidneys with routine light microscopy did not show definitive morphological findings, and electron microscopic analyses were required to detect limited injuries such as loss of brush border microvilli and mitochondrial deformities. Limited injuries have been recently designated as sublethal tubular cell injury. As humans with renal impairment, either with or without CLD, often show almost normal tubules, sublethal injury has been of particular interest. In this study, the injuries were associated with mitochondrial aberrations and oxidative stress, a possible mechanism for sublethal injury. Intriguingly, two defense mechanisms were associated with this injury that prevent it from progressing to apparent cell death: autophagy and single-cell extrusion with regeneration. Furthermore, the renal impairment of this model progressed to chronic kidney disease with interstitial fibrosis after long-term DDC feeding. These findings indicated that DDC induces renal impairment with sublethal tubular cell injury from the early phase, leading to chronic kidney disease. Importantly, this CLD mouse model could be useful for studying the pathophysiological mechanisms of

  4. Bio-mathematical models of viral dynamics to tailor antiviral therapy in chronic viral hepatitis

    Science.gov (United States)

    Brunetto, Maurizia Rossana; Colombatto, Piero; Bonino, Ferruccio

    2009-01-01

    The simulation of the dynamics of viral infections by mathematical equations has been applied successfully to the study of viral infections during antiviral therapy. Standard models applied to viral hepatitis describe the viral load decline in the first 2-4 wk of antiviral therapy, but do not adequately simulate the dynamics of viral infection for the following period. The hypothesis of a constant clearance rate of the infected cells provides an unrealistic estimation of the time necessary to reach the control or the clearance of hepatitis B virus (HBV)/hepatitis C virus (HCV) infection. To overcome the problem, we have developed a new multiphasic model in which the immune system activity is modulated by a negative feedback caused by the infected cells reduction, and alanine aminotransferase kinetics serve as a surrogate marker of infected-cell clearance. By this approach, we can compute the dynamics of infected cells during the whole treatment course, and find a good correlation between the number of infected cells at the end of therapy and the long-term virological response in patients with chronic hepatitis C. The new model successfully describes the HBV infection dynamics far beyond the third month of antiviral therapy under the assumption that the sum of infected and non-infected cells remains roughly constant during therapy, and both target and infected cells concur in the hepatocyte turnover. In clinical practice, these new models will allow the development of simulators of treatment response that will be used as an “automatic pilot” for tailoring antiviral therapy in chronic hepatitis B as well as chronic hepatitis C patients. PMID:19195054

  5. Renal Impairment with Sublethal Tubular Cell Injury in a Chronic Liver Disease Mouse Model.

    Directory of Open Access Journals (Sweden)

    Tokiko Ishida

    Full Text Available The pathogenesis of renal impairment in chronic liver diseases (CLDs has been primarily studied in the advanced stages of hepatic injury. Meanwhile, the pathology of renal impairment in the early phase of CLDs is poorly understood, and animal models to elucidate its mechanisms are needed. Thus, we investigated whether an existing mouse model of CLD induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC shows renal impairment in the early phase. Renal injury markers, renal histology (including immunohistochemistry for tubular injury markers and transmission electron microscopy, autophagy, and oxidative stress were studied longitudinally in DDC- and standard diet-fed BALB/c mice. Slight but significant renal dysfunction was evident in DDC-fed mice from the early phase. Meanwhile, histological examinations of the kidneys with routine light microscopy did not show definitive morphological findings, and electron microscopic analyses were required to detect limited injuries such as loss of brush border microvilli and mitochondrial deformities. Limited injuries have been recently designated as sublethal tubular cell injury. As humans with renal impairment, either with or without CLD, often show almost normal tubules, sublethal injury has been of particular interest. In this study, the injuries were associated with mitochondrial aberrations and oxidative stress, a possible mechanism for sublethal injury. Intriguingly, two defense mechanisms were associated with this injury that prevent it from progressing to apparent cell death: autophagy and single-cell extrusion with regeneration. Furthermore, the renal impairment of this model progressed to chronic kidney disease with interstitial fibrosis after long-term DDC feeding. These findings indicated that DDC induces renal impairment with sublethal tubular cell injury from the early phase, leading to chronic kidney disease. Importantly, this CLD mouse model could be useful for studying the

  6. Bio-mathematical models of viral dynamics to tailor antiviral therapy in chronic viral hepatitis

    Institute of Scientific and Technical Information of China (English)

    Maurizia Rossana Brunetto; Piero Colombatto; Ferruccio Bonino

    2009-01-01

    The simulation of the dynamics of viral infections by mathematical equations has been applied successfully to the study of viral infections during antiviral therapy. Standard models applied to viral hepatitis describe the viral load decline in the first 2-4 wk of antiviral therapy, but do not adequately simulate the dynamics of viral infection for the following period. The hypothesis of a constant clearance rate of the infected cells provides an unrealistic estimation of the time necessary to reach the control or the clearance of hepatitis B virus (HBV)/ hepatitis C virus (HCV) infection. To overcome the problem, we have developed a new multiphasic model in which the immune system activity is modulated by a negative feedback caused by the infected cells reduction, and alanine aminotransferase kinetics serve as a surrogate marker of infected-cell clearance. By this approach, we can compute the dynamics of infected cells during the whole treatment course, and find a good correlation between the number of infected cells at the end of therapy and the long-term virological response in patients with chronic hepatitis C. The new model successfully describes the HBV infection dynamics far beyond the third month of antiviral therapy under the assumption that the sum of infected and non-infected cells remains roughly constant during therapy, and both target and infected cells concur in the hepatocyte turnover. In clinical practice, these new models will allow the development of simulators of treatment response that will be used as an "automatic pilot" for tailoring antiviral therapy in chronic hepatitis B as well as chronic hepatitis C patients.

  7. Quercetin attenuates neuronal death against aluminum-induced neurodegeneration in the rat hippocampus.

    Science.gov (United States)

    Sharma, D R; Wani, W Y; Sunkaria, A; Kandimalla, R J; Sharma, R K; Verma, D; Bal, A; Gill, K D

    2016-06-02

    Aluminum is a light weight and toxic metal present ubiquitously on earth, which has gained considerable attention due to its neurotoxic effects. It also has been linked ecologically and epidemiologically to several neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Guamanian-Parkinsonian complex and Amyotrophic lateral sclerosis (ALS). The mechanism of aluminum neurotoxicity is poorly understood, but it is well documented that aluminum generates reactive oxygen species (ROS). Enhanced ROS production leads to disruption of cellular antioxidant defense systems and release of cytochrome c (cyt-c) from mitochondria to cytosol resulting in apoptotic cell death. Quercetin (a natural flavonoid) protects it from oxidative damage and has been shown to decrease mitochondrial damage in various animal models of oxidative stress. We hypothesized that if oxidative damage to mitochondria does play a significant role in aluminum-induced neurodegeneration, and then quercetin should ameliorate neuronal apoptosis. Administration of quercetin (10 mg/kg body wt/day) reduced aluminum (10 mg/kg body wt/day)-induced oxidative stress (decreased ROS production, increased mitochondrial superoxide dismutase (MnSOD) activity). In addition, quercetin also prevents aluminum-induced translocation of cyt-c, and up-regulates Bcl-2, down-regulates Bax, p53, caspase-3 activation and reduces DNA fragmentation. Quercetin also obstructs aluminum-induced neurodegenerative changes in aluminum-treated rats as seen by Hematoxylin and Eosin (H&E) staining. Further electron microscopic studies revealed that quercetin attenuates aluminum-induced mitochondrial swelling, loss of cristae and chromatin condensation. These results indicate that treatment with quercetin may represent a therapeutic strategy to attenuate the neuronal death against aluminum-induced neurodegeneration.

  8. Self-mutilation in neurodegeneration with brain iron accumulation

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    Sadanandavalli Retnaswami Chandra

    2015-01-01

    Full Text Available Neurodegeneration with brain iron accumulation (NBIA is the term applied to a heterogeneous group of disorders resulting in iron deposition in the basal ganglia. Well-known phenotypic features are progressive regression with extra pyramidal involvement and a variable course. A 10-year-old child born to consanguineous parents presented with progressive generalized opisthotonic dystonia, retrocollis, oromandibular dyskinesias, apraxia for swallowing, optic atrophy and severe self-mutilation of lips. MR imaging showed brain iron accumulation. Other causes of self-mutilation were excluded. Early infantile onset, ophisthotonic dystonia with oromandibular dyskinesias and characteristic MR images are suggestive of NBIA. There is only one case reported in the literature of self-mutilation in this condition.

  9. Vitamin E. Neurochemistry and implications for neurodegeneration in Parkinson's disease.

    Science.gov (United States)

    Vatassery, G T

    1992-09-30

    Recently there has been a great deal of interest in the potential therapeutic use of supplemental vitamin E in amelioration of diseases of the nervous system. Even though many studies have provided encouraging results, the mechanism of any beneficial effect remains elusive. Experimental studies suggest that the presence of high levels of vitamin E in tissues prior to injury is essential for biological efficacy because administration of the vitamin after insult is often ineffective. The rationale for this phenomenon is unknown at present. Some of the remaining areas of investigation include the biochemical interaction of vitamin E with other biological antioxidant substances such as vitamin C and sulfhydryl compounds; the relative potencies of different molecular forms of tocopherols, such as trienols and various optical isomers; and the optimal dosage and mode of administration of the most potent tocopherol molecule. Future research on these and other topics will shed more light on the effective use of vitamin E in neurodegeneration.

  10. Metals and Neurodegeneration [version 1; referees: 3 approved

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    Pan Chen

    2016-03-01

    Full Text Available Metals play important roles in the human body, maintaining cell structure and regulating gene expression, neurotransmission, and antioxidant response, to name a few. However, excessive metal accumulation in the nervous system may be toxic, inducing oxidative stress, disrupting mitochondrial function, and impairing the activity of numerous enzymes. Damage caused by metal accumulation may result in permanent injuries, including severe neurological disorders. Epidemiological and clinical studies have shown a strong correlation between aberrant metal exposure and a number of neurological diseases, including Alzheimer’s disease, amyotrophic lateral sclerosis, autism spectrum disorders, Guillain–Barré disease, Gulf War syndrome, Huntington’s disease, multiple sclerosis, Parkinson’s disease, and Wilson’s disease. Here, we briefly survey the literature relating to the role of metals in neurodegeneration.

  11. Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice.

    Science.gov (United States)

    Matak, Pavle; Matak, Andrija; Moustafa, Sarah; Aryal, Dipendra K; Benner, Eric J; Wetsel, William; Andrews, Nancy C

    2016-03-29

    Disrupted brain iron homeostasis is a common feature of neurodegenerative disease. To begin to understand how neuronal iron handling might be involved, we focused on dopaminergic neurons and asked how inactivation of transport proteins affected iron homeostasis in vivo in mice. Loss of the cellular iron exporter, ferroportin, had no apparent consequences. However, loss of transferrin receptor 1, involved in iron uptake, caused neuronal iron deficiency, age-progressive degeneration of a subset of dopaminergic neurons, and motor deficits. There was gradual depletion of dopaminergic projections in the striatum followed by death of dopaminergic neurons in the substantia nigra. Damaged mitochondria accumulated, and gene expression signatures indicated attempted axonal regeneration, a metabolic switch to glycolysis, oxidative stress, and the unfolded protein response. We demonstrate that loss of transferrin receptor 1, but not loss of ferroportin, can cause neurodegeneration in a subset of dopaminergic neurons in mice.

  12. Age-Related Neurodegeneration and Memory Loss in Down Syndrome

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    Jason P. Lockrow

    2012-01-01

    Full Text Available Down syndrome (DS is a condition where a complete or segmental chromosome 21 trisomy causes variable intellectual disability, and progressive memory loss and neurodegeneration with age. Many research groups have examined development of the brain in DS individuals, but studies on age-related changes should also be considered, with the increased lifespan observed in DS. DS leads to pathological hallmarks of Alzheimer's disease (AD by 40 or 50 years of age. Progressive age-related memory deficits occurring in both AD and in DS have been connected to degeneration of several neuronal populations, but mechanisms are not fully elucidated. Inflammation and oxidative stress are early events in DS pathology, and focusing on these pathways may lead to development of successful intervention strategies for AD associated with DS. Here we discuss recent findings and potential treatment avenues regarding development of AD neuropathology and memory loss in DS.

  13. Tryptophan, Neurodegeneration and HIV-Associated Neurocognitive Disorder

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    Nicholas W.S. Davies

    2010-06-01

    Full Text Available This review presents an up-to-date assessment of the role of the tryptophan metabolic and catabolic pathways in neurodegenerative disease and HIV-associated neurocognitive disorder. The kynurenine pathway and the effects of each of its enzymes and products are reviewed. The differential expression of the kynurenine pathway in cells within the brain, including inflammatory cells, is explored given the increasing recognition of the importance of inflammation in neurodegenerative disease. An overview of common mechanisms of neurodegeneration is presented before a review and discussion of the evidence for a pathogenetic role of the kynurenine pathway in Alzheimer’s disease, HIV-associated neurocognitive disorder, Huntington’s disease, motor neurone disease, and Parkinson’s disease.

  14. Implications of mitochondrial dynamics on neurodegeneration and on hypothalamic dysfunction

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    Antonio eZorzano

    2015-06-01

    Full Text Available Mitochondrial dynamics is a term that encompasses the movement of mitochondria along the cytoskeleton, regulation of their architecture, and connectivity mediated by tethering and fusion/fission. The importance of these events in cell physiology and pathology has been partially unraveled with the identification of the genes responsible for the catalysis of mitochondrial fusion and fission. Mutations in two mitochondrial fusion genes (MFN2 and OPA1 cause neurodegenerative diseases, namely Charcot-Marie Tooth type 2A and autosomal dominant optic atrophy. Alterations in mitochondrial dynamics may be involved in the pathophysiology of prevalent neurodegenerative conditions. Moreover, impairment of the activity of mitochondrial fusion proteins dysregulates the function of hypothalamic neurons, leading to alterations in food intake and in energy homeostasis. Here we review selected findings in the field of mitochondrial dynamics and their relevance for neurodegeneration and hypothalamic dysfunction.

  15. Utility of Modeling End-Stage Liver Disease in Children with Chronic Liver Disease

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    Hamid Reza Kianifar

    2014-01-01

    Full Text Available Introduction: Chronic liver diseases consist of wide spectrum disorders that may be complicated by cirrhosis and therefore need to transplantation. The pediatric end-stage liver disease (PELD score and model of end-stage liver disease (MELD score has been used as predictors of mortality chronic liver diseases listed for liver transplantation. The aim of this study is evaluation of relation between PELDMELD score and evidence of cirrhosis in children with choronic liver disease.   Materials and Method: This cross-sectional study conducted on 106 patients of chronic liver disease referred to Ghaem Haspital, Mashhad University of Medical Science, Iran during 24 months period (2010-2013. PELD and MELD score were calculated for all patients. Clincal and patholoogical findings of cirrhosis were recorded.   Results: Mean age of patients was 68/3 ± 41.8 months. Mean PELDMELD score was -1/59± 9/64. There was significant correlation between PELDMELD score and clinical icter, spelenomegaly, evidence of hepatopulminary syndrome, esophageal varices, evidence of cirrhosis in tissue specimences.   Conclusion: PELDMELD score appear to be benefit for detection of cirrhotic children among paients with choronic liver disease.

  16. Modeling the oxygen uptake kinetics during exercise testing of patients with chronic obstructive pulmonary diseases using nonlinear mixed models

    DEFF Research Database (Denmark)

    Baty, Florent; Ritz, Christian; van Gestel, Arnoldus;

    2016-01-01

    regression. Simultaneous modeling of multiple kinetics requires nonlinear mixed models methodology. To the best of our knowledge, no such curve-fitting approach has been used to analyze multiple [Formula: see text]O2 kinetics in both research and clinical practice so far. METHODS: In the present study, we...... describe functionality of the R package medrc that extends the framework of the commonly used packages drc and nlme and allows fitting nonlinear mixed effects models for automated nonlinear regression modeling. The methodology was applied to a data set including 6MWT [Formula: see text]O2 kinetics from 61...... patients with chronic obstructive pulmonary disease (disease severity stage II to IV). The mixed effects approach was compared to a traditional curve-by-curve approach. RESULTS: A six-parameter nonlinear regression model was jointly fitted to the set of [Formula: see text]O2 kinetics. Significant...

  17. Microglial cell dysregulation in Brain Aging and Neurodegeneration.

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    Rommy eVon Bernhardi

    2015-07-01

    Full Text Available Aging is the main risk factor for neurodegenerative diseases. In aging, microglia undergo phenotypic changes compatible with their activation. Glial activation can lead to neuroinflammation, which is increasingly accepted as part of the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD. We hypothesize that in aging, aberrant microglia activation leads to a deleterious environment and neurodegeneration. In aged mice, microglia exhibit an increased expression of cytokines and an exacerbated inflammatory response to pathological changes. Whereas LPS increases nitric oxide secretion in microglia from young mice, induction of reactive oxygen species (ROS predominates in older mice. Furthermore, there is accumulation of DNA oxidative damage in mitochondria of microglia during aging, and also an increased intracellular ROS production. Increased ROS activates the redox-sensitive nuclear factor kappa B, which promotes more neuroinflammation, and can be translated in functional deficits, such as cognitive impairment. Mitochondria-derived ROS and cathepsin B, are also necessary for the microglial cell production of interleukin-1β, a key inflammatory cytokine. Interestingly, whereas the regulatory cytokine TGFβ1 is also increased in the aged brain, neuroinflammation persists. Assessing this apparent contradiction, we have reported that TGFβ1 induction and activation of Smad3 signaling after inflammatory stimulation are reduced in adult mice. Other protective functions, such as phagocytosis, although observed in aged animals, become not inducible by inflammatory stimuli and TGFβ1. Here, we discuss data suggesting that mitochondrial and endolysosomal dysfunction could at least partially mediate age-associated microglial cell changes, and, together with the impairment of the TGFβ1-Smad3 pathway, could result in a reduction of protective activation and a facilitation of cytotoxic activation of microglia, resulting in the

  18. Characterization of the innate immune response to chronic aspiration in a novel rodent model

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    Lin Shu S

    2007-11-01

    Full Text Available Abstract Background Although chronic aspiration has been associated with several pulmonary diseases, the inflammatory response has not been characterized. A novel rodent model of chronic aspiration was therefore developed in order to investigate the resulting innate immune response in the lung. Methods Gastric fluid or normal saline was instilled into the left lung of rats (n = 48 weekly for 4, 8, 12, or 16 weeks (n = 6 each group. Thereafter, bronchoalveolar lavage specimens were collected and cellular phenotypes and cytokine concentrations of IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, GM-CSF, IFN-gamma, TNF-alpha, and TGF-beta were determined. Results Following the administration of gastric fluid but not normal saline, histologic specimens exhibited prominent evidence of giant cells, fibrosis, lymphocytic bronchiolitis, and obliterative bronchiolitis. Bronchoalveolar lavage specimens from the left (treated lungs exhibited consistently higher macrophages and T cells with an increased CD4:CD8 T cell ratio after treatment with gastric fluid compared to normal saline. The concentrations of IL-1alpha, IL-1beta, IL-2, TNF-alpha and TGF-beta were increased in bronchoalveolar lavage specimens following gastric fluid aspiration compared to normal saline. Conclusion This represents the first description of the pulmonary inflammatory response that results from chronic aspiration. Repetitive aspiration events can initiate an inflammatory response consisting of macrophages and T cells that is associated with increased TGF-beta, TNF-alpha, IL-1alpha, IL-1beta, IL-2 and fibrosis in the lung. Combined with the observation of gastric fluid-induced lymphocyitic bronchiolitis and obliterative bronchiolitis, these findings further support an association between chronic aspiration and pulmonary diseases, such as obliterative bronchiolitis, pulmonary fibrosis, and asthma.

  19. Methamphetamine mediates immune dysregulation in a murine model of chronic viral infection.

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    Uma eSriram

    2015-08-01

    Full Text Available Methamphetamine (METH is a highly addictive psychostimulant that not only affects the brain and cognitive functions but also greatly impacts the host immune system, rendering the body susceptible to infections and exacerbating the severity of disease. Although there is gathering evidence about METH abuse and increased incidence of HIV and other viral infections, not much is known about the effects on the immune system in a chronic viral infection setting. We have used the lymphocytic choriomeningitis virus (LCMV chronic mouse model of viral infection in a chronic METH environment and demonstrate that METH significantly increases CD3 marker on splenocytes and programmed death -1 (PD-1 expression on T cells, a cell surface signaling molecule known to inhibit T cell function and cause exhaustion in a lymphoid organ. Many of these METH effects were more pronounced during early stage of infection, which are gradually attenuated during later stages of infection. An essential cytokine for T-lymphocyte homeostasis, Interleukin-2 (IL-2 in serum was prominently reduced in METH-exposed infected mice. In addition, the serum pro-inflammatory (TNF, IL12 p70, IL1β, IL-6 and KC-GRO and Th2 (IL-2, IL-10 and IL-4 cytokine profiles were also altered in the presence of METH. Interestingly CXCR3, an inflammatory chemokine receptor, showed significant increase in the METH treated LCMV infected mice. Similarly, compared to only infected mice, epidermal growth factor receptor (EGFR in METH exposed LCMV infected mice were up regulated. Collectively, our data suggest that METH alters systemic, peripheral immune responses and modulates key markers on T cells involved in pathogenesis of chronic viral infection.

  20. Antidepressant-like effects of BCEF0083 in the chronic unpredictable stress models in mice

    Institute of Scientific and Technical Information of China (English)

    ZHOU Lan-lan; MING Liang; MA Chuan-geng; CHENG Yan; JIANG Qin

    2005-01-01

    Background Up to now there have been no satisfactory drugs to treat psychiatric disorders, and now bioactive compound from entomagenous fungi (BCEF0083) is a new type of bioactive compound from entomopathogenic fungi. Our previous investigations have shown that BCEF has an inhibition effect on monoamine oxidase. So, BCEF may be a latent antidepressant. This study aimed at observing the antidepressant effects and its mechanism of BCEF in the chronic unpredictable stress models in mice. Methods The antidepressant effects of BCEF were examined on the chronic unpredictable stress models in mice. Sixty mice were randomly divided to six groups. Animals were housed and isolated except saline group. Mice were exposed to different stressors per day randomly from day 1 to day 21. Body weight were weighed on day 1,day 10 and on day 21 during the 21-day stress procedure. Awarding response was detected by using method of calculating the 24-hour consumption of saccharum water. Step through test was used to evaluate the behavioral response. AVP contents in plasma were also detected by using radioimmunoassays. Results Chronic unpredictable stress resulted in a significant decrease of the body weight and could apparently cause escape behavior disturbance and gradual reduction of sensitivity to reward in animal models. Drug treatment (BCEF 25, 50, 100 mg/kg) could significantly ameliorate the decreased body weight and effectively reverse the escape behavior disturbance. The gradual reduction of sensitivity to reward, the anhedonic state, was also effectively reversed by BCEF. BCEF (50, 100 mg/kg) could also effectively restore the AVP content in the plasma.Conclusions This evidence suggests that BCEF can effectively inhibit the depression behavior and show strong antidepressant effect. BCEF can effectively restore the plasma AVP release and this may be an important mechanism of its antidepressant effect.

  1. Association between endothelial dysfunction and depression-like symptoms in chronic mild stress model of depression

    DEFF Research Database (Denmark)

    Bouzinova, Elena; Bødtkjer, Donna Marie Briggs; Kudryavtseva, Olga;

    2014-01-01

    OBJECTIVE: Cardiovascular diseases have high comorbidity with major depression. Endothelial dysfunction may explain the adverse cardiovascular outcome in depression; therefore, we analyzed it in vitro. In the chronic mild stress model, some rats develop depression-like symptoms (including......-like response) was reduced in anhedonic rats (p depression-like symptoms are associated with reduced endothelium-dependent relaxation due to suppressed...... endothelium-dependent hyperpolarization-like relaxation despite up-regulation of the NO and COX-2-dependent pathways in rat mesenteric arteries. These changes could affect peripheral resistance and organ perfusion in major depression....

  2. Analysis of airway secretions in a model of sulfur dioxide induced chronic obstructive pulmonary disease (COPD

    Directory of Open Access Journals (Sweden)

    Fischer Axel

    2006-06-01

    Full Text Available Abstract Hypersecretion and chronic phlegm are major symptoms of chronic obstructive pulmonary disease (COPD but animal models of COPD with a defined functional hypersecretion have not been established so far. To identify an animal model of combined morphological signs of airway inflammation and functional hypersecretion, rats were continuously exposed to different levels of sulfur dioxide (SO2, 5 ppm, 10 ppm, 20 ppm, 40 ppm, 80 ppm for 3 (short-term or 20–25 (long-term days. Histology revealed a dose-dependent increase in edema formation and inflammatory cell infiltration in short-term-exposed animals. The submucosal edema was replaced by fibrosis after long-term-exposure. The basal secretory activity was only significantly increased in the 20 ppm group. Also, stimulated secretion was significantly increased only after exposure to 20 ppm. BrdU-assays and AgNOR-analysis demonstrated cellular metaplasia and glandular hypertrophy rather than hyperplasia as the underlying morphological correlate of the hypersecretion. In summary, SO2-exposure can lead to characteristic airway remodeling and changes in mucus secretion in rats. As only long-term exposure to 20 ppm leads to a combination of hypersecretion and airway inflammation, only this mode of exposure should be used to mimic human COPD. Concentrations less or higher than 20 ppm or short term exposure do not induce the respiratory symptom of hypersecretion. The present model may be used to characterize the effects of new compounds on mucus secretion in the background of experimental COPD.

  3. Challenge models to assess new therapies in chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    van der Merwe R

    2012-09-01

    Full Text Available René van der Merwe,1 Nestor A Molfino2,31Respiratory Clinical Development, MedImmune Ltd, Cambridge, UK; 2Respiratory Clinical Development, MedImmune, LLC, Gaithersburg, MD, USA, 3KaloBios Pharmaceuticals, South San Francisco, CA, USAAbstract: Chronic obstructive pulmonary disease (COPD is a major cause of morbidity and mortality. Current therapies confer partial benefits either by incompletely improving airflow limitation or by reducing acute exacerbations, hence new therapies are desirable. In the absence of robust early predictors of clinical efficacy, the potential success of novel therapeutic agents in COPD will not entirely be known until the drugs enter relatively large and costly clinical trials. New predictive models in humans, and new study designs are being sought to allow for confirmation of pharmacodynamic and potentially clinically meaningful effects in early development. This review focuses on human challenge models with lipopolysaccharide endotoxin, ozone, and rhinovirus, in the early clinical development phases of novel therapeutic agents for the treatment and reduction of exacerbations in COPD.Keywords: chronic obstructive pulmonary disease, challenge models, therapy assessment

  4. Autophagy in retinal ganglion cells in a rhesus monkey chronic hypertensive glaucoma model.

    Directory of Open Access Journals (Sweden)

    Shuifeng Deng

    Full Text Available Primary open angle glaucoma (POAG is a neurodegenerative disease characterized by physiological intraocular hypertension that causes damage to the retinal ganglion cells (RGCs. In the past, RGC damage in POAG was suggested to have been attributed to RGC apoptosis. However, in the present study, we applied a model closer to human POAG through the use of a chronic hypertensive glaucoma model in rhesus monkeys to investigate whether another mode of progressive cell death, autophagy, was activated in the glaucomatous retinas. First, in the glaucomatous retinas, the levels of LC3B-II, LC3B-II/LC3B-I and Beclin 1 increased as demonstrated by Western blot analyses, whereas early or initial autophagic vacuoles (AVi and late or degraded autophagic vacuoles (AVd accumulated in the ganglion cell layer (GCL and in the inner plexiform layer (IPL as determined by transmission electron microscopy (TEM analysis. Second, lysosome activity and autophagosome-lysosomal fusion increased in the RGCs of the glaucomatous retinas, as demonstrated by Western blotting against lysosome associated membrane protein-1 (LAMP1 and double labeling against LC3B and LAMP1. Third, apoptosis was activated in the glaucomatous eyes with increased levels of caspase-3 and cleaved caspase-3 and an increased number of TUNEL-positive RGCs. Our results suggested that autophagy was activated in RGCs in the chronic hypertensive glaucoma model of rhesus monkeys and that autophagy may have potential as a new target for intervention in glaucoma treatment.

  5. MODELING CHRONIC DISEASE PATIENT FLOWS DIVERTED FROM EMERGENCY DEPARTMENTS TO PATIENT-CENTERED MEDICAL HOMES.

    Science.gov (United States)

    Diaz, Rafael; Behr, Joshua; Kumar, Sameer; Britton, Bruce

    Chronic Disease is defined as a long lasting health condition, which can develop and/or worsen over an extended time, but which can also be controlled. The monetary and budgetary toll due to its persistent nature has become unsustainable and requires pressing actions to limit their incidence and burden. This paper demonstrates the utility of the System Dynamics approach to simulate the behavior of key factors involved in the implementation of chronic disease management. We model the patient flow diversion from emergency departments (ED) to patient-centered medical homes (PCMH), with emphasis on the visit rates, as well as the effect of insurance coverage, in an effort to assure continuity of quality care for Asthma patients at lower costs. The model is used as an evaluative method to identify conditions of a maintained health status through adequate policy planning, in terms of resources and capacity. This approach gives decision makers the ability to track the level of implementation of the intervention and generate knowledge about dynamics between population demands and the intervention effectiveness. The functionality of the model is demonstrated through the consideration of hypothetical scenarios executed using sensitivity analysis.

  6. International care models for chronic kidney disease: methods and economics--United States.

    Science.gov (United States)

    Crooks, Peter

    2004-01-01

    In the United States, there is a major chronic kidney disease (CKD) problem with over 8 million adults having stage 3 or 4 CKD. There is good medical evidence that many of these patients can benefit from focused interventions. And while there are strong theoretical reasons to believe these interventions are cost-effective, there are little published data to back up this assertion. However, despite the lack of financial data proving cost-effectiveness and against the background of a disorganized health care system in the US, some models of CKD care are being employed. At the present time, the most comprehensive models of care in the US are emerging in vertically integrated health care programs. Other models of care are developing in the setting of managed care health plans that employ CKD disease management programs, either developed internally or in partnership with renal disease management companies.

  7. Space-time Bayesian survival modeling of chronic wasting disease in deer.

    Science.gov (United States)

    Song, Hae-Ryoung; Lawson, Andrew

    2009-09-01

    The primary objectives of this study are to describe the spatial and temporal variation in disease prevalence of chronic wasting disease (CWD), to assess the effect of demographic factors such as age and sex on disease prevalence and to model the disease clustering effects over space and time. We propose a Bayesian hierarchical survival model where latent parameters capture temporal and spatial trends in disease incidence, incorporating several individual covariates and random effects. The model is applied to a data set which consists of 65085 harvested deer in Wisconsin from 2002 to 2006. We found significant sex effects, spatial effects, temporal effects and spatio-temporal interacted effects in CWD infection in deer in Wisconsin. The risk of infection for male deer was significantly higher than that of female deer, and CWD has been significantly different over space, time, and space and time based on the harvest samples.

  8. Effects of Exercise on Behavior and Peripheral Blood Lymphocyte Apoptosis in a Rat Model of Chronic Fatigue Syndrome

    Institute of Scientific and Technical Information of China (English)

    邹军; 苑建齐; 吕爽; 屠嘉衡

    2010-01-01

    This study examined the effects of exercise on behavior and peripheral blood leukocyte apoptosis in a rat model of chronic fatigue syndrome(CFS).Thirty-six healthy male Sprague-Dawley rats were equally randomized into 3 groups:the control group,CFS model group and the exercise group in terms of body weight.A total of 25 rats entered the final statistical analysis due to 11 deaths during the study.CFS model was established by subjecting the rats in CFS model group and exercise group to electric shock,chronic...

  9. The effect of pH on chronic aquatic nickel toxicity is dependent on the pH itself: Extending the chronic nickel bioavailability models.

    Science.gov (United States)

    Nys, Charlotte; Janssen, Colin R; Van Sprang, Patrick; De Schamphelaere, Karel A C

    2016-05-01

    The environmental quality standard for Ni in the European Commission's Water Framework Directive is bioavailability based. Although some of the available chronic Ni bioavailability models are validated only for pH ≤ 8.2, a considerable fraction of European surface waters has a pH > 8.2. Therefore, the authors investigated the effect of a change in pH from 8.2 to 8.7 on chronic Ni toxicity in 3 invertebrate (Daphnia magna, Lymnaea stagnalis, and Brachionus calyciflorus) and 2 plant species (Pseudokirchneriella subcapitata and Lemna minor). Nickel toxicity was almost always significantly higher at pH 8.7 than at pH 8.2. To test whether the existing chronic Ni bioavailability models developed for pH ≤ 8.2 can be used at higher pH levels, Ni toxicity at pH 8.7 was predicted based on Ni toxicity observed at pH 8.2. This resulted in a consistent underestimation of toxicity. The results suggest that the effect of pH on Ni(2+) toxicity is dependent on the pH itself: the slope of the pH effect is steeper above than below pH 8.2 for species for which a species-specific bioavailability model exists. Therefore, the existing chronic Ni bioavailability models were modified to allow predictions of chronic Ni toxicity to invertebrates and plants in the pH range of 8.2 to 8.7 by applying a pH slope (SpH ) dependent on the pH of the target water. These modified Ni bioavailability models resulted in more accurate predictions of Ni toxicity to all 5 species (within 2-fold error), without the bias observed using the bioavailability models developed for pH ≤ 8.2. The results of the present study can decrease the uncertainty in implementing the bioavailability-based environmental quality standard under the Water Framework Directive for high-pH regions in Europe.

  10. Beneficial effect of prolonged heme oxygenase 1 activation in a rat model of chronic heart failure

    Directory of Open Access Journals (Sweden)

    Massimo Collino

    2013-07-01

    We and others have previously demonstrated that heme oxygenase 1 (HO-1 induction by acute hemin administration exerts cardioprotective effects. Here, we developed a rat model of heart failure to investigate whether a long-term induction of HO-1 by chronic hemin administration exerted protective effects. Sprague Dawley rats that underwent permanent ligation of the left coronary artery were closely monitored for survival rate analysis and sacrificed on day 28 post-operation. Administration of hemin (4 mg/kg body weight every other day for 4 weeks induced a massive increase in HO-1 expression and activity, as shown by the increased levels of the two main metabolic products of heme degradation, bilirubin and carbon monoxide (CO. These effects were associated with significant improvement in survival and reduced the extension of myocardial damage. The ischemic hearts of the hemin-treated animals displayed reduced oxidative stress and apoptosis in comparison with the non-treated rats, as shown by the decreased levels of lipid peroxidation, free-radical-induced DNA damage, caspase-3 activity and Bax expression. Besides, chronic HO-1 activation suppressed the elevated levels of myeloperoxidase (MPO activity, interleukin 1β (IL-1β production and tumor necrosis factor-α (TNFα production that were evoked by the ischemic injury, and increased the plasma level of the anti-inflammatory cytokine IL-10. Interestingly, HO-1 inhibitor zinc protoporphyrin IX (ZnPP-IX; 1 mg/kg lowered bilirubin and CO concentrations to control values, thus abolishing all the cardioprotective effects of hemin. In conclusion, the results demonstrate that chronic HO-1 activation by prolonged administration of hemin improves survival and exerts protective effects in a rat model of myocardial ischemia by exerting a potent antioxidant activity and disrupting multiple levels of the apoptotic and inflammatory cascade.

  11. Path analysis of the chronicity of depression using the comprehensive developmental model framework.

    Science.gov (United States)

    Fandiño-Losada, Andrés; Bangdiwala, Shrikant I; Lavebratt, Catharina; Forsell, Yvonne

    2016-07-01

    Background Depressive disorder is recognized as recurrent or chronic in the majority of affected individuals; but literature is not consistent about determinants of the disorder course. Aims To analyse the relationships between familial, personal and environmental characteristics in different life phases and their effects on the chronicity of depression in a population-based sample. Methods It was a longitudinal panel study with three waves (W1-W3) for 651 adult men and women with diagnosis of minor/major depression or dysthymia at W1 of the Swedish PART (mental health, work and relations) study. Risk factors and co-morbidities were assessed with questionnaires. The main outcome was an episode of minor/major depression or dysthymia at 10-12 years of follow-up (W3). Liability for depressive episodes was determined using exploratory structural equation modelling (SEM), following a path approach with step-wise specification searches. Results Most of the risk factors determined, directly or indirectly, depression severity at W3. Somatic trait anxiety, partner loss and other negative life events at W1, depressive symptoms at W2, and life difficulties and other dependent life events at W3 had direct effects on the outcome. Conclusions SEM model revealed complex and intertwined psychopathological pathways leading to chronicity of depression, given previous episodes, which could be assembled in two main mechanisms: a depressive-internalizing path and an adversity path comprised of life events. Pathways are simpler than those of depression occurrence, emphasizing the relevance of personality factors as depression determinants, and excluding disability levels, co-morbidities and social support. These novel findings need to be replicated in future studies.

  12. Robust and enduring atorvastatin-mediated memory recovery following the 4-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion in middle-aged rats.

    Science.gov (United States)

    Zaghi, Gislene Gonçalves Dias; Godinho, Jacqueline; Ferreira, Emilene Dias Fiuza; Ribeiro, Matheus Henrique Dal Molin; Previdelli, Isolde Santos; de Oliveira, Rúbia Maria Weffort; Milani, Humberto

    2016-02-01

    Chronic cerebral hypoperfusion (CCH) is a common condition associated with the development and/or worsening of age-related dementia.We previously reported persistent memory loss and neurodegeneration after CCH in middle-aged rats. Statin-mediated neuroprotection has been reported after acute cerebral ischemia. Unknown, however, is whether statins can alleviate the outcome of CCH. The present study investigated whether atorvastatin attenuates the cognitive and neurohistological outcome of CCH. Rats (12–15 months old) were trained in a non-food-rewarded radial maze, and then subjected to CCH. Atorvastatin (10 mg/kg, p.o.) was administered for 42 days or 15 days, beginning 5 h after the first occlusion stage. Retrograde memory performance was assessed at 7, 14, 21, 28, and 35 days of CCH, and expressed by “latency,” “number of reference memory errors” and “number of working memory errors.” Neurodegeneration was then examined at the hippocampus and cerebral cortex. Compared to sham, CCH caused profound and persistent memory loss in the vehicle-treated groups, as indicated by increased latency (91.2% to 107.3%) and number of errors (123.5% to 2508.2%), effects from which the animals did not spontaneously recover across time. This CCH-induced retrograde amnesia was completely prevented by atorvastatin (latency: −4.3% to 3.3%; reference/working errors: −2.5% to 45.7%), regardless of the treatment duration. This effect was sustained during the entire behavioral testing period (5 weeks), even after discontinuing treatment. This robust and sustained memory-protective effect of atorvastatin occurred in the absence of neuronal rescue (39.58% to 56.45% cell loss). We suggest that atorvastatin may be promising for the treatment of cognitive sequelae associated with CCH.

  13. T-regulatory cell treatment prevents chronic rejection of heart allografts in a murine mixed chimerism model

    OpenAIRE

    Pilat, Nina; Farkas, Andreas M.; Mahr, Benedikt; Schwarz, Christoph; Unger, Lukas; Hock, Karin; Oberhuber, Rupert; Aumayr, Klaus; Wrba, Fritz; Wekerle, Thomas

    2014-01-01

    Background The mixed chimerism approach induces donor-specific tolerance in both pre-clinical models and clinical pilot trials. However, chronic rejection of heart allografts and acute rejection of skin allografts were observed in some chimeric animals despite persistent hematopoietic chimerism and tolerance toward donor antigens in vitro. We tested whether additional cell therapy with regulatory T cells (Tregs) is able to induce full immunologic tolerance and prevent chronic rejection. Metho...

  14. Comparative experimental evaluation of the efficacy of Prostamol Uno and Samprost on rat model of chronic aseptic prostate inflammation.

    Science.gov (United States)

    Pahomova, A V; Borovskaja, T G; Fomina, T I; Ermolaeva, L A; Vychuzhanina, A V; Rumpel, O A; Granstrem, O K; Baranova, O V

    2011-11-01

    Comparative experimental evaluation of the efficiency of prostatotropic drugs Prostamol Uno and Samprost on the model of the chronic aseptic prostate inflammation in rats was performed. It was established that peptide drug Samprost decelerates sclerotic processes in the prostate gland to a greater extent than herbal preparation Prostamol Uno. Both products equally stimulate secretory activity of the gland. Prostamol Uno, unlike Samprost, prevents the development of reduced sexual motivation, one of the complications of chronic prostatitis.

  15. Predicting the Response to Intravenous Immunoglobulins in an Animal Model of Chronic Neuritis

    Science.gov (United States)

    Pfaff, Johannes; Mathys, Christian; Mausberg, Anne K.; Bendszus, Martin; Pham, Mirko; Hartung, Hans-Peter; Kieseier, Bernd C.

    2016-01-01

    Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a disabling autoimmune disorder of the peripheral nervous system (PNS). Intravenous immunoglobulins (IVIg) are effective in CIDP, but the treatment response varies greatly between individual patients. Understanding this interindividual variability and predicting the response to IVIg constitute major clinical challenges in CIDP. We previously established intercellular adhesion molecule (ICAM)-1 deficient non-obese diabetic (NOD) mice as a novel animal model of CIDP. Here, we demonstrate that similar to human CIDP patients, ICAM-1 deficient NOD mice respond to IVIg treatment by clinical and histological measures. Nerve magnetic resonance imaging and histology demonstrated that IVIg ameliorates abnormalities preferentially in distal parts of the sciatic nerve branches. The IVIg treatment response also featured great heterogeneity allowing us to identify IVIg responders and non-responders. An increased production of interleukin (IL)-17 positively predicted IVIg treatment responses. In human sural nerve biopsy sections, high numbers of IL-17 producing cells were associated with younger age and shorter disease duration. Thus, our novel animal model can be utilized to identify prognostic markers of treatment responses in chronic inflammatory neuropathies and we identify IL-17 production as one potential such prognostic marker. PMID:27711247

  16. A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis.

    Directory of Open Access Journals (Sweden)

    Nina Fransén-Pettersson

    Full Text Available Here we characterize a new animal model that spontaneously develops chronic inflammation and fibrosis in multiple organs, the non-obese diabetic inflammation and fibrosis (N-IF mouse. In the liver, the N-IF mouse displays inflammation and fibrosis particularly evident around portal tracts and central veins and accompanied with evidence of abnormal intrahepatic bile ducts. The extensive cellular infiltration consists mainly of macrophages, granulocytes, particularly eosinophils, and mast cells. This inflammatory syndrome is mediated by a transgenic population of natural killer T cells (NKT induced in an immunodeficient NOD genetic background. The disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can inhibit the disease phenotype. Because of the fibrotic component, early on-set, spontaneous nature and reproducibility, this novel mouse model provides a unique tool to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into fibrosis and to evaluate intervention protocols for treating conditions of fibrotic disorders.

  17. Development of chronic and acute golden Syrian hamster infection models with Leptospira borgpetersenii serovar Hardjo.

    Science.gov (United States)

    Zuerner, R L; Alt, D P; Palmer, M V

    2012-03-01

    The golden Syrian hamster (Mesocricetus auratus) is frequently used as a model to study virulence for several Leptospira species. Onset of an acute lethal infection following inoculation with several pathogenic Leptospira species has been widely adopted for pathogenesis studies. An important exception is the outcome following inoculation of hamsters with live L. borgpetersenii serovar Hardjo, the primary cause of bovine leptospirosis and a cause of human infections. Typically, inoculation of hamsters with L. borgpetersenii serovar Hardjo fails to induce clinical signs of infection. In this study, the authors defined LD(50) and ID(50) for 2 strains of L. borgpetersenii serovar Hardjo: JB197 and 203. Both strains infected hamsters with ID(50) values of approximately 1.5 × 10(2) bacteria yet differed in tissue invasion and interaction with leukocytes, resulting in widely divergent clinical outcomes. Hamsters infected with strain 203 established renal colonization within 4 days postinfection and remained asymptomatic with chronic renal infections similar to cattle infected with serovar Hardjo. In contrast, hamsters infected with strain JB197 developed a rapidly debilitating disease typical of acute leptospirosis common in accidental hosts (eg, humans) with an LD(50) of 3.6 × 10(4) bacteria. Evidence that strain JB197 resides in both extracellular and intracellular environments during hamster infection was obtained. Development of models that result in chronic and acute forms of leptospirosis provides a platform to study L. borgpetersenii pathogenesis and to test vaccines for the prevention of leptospirosis.

  18. Globulin-platelet model predicts minimal fibrosis and cirrhosis in chronic hepatitis B virus infected patients

    Institute of Scientific and Technical Information of China (English)

    Xu-Dong Liu; Jian-Lin Wu; Jian Liang; Tao Zhang,; Qing-Shou Sheng

    2012-01-01

    AIM:To establish a simple model consisting of the routine laboratory variables to predict both minimal fibrosis and cirrhosis in chronic hepatitis B virus (HBV)-infected patients.METHODS:We retrospectively investigated 114 chronic HBV-infected patients who underwent liver biopsy in two different hospitals.Thirteen parameters were analyzed by step-wise regression analysis and correlation analysis.A new fibrosis index [globulin/platelet (GP) model] was developed,including globulin (GLOB) and platelet count (PLT).GP model =GLOB (g/mL) x 100/PLT (x 109/L).We evaluated the receiver operating characteristics analysis used to predict minimal fibrosis and compared six other available models.RESULTS:Thirteen clinical biochemical and hematological variables [sex,age,PLT,alanine aminotransferase,aspartate aminotransferase (AST),albumin,GLOB,total bilirubin (T.bil),direct bilirubin (D.bil),glutamyl transferase,alkaline phosphatase,HBV DNA and prothrombin time (PT)] were analyzed according to three stages of liver fibrosis (F0-F1,F2-F3 and F4).Bivariate Spearman's rank correlation analysis showed that six variables,including age,PLT,T.bil,D.bil,GLOB and PT,were correlated with the three fibrosis stages (FS).Correlation coefficients were 0.23,-0.412,0.208,0.220,0.314 and 0.212; and P value was 0.014,< 0.001,0.026,0.018,0.001 and 0.024,respectively.Univariate analysis revealed that only PLT and GLOB were significantly different in the three FS (PLT:F =11.772,P <0.001; GLOB:F =6.612,P =0.002).Step-wise multiple regression analysis showed that PLT and GLOB were also independently correlated with FS (R2 =0.237).By Spearman's rank correlation analysis,GP model was significantly correlated with the three FS (r =0.466,P < 0.001).The median values in F0-F1,F2-F3 and F4 were 1.461,1.720 and 2.634.Compared with the six available models (fibrosis index,AST-platelet ratio,FIB-4,fibrosis-cirrhosis index and age-AST model and age-PLT ratio),GP model showed a highest correlation

  19. Pharmacological characterisation of anti-inflammatory compounds in acute and chronic mouse models of cigarette smoke-induced inflammation

    Directory of Open Access Journals (Sweden)

    Mok Joanie

    2010-09-01

    Full Text Available Abstract Background Candidate compounds being developed to treat chronic obstructive pulmonary disease are typically assessed using either acute or chronic mouse smoking models; however, in both systems compounds have almost always been administered prophylactically. Our aim was to determine whether the prophylactic effects of reference anti-inflammatory compounds in acute mouse smoking models reflected their therapeutic effects in (more clinically relevant chronic systems. Methods To do this, we started by examining the type of inflammatory cell infiltrate which occurred after acute (3 days or chronic (12 weeks cigarette smoke exposure (CSE using female, C57BL/6 mice (n = 7-10. To compare the effects of anti-inflammatory compounds in these models, mice were exposed to either 3 days of CSE concomitant with compound dosing or 14 weeks of CSE with dosing beginning after week 12. Budesonide (1 mg kg-1; i.n., q.d., roflumilast (3 mg kg-1; p.o., q.d. and fluvastatin (2 mg kg-1; p.o., b.i.d. were dosed 1 h before (and 5 h after for fluvastatin CSE. These dose levels were selected because they have previously been shown to be efficacious in mouse models of lung inflammation. Bronchoalveolar lavage fluid (BALF leukocyte number was the primary endpoint in both models as this is also a primary endpoint in early clinical studies. Results To start, we confirmed that the inflammatory phenotypes were different after acute (3 days versus chronic (12 weeks CSE. The inflammation in the acute systems was predominantly neutrophilic, while in the more chronic CSE systems BALF neutrophils (PMNs, macrophage and lymphocyte numbers were all increased (p Conclusions These results demonstrate that the acute, prophylactic systems can be used to identify compounds with therapeutic potential, but may not predict a compound's efficacy in chronic smoke exposure models.

  20. A two-phase model for chronic disease processes under intermittent inspection.

    Science.gov (United States)

    Wu, Ying; Cook, Richard J

    2017-02-26

    A model is developed for chronic diseases with an indolent phase that is followed by a phase with more active disease resulting in progression and damage. The time scales for the intensity functions for the active phase are more naturally based on the time since the start of the active phase, corresponding to a semi-Markov formulation. This two-phase model enables one to fit a separate regression model for the duration of the indolent phase and intensity-based models for the more active second phase. In cohort studies for which the disease status is only known at a series of clinical assessment times, transition times are interval-censored, which means the time origin for phase II is interval-censored. Weakly parametric models with piecewise constant baseline hazard and rate functions are specified, and an expectation-maximization algorithm is described for model fitting. Simulation studies examining the performance of the proposed model show good performance under maximum likelihood and two-stage estimation. An application to data from the motivating study of disease progression in psoriatic arthritis illustrates the procedure and identifies new human leukocyte antigens associated with the duration of the indolent phase. Copyright © 2017 John Wiley & Sons, Ltd.

  1. The phosphodiesterase type 2 inhibitor BAY 60-7550 reverses functional impairments induced by brain ischemia by decreasing hippocampal neurodegeneration and enhancing hippocampal neuronal plasticity.

    Science.gov (United States)

    Soares, Ligia Mendes; Meyer, Erika; Milani, Humberto; Steinbusch, Harry W M; Prickaerts, Jos; de Oliveira, Rúbia M Weffort

    2017-02-01

    Cognitive and affective impairments are the most characterized consequences following cerebral ischemia. BAY 60-7550, a selective phosphodiesterase type 2 inhibitor (PDE2-I), presents memory-enhancing and anxiolytic-like properties. The behavioral effects of BAY 60-7550 have been associated with its ability to prevent hydrolysis of both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) thereby interfering with neuronal plasticity. Here, we hypothesize that PDE2-I treatment could promote functional recovery after brain ischemia. Mice C57Bl/6 were submitted to bilateral common carotid artery occlusion (BCCAO), an experimental model of transient brain ischemia, for 20 min. During 21 days after reperfusion, the animals were tested in a battery of behavioral tests including the elevated zero maze (EZM), object location task (OLT) and forced swim test (FST). The effects of BAY 60-7550 were evaluated on neuronal nuclei (NeuN), caspase-9, cAMP response element-binding protein (CREB), phosphorylated CREB (pCREB) and brain-derived neurotrophic factor (BDNF) expression in the hippocampus. BCCAO increased anxiety levels, impaired hippocampus-dependent cognitive function and induced despair-like behavior in mice. Hippocampal neurodegeneration was evidenced by a decrease in NeuN and increase incaspase-9 protein levels in BCCAO mice. Ischemic mice also showed low BDNF protein levels in the hippocampus. Repeated treatment with BAY 60-7550 attenuated the behavioral impairments induced by BCCAO in mice. Concomitantly, BAY 60-7550 enhanced expression of pCREB and BDNF protein levels in the hippocampus of ischemic mice. The present findings suggest that chronic inhibition of PDE2 provides functional recovery in BCCAO mice possibly by augmenting hippocampal neuronal plasticity.

  2. Dystonia in neurodegeneration with brain iron accumulation : outcome of bilateral pallidal stimulation

    NARCIS (Netherlands)

    Timmermann, L.; Pauls, K. A. M.; Wieland, K.; Jech, R.; Kurlemann, G.; Sharma, N.; Gill, S. S.; Haenggeli, C. A.; Hayflick, S. J.; Hogarth, P.; Leenders, K. L.; Limousin, P.; Malanga, C. J.; Moro, E.; Ostrem, J. L.; Revilla, F. J.; Santens, P.; Schnitzler, A.; Tisch, S.; Valldeoriola, F.; Vesper, J.; Volkmann, J.; Woitalla, D.; Peker, S.

    2010-01-01

    Neurodegeneration with brain iron accumulation encompasses a heterogeneous group of rare neurodegenerative disorders that are characterized by iron accumulation in the brain. Severe generalized dystonia is frequently a prominent symptom and can be very disabling, causing gait impairment, difficulty

  3. Brain, blood, and iron : Perspectives on the roles of erythrocytes and iron in neurodegeneration

    NARCIS (Netherlands)

    Prohaska, Rainer; Sibon, Ody C. M.; Rudnicki, Dobrila D.; Danek, Adrian; Hayflick, Susan J.; Verhaag, Esther M.; Vonk, Jan J.; Margolis, Russell L.; Walker, Ruth H.

    2012-01-01

    The terms "neuroacanthocytosis" (NA) and "neurodegeneration with brain iron accumulation" (NBIA) both refer to groups of genetically heterogeneous disorders, classified together due to similarities of their phenotypic or pathological findings. Even collectively, the disorders that comprise these set

  4. DISTURBANCES OF BIOLOGICAL RHYTHMS IN A RAT CHRONIC MILD STRESS MODEL OF DEPRESSION

    DEFF Research Database (Denmark)

    Christiansen, Sofie; Wiborg, Ove; Bouzinova, Elena

    Aim: The focus of this project is to identify biomarkers related to circadian disturbances in major depressive disorder. Background: A large body of clinical data from depressed individuals showed that sleep, temperature, hormones, physiological states and moodchanges are consistent...... validated animal model of depression, the chronic mild stress model (CMS). Depression-like and control rats were killed by decapitation within 24 h. Trunk blood, brain and liver tissue were collected. The quantitative amount of plasma corticosterone and melatonin were measured using an ELISA and RIA kit...... that depression-like animals showed an abnormal circadian rhythm in the liver and in subregions of the rat brains related to depression. However, the SCN was partly protected against stress. We found an increased level of corticosteron and melatonin, in the depression-like animals as well as a shifted circadian...

  5. Drosophila as a model for intestinal dysbiosis and chronic inflammatory diseases.

    Science.gov (United States)

    Lee, Kyung-Ah; Lee, Won-Jae

    2014-01-01

    The association between deregulated intestinal microbial consortia and host diseases has been recognized since the birth of microbiology over a century ago. Intestinal dysbiosis refers to a state where living metazoans harbor harmful intestinal microflora. However, there is still an issue of whether causality arises from the host or the microbe because it is unclear whether deregulation of the gut microbiota community is the consequence or cause of the host disease. Recent studies using Drosophila and its simple microbiota have provided a valuable model system for dissecting the molecular mechanisms of intestinal dysbiosis. In this review, we examine recent exciting observations in Drosophila gut-microbiota interactions, particularly the links among the host immune genotype, the microbial community structure, and the host inflammatory phenotype. Future genetic analyses using Drosophila model system will provide a valuable outcome for understanding the evolutionarily conserved mechanisms that underlie intestinal dysbiosis and chronic inflammatory diseases.

  6. Modelling management of chronic illness in everyday life: A common-sense approach

    Directory of Open Access Journals (Sweden)

    Howard Leventhal

    2016-04-01

    Full Text Available The Commonsense Model of Self-Regulation (CSM has a history of over 50 years as a theoretical framework that explicates the processes by which individuals form cognitive, affective, and behavioral representations of health threats. This article summarizes the major components of individuals' "commonsense models", the underlying assumptions of the CSM as a theory of dynamic behavior change, and the major empirical evidence that have developed these aspects of the CSM since its inception. We also discuss ongoing changes to the theory itself as well as its use in medical practice for optimizing patients' self-management of chronic health threats. The final section focuses on future directions for the theory and its application.

  7. A partial hearing animal model for chronic electro-acoustic stimulation

    Science.gov (United States)

    Irving, S.; Wise, A. K.; Millard, R. E.; Shepherd, R. K.; Fallon, J. B.

    2014-08-01

    Objective. Cochlear implants (CIs) have provided some auditory function to hundreds of thousands of people around the world. Although traditionally carried out only in profoundly deaf patients, the eligibility criteria for implantation have recently been relaxed to include many partially-deaf patients with useful levels of hearing. These patients receive both electrical stimulation from their implant and acoustic stimulation via their residual hearing (electro-acoustic stimulation; EAS) and perform very well. It is unclear how EAS improves speech perception over electrical stimulation alone, and little evidence exists about the nature of the interactions between electric and acoustic stimuli. Furthermore, clinical results suggest that some patients that undergo cochlear implantation lose some, if not all, of their residual hearing, reducing the advantages of EAS over electrical stimulation alone. A reliable animal model with clinically-relevant partial deafness combined with clinical CIs is important to enable these issues to be studied. This paper outlines such a model that has been successfully used in our laboratory. Approach. This paper outlines a battery of techniques used in our laboratory to generate, validate and examine an animal model of partial deafness and chronic CI use. Main results. Ototoxic deafening produced bilaterally symmetrical hearing thresholds in neonatal and adult animals. Electrical activation of the auditory system was confirmed, and all animals were chronically stimulated via adapted clinical CIs. Acoustic compound action potentials (CAPs) were obtained from partially-hearing cochleae, using the CI amplifier. Immunohistochemical analysis allows the effects of deafness and electrical stimulation on cell survival to be studied. Significance. This animal model has applications in EAS research, including investigating the functional interactions between electric and acoustic stimulation, and the development of techniques to maintain residual

  8. Copper balance and ceruloplasmin in chronic hepatitis in a Wilson disease animal model, LEC rats

    Energy Technology Data Exchange (ETDEWEB)

    Komatsu, Yutaka; Ogra, Yasumitsu; Suzuki, Kazuo T. [Graduate School of Pharmaceutical Sciences, Chiba University, Inage, Chiba 263-8522 (Japan)

    2002-09-01

    In an animal model of Wilson disease, Long-Evans rats with cinnamon-colored coat (LEC rats), copper (Cu) accumulates in the liver with age up to the onset of acute hepatitis owing to a hereditary defective transporter for the efflux of Cu, ATP7B. The plasma Cu concentration is low in LEC rats because of the excretion of apo-ceruloplasmin (apo-Cp). However, toward and after the onset of chronic hepatitis, plasma Cu concentration increases in the form of holo-Cp, while the liver Cu concentration is maintained at a constant level without the occurrence of fulminant hepatitis. In the present study, the material balance of Cu was studied in LEC rats with chronic hepatitis in order to elucidate the mechanisms underlying the increase of holo-Cp in plasma and the maintenance of Cu at a constant level in the liver. The relationship between the Cu concentration and ferroxidase activity of Cp was analyzed in the plasma of LEC rats of different ages and of Wistar rats fed a Cu-deficient diet for different durations. Cu was suggested to be delivered to Cp in an all-or-nothing manner, resulting in the excretion of fully Cu-occupied holo-Cp (Cu{sub 6}-Cp) or totally Cu-unoccupied Cu{sub 0}-Cp (apo-Cp), but not partially Cu-occupied Cu{sub n}-Cp (where n=1-5). The increase of holo-Cp in acute and chronic hepatitis in LEC rats was explained by the delivery of Cu, accumulating in the non-metallothionein-bound form, to Cp outside the Golgi apparatus of the liver. The plasma Cu concentration and ferroxidase activity were proposed to be specific indicators of the appearance of non-metallothionein-bound Cu in the liver of LEC rats. (orig.)

  9. Nociceptive and Inflammatory Mediator Upregulation in a Mouse Model of Chronic Prostatitis

    Science.gov (United States)

    Schwartz, Erica S.; Xie, Amy; La, Jun-Ho; Gebhart, G.F.

    2015-01-01

    Chronic nonbacterial prostatitis, characterized by genitourinary pain in the pelvic region in the absence of an identifiable cause, is common in adult males. Surprisingly, the sensory innervation of the prostate and mediators that sensitize its innervation have received little attention. We thus characterized a mouse model of chronic prostatitis, focusing on the prostate innervation and how organ inflammation affects gene expression of putative nociceptive markers in prostate afferent somata in dorsal root ganglia (DRG) and mediators in the prostate. Retrograde tracing (fast blue, FB) from the prostate revealed that thoracolumbar (TL) and lumbosacral (LS) DRG are the principal sources of somata of prostate afferents. Nociceptive markers (e.g., TRP, TREK and P2X channels) were upregulated in FB-labeled TL and LS somata for up to four weeks after inflaming the prostate (intra-prostate injection of zymosan). Prostatic inflammation was evident histologically, by monocyte infiltration and a significant increase in mast cell tryptase activity 14, 21 and 28 days after zymosan injection. Interleukin-10 and NGF were also significantly upregulated in the prostate throughout the four weeks of inflammation. Open field pain-related behaviors (e.g., rearing) were unchanged in prostate-inflamed mice, suggesting the absence of ongoing nociception, but withdrawal thresholds to lower abdominal pressure were significantly reduced. The increases in IL-10, mast cell tryptase and NGF in the inflamed prostate were cotemporaneous with reduced thresholds to probing of the abdomen and upregulation of nociceptive markers in DRG somata innervating the prostate. The results provide insight and direction for study of mechanisms underlying pain in chronic prostatitis. PMID:25915147

  10. Cytokine and Chemokine Expression in Kidneys during Chronic Leptospirosis in Reservoir and Susceptible Animal Models.

    Directory of Open Access Journals (Sweden)

    Mariko Matsui

    Full Text Available Leptospirosis is caused by pathogenic spirochetes of the genus Leptospira. Humans can be infected after exposure to contaminated urine of reservoir animals, usually rodents, regarded as typical asymptomatic carriers of leptospires. In contrast, accidental hosts may present an acute form of leptospirosis with a range of clinical symptoms including the development of Acute Kidney Injury (AKI. Chronic Kidney Disease (CKD is considered as a possible AKI-residual sequela but little is known about the renal pathophysiology consequent to leptospirosis infection. Herein, we studied the renal morphological alterations in relation with the regulation of inflammatory cytokines and chemokines, comparing two experimental models of chronic leptospirosis, the golden Syrian hamster that survived the infection, becoming carrier of virulent leptospires, and the OF1 mouse, a usual reservoir of the bacteria. Animals were monitored until 28 days after injection with a virulent L. borgpetersenii serogroup Ballum to assess chronic infection. Hamsters developed morphological alterations in the kidneys with tubulointerstitial nephritis and fibrosis. Grading of lesions revealed higher scores in hamsters compared to the slight alterations observed in the mouse kidneys, irrespective of the bacterial load. Interestingly, pro-fibrotic TGF-β was downregulated in mouse kidneys. Moreover, cytokines IL-1β and IL-10, and chemokines MIP-1α/CCL3 and IP-10/CXCL-10 were significantly upregulated in hamster kidneys compared to mice. These results suggest a possible maintenance of inflammatory processes in the hamster kidneys with the infiltration of inflammatory cells in response to bacterial carriage, resulting in alterations of renal tissues. In contrast, lower expression levels in mouse kidneys indicated a better regulation of the inflammatory response and possible resolution processes likely related to resistance mechanisms.

  11. Chronic pancreatitis

    Science.gov (United States)

    Chronic pancreatitis - chronic; Pancreatitis - chronic - discharge; Pancreatic insufficiency - chronic; Acute pancreatitis - chronic ... alcohol abuse over many years. Repeated episodes of acute ... chronic pancreatitis. Genetics may be a factor in some cases. ...

  12. The proteasome inhibitor MG132 attenuates skeletal muscle atrophy in a rat model of chronic obstructive pulmonary disease

    Institute of Scientific and Technical Information of China (English)

    马碧蔓

    2013-01-01

    Objective To investigate the effect of the proteasome inhibitor MG-132 on skeletal muscle atrophy in a rat model of chronic obstructive pulmonary disease (COPD) and is potential mechanisms.Methods The COPD rat model was established by instillation of LPS and exposure

  13. Support vector machines for seizure detection in an animal model of chronic epilepsy

    Science.gov (United States)

    Nandan, Manu; Talathi, Sachin S.; Myers, Stephen; Ditto, William L.; Khargonekar, Pramod P.; Carney, Paul R.

    2010-06-01

    We compare the performance of three support vector machine (SVM) types: weighted SVM, one-class SVM and support vector data description (SVDD) for the application of seizure detection in an animal model of chronic epilepsy. Large EEG datasets (273 h and 91 h respectively, with a sampling rate of 1 kHz) from two groups of rats with chronic epilepsy were used in this study. For each of these EEG datasets, we extracted three energy-based seizure detection features: mean energy, mean curve length and wavelet energy. Using these features we performed twofold cross-validation to obtain the performance statistics: sensitivity (S), specificity (K) and detection latency (τ) as a function of control parameters for the given SVM. Optimal control parameters for each SVM type that produced the best seizure detection statistics were then identified using two independent strategies. Performance of each SVM type is ranked based on the overall seizure detection performance through an optimality index metric (O). We found that SVDD not only performed better than the other SVM types in terms of highest value of the mean optimality index metric (\\skew3\\bar{O} ) but also gave a more reliable performance across the two EEG datasets.

  14. Transient and persistent metabolomic changes in plasma following chronic cigarette smoke exposure in a mouse model.

    Science.gov (United States)

    Cruickshank-Quinn, Charmion I; Mahaffey, Spencer; Justice, Matthew J; Hughes, Grant; Armstrong, Michael; Bowler, Russell P; Reisdorph, Richard; Petrache, Irina; Reisdorph, Nichole

    2014-01-01

    Cigarette smoke exposure is linked to the development of a variety of chronic lung and systemic diseases in susceptible individuals. Metabolomics approaches may aid in defining disease phenotypes, may help predict responses to treatment, and could identify biomarkers of risk for developing disease. Using a mouse model of chronic cigarette smoke exposure sufficient to cause mild emphysema, we investigated whether cigarette smoke induces distinct metabolic profiles and determined their persistence following smoking cessation. Metabolites were extracted from plasma and fractionated based on chemical class using liquid-liquid and solid-phase extraction prior to performing liquid chromatography mass spectrometry-based metabolomics. Metabolites were evaluated for statistically significant differences among group means (p-value≤0.05) and fold change ≥1.5). Cigarette smoke exposure was associated with significant differences in amino acid, purine, lipid, fatty acid, and steroid metabolite levels compared to air exposed animals. Whereas 60% of the metabolite changes were reversible, 40% of metabolites remained persistently altered even following 2 months of smoking cessation, including nicotine metabolites. Validation of metabolite species and translation of these findings to human plasma metabolite signatures induced by cigarette smoking may lead to the discovery of biomarkers or pathogenic pathways of smoking-induced disease.

  15. Transient and persistent metabolomic changes in plasma following chronic cigarette smoke exposure in a mouse model.

    Directory of Open Access Journals (Sweden)

    Charmion I Cruickshank-Quinn

    Full Text Available Cigarette smoke exposure is linked to the development of a variety of chronic lung and systemic diseases in susceptible individuals. Metabolomics approaches may aid in defining disease phenotypes, may help predict responses to treatment, and could identify biomarkers of risk for developing disease. Using a mouse model of chronic cigarette smoke exposure sufficient to cause mild emphysema, we investigated whether cigarette smoke induces distinct metabolic profiles and determined their persistence following smoking cessation. Metabolites were extracted from plasma and fractionated based on chemical class using liquid-liquid and solid-phase extraction prior to performing liquid chromatography mass spectrometry-based metabolomics. Metabolites were evaluated for statistically significant differences among group means (p-value≤0.05 and fold change ≥1.5. Cigarette smoke exposure was associated with significant differences in amino acid, purine, lipid, fatty acid, and steroid metabolite levels compared to air exposed animals. Whereas 60% of the metabolite changes were reversible, 40% of metabolites remained persistently altered even following 2 months of smoking cessation, including nicotine metabolites. Validation of metabolite species and translation of these findings to human plasma metabolite signatures induced by cigarette smoking may lead to the discovery of biomarkers or pathogenic pathways of smoking-induced disease.

  16. Cartilage contact pressure elevations in dysplastic hips: a chronic overload model

    Directory of Open Access Journals (Sweden)

    Grosland Nicole M

    2006-10-01

    Full Text Available Abstract Background Developmental dysplasia of the hip (DDH is a condition in which bone growth irregularities subject articular cartilage to higher mechanical stresses, increase susceptibility to subluxation, and elevate the risk of early osteoarthritis. Study objectives were to calculate three-dimensional cartilage contact stresses and to examine increases of accumulated pressure exposure over a gait cycle that may initiate the osteoarthritic process in the human hip, in the absence of trauma or surgical intervention. Methods Patient-specific, non-linear, contact finite element models, constructed from computed tomography arthrograms using a custom-built meshing program, were subjected to normal gait cycle loads. Results Peak contact pressures for dysplastic and asymptomatic hips ranged from 3.56 – 9.88 MPa. Spatially discriminatory cumulative contact pressures ranged from 2.45 – 6.62 MPa per gait cycle. Chronic over-pressure doses, for 2 million cycles per year over 20 years, ranged from 0.463 – 5.85 MPa-years using a 2-MPa damage threshold. Conclusion There were significant differences between the normal control and the asymptomatic hips, and a trend towards significance between the asymptomatic and symptomatic hips of patients afflicted with developmental dysplasia of the hip. The magnitudes of peak cumulative contact pressure differed between apposed articular surfaces. Bone irregularities caused localized pressure elevations and an upward trend between chronic over-pressure exposure and increasing Severin classification.

  17. Evaluation of protective effect of Aegle marmelos Corr. in an animal model of chronic fatigue syndrome

    Directory of Open Access Journals (Sweden)

    Vanphawng Lalremruta

    2012-01-01

    Full Text Available Objective: To evaluate ethanolic extract of leaves of Aegle marmelos in an experimental animal model of chronic fatigue syndrome for potential therapeutic benefit. Materials and Methods: Age/weight-matched female Wistar albino rats were grouped into five groups. (Group I- V (n = 8. Group I served as naïve control and II served as stress control. Except for group I animals, other group animals were subjected to forced swimming every day for 15 minutes to induce a state of chronic fatigue and simultaneously treated with ethanolic extract of Aegle marmelos (EEAM 150 and 250 mg/kg b.w. and Imipramine (20 mg.kg b.w., respectively. Duration of immobility, anxiety level and locomotor activity were assessed on day 1, 7, 14 and 21 followed by biochemical estimation of oxidative biomarkers at the end of the study. Results: Treatment with EEAM (150 and 250 mg/kg b.w. resulted in a statistically significant and dose dependent reduction (P <0.001 in the duration of immobility, reduction in anxiety and increase in locomotor activity. Dose dependent and significant reduction in LPO level and increase in CAT and SOD was observed in extract treated animals. Conclusion: The results are suggestive of potential protective effect of A. marmelos against experimentally induced CFS.

  18. Downregulated GABA and BDNF-TrkB Pathway in Chronic Cyclothiazide Seizure Model

    Directory of Open Access Journals (Sweden)

    Shuzhen Kong

    2014-01-01

    Full Text Available Cyclothiazide (CTZ has been reported to simultaneously enhance glutamate receptor excitation and inhibit GABAA receptor inhibition, and in turn it evokes epileptiform activities in hippocampal neurons. It has also been shown to acutely induce epileptic seizure behavior in freely moving rats. However, whether CTZ induced seizure rats could develop to have recurrent seizure still remains unknown. In the current study, we demonstrated that 46% of the CTZ induced seizure rats developed to have recurrent seizure behavior as well as epileptic EEG with a starting latency between 2 weeks and several months. In those chronic seizure rats 6 months after the seizure induction by the CTZ, our immunohistochemistry results showed that both GAD and GAT-1 were significantly decreased across CA1, CA3, and dentate gyrus area of the hippocampus studied. In addition, both BDNF and its receptor TrkB were also decreased in hippocampus of the chronic CTZ seizure rats. Our results indicate that CTZ induced seizure is capable of developing to have recurrent seizure, and the decreased GABA synthesis and transport as well as the impaired BDNF-TrkB signaling pathway may contribute to the development of the recurrent seizure. Thus, CTZ seizure rats may provide a novel animal model for epilepsy study and anticonvulsant drug testing in the future.

  19. Behavioural and EEG effects of chronic rapamycin treatment in a mouse model of tuberous sclerosis complex.

    Science.gov (United States)

    Cambiaghi, Marco; Cursi, Marco; Magri, Laura; Castoldi, Valerio; Comi, Giancarlo; Minicucci, Fabio; Galli, Rossella; Leocani, Letizia

    2013-04-01

    Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder caused by mutation in either Tsc1 or Tsc2 genes that leads to the hyper activation of the mTOR pathway, a key signalling pathway for synaptic plasticity. TSC is characterized by benign tumors arising in different organs and severe neuropsychiatric symptoms, such as epilepsy, intellectual disability, autism, anxiety and depressive behaviour. Rapamycin is a potent inhibitor of mTOR and its efficacy in treating epilepsy and neurological symptoms remains elusive. In a mouse model in which Tsc1 has been deleted in embryonic telencephalic neural stem cells, we analyzed anxiety- and depression-like behaviour by elevated-plus maze (EPM), open-field test (OFT), forced-swim test (FST) and tail-suspension test (TST), after chronic administration of rapamycin. In addition, spectral analysis of background EEG was performed. Rapamycin-treated mutant mice displayed a reduction in anxiety- and depression-like phenotype, as shown by the EPM/OFT and FST, respectively. These results were inline with EEG power spectra outcomes. The same effects of rapamycin were observed in wild-type mice. Notably, in heterozygous animals we did not observe any EEG and/or behavioural variation after rapamycin treatment. Together these results suggest that both TSC1 deletion and chronic rapamycin treatment might have a role in modulating behaviour and brain activity, and point out to the potential usefulness of background EEG analysis in tracking brain dysfunction in parallel with behavioural testing.

  20. Seizure entrainment with polarizing low-frequency electric fields in a chronic animal epilepsy model

    Science.gov (United States)

    Sunderam, Sridhar; Chernyy, Nick; Peixoto, Nathalia; Mason, Jonathan P.; Weinstein, Steven L.; Schiff, Steven J.; Gluckman, Bruce J.

    2009-08-01

    Neural activity can be modulated by applying a polarizing low-frequency (Lt100 Hz) electric field (PLEF). Unlike conventional pulsed stimulation, PLEF stimulation has a graded, modulatory effect on neuronal excitability, and permits the simultaneous recording of neuronal activity during stimulation suitable for continuous feedback control. We tested a prototype system that allows for simultaneous PLEF stimulation with minimal recording artifact in a chronic tetanus toxin animal model (rat) of hippocampal epilepsy with spontaneous seizures. Depth electrode local field potentials recorded during seizures revealed a characteristic pattern of field postsynaptic potentials (fPSPs). Sinusoidal voltage-controlled PLEF stimulation (0.5-25 Hz) was applied in open-loop cycles radially across the CA3 of ventral hippocampus. For stimulated seizures, fPSPs were transiently entrained with the PLEF waveform. Statistical significance of entrainment was assessed with Thomson's harmonic F-test, with 45/132 stimulated seizures in four animals individually demonstrating significant entrainment (p < 0.04). Significant entrainment for multiple presentations at the same frequency (p < 0.01) was observed in three of four animals in 42/64 stimulated seizures. This is the first demonstration in chronically implanted freely behaving animals of PLEF modulation of neural activity with simultaneous recording.

  1. Seizure entrainment with polarizing low frequency electric fields in a chronic animal epilepsy model

    Science.gov (United States)

    Sunderam, Sridhar; Chernyy, Nick; Peixoto, Nathalia; Mason, Jonathan P.; Weinstein, Steven L.; Schiff, Steven J.; Gluckman, Bruce J.

    2009-01-01

    Neural activity can be modulated by applying a polarizing low frequency (≪ 100 Hz) electric field (PLEF). Unlike conventional pulsed stimulation, PLEF stimulation has a graded, modulatory effect on neuronal excitability, and permits the simultaneous recording of neuronal activity during stimulation suitable for continuous feedback control. We tested a prototype system that allows for simultaneous PLEF stimulation with minimal recording artifact in a chronic tetanus toxin animal model (rat) of hippocampal epilepsy with spontaneous seizures. Depth electrode local field potentials recorded during seizures revealed a characteristic pattern of field postsynaptic potentials (fPSPs). Sinusoidal voltage-controlled PLEF stimulation (0.5–25 Hz) was applied in open-loop cycles radially across the CA3 of ventral hippocampus. For stimulated seizures, fPSPs were transiently entrained with the PLEF waveform. Statistical significance of entrainment was assessed with Thomson’s harmonic F-test, with 45/132 stimulated seizures in 4 animals individually demonstrating significant entrainment (p < 0.04). Significant entrainment for multiple presentations at the same frequency (p < 0.01) was observed in 3 of 4 animals in 42/64 stimulated seizures. This is the first demonstration in chronically implanted freely behaving animals of PLEF modulation of neural activity with simultaneous recording. PMID:19602730

  2. Prophylactic Chronic Zinc Administration Increases Neuroinflammation in a Hypoxia-Ischemia Model

    Directory of Open Access Journals (Sweden)

    Constantino Tomas-Sanchez

    2016-01-01

    Full Text Available Acute and subacute administration of zinc exert neuroprotective effects in hypoxia-ischemia animal models; yet the effect of chronic administration of zinc still remains unknown. We addressed this issue by injecting zinc at a tolerable dose (0.5 mg/kg weight, i.p. for 14 days before common carotid artery occlusion (CCAO in a rat. After CCAO, the level of zinc was measured by atomic absorption spectrophotometry, nitrites were determined by Griess method, lipoperoxidation was measured by Gerard-Monnier assay, and mRNA expression of 84 genes coding for cytokines, chemokines, and their receptors was measured by qRT-PCR, whereas nitrotyrosine, chemokines, and their receptors were assessed by ELISA and histopathological changes in the temporoparietal cortex-hippocampus at different time points. Long-term memory was evaluated using Morris water maze. Following CCAO, a significant increase in nitrosative stress, inflammatory chemokines/receptors, and cell death was observed after 8 h, and a 2.5-fold increase in zinc levels was detected after 7 days. Although CXCL12 and FGF2 protein levels were significantly increased, the long-term memory was impaired 12 days after reperfusion in the Zn+CCAO group. Our data suggest that the chronic administration of zinc at tolerable doses causes nitrosative stress, toxic zinc accumulation, and neuroinflammation, which might account for the neuronal death and cerebral dysfunction after CCAO.

  3. Optic neuritis and retinal ganglion cell loss in a chronic murine model of multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Thomas eQuinn

    2011-08-01

    Full Text Available Multiple sclerosis (MS and its animal model experimental autoimmune encephalomyelitis (EAE are neurodegenerative diseases with characteristic inflammatory demyelination in the central nervous system, including the optic nerve. Neuronal and axonal damage is considered to be the main cause of long-term disability in patients with MS. Neuronal loss, including retinal ganglion cell (RGC apoptosis in eyes with optic neuritis, also occurs in EAE. However, there is significant variability in the clinical course and level of neuronal damage in MS and EAE. The current studies examine the mechanisms and kinetics of RGC loss in C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein to induce a chronic EAE disease. Clinical progression of EAE was scored daily and vision was assessed by optokinetic responses. At various time points, RGCs were counted and optic nerves were examined for inflammatory cell infiltration. Almost all EAE mice develop optic neuritis by day 15 post-immunization; however, RGC loss is delayed in these mice. No RGC loss is detected 25 days post-immunization, whereas RGC numbers in EAE mice significantly and progressively decrease compared to controls from 35-50 days post-immunization. The delayed time course of RGC loss is in stark contrast to that reported in relapsing EAE, as well as in rats with chronic EAE. Results suggest that different clinical disease courses of optic nerve inflammation may trigger distinct mechanisms of neuronal damage, or RGCs in different rodent strains may have variable resistance to neuronal degeneration.

  4. Downregulated GABA and BDNF-TrkB pathway in chronic cyclothiazide seizure model.

    Science.gov (United States)

    Kong, Shuzhen; Cheng, Zhihua; Liu, Jianhui; Wang, Yun

    2014-01-01

    Cyclothiazide (CTZ) has been reported to simultaneously enhance glutamate receptor excitation and inhibit GABAA receptor inhibition, and in turn it evokes epileptiform activities in hippocampal neurons. It has also been shown to acutely induce epileptic seizure behavior in freely moving rats. However, whether CTZ induced seizure rats could develop to have recurrent seizure still remains unknown. In the current study, we demonstrated that 46% of the CTZ induced seizure rats developed to have recurrent seizure behavior as well as epileptic EEG with a starting latency between 2 weeks and several months. In those chronic seizure rats 6 months after the seizure induction by the CTZ, our immunohistochemistry results showed that both GAD and GAT-1 were significantly decreased across CA1, CA3, and dentate gyrus area of the hippocampus studied. In addition, both BDNF and its receptor TrkB were also decreased in hippocampus of the chronic CTZ seizure rats. Our results indicate that CTZ induced seizure is capable of developing to have recurrent seizure, and the decreased GABA synthesis and transport as well as the impaired BDNF-TrkB signaling pathway may contribute to the development of the recurrent seizure. Thus, CTZ seizure rats may provide a novel animal model for epilepsy study and anticonvulsant drug testing in the future.

  5. Prophylactic Chronic Zinc Administration Increases Neuroinflammation in a Hypoxia-Ischemia Model

    Science.gov (United States)

    Tomas-Sanchez, Constantino; Blanco-Alvarez, Victor Manuel; Gonzalez-Barrios, Juan Antonio; Martinez-Fong, Daniel; Garcia-Robles, Guadalupe; Soto-Rodriguez, Guadalupe; Torres-Soto, Maricela; Gonzalez-Vazquez, Alejandro; Aguilar-Peralta, Ana Karina; Garate-Morales, José-Luis; Aguilar-Carrasco, Luis-Angel; Limón, Daniel I.; Cebada, Jorge

    2016-01-01

    Acute and subacute administration of zinc exert neuroprotective effects in hypoxia-ischemia animal models; yet the effect of chronic administration of zinc still remains unknown. We addressed this issue by injecting zinc at a tolerable dose (0.5 mg/kg weight, i.p.) for 14 days before common carotid artery occlusion (CCAO) in a rat. After CCAO, the level of zinc was measured by atomic absorption spectrophotometry, nitrites were determined by Griess method, lipoperoxidation was measured by Gerard-Monnier assay, and mRNA expression of 84 genes coding for cytokines, chemokines, and their receptors was measured by qRT-PCR, whereas nitrotyrosine, chemokines, and their receptors were assessed by ELISA and histopathological changes in the temporoparietal cortex-hippocampus at different time points. Long-term memory was evaluated using Morris water maze. Following CCAO, a significant increase in nitrosative stress, inflammatory chemokines/receptors, and cell death was observed after 8 h, and a 2.5-fold increase in zinc levels was detected after 7 days. Although CXCL12 and FGF2 protein levels were significantly increased, the long-term memory was impaired 12 days after reperfusion in the Zn+CCAO group. Our data suggest that the chronic administration of zinc at tolerable doses causes nitrosative stress, toxic zinc accumulation, and neuroinflammation, which might account for the neuronal death and cerebral dysfunction after CCAO. PMID:27635404

  6. The role of Chinese herbal medicines in a rat model of chronic colitis

    Institute of Scientific and Technical Information of China (English)

    Xiao Lan Tian; Marisabel Mourelle; Yu Ling Li; Francisco Guarner; Juan-R Malagelada

    2000-01-01

    AIM To investigate a mixture of traditional Chinese medicine (TCM) in the prevention of chronic colitis inrats.METHODS Sixty rats were divided into 3 groups. Colitis was induced by trinitrobenzene-sulfonic acid(TNB). On day 10, all the survived rats were killed, the mortality and intestinal obstruction rate werecalculated, the colonic lesion score was assessed and collagenase activity and collagen concentration weremeasured.RESULTS The survival rate was much lower and intestinal obstruction rate much higher in TNB than thosein TCM, they were 53% and 81% vs. 80% and 24% (P<0.05 and P<0.01, respectively). There were alsosignificant differences in colonic stricture score and colonic weight between TNB and TCM groups (1.75±1.2 vs 0.22±0.67 and 0.57±0.36 vs 0.31±0.10, P<0.01 and P<0.05, respectively). No hydroxyprolineand collagenase activity differences were found between the two groups.CONCLUSION This mixture of TCM prevents the formation of intestinal stricture, increases the survivalrate and decreases intestinal obstruction rate in a rat model of chronic colitis.

  7. Hormetic Effect of Chronic Hypergravity in a Mouse Model of Allergic Asthma and Rhinitis

    Science.gov (United States)

    Jang, Tae Young; Jung, Ah-Yeoun; Kim, Young Hyo

    2016-06-01

    We aimed to evaluate the effect of chronic hypergravity in a mouse model of allergic asthma and rhinitis. Forty BALB/c mice were divided as: group A (n = 10, control) sensitized and challenged with saline, group B (n = 10, asthma) challenged by intraperitoneal and intranasal ovalbumin (OVA) to induce allergic asthma and rhinitis, and groups C (n = 10, asthma/rotatory control) and D (n = 10, asthma/hypergravity) exposed to 4 weeks of rotation with normogravity (1G) or hypergravity (5G) during induction of asthma/rhinitis. Group D showed significantly decreased eosinophils, neutrophils, and lymphocytes in their BAL fluid compared with groups B and C (p lung homogenate, the expression of IL-1β was significantly upregulated (p lung parenchyma and turbinate, and the thickness of respiratory epithelium was significantly reduced in group D (p < 0.05). The expression of Bcl-2 and heme oxygenase-1 were significantly downregulated, Bax and extracellular dismutase significantly upregulated in Group D. Therefore, chronic hypergravity could have a hormetic effect for allergic asthma and rhinitis via regulation of genes involved in antioxidative and proapoptotic pathways. It is possible that we could use hypergravity machinery for treating allergic respiratory disorders.

  8. Prostatic inflammation induces fibrosis in a mouse model of chronic bacterial infection.

    Directory of Open Access Journals (Sweden)

    Letitia Wong

    Full Text Available Inflammation of the prostate is strongly correlated with development of lower urinary tract symptoms and several studies have implicated prostatic fibrosis in the pathogenesis of bladder outlet obstruction. It has been postulated that inflammation induces prostatic fibrosis but this relationship has never been tested. Here, we characterized the fibrotic response to inflammation in a mouse model of chronic bacterial-induced prostatic inflammation. Transurethral instillation of the uropathogenic E. coli into C3H/HeOuJ male mice induced persistent prostatic inflammation followed by a significant increase in collagen deposition and hydroxyproline content. This fibrotic response to inflammation was accompanied with an increase in collagen synthesis determined by the incorporation of 3H-hydroxyproline and mRNA expression of several collagen remodeling-associated genes, including Col1a1, Col1a2, Col3a1, Mmp2, Mmp9, and Lox. Correlation analysis revealed a positive correlation of inflammation severity with collagen deposition and immunohistochemical staining revealed that CD45+VIM+ fibrocytes were abundant in inflamed prostates at the time point coinciding with increased collagen synthesis. Furthermore, flow cytometric analysis demonstrated an increased percentage of these CD45+VIM+ fibrocytes among collagen type I expressing cells. These data show-for the first time-that chronic prostatic inflammation induces collagen deposition and implicates fibrocytes in the fibrotic process.

  9. Wakame (Undaria pinnatifida ) modulates hyperphosphatemia in a rat model of chronic renal failure.

    Science.gov (United States)

    Katai, Kanako; Iwamoto, Aya; Kimura, Yuka; Oshima, Yuki; Arioka, Saori; Morimi, Yuki; Omuro, Ayaka; Nakasa, Teruko

    2015-01-01

    In chronic renal failure, inorganic phosphate (Pi) retention speeds up the progression to end-stage renal disease. The current therapy for hyperphosphatemia in patients with chronic renal failure consists of dietary Pi restriction combined with administration of Pi binders, but each therapy has practical problems. Thus, the discovery of foods or nutrients that inhibit Pi absorption may be useful for the treatment of hyperphosphatemia. In the present study, we investigated whether wakame (Undaria pinnatifida) is a useful food for the prevention of hyperphosphatemia in a rat model of renal failure. Feeding a diet containing 5% wakame significantly decreased plasma and urinary Pi levels and increased the amount of fecal Pi. In addition, wakame significantly reduced plasma blood urea nitrogen and plasma Pi levels in 5/6 nephrectomized rats fed a high-Pi diet. Biochemical analyses showed that the reduction of intestinal Pi absorption is the main reason for the decrease in plasma Pi levels in rats fed a diet containing wakame. In addition, feeding alginic acid and fucoidan, major components of wakame fiber, was effective in reducing plasma Pi levels in normal rats. Finally, we concluded that wakame may be a useful food for the prevention of hyperphosphatemia in rodents.

  10. Using Mobile Health to Support the Chronic Care Model: Developing an Institutional Initiative

    Directory of Open Access Journals (Sweden)

    Shantanu Nundy

    2012-01-01

    Full Text Available Background. Self-management support and team-based care are essential elements of the Chronic Care Model but are often limited by staff availability and reimbursement. Mobile phones are a promising platform for improving chronic care but there are few examples of successful health system implementation. Program Development. An iterative process of program design was built upon a pilot study and engaged multiple institutional stakeholders. Patients identified having a “human face” to the pilot program as essential. Stakeholders recognized the need to integrate the program with primary and specialty care but voiced concerns about competing demands on clinician time. Program Description. Nurse administrators at a university-affiliated health plan use automated text messaging to provide personalized self-management support for member patients with diabetes and facilitate care coordination with the primary care team. For example, when a patient texts a request to meet with a dietitian, a nurse-administrator coordinates with the primary care team to provide a referral. Conclusion. Our innovative program enables the existing health system to support a de novo care management program by leveraging mobile technology. The program supports self-management and team-based care in a way that we believe engages patients yet meets the limited availability of providers and needs of health plan administrators.

  11. Immune System Modifications Induced in a Mouse Model of Chronic Exposure to (90)Sr.

    Science.gov (United States)

    Synhaeve, Nicholas; Musilli, Stefania; Stefani, Johanna; Nicolas, Nour; Delissen, Olivia; Dublineau, Isabelle; Bertho, Jean-Marc

    2016-03-01

    Strontium 90 ((90)Sr) remains in the environment long after a major nuclear disaster occurs. As a result, populations living on contaminated land are potentially exposed to daily ingesting of low quantities of (90)Sr. The potential long-term health effects of such chronic contamination are unknown. In this study, we used a mouse model to evaluate the effects of (90)Sr ingestion on the immune system, the animals were chronically exposed to (90)Sr in drinking water at a concentration of 20 kBq/l, for a daily ingestion of 80-100 Bq/day. This resulted in a reduced number of CD19(+) B lymphocytes in the bone marrow and spleen in steady-state conditions. In contrast, the results from a vaccine experiment performed as a functional test of the immune system showed that in response to T-dependent antigens, there was a reduction in IgG specific to tetanus toxin (TT), a balanced Th1/Th2 response inducer antigen, but not to keyhole limpet hemocyanin (KLH), a strong Th2 response inducer antigen. This was accompanied by a reduction in Th1 cells in the spleen, consistent with the observed reduction in specific IgG concentration. The precise mechanisms by which (90)Sr acts on the immune system remain to be elucidated. However, our results suggest that (90)Sr ingestion may be responsible for some of the reported effects of internal contamination on the immune system in civilian populations exposed to the Chernobyl fallout.

  12. The Sensitization Model to Explain How Chronic Pain Exists Without Tissue Damage

    NARCIS (Netherlands)

    van Wilgen, C. Paul; Keizer, Doeke

    2012-01-01

    The interaction of nurses with chronic pain patients is often difficult. One of the reasons is that chronic pain is difficult to explain, because no obvious anatomic defect or tissue damage is present. There is now enough evidence available indicating that chronic pain syndromes such as low back pai

  13. LINGO-1 and Neurodegeneration: Pathophysiologic Clues for Essential Tremor.

    Science.gov (United States)

    Zhou, Zhi-Dong; Sathiyamoorthy, Sushmitha; Tan, Eng-King

    2012-01-01

    Essential tremor (ET), one of the most common adult-onset movement disorders, has been associated with cerebellar Purkinje cell degeneration and formation of brainstem Lewy bodies. Recent findings suggest that genetic variants of the leucine-rich repeat and Ig domain containing 1 (LINGO-1) gene could be risk factors for ET. The LINGO-1 protein contains both leucine-rich repeat (LRR) and immunoglobulin (Ig)-like domains in its extracellular region, as well as a transmembrane domain and a short cytoplasmic tail. LINGO-1 can form a ternary complex with Nogo-66 receptor (NgR1) and p75. Binding of LINGO-1 with NgR1 can activate the NgR1 signaling pathway, leading to inhibition of oligodendrocyte differentiation and myelination in the central nervous system. LINGO-1 has also been found to bind with epidermal growth factor receptor (EGFR) and induce downregulation of the activity of EGFR-PI3K-Akt signaling, which might decrease Purkinje cell survival. Therefore, it is possible that genetic variants of LINGO-1, either alone or in combination with other genetic or environmental factors, act to increase LINGO-1 expression levels in Purkinje cells and confer a risk to Purkinje cell survival in the cerebellum.Here, we provide a concise summary of the link between LINGO-1 and neurodegeneration and discuss various hypotheses as to how this could be potentially relevant to ET pathogenesis.

  14. Application of medical cannabis in patients with the neurodegeneration disorders

    Directory of Open Access Journals (Sweden)

    Lidia Kotuła

    2014-04-01

    Full Text Available Medical cannabis is the dried flowers of the female Cannabis sativa L. plant. Cannabis contains a number of active elements, including dronabinol (THC and cannabidiol (CBD. Dronabinol is usually the main ingredient. The body’s own cannabinoid system has been identified. The discovery of this system, which comprises endocannabinoids and receptors, confirmed that cannabis has a positive effect on certain illnesses and conditions. Two types of cannabinoid receptors have been identified: CB1 and CB2 receptors. The first type CB1 is mostly found in the central nervous system, modulate pain. It also has an anti-emetic effect, and has influence on the memory and the motor system. The second type of receptors CB2 is peripheral, and it is primarily found in immune system cells and it is responsible for the immunomodulatory effects of cannabinoids. Medical cannabis can help in cases of the neurodegeneration disorders, for example Parkinson’s disease, Huntington’s Disease, Amyotrophic Lateral Sclerosis. Patients generally tolerate medical cannabis well.

  15. Common features at the start of the neurodegeneration cascade.

    Directory of Open Access Journals (Sweden)

    Rubén Hervás

    Full Text Available Amyloidogenic neurodegenerative diseases are incurable conditions with high social impact that are typically caused by specific, largely disordered proteins. However, the underlying molecular mechanism remains elusive to established techniques. A favored hypothesis postulates that a critical conformational change in the monomer (an ideal therapeutic target in these "neurotoxic proteins" triggers the pathogenic cascade. We use force spectroscopy and a novel methodology for unequivocal single-molecule identification to demonstrate a rich conformational polymorphism in the monomer of four representative neurotoxic proteins. This polymorphism strongly correlates with amyloidogenesis and neurotoxicity: it is absent in a fibrillization-incompetent mutant, favored by familial-disease mutations and diminished by a surprisingly promiscuous inhibitor of the critical monomeric β-conformational change, neurotoxicity, and neurodegeneration. Hence, we postulate that specific mechanostable conformers are the cause of these diseases, representing important new early-diagnostic and therapeutic targets. The demonstrated ability to inhibit the conformational heterogeneity of these proteins by a single pharmacological agent reveals common features in the monomer and suggests a common pathway to diagnose, prevent, halt, or reverse multiple neurodegenerative diseases.

  16. REM sleep behavior disorder: from dreams to neurodegeneration.

    Science.gov (United States)

    Postuma, Ronald B; Gagnon, Jean-Francois; Montplaisir, Jacques Y

    2012-06-01

    REM sleep behavior disorder is a unique parasomnia characterized by dream enactment behavior during REM sleep. Unless triggered by pharmacologic agents such as antidepressants, it is generally related to damage of pontomedullary brainstem structures. Idiopathic REM sleep behavior disorder (RBD) is a well-established risk factor for neurodegenerative disease. Prospective studies have estimated that at least 40-65% of patients with idiopathic RBD will eventually develop a defined neurodegenerative phenotype, almost always a 'synucleinopathy' (Parkinson's disease, Lewy Body dementia or multiple system atrophy). In most cases, patients appear to develop a syndrome with overlapping features of both Parkinson's disease and Lewy body dementia. The interval between RBD onset and disease onset averages 10-15 years, suggesting a promisingly large window for intervention into preclinical disease stages. The ability of RBD to predict disease has major implications for design and development of neuroprotective therapy, and testing of other predictive markers of synuclein-mediated neurodegeneration. Recent studies in idiopathic RBD patients have demonstrated that olfaction, color vision, severity of REM atonia loss, transcranial ultrasound of the substantia nigra, and dopaminergic neuroimaging can predict development of neurodegenerative disease.

  17. Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tau

    Science.gov (United States)

    Santa-Maria, Ismael; Alaniz, Maria E.; Renwick, Neil; Cela, Carolina; Fulga, Tudor A.; Van Vactor, David; Tuschl, Thomas; Clark, Lorraine N.; Shelanski, Michael L.; McCabe, Brian D.; Crary, John F.

    2015-01-01

    Tau is a highly abundant and multifunctional brain protein that accumulates in neurofibrillary tangles (NFTs), most commonly in Alzheimer’s disease (AD) and primary age-related tauopathy. Recently, microRNAs (miRNAs) have been linked to neurodegeneration; however, it is not clear whether miRNA dysregulation contributes to tau neurotoxicity. Here, we determined that the highly conserved brain miRNA miR-219 is downregulated in brain tissue taken at autopsy from patients with AD and from those with severe primary age-related tauopathy. In a Drosophila model that produces human tau, reduction of miR-219 exacerbated tau toxicity, while overexpression of miR-219 partially abrogated toxic effects. Moreover, we observed a bidirectional modulation of tau levels in the Drosophila model that was dependent on miR-219 expression or neutralization, demonstrating that miR-219 regulates tau in vivo. In mammalian cellular models, we found that miR-219 binds directly to the 3′-UTR of the tau mRNA and represses tau synthesis at the post-transcriptional level. Together, our data indicate that silencing of tau by miR-219 is an ancient regulatory mechanism that may become perturbed during neurofibrillary degeneration and suggest that this regulatory pathway may be useful for developing therapeutics for tauopathies. PMID:25574843

  18. Trichloroethylene induces dopaminergic neurodegeneration in Fisher 344 rats.

    Science.gov (United States)

    Liu, Mei; Choi, Dong-Young; Hunter, Randy L; Pandya, Jignesh D; Cass, Wayne A; Sullivan, Patrick G; Kim, Hyoung-Chun; Gash, Don M; Bing, Guoying

    2010-02-01

    Trichloroethylene, a chlorinated solvent widely used as a degreasing agent, is a common environmental contaminant. Emerging evidence suggests that chronic exposure to trichloroethylene may contribute to the development of Parkinson's disease. The purpose of this study was to determine if selective loss of nigrostriatal dopaminergic neurons could be reproduced by systemic exposure of adult Fisher 344 rats to trichloroethylene. In our experiments, oral administration of trichloroethylene induced a significant loss of dopaminergic neurons in the substantia nigra pars compacta in a dose-dependent manner, whereas the number of both cholinergic and GABAergic neurons were not decreased in the striatum. There was a robust decline in striatal levels of 3, 4-dihydroxyphenylacetic acid without a significant depletion of striatal dopamine. Rats treated with trichloroethylene showed defects in rotarod behavior test. We also found a significantly reduced mitochondrial complex I activity with elevated oxidative stress markers and activated microglia in the nigral area. In addition, we observed intracellular alpha-synuclein accumulation in the dorsal motor nucleus of the vagus nerve, with some in nigral neurons, but little in neurons of cerebral cortex. Overall, our animal model exhibits some important features of Parkinsonism, and further supports that trichloroethylene may be an environmental risk factors for Parkinson's disease.

  19. Brain viral burden, neuroinflammation and neurodegeneration in HAART-treated HIV positive injecting drug users.

    Science.gov (United States)

    Smith, Donald B; Simmonds, Peter; Bell, Jeanne E

    2014-02-01

    The long-term impact of chronic human immunodeficiency virus (HIV) infection on brain status in injecting drug users (IDU) treated with highly active antiretroviral therapy (HAART) is unknown. Viral persistence in the brain with ongoing neuroinflammation may predispose to Alzheimer-like neurodegeneration. In this study, we investigated the brains of ten HAART-treated individuals (six IDU and four non-DU), compared with ten HIV negative controls (six IDU and four non-DU). HIV DNA levels in brain tissue were correlated with plasma and lymphoid tissue viral loads, cognitive status, microglial activation and Tau protein and amyloid deposition. Brain HIV proviral DNA levels were low in most cases but higher in HIV encephalitis (n = 2) and correlated significantly with levels in lymphoid tissue (p = 0.0075), but not with those in plasma. HIV positive subjects expressed more Tau protein and amyloid than HIV negative controls (highest in a 58 year old), as did IDU, but brain viral loads showed no relation to Tau and amyloid. Microglial activation linked significantly to HIV positivity (p = 0.001) and opiate abuse accentuated these microglial changes (p = 0.05). This study confirms that HIV DNA persists in brains despite HAART and that opiate abuse adds to the risk of brain damage in HIV positive subjects. Novel findings in this study show that (1) plasma levels are not a good surrogate indicator of brain status, (2) viral burden in brain and lymphoid tissues is related, and (3) while Tau and amyloid deposition is increased in HIV positive IDU, this is not specifically related to increased HIV burden within the brain.

  20. Dementia, preclinical studies in neurodegeneration and its potential for translational medicine in SouthAmerica

    Directory of Open Access Journals (Sweden)

    Gloria Patricia Cardona Gomez

    2016-12-01

    Full Text Available Latin-American people with dementia will increase in a 368% in 2050, higher than USA and Europe. In addition, to sporadic dementia type Alzheimer and vascular dementia progression after Cerebrovascular disease, the statistics are increased in Colombia by specific populations affected with pure neurodegenerative and vascular dementias like autosomical dominant familial Alzheimer´s disease and CADASIL. In spite of the enormous human and economical effort and investment, neither sporadic nor genetic kinds of dementia progression have been prevented or blocked yet. Currently, exist several animal models that partially solve the understanding of the neurodegenerative etiopathogenesis and its treatment. However, when the potential therapies are translated to humans, those do not work or present a limited action. Main difficulties are the diverse comorbility associated to the cause and/or several affected brain regions, reducing the efficacy of some therapies which are limited to a tissue-specific action or modulating a kind of neurotransmission. Global investigation suggests that a general prevention could be achieved with the improvement in the quality of lifestyle, including healthy diet, physical and mental activity, and avoiding mechanical or chemical pro-inflammatory events in an early stage in the most of non-communicable diseases. In this review, we present some molecular targets and preclinical studies in animal models to propose strategies that could be useful in a future translation to prevent or block neurodegeneration: One is gene therapy silencing pathogenic genes in critical brain areas where excitotoxicity arise and spread. Another is to take advantage of the natural source and its wide biodiversity of natural products some of them identified by the blocking and prevention of neurodegeneration. On the other side, the casuistic of pure dementias in the Latin-American region give an exceptional opportunity to understand the pathogenesis

  1. Intestinal inflammation in TNBS sensitized rats as a model of chronic inflammatory bowel disease

    Directory of Open Access Journals (Sweden)

    N. Selve

    1992-01-01

    Full Text Available An enteritis, based on a delayed-type hypersensitivity reaction, was induced in TNBS (2,4,4-trinitrobenzenesulphonic acid sensitized rats by multiple intrajejunal challenge with TNBS via an implanted catheter. This treatment induced chronic inflammation of the distal small intestine characterized by intense hyperaemia, oedema and gut wall thickening as assessed by macroscopic scoring and weighing a defined part of the dissected intestine. Histologically, the inflammatory response included mucosal and submucosal cell infiltration by lymphocytes and histiocytes, transmural granulomatous inflammation with multinucleated cells and activated mesenteric lymph nodes. Ex vivo stimulated release of the inflammatory mediator LTB4 in the dissected part of the intestine was increased following TNBS treatment. Drug treatment with sulphasalazine or 5-aminosalicylic acid improved the enteritis score and attenuated TNBS induced oedema formation and LTB4 production. The applicability and relevance of this new model are discussed with respect to drug development and basic research of inflammatory bowel diseases.

  2. Long term treatment with gabapentin in an animal model of chronic neuropathic pain

    DEFF Research Database (Denmark)

    Baastrup, C. S.; Andrews, N.; Wegener, Gregers

    2013-01-01

    In preclinical animal pain research potential efficacy of a drug is often evaluate after a single exposure, which is in contrast to the long lasting treatment needed in chronic neuropathic pain (CNP) patients. Gabapentin remains one of the most efficacious drugs in the treatment of CNP. The aims...... of the study were to evaluate the spinal cord contusion (SCC) model and 2 different measures of painlike behaviour using a long term treatment schedule with gabapentin. Furthermore the effect on mobility and on anxiety, a pain-related behaviour, was included. 40 Female SD rats with a T13 SCC and sham animals...... was measured after initial dose, 1 and 6 weeks of treatment. Preliminary results show that saline-treated SCC animals (N=10) have significantly lower MST with supra-spinal responses on the thorax compared to saline-treated shams (N=10), and gabapentin-treated SCC (N=10) and sham animals (N=10) throughout...

  3. Model and Processes of Acceptance and Commitment Therapy (ACT) for Chronic Pain Including a Closer Look at the Self.

    Science.gov (United States)

    Yu, Lin; McCracken, Lance M

    2016-02-01

    Acceptance and commitment therapy (ACT) is one of the so called "third-wave" cognitive behavioral therapies. It has been increasingly applied to chronic pain, and there is accumulating evidence to support its effectiveness. ACT is based on a model of general human functioning called the psychological flexibility (PF) model. Most facets of the PF model have been examined in chronic pain. However, a potential key facet related to "self" appears underappreciated. Indeed, a positive or healthy sense of self seems essential to our well-being, and there have been numerous studies of the self in chronic pain. At the same time, these studies are not currently well organized or easy to summarize. This lack of clarity and integration creates barriers to progress in this area of research. PF with its explicit inclusion of self-related therapeutic processes within a broad, integrative, theoretical model may help. The current review summarizes the PF model in the context of chronic pain with a specific emphasis on the parts of the model that address self-related processes.

  4. Intravesical Dimethyl Sulfoxide Inhibits Acute and Chronic Bladder Inflammation in Transgenic Experimental Autoimmune Cystitis Models

    Directory of Open Access Journals (Sweden)

    Ronald Kim

    2011-01-01

    Full Text Available New animal models are greatly needed in interstitial cystitis/painful bladder syndrome (IC/PBS research. We recently developed a novel transgenic cystitis model (URO-OVA mice that mimics certain key aspects of IC/PBS pathophysiology. This paper aimed to determine whether URO-OVA cystitis model was responsive to intravesical dimethyl sulfoxide (DMSO and if so identify the mechanisms of DMSO action. URO-OVA mice developed acute cystitis upon adoptive transfer of OVA-specific OT-I splenocytes. Compared to PBS-treated bladders, the bladders treated with 50% DMSO exhibited markedly reduced bladder histopathology and expression of various inflammatory factor mRNAs. Intravesical DMSO treatment also effectively inhibited bladder inflammation in a spontaneous chronic cystitis model (URO-OVA/OT-I mice. Studies further revealed that DMSO could impair effector T cells in a dose-dependent manner in vitro. Taken together, our results suggest that intravesical DMSO improves the bladder histopathology of IC/PBS patients because of its ability to interfere with multiple inflammatory and bladder cell types.

  5. Nucleolar disruption and cajal body disassembly are nuclear hallmarks of DNA damage-induced neurodegeneration in purkinje cells.

    Science.gov (United States)

    Baltanás, Fernando C; Casafont, Iñigo; Weruaga, Eduardo; Alonso, José R; Berciano, María T; Lafarga, Miguel

    2011-07-01

    The Purkinje cell (PC) degeneration (pcd) phenotype results from mutation in nna1 gene and is associated with the degeneration and death of PCs during the postnatal life. Although the pcd mutation is a model of the ataxic mouse, it shares clinical and pathological characteristics of inherited human spinocerebellar ataxias. PC degeneration in pcd mice provides a useful neuronal system to study nuclear mechanisms involved in DNA damage-dependent neurodegeneration, particularly the contribution of nucleoli and Cajal bodies (CBs). Both nuclear structures are engaged in housekeeping functions for neuronal survival, the biogenesis of ribosomes and the maturation of snRNPs and snoRNPs required for pre-mRNA and pre-rRNA processing, respectively. In this study, we use ultrastructural analysis, in situ transcription assay and molecular markers for DNA damage, nucleoli and CB components to demonstrate that PC degeneration involves the progressive accumulation of nuclear DNA damage associated with disruption of nucleoli and CBs, disassembly of polyribosomes into monoribosomes, ribophagy and shut down of nucleolar and extranucleolar transcription. Microarray analysis reveals that four genes encoding repressors of nucleolar rRNA synthesis (p53, Rb, PTEN and SNF2) are upregulated in the cerebellum of pcd mice. Collectively, these data support that nucleolar and CB alterations are hallmarks of DNA damage-induced neurodegeneration.

  6. Intranasal "painless" human Nerve Growth Factor [corrected] slows amyloid neurodegeneration and prevents memory deficits in App X PS1 mice.

    Directory of Open Access Journals (Sweden)

    Simona Capsoni

    Full Text Available Nerve Growth Factor (NGF is being considered as a therapeutic candidate for Alzheimer's disease (AD treatment but the clinical application is hindered by its potent pro-nociceptive activity. Thus, to reduce systemic exposure that would induce pain, in recent clinical studies NGF was administered through an invasive intracerebral gene-therapy approach. Our group demonstrated the feasibility of a non-invasive intranasal delivery of NGF in a mouse model of neurodegeneration. NGF therapeutic window could be further increased if its nociceptive effects could be avoided altogether. In this study we exploit forms of NGF, mutated at residue R100, inspired by the human genetic disease HSAN V (Hereditary Sensory Autonomic Neuropathy Type V, which would allow increasing the dose of NGF without triggering pain. We show that "painless" hNGF displays full neurotrophic and anti-amyloidogenic activities in neuronal cultures, and a reduced nociceptive activity in vivo. When administered intranasally to APPxPS1 mice ( n = 8, hNGFP61S/R100E prevents the progress of neurodegeneration and of behavioral deficits. These results demonstrate the in vivo neuroprotective and anti-amyloidogenic properties of hNGFR100 mutants and provide a rational basis for the development of "painless" hNGF variants as a new generation of therapeutics for neurodegenerative diseases.

  7. Cyclophilin D-dependent mitochondrial permeability transition is not involved in neurodegeneration in mnd2 mutant mice.

    Science.gov (United States)

    Ideguchi, Kan; Shimizu, Shigeomi; Okumura, Meinoshin; Tsujimoto, Yoshihide

    2010-03-05

    Parkinson's disease (PD) is a common neurodegenerative disorder. The motor neuron degeneration 2 mutant (mnd2) mouse exhibits loss of striatal neurons, muscle wasting, weight loss, and death within 40days of birth, and is considered to be a useful animal model of PD. mnd2 was identified as an autosomal recessive mutation in the HtrA2/Omi gene, which encodes a mitochondrial serine protease. Omi-deficient mitochondria are more sensitive to mitochondrial permeability transition (mPT), which raises the possibility that mPT plays a role in motor neurodegeneration in mnd2 mice. Given that cyclophilin D (CypD)-deficient mitochondria are resistant to mPT, we examined whether CypD-dependent mPT is involved in the pathogenesis of neurodegenerative disorders in mnd2 mice by generating CypD-deficient mnd2 mice. Brain mitochondria isolated from CypD-deficient mnd2 mice were more resistant to Ca(2+)-induced mPT than those of mnd2 mice. However, both mnd2 mice and CypD-deficient mnd2 mice showed similar survival periods and phenotypes, including the lack of weight gain, muscle wasting, and resting tremor. Our data suggest that CypD-dependent mPT does not play a major role in neurodegeneration in mnd2 mice.

  8. Effects of acute or chronic administration of substituted benzamides in experimental models of depression in rats.

    Science.gov (United States)

    Drago, F; Arezzi, A; Virzì, A

    2000-12-01

    The effects of substituted benzamides, sulpiride and raclopride on experimental models of depression were studied in male rats after acute or chronic administration in comparison to those of the classical antidepressant, clomipramine. In contrast to clomipramine (50 mg/kg), acute doses of sulpiride or raclopride (1 or 5 mg/kg) failed to change the behavioral response of animals tested in the despair (constrained swim) test or in the model of reserpine-induced changes in the open field behavior. These doses also did not modify the grooming response of rats exposed to a novel environment. Sulpiride or raclopride 10 mg/kg increased the immobility time in the despair test and reduced novelty-induced grooming. The repeated injection for 21 days of sulpiride or raclopride (1 or 5 mg/kg, but not 10 mg/kg) induced a reduction of the immobility period during the constrained swim test similar to that following the chronic treatment with clomipramine 50 mg/kg. This appeared to be a clear-cut reversed dose-response relationship for both substituted benzamides, being the dose potency 1 mg/kg>5 mg/kg>10 mg/kg. Raclopride was more potent than sulpiride in this respect. Furthermore, like clomipramine, sulpiride (1 or 5 mg/kg) and raclopride (1 mg/kg) antagonized reserpine-induced changes in the open field behavior and enhanced novelty-induced grooming. These results indicate that, in contrast to acute injection, repeated administration of small doses of the substituted benzamides, sulpiride or raclopride induce an effect similar to that of the classical antidepressant, clomipramine. The reverse dose-response relationship suggests that these drugs in small doses act on presynaptic dopamine D(2) receptors. This may be consistent with a postsynaptic action of greater doses that exert sedative effects and increase immobility time in the despair test.

  9. Novel Mechanism for Reducing Acute and Chronic Neurodegeneration After Traumatic Brain Injury

    Science.gov (United States)

    2016-07-01

    PRINCIPAL INVESTIGATOR: Bruce Lyeth, Ph.D. CONTRACTING ORGANIZATION: University of California, Davis Davis, CA 95616 REPORT DATE: July 2016 TYPE OF...PERFORMING ORGANIZATION REPORT NUMBER UNIVERSITY OF CALIFORNIA, DAVIS 1850 RESEARCH PARK DR, STE 300 DAVIS CA 95618-6134 9. SPONSORING / MONITORING...stage using computer software (Stereo Investigator). The region of interest was outlined under 4X magnification (Figure 4B). Criterion for counting

  10. Calcium dysregulation contributes to neurodegeneration in FTLD patient iPSC-derived neurons

    Science.gov (United States)

    Imamura, Keiko; Sahara, Naruhiko; Kanaan, Nicholas M.; Tsukita, Kayoko; Kondo, Takayuki; Kutoku, Yumiko; Ohsawa, Yutaka; Sunada, Yoshihide; Kawakami, Koichi; Hotta, Akitsu; Yawata, Satoshi; Watanabe, Dai; Hasegawa, Masato; Trojanowski, John Q.; Lee, Virginia M.-Y.; Suhara, Tetsuya; Higuchi, Makoto; Inoue, Haruhisa

    2016-01-01

    Mutations in the gene MAPT encoding tau, a microtubules-associated protein, cause a subtype of familial neurodegenerative disorder, known as frontotemporal lobar degeneration tauopathy (FTLD-Tau), which presents with dementia and is characterized by atrophy in the frontal and temporal lobes of the brain. Although induced pluripotent stem cell (iPSC) technology has facilitated the investigation of phenotypes of FTLD-Tau patient neuronal cells in vitro, it remains unclear how FTLD-Tau patient neurons degenerate. Here, we established neuronal models of FTLD-Tau by Neurogenin2-induced direct neuronal differentiation from FTLD-Tau patient iPSCs. We found that FTLD-Tau neurons, either with an intronic MAPT mutation or with an exonic mutation, developed accumulation and extracellular release of misfolded tau followed by neuronal death, which we confirmed by correction of the intronic mutation with CRISPR/Cas9. FTLD-Tau neurons showed dysregulation of the augmentation of Ca2+ transients evoked by electrical stimulation. Chemogenetic or pharmacological control of neuronal activity-relevant Ca2+ influx by the introduction of designer receptors exclusively activated by designer drugs (DREADDs) or by the treatment with glutamate receptor blockers attenuated misfolded tau accumulation and neuronal death. These data suggest that neuronal activity may regulate neurodegeneration in tauopathy. This FTLD-Tau model provides mechanistic insights into tauopathy pathogenesis and potential avenues for treatments. PMID:27721502

  11. Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects against Neurodegeneration in Experimental Multiple Sclerosis*

    Science.gov (United States)

    Warne, Justin; Pryce, Gareth; Hill, Julia M.; Shi, Xiao; Lennerås, Felicia; Puentes, Fabiola; Kip, Maarten; Hilditch, Laura; Walker, Paul; Simone, Michela I.; Chan, A. W. Edith; Towers, Greg J.; Coker, Alun R.; Duchen, Michael R.; Szabadkai, Gyorgy; Baker, David; Selwood, David L.

    2016-01-01

    The mitochondrial permeability transition pore is a recognized drug target for neurodegenerative conditions such as multiple sclerosis and for ischemia-reperfusion injury in the brain and heart. The peptidylprolyl isomerase, cyclophilin D (CypD, PPIF), is a positive regulator of the pore, and genetic down-regulation or knock-out improves outcomes in disease models. Current inhibitors of peptidylprolyl isomerases show no selectivity between the tightly conserved cyclophilin paralogs and exhibit significant off-target effects, immunosuppression, and toxicity. We therefore designed and synthesized a new mitochondrially targeted CypD inhibitor, JW47, using a quinolinium cation tethered to cyclosporine. X-ray analysis was used to validate the design concept, and biological evaluation revealed selective cellular inhibition of CypD and the permeability transition pore with reduced cellular toxicity compared with cyclosporine. In an experimental autoimmune encephalomyelitis disease model of neurodegeneration in multiple sclerosis, JW47 demonstrated significant protection of axons and improved motor assessments with minimal immunosuppression. These findings suggest that selective CypD inhibition may represent a viable therapeutic strategy for MS and identify quinolinium as a mitochondrial targeting group for in vivo use. PMID:26679998

  12. Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects against Neurodegeneration in Experimental Multiple Sclerosis.

    Science.gov (United States)

    Warne, Justin; Pryce, Gareth; Hill, Julia M; Shi, Xiao; Lennerås, Felicia; Puentes, Fabiola; Kip, Maarten; Hilditch, Laura; Walker, Paul; Simone, Michela I; Chan, A W Edith; Towers, Greg J; Coker, Alun R; Duchen, Michael R; Szabadkai, Gyorgy; Baker, David; Selwood, David L

    2016-02-26

    The mitochondrial permeability transition pore is a recognized drug target for neurodegenerative conditions such as multiple sclerosis and for ischemia-reperfusion injury in the brain and heart. The peptidylprolyl isomerase, cyclophilin D (CypD, PPIF), is a positive regulator of the pore, and genetic down-regulation or knock-out improves outcomes in disease models. Current inhibitors of peptidylprolyl isomerases show no selectivity between the tightly conserved cyclophilin paralogs and exhibit significant off-target effects, immunosuppression, and toxicity. We therefore designed and synthesized a new mitochondrially targeted CypD inhibitor, JW47, using a quinolinium cation tethered to cyclosporine. X-ray analysis was used to validate the design concept, and biological evaluation revealed selective cellular inhibition of CypD and the permeability transition pore with reduced cellular toxicity compared with cyclosporine. In an experimental autoimmune encephalomyelitis disease model of neurodegeneration in multiple sclerosis, JW47 demonstrated significant protection of axons and improved motor assessments with minimal immunosuppression. These findings suggest that selective CypD inhibition may represent a viable therapeutic strategy for MS and identify quinolinium as a mitochondrial targeting group for in vivo use.

  13. Neurogenesis and neuroprotection in postischemic brain neurodegeneration with Alzheimer phenotype: is there a role for curcumin?

    Science.gov (United States)

    Pluta, Ryszard; Bogucka-Kocka, Anna; Ułamek-Kozioł, Marzena; Furmaga-Jabłońska, Wanda; Januszewski, Sławomir; Brzozowska, Judyta; Jabłoński, Mirosław; Kocki, Janusz

    2015-01-01

    For thousands of years, humankind has used plants for therapeutics. Nowadays, there is a renewed public interest in naturally occurring treatments with minimal toxicity and diets related to health. Alterations in hippocampal neurogenesis have been recognized as an integral part of brain ischemia. Neuronal stem/progenitor cells in the hippocampus are positively and negatively regulated by intrinsic and extrinsic agents. One positive regulator of neurogenesis in the hippocampus is curcumin in the diet. This review provides an assessment of the current state of the field in hippocampal neurogenesis and neuroprotection studies in brain ischemia and focuses on the role of curcumin in the diet. Data suggest that dietary intake of curcumin enhances neurogenesis. Recent studies performed in ischemic models have suggested that curcumin also has neuroprotective features. One potential mechanism to explain several of the general health benefits associated with curcumin is that it may prevent ageing-associated changes in cellular proteins that lead to protein insolubility and aggregation after ischemia such as β-amyloid peptide and tau protein. Here, we also review the evidence from ischemic models that curcumin improves cognition and health span by overexpression of life supporting genes and preventing or delaying the onset of neurodegenerative changes. Available data provide evidence that curcumin induces neurogenesis and neuroprotection and may provide a novel therapeutic agent for both regenerative medicine and for the treatment of neurodegenerative diseases such as postischemic brain neurodegeneration with Alzheimer phenotype.

  14. The chronic psychosocial stress paradigm in male tree shrews: evaluation of a novel animal model for depressive disorders.

    Science.gov (United States)

    van Kampen, Marja; Kramer, Marian; Hiemke, Christoph; Flügge, Gabriele; Fuchs, Eberhard

    2002-02-01

    To improve our knowledge of the causal mechanisms of stress-related disorders such as depression, we need animal models that mirror the situation in patients. One promising model is the chronic psychosocial stress paradigm in male tree shrews, which is based on the territorial behaviour of these animals that can be used to establish naturally occurring challenging situations under experimental control in the laboratory. Co-existence of two males in visual and olfactory contact leads to a stable dominant-subordinate relationship, with subordinates showing distinct stress-induced behavioural and neuroendocrine alterations that are comparable to the symptoms observed during episodes of depression in patients such as constantly elevated circulating glucocorticoid hormones due to a chronic hyperactivity of the hypothalamic-pituitary-adrenal axis. To elucidate whether the chronic psychosocial stress model in tree shrews besides its "face validity" for depression also has "predictive validity", we treated subordinate tree shrews with the tricyclic antidepressant clomipramine and found a time-dependent restoration of both endocrine and behavioural parameters. In contrast, the anxiolytic diazepam was ineffective. Although the chronic psychosocial stress model in tree shrews requires further validation, it has sufficient face, predictive, and construct validity to become an interesting non-rodent model for research on the etiology and pathophysiology of depression.

  15. [Case management and complex chronic diseases: concepts, models, evidence and uncertainties].

    Science.gov (United States)

    Morales-Asencio, José Miguel

    2014-01-01

    Chronic diseases are the greatest challenge for Health Care, but the conventional health care models have failed noticeably. Nurses are one of the main providers of the services developed to tackle this challenge, with special emphasis on case management, as one of the most common forms. But, one of the key problems is that case management is poorly conceptualized, and with the diversity of experience available, make its development and comparative evaluation difficult. An in-depth review on case management definition and concepts is presented in this article, with a description of the models, ingredients and the effectiveness reported in various studies. The remaining uncertainties in case management, such as the heterogeneity of designs and target populations, the weak description of the components, and the scarce use of research models for complex interventions, are also discussed. Finally, some key factors for a successful implementation of case management are detailed, such as a clear definition of accountability and roles, the existence of support to guarantee the competence of case managers, the use of valid mechanisms for case finding, adjusted caseload, accessible and team-shared record systems, or the integration of health and social services.

  16. Excisional wound healing is delayed in a murine model of chronic kidney disease.

    Directory of Open Access Journals (Sweden)

    Akhil K Seth

    Full Text Available BACKGROUND: Approximately 15% of the United States population suffers from chronic kidney disease (CKD, often demonstrating an associated impairment in wound healing. This study outlines the development of a surgical murine model of CKD in order to investigate the mechanisms underlying this impairment. METHODS: CKD was induced in mice by partial cauterization of one kidney cortex and contralateral nephrectomy, modifying a previously published technique. After a minimum of 6-weeks, splinted, dorsal excisional wounds were created to permit assessment of wound healing parameters. Wounds were harvested on postoperative days (POD 0, 3, 7, and 14 for histological, immunofluorescent, and quantitative PCR (qPCR. RESULTS: CKD mice exhibited deranged blood chemistry and hematology profiles, including profound uremia and anemia. Significant decreases in re-epithelialization and granulation tissue deposition rates were found in uremic mice wounds relative to controls. On immunofluorescent analysis, uremic mice demonstrated significant reductions in cellular proliferation (BrdU and angiogenesis (CD31, with a concurrent increase in inflammation (CD45 as compared to controls. CKD mice also displayed differential expression of wound healing-related genes (VEGF, IL-1β, eNOS, iNOS on qPCR. CONCLUSIONS: These findings represent the first reported investigation of cutaneous healing in a CKD animal model. Ongoing studies of this significantly delayed wound healing phenotype include the establishment of renal failure model in diabetic strains to study the combined effects of CKD and diabetes.

  17. Multivariable Model for Time to First Treatment in Patients With Chronic Lymphocytic Leukemia

    Science.gov (United States)

    Wierda, William G.; O'Brien, Susan; Wang, Xuemei; Faderl, Stefan; Ferrajoli, Alessandra; Do, Kim-Anh; Garcia-Manero, Guillermo; Cortes, Jorge; Thomas, Deborah; Koller, Charles A.; Burger, Jan A.; Lerner, Susan; Schlette, Ellen; Abruzzo, Lynne; Kantarjian, Hagop M.; Keating, Michael J.

    2011-01-01

    Purpose The clinical course for patients with chronic lymphocytic leukemia (CLL) is diverse; some patients have indolent disease, never needing treatment, whereas others have aggressive disease requiring early treatment. We continue to use criteria for active disease to initiate therapy. Multivariable analysis was performed to identify prognostic factors independently associated with time to first treatment for patients with CLL. Patients and Methods Traditional laboratory, clinical prognostic, and newer prognostic factors such as fluorescent in situ hybridization (FISH), IGHV mutation status, and ZAP-70 expression evaluated at first patient visit to MD Anderson Cancer Center were correlated by multivariable analysis with time to first treatment. This multivariable model was used to develop a nomogram—a weighted tool to calculate 2- and 4-year probability of treatment and estimate median time to first treatment. Results There were 930 previously untreated patients who had traditional and new prognostic factors evaluated; they did not have active CLL requiring initiation of treatment within 3 months of first visit and were observed for time to first treatment. The following were independently associated with shorter time to first treatment: three involved lymph node sites, increased size of cervical lymph nodes, presence of 17p deletion or 11q deletion by FISH, increased serum lactate dehydrogenase, and unmutated IGHV mutation status. Conclusion We developed a multivariable model that incorporates traditional and newer prognostic factors to identify patients at high risk for progression to treatment. This model may be useful to identify patients for early interventional trials. PMID:21969505

  18. l-Carnitine improves cognitive and renal functions in a rat model of chronic kidney disease.

    Science.gov (United States)

    Abu Ahmad, Nur; Armaly, Zaher; Berman, Sylvia; Jabour, Adel; Aga-Mizrachi, Shlomit; Mosenego-Ornan, Efrat; Avital, Avi

    2016-10-01

    Over the past decade, the prevalence of chronic kidney disease (CKD) has reached epidemic proportions. The search for novel pharmacological treatment for CKD has become an area of intensive clinical research. l-Carnitine, considered as the "gatekeeper" responsible for admitting long chain fatty acids into cell mitochondria. l-Carnitine synthesis and turnover are regulated mainly by the kidney and its levels inversely correlate with serum creatinine of normal subjects and CKD patients. Previous studies showed that l-carnitine administration to elderly people is improving and preserving cognitive function. As yet, there are no clinical intervention studies that investigated the effect of l-carnitine administration on cognitive impairment evidenced in CKD patients. Thus, we aimed to investigate the effects of l-carnitine treatment on renal function and on the cognitive performance in a rat model of progressive CKD. To assess the role of l-carnitine on CKD condition, we estimated the renal function and cognitive abilities in a CKD rat model. We found that all CKD animals exhibited renal function deterioration, as indicated by elevated serum creatinine, BUN, and ample histopathological abnormalities. l-Carnitine treatment of CKD rats significantly reduced serum creatinine and BUN, attenuated renal hypertrophy and decreased renal tissue damage. In addition, in the two way shuttle avoidance learning, CKD animals showed cognitive impairment which recovered by the administration of l-carnitine. We conclude that in a rat model of CKD, l-carnitine administration significantly improved cognitive and renal functions.

  19. Macro-level modeling of the response of C. elegans reproduction to chronic heat stress.

    Directory of Open Access Journals (Sweden)

    Patrick D McMullen

    2012-01-01

    Full Text Available A major goal of systems biology is to understand how organism-level behavior arises from a myriad of molecular interactions. Often this involves complex sets of rules describing interactions among a large number of components. As an alternative, we have developed a simple, macro-level model to describe how chronic temperature stress affects reproduction in C. elegans. Our approach uses fundamental engineering principles, together with a limited set of experimentally derived facts, and provides quantitatively accurate predictions of performance under a range of physiologically relevant conditions. We generated detailed time-resolved experimental data to evaluate the ability of our model to describe the dynamics of C. elegans reproduction. We find considerable heterogeneity in responses of individual animals to heat stress, which can be understood as modulation of a few processes and may represent a strategy for coping with the ever-changing environment. Our experimental results and model provide quantitative insight into the breakdown of a robust biological system under stress and suggest, surprisingly, that the behavior of complex biological systems may be determined by a small number of key components.

  20. Probability Prediction in Multistate Survival Models for Patients with Chronic Myeloid Leukaemia

    Institute of Scientific and Technical Information of China (English)

    FANG Ya; Hein Putter

    2005-01-01

    In order to find an appropriate model suitable for a multistate survival experiment, 634 patients with chronic myeloid leukaemia (CML) were selected to illustrate the method of analysis.After transplantation, there were 4 possible situations for a patient: disease free, relapse but still alive, death before relapse, and death after relapse. The last 3 events were considered as treatment failure. The results showed that the risk of death before relapse was higher than that of the relapse,especially in the first year after transplantation with competing-risk method. The result of patients with relapse time less than 12 months was much poor by the Kaplan-Meier method. And the multistate survival models were developed, which were detailed and informative based on the analysis of competing risks and Kaplan-Meier analysis. With the multistate survival models, a further analysis on conditional probability was made for patients who were disease free and still alive at month 12 after transplantation. It was concluded that it was possible for an individual patient to predict the 4 possible probabilities at any time. Also the prognoses for relapse either death or not and death either before or afterrelapse may be given. Furthermore, the conditional probabilities for patients who were disease free and still alive in a given time after transplantation can be predicted.

  1. Neurodegeneration with brain iron accumulation: update on pathogenic mechanisms.

    Directory of Open Access Journals (Sweden)

    Sonia eLevi

    2014-05-01

    Full Text Available Perturbation of iron distribution is observed in many neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease, but the comprehension of the metal role in the development and progression of such disorders is still very limited. The combination of more powerful brain imaging techniques and faster genomic DNA sequencing procedures has allowed the description of a set of genetic disorders characterized by a constant and often early accumulation of iron in specific brain regions and the identification of the associated genes; these disorders are now collectively included in the category of Neurodegeneration with Brain Iron Accumulation (NBIA. So far 10 different genetic forms have been described but this number is likely to increase in short time. Two forms are linked to mutations in genes directly involved in iron metabolism: Neuroferritinopathy, associated to mutations in the FTL gene and Aceruloplasminaemia, where the ceruloplasmin gene product is defective. In the other forms the connection with iron metabolism is not evident at all and the genetic data let infer the involvement of other pathways: Pank2, COASY,Pla2G6, C19orf12, and FA2H genes seem to be related to lipid metabolism and to mitochondria functioning, WDR45 and ATP13A2 genes are implicated in lysosomal and autophagosome activity, while the C2orf37 gene encodes a nucleolar protein of unknown function. There is much hope in the scientific community that the study of the NBIA forms may provide important insight as to the link between brain iron metabolism and neurodegenerative mechanisms and eventually pave the way for new therapeutic avenues also for the more common neurodegenerative disorders. In this work we will review the most recent findings in the molecular mechanisms underlining the most common forms of NBIA and analyze their possible link with brain iron metabolism.

  2. Disruption of the MAP1B-related Protein FUTSCH Leads to Changes in the Neuronal Cytoskeleton, Axonal Transport Defects, and Progressive Neurodegeneration in DrosophilaD⃞V⃞

    Science.gov (United States)

    da Cruz, Alexandre Bettencourt; Schwärzel, Martin; Schulze, Sabine; Niyyati, Mahtab; Heisenberg, Martin; Kretzschmar, Doris

    2005-01-01

    The elaboration of neuronal axons and dendrites is dependent on a functional cytoskeleton. Cytoskeletal components have been shown to play a major role in the maintenance of the nervous system through adulthood, and changes in neurofilaments and microtubule-associated proteins (MAPs) have been linked to a variety of neurodegenerative diseases. Here we show that Futsch, the fly homolog of MAP1B, is involved in progressive neurodegeneration. Although Futsch is widely expressed throughout the CNS, degeneration in futscholk primarily occurs in the olfactory system and mushroom bodies. Consistent with the predicted function of Futsch, we find abnormalities in the microtubule network and defects in axonal transport. Degeneration in the adult brain is preceded by learning deficits, revealing a neuronal dysfunction before detectable levels of cell death. Futsch is negatively regulated by the Drosophila Fragile X mental retardation gene, and a mutation in this gene delays the onset of neurodegeneration in futscholk. A similar effect is obtained by expression of either fly or bovine tau, suggesting a certain degree of functional redundancy of MAPs. The futscholk mutants exhibit several characteristics of human neurodegenerative diseases, providing an opportunity to study the role of MAPs in progressive neurodegeneration within an experimentally accessible, in vivo model system. PMID:15772149

  3. Disruption of the MAP1B-related protein FUTSCH leads to changes in the neuronal cytoskeleton, axonal transport defects, and progressive neurodegeneration in Drosophila.

    Science.gov (United States)

    Bettencourt da Cruz, Alexandre; Schwärzel, Martin; Schulze, Sabine; Niyyati, Mahtab; Heisenberg, Martin; Kretzschmar, Doris

    2005-05-01

    The elaboration of neuronal axons and dendrites is dependent on a functional cytoskeleton. Cytoskeletal components have been shown to play a major role in the maintenance of the nervous system through adulthood, and changes in neurofilaments and microtubule-associated proteins (MAPs) have been linked to a variety of neurodegenerative diseases. Here we show that Futsch, the fly homolog of MAP1B, is involved in progressive neurodegeneration. Although Futsch is widely expressed throughout the CNS, degeneration in futsch(olk) primarily occurs in the olfactory system and mushroom bodies. Consistent with the predicted function of Futsch, we find abnormalities in the microtubule network and defects in axonal transport. Degeneration in the adult brain is preceded by learning deficits, revealing a neuronal dysfunction before detectable levels of cell death. Futsch is negatively regulated by the Drosophila Fragile X mental retardation gene, and a mutation in this gene delays the onset of neurodegeneration in futsch(olk). A similar effect is obtained by expression of either fly or bovine tau, suggesting a certain degree of functional redundancy of MAPs. The futsch(olk) mutants exhibit several characteristics of human neurodegenerative diseases, providing an opportunity to study the role of MAPs in progressive neurodegeneration within an experimentally accessible, in vivo model system.

  4. Hydrolysis-dependent absorption of disaccharides in the rat small intestine (chronic experiments and mathematical modeling).

    Science.gov (United States)

    Gromova, L V; Gruzdkov, A A

    1999-06-01

    In order to throw light on the mechanisms responsible for the enzyme-dependent absorption of disaccharides membrane hydrolysis of maltose and trehalose and the absorption of glucose (free and that derived from disaccharides) were studied in isolated loops (20 cm) of the rat small intestine in chronic experiments. The rates of glucose absorption were 0.26-0.81 micromol x min(-1) x cm(-1) when the loop was perfused with a 12.5 to 75.0 mmol/l free glucose solution, which is only insignificantly higher than the rates observed during perfusion with equivalent maltose solutions. The coupling coefficient (the ratio of glucose absorption rate to the rate of disaccharide hydrolysis) decreased from 0.90 to 0.60 with the increasing maltose concentrations in the infusate from 6.25 to 37.5 mmol/l, but remained unchanged (approximately 0.95) within the same range of trehalose concentrations. The permeability of the pre-epithelial barrier was equivalent to that of unstirred water layer of less than 40 microm thickness. Fluid absorption was within the range of 0.73-2.55 microl x min(-1) x cm(-1), and it showed a correlation with the rates of glucose absorption. The results agree with a model developed on the assumption that free glucose and that released from disaccharides share the same membrane transporters. It could be concluded that a close coupling of disaccharide hydrolysis with derived glucose absorption in chronic experiments is achieved mainly due to a high activity of glucose transporters, which are presumably not associated with membrane disaccharidases. The transcellular active transport is a predominant mechanism of disaccharide-derived glucose absorption under conditions close to physiological.

  5. EFFECTS OF RADIX ANGELICAE SINENSIS AND SHUANGHUANGLIAN ON A RAT MODEL OF CHRONIC PSEUDOMONAS AERUGINOSA PNEUMONIA

    Institute of Scientific and Technical Information of China (English)

    H.K.Johansen; C.Moser; V.Faber; A.Khamzmi; J.Rygaard; N.Hφiby; Z.J.Song

    2000-01-01

    Objective. To study the effects of two kinds of Chinese herbal medicine, Radix angelicae sinensis(RAS) (当归)and Shuanghuanglian(SHL)(双黄连) on chronic Pseudomortas aerug/nosa(PA)lung infection in a rat model mimicking cystic fibrosis(CF).Methods. Rats were divided into RAS, SIlL and control groups. All rats were challenged intratracheally with alginate embedded PA and the trealments with herbal medicine started on the same day of challenge. The drugs were administered subcutaneously once a day for ten days and the control group was treated with sterile saline. The rats were sacrificed two weeks after challenge. Results. Significantly improved lung bacterial clearance(P <0.05, P < 0.01) and milder macroecopic lung pathology (P<0.005) were found in the two treated groups compared to the control group. In tbe SHL treated group, the neutrophil percent in the peripheral blood leukocytes(P < 0.05), the anti-PA IgG level in serum (P < 0.05), the incidence of lung abscesses(P < 0.005) and the incidence of acnte lung inflammafion(P < 0.05) were signitlcanfly lower than in the control group. The RAS treatment reduced fever(P < 0.05), decreased the incidence of lung abscesses(P <0.005) and lung mast cell number (P< 0.05), and lowered anti-PA IgG1 level in serum(P< 0.05) when compared to the control group. The anti-PA bacterial activity test in SHL was weakly positive whereas in RAS it was negative. Conclusion. The treatment with both herbal medicines could increase the resistance of the rats against PA lung infection and they therefore might be potential premising drugs for stimulation of the immtme system in CF patients with chronic PA lung infection.

  6. Centering as a model for group visits among women with chronic pelvic pain.

    Science.gov (United States)

    Chao, Maria T; Abercrombie, Priscilla D; Duncan, Larissa G

    2012-01-01

    Providing comprehensive care for chronic pelvic pain is impeded by time and resource constraints of the standard health care visit. To provide patient education, psychosocial support, and health care assessment, we developed group visits for women with chronic pelvic pain using an evidence-based, holistic nursing approach. In this article, we describe the structure of group visits, the process of conducting Centering group visits focused on empowerment, and the content of a holistic curriculum for women with chronic pelvic pain.

  7. Modeling Red Blood Cell and Iron Dynamics in Patients with Chronic Kidney Disease

    Science.gov (United States)

    2012-02-10

    Abstract Chronic kidney disease causes a slow loss of kidney function over time and can even- tually lead to End Stage Renal Disease, where a patient must...AVAILABILITY STATEMENT Approved for public release; distribution unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Chronic kidney disease causes a slow...Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std Z39-18 1 Introduction It is estimated that 31 million Americans have chronic kidney disease ( CKD

  8. Assessment of a primary and tertiary care integrated management model for chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Peiro Meritxell

    2009-02-01

    Full Text Available Abstract Background The diagnosis and treatment of patients with chronic obstructive pulmonary disease (COPD in Spain continues to present challenges, and problems are exacerbated when there is a lack of coordinated follow-up between levels of care. This paper sets out the protocol for assessing the impact of an integrated management model for the care of patients with COPD. The new model will be evaluated in terms of 1 improvement in the rational utilization of health-care services and 2 benefits reflected in improved health status and quality of life for patients. Methods/Design A quasi-experimental study of the effectiveness of a COPD management model called COPD PROCESS. The patients in the study cohorts will be residents of neighborhoods served by two referral hospitals in Barcelona, Spain. One area comprises the intervention group (n = 32,248 patients and the other the control group (n = 32,114 patients. The study will include pre- and post-intervention assessment 18 months after the program goes into effect. Analyses will be on two datasets: clinical and administrative data available for all patients, and clinical assessment information for a cohort of 440 patients sampled randomly from the intervention and control areas. The main endpoints will be the hospitalization rates in the two health-care areas and quality-of-life measures in the two cohorts. Discussion The COPD PROCESS model foresees the integrated multidisciplinary management of interventions at different levels of the health-care system through coordinated routine clinical practice. It will put into practice diagnostic and treatment procedures that are based on current evidence, multidisciplinary consensus, and efficient use of available resources. Care pathways in this model are defined in terms of patient characteristics, level of disease severity and the presence or absence of exacerbation. The protocol covers the full range of care from primary prevention to treatment of

  9. The Chronic Care Model: A Collaborative Approach to Preventing and Treating Asthma in Infants and Young Children

    Science.gov (United States)

    Wessel, Lois; Spain, Jacqueline

    2005-01-01

    The authors that a collaborative approach between parents and professionals is the best way to care for a young child with asthma. They use Ed Wagner's transdisciplinary 1998 Chronic Care Model as their preferred method for collaboration. More than 5 million children in the U.S. are currently affected by asthma, and a growing body of evidence…

  10. Hepatitis E virus genotype three infection of human liver chimeric mice as a model for chronic HEV infection

    NARCIS (Netherlands)

    M.D.B. van de Garde (Martijn); S.D. Pas (Suzan); G. van der Net (Guido); R.A. de Man (Robert); A.D.M.E. Osterhaus (Albert); B.L. Haagmans (Bart); A. Boonstra (Andre); T. Vanwolleghem (Thomas)

    2016-01-01

    textabstractGenotype (gt) 3 hepatitis E virus (HEV) infections are emerging in Western countries. Immunosuppressed patients are at risk of chronic HEV infection and progressive liver damage, but no adequate model system currently mimics this disease course. Here we explore the possibilities of in vi

  11. Memory deficit associated with increased brain proinflammatory cytokine levels and neurodegeneration in acute ischemic stroke

    Directory of Open Access Journals (Sweden)

    Bruno Silva

    2015-08-01

    Full Text Available The present study aimed to investigate behavioral changes and neuroinflammatory process following left unilateral common carotid artery occlusion (UCCAO, a model of cerebral ischemia. Post-ischemic behavioral changes following 15 min UCCAO were recorded 24 hours after reperfusion. The novel object recognition task was used to assess learning and memory. After behavioral test, brains from sham and ischemic mice were removed and processed to evaluate central nervous system pathology by TTC and H&E techniques as well as inflammatory mediators by ELISA. UCCAO promoted long-term memory impairment after reperfusion. Infarct areas were observed in the cerebrum by TTC stain. Moreover, the histopathological analysis revealed cerebral necrotic cavities surrounded by ischemic neurons and hippocampal neurodegeneration. In parallel with memory dysfunction, brain levels of TNF-a, IL-1b and CXCL1 were increased post ischemia compared with sham-operated group. These findings suggest an involvement of central nervous system inflammatory mediators and brain damage in cognitive impairment following unilateral acute ischemia.

  12. Association between a genetic variant of type-1 cannabinoid receptor and inflammatory neurodegeneration in multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Silvia Rossi

    Full Text Available Genetic ablation of type-1 cannabinoid receptors (CB1Rs exacerbates the neurodegenerative damage of experimental autoimmune encephalomyelitis, the rodent model of multiple sclerosis (MS. To address the role on CB1Rs in the pathophysiology of human MS, we first investigated the impact of AAT trinucleotide short tandem repeat polymorphism of CNR1 gene on CB1R cell expression, and secondly on the inflammatory neurodegeneration process responsible for irreversible disability in MS patients. We found that MS patients with long AAT repeats within the CNR1 gene (≥12 in both alleles had more pronounced neuronal degeneration in response to inflammatory white matter damage both in the optic nerve and in the cortex. Optical Coherence Tomography (OCT, in fact, showed more severe alterations of the retinal nerve fiber layer (RNFL thickness and of the macular volume (MV after an episode of optic neuritis in MS patients carrying the long AAT genotype of CNR1. MS patients with long AAT repeats also had magnetic resonance imaging (MRI evidence of increased gray matter damage in response to inflammatory lesions of the white matter, especially in areas with a major role in cognition. In parallel, visual abilities evaluated at the low contrast acuity test, and cognitive performances were negatively influenced by the long AAT CNR1 genotype in our sample of MS patients. Our results demonstrate the biological relevance of the (AATn CNR1 repeats in the inflammatory neurodegenerative damage of MS.

  13. Phosphatidylinositol-glycan-phospholipase D is involved in neurodegeneration in prion disease.

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    Jae-Kwang Jin

    Full Text Available PrPSc is formed from a normal glycosylphosphatidylinositol (GPI-anchored prion protein (PrPC by a posttranslational modification. Most GPI-anchored proteins have been shown to be cleaved by GPI phospholipases. Recently, GPI-phospholipase D (GPI-PLD was shown to be a strictly specific enzyme for GPI anchors. To investigate the involvement of GPI-PLD in the processes of neurodegeneration in prion diseases, we examined the mRNA and protein expression levels of GPI-PLD in the brains of a prion animal model (scrapie, and in both the brains and cerebrospinal fluids (CSF of sporadic and familial Creutzfeldt-Jakob disease (CJD patients. We found that compared with controls, the expression of GPI-PLD was dramatically down-regulated in the brains of scrapie-infected mice, especially in the caveolin-enriched membrane fractions. Interestingly, the observed decrease in GPI-PLD expression levels began at the same time that PrPSc began to accumulate in the infected brains and this decrease was also observed in both the brain and CSF of CJD patients; however, no differences in expression were observed in either the brains or CSF specimens from Alzheimer's disease patients. Taken together, these results suggest that the down-regulation of GPI-PLD protein may be involved in prion propagation in the brains of prion diseases.

  14. Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus.

    Science.gov (United States)

    Sohn, Elliott H; van Dijk, Hille W; Jiao, Chunhua; Kok, Pauline H B; Jeong, Woojin; Demirkaya, Nazli; Garmager, Allison; Wit, Ferdinand; Kucukevcilioglu, Murat; van Velthoven, Mirjam E J; DeVries, J Hans; Mullins, Robert F; Kuehn, Markus H; Schlingemann, Reinier Otto; Sonka, Milan; Verbraak, Frank D; Abràmoff, Michael David

    2016-05-10

    Diabetic retinopathy (DR) has long been recognized as a microvasculopathy, but retinal diabetic neuropathy (RDN), characterized by inner retinal neurodegeneration, also occurs in people with diabetes mellitus (DM). We report that in 45 people with DM and no to minimal DR there was significant, progressive loss of the nerve fiber layer (NFL) (0.25 μm/y) and the ganglion cell (GC)/inner plexiform layer (0.29 μm/y) on optical coherence tomography analysis (OCT) over a 4-y period, independent of glycated hemoglobin, age, and sex. The NFL was significantly thinner (17.3 μm) in the eyes of six donors with DM than in the eyes of six similarly aged control donors (30.4 μm), although retinal capillary density did not differ in the two groups. We confirmed significant, progressive inner retinal thinning in streptozotocin-induced "type 1" and B6.BKS(D)-Lepr(db)/J "type 2" diabetic mouse models on OCT; immunohistochemistry in type 1 mice showed GC loss but no difference in pericyte density or acellular capillaries. The results suggest that RDN may precede the established clinical and morphometric vascular changes caused by DM and represent a paradigm shift in our understanding of ocular diabetic complications.

  15. O-GlcNAcylation: A regulator of tau pathology and neurodegeneration.

    Science.gov (United States)

    Gong, Cheng-Xin; Liu, Fei; Iqbal, Khalid

    2016-10-01

    O-GlcNAcylation is the posttranslational modification of intracellular proteins by O-linked β-N-acetylglucosamine (O-GlcNAc). The discovery of O-GlcNAc modification of tau and its impact on tau phosphorylation has attracted recent research interest in O-GlcNAc studies in the Alzheimer's disease (AD) field. Modification of proteins by O-GlcNAc occurs extensively in the brain. The expressions and activities of the enzymes catalyzing O-GlcNAc cycling are several-fold higher in the brain than in the peripheral tissues. The O-GlcNAcylation levels of brain proteins including tau are decreased in AD brain, probably due to decreased brain glucose metabolism. The reduction of brain O-GlcNAcylation appears to mediate the molecular mechanism by which decreased brain glucose metabolism contributes to neurodegeneration. Studies on mouse models of tauopathies suggest a neuroprotective role of pharmacological elevation of brain O-GlcNAc, which could potentially be a promising approach for treating AD and other neurodegenerative diseases.

  16. Protective effects of triptolide on retinal ganglion cells in a rat model of chronic glaucoma

    Directory of Open Access Journals (Sweden)

    Yang F

    2015-11-01

    Full Text Available Fan Yang, Dongmei Wang, Lingling Wu, Ying Li Ophthalmology Department, Peking University Third Hospital, Beijing, People’s Republic of China Purpose: To study the effects of triptolide, a Chinese herb extract, on retinal ganglion cells (RGCs in a rat model of chronic glaucoma.Methods: Eighty Wistar rats were randomly divided into triptolide group (n=40 and normal saline (NS group (n=40. Angle photocoagulation was used to establish the model of glaucoma, with right eye as laser treated eye and left eye as control eye. Triptolide group received triptolide intraperitoneally daily, while NS group received NS. Intraocular pressure (IOP, anti-CD11b immunofluorescent stain in retina and optic nerve, RGCs count with Nissel stain and microglia count with anti-CD11b immunofluorescence stain in retina flat mounts, retinal tumor necrosis factor (TNF-α mRNA detection by reverse transcription–polymerase chain reaction, and double immunofluorescent labeling with anti-TNF-α and anti-CD11b in retinal frozen section were performed.Results: Mean IOP of the laser treated eyes significantly increased 3 weeks after photocoagulation (P<0.05, with no statistical difference between the two groups (P>0.05. RGCs survival in the laser treated eyes was significantly improved in the triptolide group than the NS group (P<0.05. Microglia count in superficial retina of the laser treated eyes was significantly less in the triptolide group (30.40±4.90 than the NS group (35.06±7.59 (P<0.05. TNF-α mRNA expression in the retina of the laser treated eyes in the triptolide group decreased by 60% compared with that in the NS group (P<0.01. The double immunofluorescent labeling showed that TNF-α was mainly distributed around the microglia.Conclusion: Triptolide improved RGCs survival in this rat model of chronic glaucoma, which did not depend on IOP decrease but might be exerted by inhibiting microglia activities and reducing TNF-α secretion. Keywords: glaucoma, triptolide

  17. Multiple sclerosis deep grey matter: the relation between demyelination, neurodegeneration, inflammation and iron.

    Science.gov (United States)

    Haider, Lukas; Simeonidou, Constantina; Steinberger, Günther; Hametner, Simon; Grigoriadis, Nikolaos; Deretzi, Georgia; Kovacs, Gabor G; Kutzelnigg, Alexandra; Lassmann, Hans; Frischer, Josa M

    2014-12-01

    In multiple sclerosis (MS), diffuse degenerative processes in the deep grey matter have been associated with clinical disabilities. We performed a systematic study in MS deep grey matter with a focus on the incidence and topographical distribution of lesions in relation to white matter and cortex in a total sample of 75 MS autopsy patients and 12 controls. In addition, detailed analyses of inflammation, acute axonal injury, iron deposition and oxidative stress were performed. MS deep grey matter was affected by two different processes: the formation of focal demyelinating lesions and diffuse neurodegeneration. Deep grey matter demyelination was most prominent in the caudate nucleus and hypothalamus and could already be seen in early MS stages. Lesions developed on the background of inflammation. Deep grey matter inflammation was intermediate between low inflammatory cortical lesions and active white matter lesions. Demyelination and neurodegeneration were associated with oxidative injury. Iron was stored primarily within oligodendrocytes and myelin fibres and released upon demyelination. In addition to focal demyelinated plaques, the MS deep grey matter also showed diffuse and global neurodegeneration. This was reflected by a global reduction of neuronal density, the presence of acutely injured axons, and the accumulation of oxidised phospholipids and DNA in neurons, oligodendrocytes and axons. Neurodegeneration was associated with T cell infiltration, expression of inducible nitric oxide synthase in microglia and profound accumulation of iron. Thus, both focal lesions as well as diffuse neurodegeneration in the deep grey matter appeared to contribute to the neurological disabilities of MS patients.

  18. Diffusion tensor imaging detects chronic microstructural changes in white and grey matter after traumatic brain injury in rat

    Directory of Open Access Journals (Sweden)

    Teemu eLaitinen

    2015-04-01

    Full Text Available Traumatic brain injury (TBI is a major cause of disability and death in people of all ages worldwide. An initial brain injury caused by external mechanical forces triggers a cascade of tissue changes that lead to a wide spectrum of symptoms and disabilities, such as cognitive deficits, mood or anxiety disorders, motor impairments, chronic pain, and epilepsy. We investigated the detectability of secondary injury at a chronic time-point using ex vivo diffusion tensor imaging (DTI in a rat model of TBI, lateral fluid percussion injury. Our analysis of ex vivo DTI data revealed persistent microstructural tissue changes in white matter tracts, such as the splenium of the corpus callosum, angular bundle, and internal capsule. Histologic examination revealed mainly loss of myelinated axons and/or iron accumulation. Grey matter areas in the thalamus exhibited an increase in fractional anisotropy associated with neurodegeneration, myelinated fiber loss, and/or calcifications at the chronic phase. In addition, we examined whether these changes could also be detected with in vivo settings at the same chronic time-point. Our results provide insight into DTI detection of microstructural changes in the chronic phase of TBI, and elucidate how these changes correlate with cellular level alterations. These findings suggest that DTI could be a useful tool for detecting potential imaging biomarkers after TBI as indicators of progressive damage or recovery

  19. Modeling the oxygen uptake kinetics during exercise testing of patients with chronic obstructive pulmonary diseases using nonlinear mixed models

    Directory of Open Access Journals (Sweden)

    Florent Baty

    2016-06-01

    Full Text Available Abstract Background The six-minute walk test (6MWT is commonly used to quantify exercise capacity in patients with several cardio-pulmonary diseases. Oxygen uptake ( V ̇ $\\dot {\\mathrm {V}}$ O2 kinetics during 6MWT typically follow 3 distinct phases (rest, exercise, recovery that can be modeled by nonlinear regression. Simultaneous modeling of multiple kinetics requires nonlinear mixed models methodology. To the best of our knowledge, no such curve-fitting approach has been used to analyze multiple V ̇ $\\dot {\\mathrm {V}}$ O2 kinetics in both research and clinical practice so far. Methods In the present study, we describe functionality of the R package medrc that extends the framework of the commonly used packages drc and nlme and allows fitting nonlinear mixed effects models for automated nonlinear regression modeling. The methodology was applied to a data set including 6MWT V ̇ $\\dot {\\mathrm {V}}$ O2 kinetics from 61 patients with chronic obstructive pulmonary disease (disease severity stage II to IV. The mixed effects approach was compared to a traditional curve-by-curve approach. Results A six-parameter nonlinear regression model was jointly fitted to the set of V ̇ $\\dot {\\mathrm {V}}$ O2 kinetics. Significant differences between disease stages were found regarding steady state V ̇ $\\dot {\\mathrm {V}}$ O2 during exercise, V ̇ $\\dot {\\mathrm {V}}$ O2 level after recovery and V ̇ $\\dot {\\mathrm {V}}$ O2 inflection point in the recovery phase. Estimates obtained by the mixed effects approach showed standard errors that were consistently lower as compared to the curve-by-curve approach. Conclusions Hereby we demonstrate the novelty and usefulness of this methodology in the context of physiological exercise testing.

  20. Metformin prevents the development of chronic heart failure in the SHHF rat model.

    Science.gov (United States)

    Cittadini, Antonio; Napoli, Raffaele; Monti, Maria Gaia; Rea, Domenica; Longobardi, Salvatore; Netti, Paolo Antonio; Walser, Marion; Samà, Mariateresa; Aimaretti, Gianluca; Isgaard, Jörgen; Saccà, Luigi

    2012-04-01

    Insulin resistance is a recently identified mechanism involved in the pathophysiology of chronic heart failure (CHF). We investigated the effects of two insulin-sensitizing drugs (metformin and rosiglitazone) in a genetic model of spontaneously hypertensive, insulin-resistant rats (SHHF). Thirty SHHF rats were randomized into three treatment groups as follows: 1) metformin (100 mg/kg per day), 2) rosiglitazone (2 mg/kg per day), and 3) no drug. Ten Sprague-Dawley rats served as normal controls. At the end of the treatment period (12 months), the cardiac phenotype was characterized by histology, echocardiography, and isolated perfused heart studies. Metformin attenuated left ventricular (LV) remodeling, as shown by reduced LV volumes, wall stress, perivascular fibrosis, and cardiac lipid accumulation. Metformin improved both systolic and diastolic indices as well as myocardial mechanical efficiency, as shown by improved ability to convert metabolic energy into mechanical work. Metformin induced a marked activation of AMP-activated protein kinase, endothelial nitric oxide synthase, and vascular endothelial growth factor and reduced tumor necrosis factor-α expression and myocyte apoptosis. Rosiglitazone did not affect LV remodeling, increased perivascular fibrosis, and promoted further cardiac lipid accumulation. In conclusion, long-term treatment with metformin, but not with rosiglitazone, prevents the development of severe CHF in the SHHF model by a wide-spectrum interaction that involves molecular, structural, functional, and metabolic-energetic mechanisms.

  1. EVALUATION OF RAT MODEL OF CHRONIC GLAUCOMA BY LIGATING EPISCLERAL VEINS

    Institute of Scientific and Technical Information of China (English)

    ZHONG Yi-sheng; CAI Kang; CHENG Yu; JIAO Qin; LIU Xiao-hong; YAO Hui-ping; ZHOU Xiao-qing

    2009-01-01

    Objective To develop and evaluate the rat model of chronic glaucoma by episcleral veins ligation (EVL). Methods Experimental glaucoma was induced unilaterally in 28 male Sprague-Dawley rats by ligating two episcleral veins. Intraocular pressure (IOP) in rats was measured by a Goldmann applanation tonometer under 3% pentobarbital sodium anesthesia. The optic nerve head and retinal vasculature were assessed by repeated fundus examinations. The amount of optic nerve axons was assessed by Image-Pro Plus image analysis system in a masked fashion. Results IOP without EVL was (19.21±1.23)mmHg, whereas the EVL eyes gained about 1.8-fold higher IOP [(33.96±2.73)mmHg] after EVL immediately (P<0.001). The elevated IOP gradually decreased over time. However, the differences were kept significant up to 8 weeks after EVL. The IOP was reduced to similar levels as contralateral eyes at 12 and 16 weeks after EVL. The glaucomatous optic nerve excavation appeared in EVL eyes at 8 weeks after EVL, and the optic nerve excavation enlarged gradually with the increasing post-operation time. The amount of optic nerve axons also significantly decreased in EVL eyes at 8 weeks after EVL, and the amount of axons decreased gradually with the increasing post-operation time. Conclusion Increase of IOP caused by EVL represents a useful and efficient model of experimental glaucoma in rats.

  2. Acupuncture Treatment of Chronic Low Back Pain by Using the Jingjin (Meridian Sinews) Model.

    Science.gov (United States)

    Legge, David

    2015-10-01

    This case report details the unexpected and sustained relief from chronic low back pain in a patient after a single acupuncture treatment. The treatment administered on that occasion was based on the jingjin (i.e., "meridian sinew") model of traditional acupuncture. Treatments based on the jingjin model involve needling the ah shi (i.e., locally tender) points in myofascial tissue along the jingjin pathway. Tight chains can be needled to treat symptoms that are either close to or at some distance from the site of the needling treatment. In this patient, the points were in the gastrocnemius muscle and the hamstring muscles, which are part of the Bladder jingjin pathway. The patient, a 69-year-old woman, had had back pain for more than 40 years. The relief from the pain occurred within a day after the treatment and, at the time of this report, the relief has persisted for 5 months. This report examines two possible mechanisms for such a result: (1) a local increase in the extensibility of the hamstrings could be responsible or (2) the complex interactions within the central nervous system that are involved in acupuncture treatment could be more important factors.

  3. Analgesic effect of gabapentin in a rat model for chronic constrictive injury

    Institute of Scientific and Technical Information of China (English)

    MA Lu-lu; LIU Wei; HUANG Yu-guang; YANG Nan; ZUO Ping-ping

    2011-01-01

    Background Gabapentin has been widely and successfully used in the clinic for many neuropathic pain syndromes since last decade,however its analgesic mechanisms are still elusive.Our study was to investigate whether Ca2+/calmodulin-dependent protein kinase II (CaMKII) contributes to the analgesic effect of gabapentin on a chronic constriction injury (CCI) model.Methods Gabapentin (2%,100 mg/kg) or saline (0.5 mil100 g) was injected intraperitoneally 15 minutes prior to surgery and then every 12 hours from postoperative day 0-4 to all rats in control,sham and CCI groups.The analgesic effect of gabapentin was assessed by measuring mechanical allodynia and thermal hyperalgesia of rats.Expression and activation of CaMKII were quantified by reverse-transcriptional polymerase chain reaction and Western blotting.Results The analgesic effect of gabapentin on mechanical allodynia and thermal hyperalgesia was significant in the CCI model,with maximal reduction reached on postoperative day 8.Gabapentin decreased the expression of the total CaMKII and phosphorylated CaMKII in CCI rats.Conclusion The analgesic effect of gabapentin on CCI rats may be related to the decreased expression and phosphorylation of CaMKII in the spinal cord.

  4. Resistance to Recombinant Human Erythropoietin Therapy in a Rat Model of Chronic Kidney Disease Associated Anemia.

    Science.gov (United States)

    Garrido, Patrícia; Ribeiro, Sandra; Fernandes, João; Vala, Helena; Rocha-Pereira, Petronila; Bronze-da-Rocha, Elsa; Belo, Luís; Costa, Elísio; Santos-Silva, Alice; Reis, Flávio

    2015-12-25

    This study aimed to elucidate the mechanisms explaining the persistence of anemia and resistance to recombinant human erythropoietin (rHuEPO) therapy in a rat model of chronic kidney disease (CKD)-associated anemia with formation of anti-rHuEPO antibodies. The remnant kidney rat model of CKD induced by 5/6 nephrectomy was used to test a long-term (nine weeks) high dose of rHuEPO (200 UI/kg bw/week) treatment. Hematological and biochemical parameters were evaluated as well as serum and tissue (kidney, liver and/or duodenum) protein and/or gene expression of mediators of erythropoiesis, iron metabolism and tissue hypoxia, inflammation, and fibrosis. Long-term treatment with a high rHuEPO dose is associated with development of resistance to therapy as a result of antibodies formation. In this condition, serum EPO levels are not deficient and iron availability is recovered by increased duodenal absorption. However, erythropoiesis is not stimulated, and the resistance to endogenous EPO effect and to rHuEPO therapy results from the development of a hypoxic, inflammatory and fibrotic milieu in the kidney tissue. This study provides new insights that could be important to ameliorate the current therapeutic strategies used to treat patients with CKD-associated anemia, in particular those that become resistant to rHuEPO therapy.

  5. PROVANN: Model System for Chronic Exposure of Larval and Adult Fish to Releases from Offshore Petroleum Platforms

    Energy Technology Data Exchange (ETDEWEB)

    Reed, M.; Rye, H. [IKU Petroleumsforskning A/S, Trondheim (Norway); Melbye, A.; Johnsen, S.

    1996-12-31

    Produced water from offshore oil and gas production platforms contains a variety of hydrocarbons, heavy metals, and production chemicals. Vertical and horizontal mixing generally brings concentrations in discharge plumes below level associated with acute effects within 500 or 1000 m of the source. Chronic effects outside this region remain a potential problem. The purpose of PROVANN, the system of models described in this paper, is to assess the potential for chronic effects from produced water. The preliminary focus is on potential bioaccumulation and boimagnification of produced water constituents in the marine food web. Other possible types of chronic effects, such as reduced fecundity, or pheromone response interference, can also be assessed to the extent that such effects may be correlated with exposure. PROVANN simulates 3-dimensional transport, dilution, and degradation of chemicals released into the water, from one or more simultaneous sources. 8 refs., 10 figs., 3 tabs.

  6. Evidence against a stem cell origin of new hepatocytes in a common mouse model of chronic liver injury.

    Science.gov (United States)

    Schaub, Johanna R; Malato, Yann; Gormond, Coralie; Willenbring, Holger

    2014-08-21

    Hepatocytes provide most liver functions, but they can also proliferate and regenerate the liver after injury. However, under some liver injury conditions, particularly chronic liver injury where hepatocyte proliferation is impaired, liver stem cells (LSCs) are thought to replenish lost hepatocytes. Conflicting results have been reported about the identity of LSCs and their contribution to liver regeneration. To address this uncertainty, we followed candidate LSC populations by genetic fate tracing in adult mice with chronic liver injury due to a choline-deficient, ethionine-supplemented diet. In contrast to previous studies, we failed to detect hepatocytes derived from biliary epithelial cells or mesenchymal liver cells beyond a negligible frequency. In fact, we failed to detect hepatocytes that were not derived from pre-existing hepatocytes. In conclusion, our findings argue against LSCs, or other nonhepatocyte cell types, providing a backup system for hepatocyte regeneration in this common mouse model of chronic liver injury.

  7. Evidence against a Stem Cell Origin of New Hepatocytes in a Common Mouse Model of Chronic Liver Injury

    Directory of Open Access Journals (Sweden)

    Johanna R. Schaub

    2014-08-01

    Full Text Available Hepatocytes provide most liver functions, but they can also proliferate and regenerate the liver after injury. However, under some liver injury conditions, particularly chronic liver injury where hepatocyte proliferation is impaired, liver stem cells (LSCs are thought to replenish lost hepatocytes. Conflicting results have been reported about the identity of LSCs and their contribution to liver regeneration. To address this uncertainty, we followed candidate LSC populations by genetic fate tracing in adult mice with chronic liver injury due to a choline-deficient, ethionine-supplemented diet. In contrast to previous studies, we failed to detect hepatocytes derived from biliary epithelial cells or mesenchymal liver cells beyond a negligible frequency. In fact, we failed to detect hepatocytes that were not derived from pre-existing hepatocytes. In conclusion, our findings argue against LSCs, or other nonhepatocyte cell types, providing a backup system for hepatocyte regeneration in this common mouse model of chronic liver injury.

  8. Modelling population-level consequences of chronic external gamma irradiation in aquatic invertebrates under laboratory conditions

    Energy Technology Data Exchange (ETDEWEB)

    Lance, Emilie [Laboratoire de modelisation pour l' expertise environnementale (LM2E) Institut de Radioprotection et de Surete Nucleaire (IRSN), PRP-ENV, SERIS, Cadarache (France); Alonzo, Frederic, E-mail: frederic.alonzo@irsn.fr [Laboratoire d' ecotoxicologie des radionucleides (LECO) Institut de Radioprotection et de Surete Nucleaire (IRSN), PRP-ENV, SERIS, Cadarache (France); Garcia-Sanchez, Laurent [Laboratoire de biogeochimie, biodisponibilite et transferts des radionucleides (L2BT) Institut de Radioprotection et de Surete Nucleaire (IRSN), PRP-ENV, SERIS, Cadarache (France); Beaugelin-Seiller, Karine; Garnier-Laplace, Jacqueline [Laboratoire de modelisation pour l' expertise environnementale (LM2E) Institut de Radioprotection et de Surete Nucleaire (IRSN), PRP-ENV, SERIS, Cadarache (France)

    2012-07-01

    We modelled population-level consequences of chronic external gamma irradiation in aquatic invertebrates under laboratory conditions. We used Leslie matrices to combine life-history characteristics (duration of life stages, survival and fecundity rates) and dose rate-response curves for hatching, survival and reproduction fitted on effect data from the FREDERICA database. Changes in net reproductive rate R{sub 0} (offspring per individual) and asymptotic population growth rate {lambda} (dimensionless) were calculated over a range of dose rates in two marine polychaetes (Neanthes arenaceodentata and Ophryotrocha diadema) and a freshwater gastropod (Physa heterostropha). Sensitivities in R{sub 0} and {lambda} to changes in life-history traits were analysed in each species. Results showed that fecundity has the strongest influence on R{sub 0}. A delay in age at first reproduction is most critical for {lambda} independent of the species. Fast growing species were proportionally more sensitive to changes in individual endpoints than slow growing species. Reduction of 10% in population {lambda} were predicted at dose rates of 6918, 5012 and 74,131 {mu}Gy{center_dot}h{sup -1} in N. arenaceodentata, O. diadema and P. heterostropha respectively, resulting from a combination of strong effects on several individual endpoints in each species. These observations made 10%-reduction in {lambda} a poor criterion for population protection. The lowest significant changes in R{sub 0} and {lambda} were respectively predicted at a same dose rate of 1412 {mu}Gy h{sup -1} in N. arenaceodentata, at 760 and 716 {mu}Gy h{sup -1} in O. diadema and at 12,767 and 13,759 {mu}Gy h{sup -1} in P. heterostropha. These values resulted from a combination of slight but significant changes in several measured endpoints and were lower than effective dose rates calculated for the individual level in O. diadema and P. heterostropha. The relevance of the experimental dataset (external irradiation rather

  9. Neuroprotective Effect of Compound Anisodine in a Mouse Model with Chronic Ocular Hypertension

    Institute of Scientific and Technical Information of China (English)

    Wen-Dong Liu; Lan-Lan Chen; Ce-Ying Shen; Li-Bin Jiang

    2015-01-01

    Background:Compound anisodine (CA) is a compound preparation made from hydrobromide anisodine and procaine hydrochloride.The former is an M-choline receptor blocker with the function of regulating the vegetative nervous system,improving microcirculation,and so on.The latter is an antioxidant with the activities ofneuroprotection.This study aimed to investigate the potential neuroprotection of CA,which affects the degeneration of the retinal ganglion cells (RGCs) in an animal model with chronic ocular hypertension.Methods:Female C57BL/6J mice (n =24) were divided randomly into four groups:Normal control group without any treatment (Group A,n =6);CA control group with feeding the CA solution (Group B,n =6);microbeads (MBs) control group with injecting MB into the anterior chamber (Group C,n =6);CA study group with MB injection and with feeding the CA solution (Group D,n =6).Intraocular pressure (IOP) was measured every 3 days after MB injection.At the 21st day,neurons were retrograde-labeled by Fluoro-Gold (FG).Animals were sacrificed on the 27th day.Retinal flat mounts were stained immunohistologically by β-Ⅲ-tubulin.FG-retrograde-labeled RGCs,β-Ⅲ-tubulin-positive RGCs,and β-Ⅲ-tubulin-positive nerve fibers were quantified.Results:Mice of Groups C and D expressed the incidence of consistent IOP elevation,which is above the IOP level of Group A with the normal one.There is no significant difference in IOP between Groups A and B (P > 0.05).On the 27th day,there were distinct loss in stained RGCs and nerve fibers from Groups C and D compared with Group A (all P < 0.00l).The quantity was significantly higher in Group D as compared to Group C (all P < 0.00l) but lower than Group A (all P < 0.001).There was no significant difference in the quantity of RGCs and nerve fibers between Groups A and B (all P > 0.05).Conclusions:These findings suggest that CA plays an importantly neuroprotective role on RGCs in a mouse model with chronic ocular hypertension.

  10. Comparisons of neurodegeneration over time between healthy ageing and Alzheimer's disease cohorts via Bayesian inference

    Science.gov (United States)

    Mengersen, Kerrie

    2017-01-01

    Objectives In recent years, large-scale longitudinal neuroimaging studies have improved our understanding of healthy ageing and pathologies including Alzheimer's disease (AD). A particular focus of these studies is group differences and identification of participants at risk of deteriorating to a worse diagnosis. For this, statistical analysis using linear mixed-effects (LME) models are used to account for correlated observations from individuals measured over time. A Bayesian framework for LME models in AD is introduced in this paper to provide additional insight often not found in current LME volumetric analyses. Setting and participants Longitudinal neuroimaging case study of ageing was analysed in this research on 260 participants diagnosed as either healthy controls (HC), mild cognitive impaired (MCI) or AD. Bayesian LME models for the ventricle and hippocampus regions were used to: (1) estimate how the volumes of these regions change over time by diagnosis, (2) identify high-risk non-AD individuals with AD like degeneration and (3) determine probabilistic trajectories of diagnosis groups over age. Results We observed (1) large differences in the average rate of change of volume for the ventricle and hippocampus regions between diagnosis groups, (2) high-risk individuals who had progressed from HC to MCI and displayed similar rates of deterioration as AD counterparts, and (3) critical time points which indicate where deterioration of regions begins to diverge between the diagnosis groups. Conclusions To the best of our knowledge, this is the first application of Bayesian LME models to neuroimaging data which provides inference on a population and individual level in the AD field. The application of a Bayesian LME framework allows for additional information to be extracted from longitudinal studies. This provides health professionals with valuable information of neurodegeneration stages, and a potential to provide a better understanding of disease pathology

  11. Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration

    Directory of Open Access Journals (Sweden)

    Maria Emilia Figueiredo-Pereira

    2015-01-01

    Full Text Available The immune response of the CNS is a defense mechanism activated upon injury to initiate repair mechanisms while chronic over-activation of the CNS immune system (termed neuroinflammation may exacerbate injury. The latter is implicated in a variety of neurological and neurodegenerative disorders such as Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, HIV dementia and prion diseases. Cyclooxygenases (COX -1 and COX-2, which are key enzymes in the conversion of arachidonic acid into bioactive prostanoids, play a central role in the inflammatory cascade. J2 prostaglandins are endogenous toxic products of cyclooxygenases, and because their levels are significantly increased upon brain injury, they are actively involved in neuronal dysfunction induced by pro-inflammatory stimuli. In this review, we highlight the mechanisms by which J2 prostaglandins (1 exert their actions, (2 potentially contribute to the transition from acute to chronic inflammation and to the spreading of neuropathology, (3 disturb the ubiquitin-proteasome pathway and mitochondrial function, and (4 contribute to neurodegenerative disorders such as Alzheimer and Parkinson diseases, and amyotrophic lateral sclerosis, as well as stroke, traumatic brain injury, and demyelination in Krabbe disease. We conclude by discussing the therapeutic potential of targeting the J2 prostaglandin pathway to prevent/delay neurodegeneration associated with neuroinflammation. In this context, we suggest a shift from the traditional view that cyclooxygenases are the most appropriate targets to treat neuroinflammation, to the notion that J2 prostaglandin pathways and other neurotoxic prostaglandins downstream from cyclooxygenases, would offer significant benefits as more effective therapeutic targets to treat chronic neurodegenerative diseases, while minimizing adverse side effects.

  12. Drug discovery from Chinese medicine against neurodegeneration in Alzheimer's and vascular dementia

    Directory of Open Access Journals (Sweden)

    So Kwok-Fai

    2011-04-01

    Full Text Available Abstract Alzheimer's disease and vascular dementia are two major diseases associated with dementia, which is common among the elderly. While the etiology of dementia is multi-factorial and complex, neurodegeneration may be the major cause of these two diseases. Effective drugs for treating dementia are still to be discovered. Current western pharmacological approaches against neurodegeneration in dementia develop symptom-relieving and disease-modifying drugs. Current integrative and holistic approaches of Chinese medicine to discovering drugs for neurodegeneration in dementia include (1 single molecules from the herbs, (2 standardized extracts from a single herb, and (3 herbal formula with definite composition. This article not only reviews the concept of dementia in western medicine and Chinese medicine but also evaluates the advantages and disadvantages of these approaches.

  13. Role of bile acids, prostaglandins and COX inhibitors in chronic esophagitis in a mouse model

    Institute of Scientific and Technical Information of China (English)

    C Poplawski; D Sosnowski; A Szaflarska-Poplawska; J Sarosiek; R McCallum; Z Bartuzi

    2006-01-01

    33 %). In HCl/P/BA/INDO group the esophagitis surface was larger than that in not treated group (33%). In HCL/P group the surface of esophagus with ulceration was significantly larger (10-fold) than that in HCl/P/BA group. The PGE2 concentration was significantly higher in HCl/P group than in HCl/P/BA group.The PGE2 concentration in lower part of esophagus was also significantly higher in middle than those in HCl and HCl/P/BA groups. In upper part of esophagus the PGE2 concentration was significantly higher in HCl/P/BA group than that in group treated with indometacine (46%). We also observed higher PGE2 concentration in middle part of esophagus in HCl/P/BA group than those in group treated with indometacine and in group treated with indometacin and NS-398 (by 52% and 43% respectively).CONCLUSION: Pepsin is the pivotal factor in the development of chronic esophageal injury. Bile acids diminish chronic esophageal injury induced by HCl/P, indicating its potential negative impact on pepsin proteolytic potential,pivotal for mucosal injury in low pH. The role of selective COX inhibitors is still unclear, and needs more investigations. This novel chronic experimental esophagitis is an excellent model for further study on the role of cytokines in genetically modified animals.

  14. Uric acid metabolism of kidney and intestine in a rat model of chronic kidney disease.

    Science.gov (United States)

    Nagura, Michito; Tamura, Yoshifuru; Kumagai, Takanori; Hosoyamada, Makoto; Uchida, Shunya

    2016-12-01

    Uric acid (UA) is a potential risk factor of the progression of chronic kidney disease (CKD). Recently, we reported that intestinal UA excretion might be enhanced via upregulation of the ATP-binding cassette transporter G2 (Abcg2) in a 5/6 nephrectomy (Nx) rat model. In the present study, we examined the mRNA and protein expressions of UA transporters, URAT1, GLUT9/URATv1, ABCG2 and NPT4 in the kidney and ileum in the same rat model. Additionally, we investigated the Abcg2 mRNA expression of ileum in hyperuricemic rat model by orally administering oxonic acid. Male Wistar rats were randomly assigned to three groups consisting of Nx group, oxonic acid-treated (Ox) group and sham-operated control group, and sacrificed at 8 weeks. Creatinine and UA were measured and the mRNA expressions of UA transporters in the kidney and intestine were evaluated by a real time PCR. UA transporters in the kidney sections were also examined by immunohistochemistry. Serum creatinine elevated in the Nx group whereas serum UA increased in the Ox group. Both the mRNA expression and the immunohistochemistry of the UA transporters were decreased in the Nx group, suggesting a marginal role in UA elevation in decreased kidney function. In contrast, the mRNA expression of Abcg2 in the ileum significantly increased in the Ox group. These results suggest that the upregulation of Abcg2 mRNA in the ileum triggered by an elevation of serum UA may play a compensatory role in increasing intestinal UA excretion.

  15. An IL28B genotype-based clinical prediction model for treatment of chronic hepatitis C.

    Directory of Open Access Journals (Sweden)

    Thomas R O'Brien

    Full Text Available BACKGROUND: Genetic variation in IL28B and other factors are associated with sustained virological response (SVR after pegylated-interferon/ribavirin treatment for chronic hepatitis C (CHC. Using data from the HALT-C Trial, we developed a model to predict a patient's probability of SVR based on IL28B genotype and clinical variables. METHODS: HALT-C enrolled patients with advanced CHC who had failed previous interferon-based treatment. Subjects were re-treated with pegylated-interferon/ribavirin during trial lead-in. We used step-wise logistic regression to calculate adjusted odds ratios (aOR and create the predictive model. Leave-one-out cross-validation was used to predict a priori probabilities of SVR and determine area under the receiver operator characteristics curve (AUC. RESULTS: Among 646 HCV genotype 1-infected European American patients, 14.2% achieved SVR. IL28B rs12979860-CC genotype was the strongest predictor of SVR (aOR, 7.56; p10% (43.3% of subjects had an SVR rate of 27.9% and accounted for 84.8% of subjects actually achieving SVR. To verify that consideration of both IL28B genotype and clinical variables is required for treatment decisions, we calculated AUC values from published data for the IDEAL Study. CONCLUSION: A clinical prediction model based on IL28B genotype and clinical variables can yield useful individualized predictions of the probability of treatment success that could increase SVR rates and decrease the frequency of futile treatment among patients with CHC.

  16. PARP inhibition treatment in a nonconventional experimental mouse model of chronic asthma.

    Science.gov (United States)

    Zaffini, Raffaela; Di Paola, Rosanna; Cuzzocrea, Salvatore; Menegazzi, Marta

    2016-12-01

    Allergic asthma is an immunological disease that occurs as a consequence of aeroallergen exposure. Inhibition of poly(ADP-ribose) polymerases (PARPs) in conventional models of asthma-like reaction has emerged as an effective anti-inflammatory and airway remodeling intervention. In a house dust mite (HDM) exposure mouse model, we investigated the impact of PARP inhibition on allergic airway inflammation, sensitization, and remodeling. Mice were intranasally exposed to a HDM extract for 5 days per week for up to 5 weeks. Mice were administered, or not, by PARP inhibitors 3-aminobenzamide (3-ABA) or 5-aminoisoquinolinone (5-AIQ) during the last 2 weeks of HDM treatment. Mice treated with PARP inhibitors after HDM stimulation showed a significant decrease in the number of total cells and eosinophils detectable in the bronchoalveolar lavage fluid as compared with the HDM-stimulated ones. In vitro HDM-stimulated splenocyte culture produced considerable amounts of the Th2 cytokines that were not affected by treatment with PARP inhibitors. Immunoglobulin levels in the serum were also unchanged. In the lung tissue, collagen deposition was decreased, whereas α-smooth muscle actin thickening was not significantly affected. Moreover, in HDM-stimulated PARP inhibitor-treated groups, we found a downregulation in the activation of signal transducer and activator of trascription-6 (STAT-6) and a significant decrease in the mRNA levels of C-C motif chemokine 11 (CCL11). In this mouse model of chronic asthma PARP inhibition treatment, although it does not affect sensitization, it effectively reduces the allergic airway inflammation and affects the remodeling through a mechanism involving STAT6 and CCL11.

  17. Modeling routes of chronic wasting disease transmission: Environmental prion persistence promotes deer population decline and extinction

    Science.gov (United States)

    Almberg, Emily S.; Cross, Paul C.; Johnson, Christopher J.; Heisey, Dennis M.; Richards, Bryan J.

    2011-01-01

    Chronic wasting disease (CWD) is a fatal disease of deer, elk, and moose transmitted through direct, animal-to-animal contact, and indirectly, via environmental contamination. Considerable attention has been paid to modeling direct transmission, but despite the fact that CWD prions can remain infectious in the environment for years, relatively little information exists about the potential effects of indirect transmission on CWD dynamics. In the present study, we use simulation models to demonstrate how indirect transmission and the duration of environmental prion persistence may affect epidemics of CWD and populations of North American deer. Existing data from Colorado, Wyoming, and Wisconsin's CWD epidemics were used to define plausible short-term outcomes and associated parameter spaces. Resulting long-term outcomes range from relatively low disease prevalence and limited host-population decline to host-population collapse and extinction. Our models suggest that disease prevalence and the severity of population decline is driven by the duration that prions remain infectious in the environment. Despite relatively low epidemic growth rates, the basic reproductive number, R0, may be much larger than expected under the direct-transmission paradigm because the infectious period can vastly exceed the host's life span. High prion persistence is expected to lead to an increasing environmental pool of prions during the early phases (i.e. approximately during the first 50 years) of the epidemic. As a consequence, over this period of time, disease dynamics will become more heavily influenced by indirect transmission, which may explain some of the observed regional differences in age and sex-specific disease patterns. This suggests management interventions, such as culling or vaccination, will become increasingly less effective as CWD epidemics progress.

  18. Electron Transport Disturbances and Neurodegeneration: From Albert Szent-Györgyi’s Concept (Szeged till Novel Approaches to Boost Mitochondrial Bioenergetics

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    Levente Szalárdy

    2015-01-01

    Full Text Available Impaired function of certain mitochondrial respiratory complexes has long been linked to the pathogenesis of chronic neurodegenerative disorders such as Parkinson’s and Huntington’s diseases. Furthermore, genetic alterations of mitochondrial genome or nuclear genes encoding proteins playing essential roles in maintaining proper mitochondrial function can lead to the development of severe systemic diseases associated with neurodegeneration and vacuolar myelinopathy. At present, all of these diseases lack effective disease modifying therapy. Following a brief commemoration of Professor Albert Szent-Györgyi, a Nobel Prize laureate who pioneered in the field of cellular respiration, antioxidant processes, and the roles of free radicals in health and disease, the present paper overviews the current knowledge on the involvement of mitochondrial dysfunction in central nervous system diseases associated with neurodegeneration including Parkinson’s and Huntington’s disease as well as mitochondrial encephalopathies. The review puts special focus on the involvement and the potential therapeutic relevance of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α, a nuclear-encoded master regulator of mitochondrial biogenesis and antioxidant responses in these disorders, the transcriptional activation of which may hold novel therapeutic value as a more system-based approach aiming to restore mitochondrial functions in neurodegenerative processes.

  19. Electron Transport Disturbances and Neurodegeneration: From Albert Szent-Györgyi's Concept (Szeged) till Novel Approaches to Boost Mitochondrial Bioenergetics.

    Science.gov (United States)

    Szalárdy, Levente; Zádori, Dénes; Klivényi, Péter; Toldi, József; Vécsei, László

    2015-01-01

    Impaired function of certain mitochondrial respiratory complexes has long been linked to the pathogenesis of chronic neurodegenerative disorders such as Parkinson's and Huntington's diseases. Furthermore, genetic alterations of mitochondrial genome or nuclear genes encoding proteins playing essential roles in maintaining proper mitochondrial function can lead to the development of severe systemic diseases associated with neurodegeneration and vacuolar myelinopathy. At present, all of these diseases lack effective disease modifying therapy. Following a brief commemoration of Professor Albert Szent-Györgyi, a Nobel Prize laureate who pioneered in the field of cellular respiration, antioxidant processes, and the roles of free radicals in health and disease, the present paper overviews the current knowledge on the involvement of mitochondrial dysfunction in central nervous system diseases associated with neurodegeneration including Parkinson's and Huntington's disease as well as mitochondrial encephalopathies. The review puts special focus on the involvement and the potential therapeutic relevance of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), a nuclear-encoded master regulator of mitochondrial biogenesis and antioxidant responses in these disorders, the transcriptional activation of which may hold novel therapeutic value as a more system-based approach aiming to restore mitochondrial functions in neurodegenerative processes.

  20. COMMD1-deficient dogs accumulate copper in hepatocytes and provide a good model for chronic hepatitis and fibrosis.

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    Robert P Favier

    Full Text Available New therapeutic concepts developed in rodent models should ideally be evaluated in large animal models prior to human clinical application. COMMD1-deficiency in dogs leads to hepatic copper accumulation and chronic hepatitis representing a Wilson's disease like phenotype. Detailed understanding of the pathogenesis and time course of this animal model is required to test its feasibility as a large animal model for chronic hepatitis. In addition to mouse models, true longitudinal studies are possible due to the size of these dogs permitting detailed analysis of the sequence of events from initial insult to final cirrhosis. Therefore, liver biopsies were taken each half year from five new born COMMD1-deficient dogs over a period of 42 months. Biopsies were used for H&E, reticulin, and rubeanic acid (copper staining. Immunohistochemistry was performed on hepatic stellate cell (HSC activation marker (alpha-smooth muscle actin, α-SMA, proliferation (Ki67, apoptosis (caspase-3, and bile duct and liver progenitor cell (LPC markers keratin (K 19 and 7. Quantitative RT-PCR and Western Blots were performed on gene products involved in the regenerative and fibrotic pathways. Maximum copper accumulation was reached at 12 months of age, which coincided with the first signs of hepatitis. HSCs were activated (α-SMA from 18 months onwards, with increasing reticulin deposition and hepatocytic proliferation in later stages. Hepatitis and caspase-3 activity (first noticed at 18 months increased over time. Both HGF and TGF-β1 gene expression peaked at 24 months, and thereafter decreased gradually. Both STAT3 and c-MET showed an increased time-dependent activation. Smad2/3 phosphorylation, indicative for fibrogenesis, was present at all time-points. COMMD1-deficient dogs develop chronic liver disease and cirrhosis comparable to human chronic hepatitis, although at much higher pace. Therefore they represent a genetically-defined large animal model to test clinical

  1. The effect of sulindac, a non-steroidal anti-inflammatory drug, attenuates inflammation and fibrosis in a mouse model of chronic pancreatitis

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    Bai Han

    2012-08-01

    Full Text Available Abstract Background Chronic pancreatitis is characterized by progressive fibrosis, pain and loss of exocrine and endocrine functions. The long-standing chronic pancreatitis and its associated pancreatic fibrosis are the most common pathogenic events involved in human pancreatic carcinogenesis, but the therapeutic strategies to chronic pancreatitis and the chemoprevention of pancreatic carcinogenesis are very limited. Methods We investigated the effect of sulindac, a non-steroidal anti-inflammatory drug (NSAID, on inhibition of chronic pancreatitis in a caerulein induced chronic pancreatitis mouse model. Results Sulindac significantly reduced the severity of chronic pancreatitis including the extent of acini loss, inflammatory cell infiltration and stromal fibrosis. The protein expression of phosphorylation of MEK/ERK was inhibited in the chronic pancreatic tissues by sulindac treatment as measured by Western blot assay. The levels of inflammatory cytokines including TNF-α and MCP-1 were also significantly decreased with sulindac treatment, as well as the expression of TGF-β, PDGF-β, SHH and Gli in the chronic pancreatic tissue detected by qPCR assay and confirmed by western blot assay. The activation of pancreatic satellet cells was also inhibited by sulindac as measured by the activity of α-smooth muscle actin (α-SMA in the pancreatic tissue of chronic pancreatitis. Conclusions Sulindac is a promising reagent for the treatment of chronic pancreatitis via inhibition of inflammatory cell infiltration and stromal fibrosis, the inhibitory effect of sulindac on chronic pancreatitis may through targeting the activation ERK/MAPK signaling pathway.

  2. Effects of Shuyusan on monoamine neurotransmitters expression in a rat model of chronic stress-induced depression

    Institute of Scientific and Technical Information of China (English)

    Yuanyuan Zhang; Jianjun Jia; Liping Chen; Zhitao Han; Yulan Zhao; Honghong Zhang; Yazhuo Hu

    2011-01-01

    Shuyusan, a traditional Chinese medicine, was shown to improve depression symptoms and behavioral scores, as well as increase 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid, and 5-hydroxytryptophan levels, in a rat model of chronic stress-induced depression. However, dopamine, noradrenalin, and 3-methoxy-4-hydroxyphenylglycol expressions remained unchanged following Shuyusan treatment. Compared with the model group, the number of 5-HT-positive neurons in layers 4-5 of the frontal cortex, as well as hippocampal CA1 and CA3 regions, significantly increased following Shuyusan treatment. These results suggested that Shuyusan improved symptoms in a rat model of chronic stress-induced depression with mechanisms that involved 5-HT, 5-HT metabolite, 5-HT precursor expressions.

  3. Cannabinoid CB2 receptor-mediated anti-nociception in models of acute and chronic pain.

    Science.gov (United States)

    Jhaveri, Maulik D; Sagar, Devi R; Elmes, Steven J R; Kendall, David A; Chapman, Victoria

    2007-08-01

    The endocannabinoid system consists of cannabinoid CB(1) and CB(2) receptors, endogenous ligands and their synthesising/metabolising enzymes. Cannabinoid receptors are present at key sites involved in the relay and modulation of nociceptive information. The analgesic effects of cannabinoids have been well documented. The usefulness of nonselective cannabinoid agonists can, however, be limited by psychoactive side effects associated with activation of CB(1) receptors. Following the recent evidence for CB(2) receptors existing in the nervous system and reports of their up-regulation in chronic pain states and neurodegenerative diseases, much research is now aimed at shedding light on the role of the CB(2) receptor in human disease. Recent studies have demonstrated anti-nociceptive effects of selective CB(2) receptor agonists in animal models of pain in the absence of CNS side effects. This review focuses on the analgesic potential of CB(2) receptor agonists for inflammatory, post-operative and neuropathic pain states and discusses their possible sites and mechanisms of action.

  4. Optical coherence tomography (OCT) of a murine model of chronic kidney disease

    Science.gov (United States)

    Wang, Hsing-Wen; Guo, Hengchang; Andrews, Peter M.; Anderson, Erik; Chen, Y.

    2015-03-01

    Chronic Kidney Disease (CKD) is characterized by a progressive loss in renal function over time. Pathology can provide valuable insights into the progression of CKD by analyzing the status of glomeruli and the uriniferous tubules over time. Optical coherence tomography (OCT) is a new procedure that can analyze the microscopic structure of the kidney in a non-invasive manner. This is especially important because there are significant artifacts associated with excision biopsies and immersion fixation procedures. Recently, we have shown that OCT can provide real time images of kidney microstructure and Doppler OCT (DOCT) can image glomerular renal blood flow in vivo without administrating exogenous contrast agents. In this study, we used OCT to evaluate CKD in a model induced by intravenous Adriamycin injection into Munich-Wistar rats. We evaluated tubular density and tubular diameter from OCT images at several post- Adriamycin induction time points and compared them with conventional light microscopic histological imaging. Proteinurea and serum creatinine were used as physiological markers of the extent of CKD. Preliminary OCT results revealed changes in tubular density due to tubular necrosis and interstitial fibrosis within the first 4 weeks following Adriamycin injection. From week 4 to 8 after Adriamycin induction, changes in tubular density and diameter occurred due to both tubular loss and tubular dilation. The results suggest OCT can provide additional information about kidney histopathology in CKD. DOCT revealed reduced blood flow in some glomeruli probably as a consequence of focal glomerularsclerosis.

  5. Betaine reverses the memory impairments in a chronic cerebral hypoperfusion rat model.

    Science.gov (United States)

    Nie, Chunjie; Nie, Huijuan; Zhao, Yin; Wu, Jianzhao; Zhang, Xiaojian

    2016-02-26

    Vascular dementia (VaD) is the second reason for the cognitive decline in aged people, but the effective therapy is still missing. The chronic cerebral hypoperfusion (CCH) had been widely found in VaD patients and is thought to be the key reason for cognitive impairment. Betaine is a natural product that had been implicated in many biological processes and had been used for the therapy of some neurodegenerative disease, such as Alzheimer's disease. In this study, we reported that betaine treatment could rescue the memory deficits induced by two-vessel occlusion (2-VO), a widely used CCH rat model. Betaine also restored the expression of PSD93, PSD95 and MAP2 to preserve the synaptic functions. Furthermore, betaine could reduce the oxidative stress by suppressing the MDA and ROS and enhancing the SOD and GSH. Overall, betaine treatment is able to rescue the memory deficits in CCH rats, which provide an experimental basis for the therapy of VaD.

  6. Complement protein C3 exacerbates prion disease in a mouse model of chronic wasting disease.

    Science.gov (United States)

    Michel, Brady; Ferguson, Adam; Johnson, Theodore; Bender, Heather; Meyerett-Reid, Crystal; Wyckoff, A Christy; Pulford, Bruce; Telling, Glenn C; Zabel, Mark D

    2013-12-01

    Accumulating evidence shows a critical role of the complement system in facilitating attachment of prions to both B cells and follicular dendritic cells and assisting in prion replication. Complement activation intensifies disease in prion-infected animals, and elimination of complement components inhibits prion accumulation, replication and pathogenesis. Chronic wasting disease (CWD) is a highly infectious prion disease of captive and free-ranging cervid populations that utilizes the complement system for efficient peripheral prion replication and most likely efficient horizontal transmission. Here we show that complete genetic or transient pharmacological depletion of C3 prolongs incubation times and significantly delays splenic accumulation in a CWD transgenic mouse model. Using a semi-quantitative prion amplification scoring system we show that C3 impacts disease progression in the early stages of disease by slowing the rate of prion accumulation and/or replication. The delayed kinetics in prion replication correlate with delayed disease kinetics in mice deficient in C3. Taken together, these data support a critical role of C3 in peripheral CWD prion pathogenesis.

  7. Alterations of taurine in the brain of chronic kainic acid epilepsy model.

    Science.gov (United States)

    Baran, H

    2006-10-01

    The aim of the study was to investigate the changes of taurine in the kainic acid (KA, 10 mg/kg, s.c.) chronic model of epilepsy, six months after KA application. The KA-rats used were divided into a group of animals showing weak behavioural response to KA (WDS, rare focal convulsion; rating scale 3 up to 3 h after KA injection). The brain regions investigated were caudate nucleus, substantia nigra, septum, hippocampus, amygdala/piriform cortex, and frontal, parietal, temporal and occipital cortices. KA-rats with rating rats with rating >3 developed spontaneous recurrent seizures and six months after injection increased taurine levels were found in the caudate nucleus (162.5% of control) and hippocampus (126.6% of control), while reduced taurine levels were seen in the septum (78.2% of control). In summary, increased taurine levels in the hippocampus may involve processes for membrane stabilisation, thus favouring recovery after neuronal hyperactivity. The increased taurine levels in the caudate nucleus could be involved in the modulation of spontaneous recurrent seizure activity.

  8. Thiazolidinedione treatment inhibits bile duct proliferation and fibrosis in a rat model of chronic cholestasis

    Institute of Scientific and Technical Information of China (English)

    Fabio Marra; Carlo Spirli; Mario Strazzabosco; Massimo Pinzani; Maurizio Parola; Raffaella DeFranco; Gaia Robino; Erica Novo; Eva Efsen; Sabrina Pastacaldi; Elena Zamara; Alessandro Vercelli; Benedetta Lottini

    2005-01-01

    AIM: To investigate the effects of troglitazone (TGZ), an anti-diabetic drug which activates peroxisome proliferatoractivated receptor-γ (PPAR-γ), for liver tissue repair, and the development of ductular reaction, following common bile duct ligation (BDL) in rats.METHODS: Rats were supplemented with TGZ (0.2% w/w in the pelleted food) for 1 wk before BDL or sham operation.Animals were killed at 1, 2, or 4 wk after surgery.RESULTS: The development of liver fibrosis was reduced in rats receiving TGZ, as indicated by significant decreases of procollagen type Ⅰ gene expression and liver hydroxyproline levels. Accumulation of α-smooth-muscle actin (SMA)-expressing cells surrounding newly formed bile ducts following BDL, as well as total hepatic levels of SMA were partially inhibited by TGZ treatment, indicating the presence of a reduced number and/or activation of hepatic stellate cells (HSC) and myofibroblasts. Development of the ductular reaction was inhibited by TGZ, as indicated by histochemical evaluation and hepatic activity of γ-glutamyltransferase (GGT).CONCLUSION: Treatment with thiazolidinedione reduces ductular proliferation and fibrosis in a model of chronic cholestasis, and suggests that limiting cholangiocyte proliferation may contribute to the lower development of scarring in this system.

  9. Protective role of hydrogen sulfide against noise-induced cochlear damage: a chronic intracochlear infusion model.

    Directory of Open Access Journals (Sweden)

    Xu Li

    Full Text Available BACKGROUND: A reduction in cochlear blood flow plays an essential role in noise-induced hearing loss (NIHL. The timely regulation of cochlear perfusion determines the progression and prognosis of NIHL. Hydrogen sulfide (H(2S has attracted increasing interest as a vasodilator in cardiovascular systems. This study identified the role of H(2S in cochlear blood flow regulation and noise protection. METHODOLOGY/PRINCIPAL FINDINGS: The gene and protein expression of the H(2S synthetase cystathionine-γ-lyase (CSE in the rat cochlea was examined using immunofluorescence and real-time PCR. Cochlear CSE mRNA levels varied according to the duration of noise exposure. A chronic intracochlear infusion model was built and artificial perilymph (AP, NaHS or DL-propargylglycine (PPG were locally administered. Local sodium hydrosulfide (NaHS significantly increased cochlear perfusion post-noise exposure. Cochlear morphological damage and hearing loss were alleviated in the NaHS group as measured by conventional auditory brainstem response (ABR, cochlear scanning electron microscope (SEM and outer hair cell (OHC count. The highest percentage of OHC loss occurred in the PPG group. CONCLUSIONS/SIGNIFICANCE: Our results suggest that H(2S plays an important role in the regulation of cochlear blood flow and the protection against noise. Further studies may identify a new preventive and therapeutic perspective on NIHL and other blood supply-related inner ear diseases.

  10. The link between unpredictable chronic mild stress model for depression and vascular inflammation?

    Science.gov (United States)

    Demirtaş, Tuğçe; Utkan, Tijen; Karson, Ayşe; Yazır, Yusufhan; Bayramgürler, Dilek; Gacar, Nejat

    2014-10-01

    Inflammation has been suggested to be associated with stress-induced depression and cardiovascular dysfunction. Tumor necrosis factor alpha (TNF-α) is a major cytokine in the activation of neuroendocrine, immune, and behavioral responses. In this study, we investigated the effects of infliximab (a TNF-α inhibitor) on endothelium-dependent vascular reactivity, systemic blood pressure, and endothelial nitric oxide synthase (eNOS) immunoreactivity in the unpredictable chronic mild stress (UCMS) model of depression in rats. There was no significant change between all groups in the systemic blood pressure. In UCMS, endothelium-dependent relaxation of the smooth muscle in response to carbachol was significantly decreased with 50 % maximal response (E max) and pD2 values compared with the controls. Infliximab was able to reverse this UCMS effect. Relaxation in response to the nitric oxide (NO) donor sodium nitroprusside and papaverine and KCl-induced contractile responses was similar between groups. In UCMS, decreased expression of eNOS was detected. Moreover, there was no significant change in UCMS + infliximab group with respect to control rats. Our results suggest that tumor necrosis factor-alpha (TNF-α) could be a major mediator of vascular dysfunction associated with UCMS, leading to decreased expression of eNOS.

  11. Attachment Style and Chronic Pain: Toward an Interpersonal Model of Pain.

    Science.gov (United States)

    Romeo, Annunziata; Tesio, Valentina; Castelnuovo, Gianluca; Castelli, Lorys

    2017-01-01

    Chronic pain (CP) is a burdensome symptom. Different psychological models have been proposed to explain the role of psychological and social factors in developing and maintaining CP. Attachment, for example, is a psychological construct of possible relevance in CP. The first studies on the role of attachment in CP did not investigate the partner's psychological factors, thus neglecting the influence of the latter. The main aim of this mini-review was to examine the more recent literature investigating the relationship between CP and attachment style. In particular, whether or not more recent studies assessed the psychological variables of a patient's partner. The articles were selected from the Medline/PubMed database using the search terms "attachment" AND "pain"; "CP" AND "attachment style," which led to nine papers being identified. The results showed that, even though the key point was still the hypothesis that an insecure attachment style is associated with CP, in recent years researchers have focused on the possible psychological aspects mediating between attachment style and CP. In particular, worrying, coping strategies, catastrophizing and perceived spouse responses to pain behavior were taken into account. Only one study considered the role of the reciprocal influence of attachment style of both patient and partner, underlining the role of real significant others' responses to pain behaviors. In conclusion, the results of the present mini-review highlight how in recent years researchers have moved toward investigating those psychological aspects that could mediate the relationship between attachment and CP, while only partially evaluating the interpersonal perspective.

  12. The Liver-Brain Axis of Alcohol-Mediated Neurodegeneration: Role of Toxic Lipids

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    Suzanne M. de la Monte

    2009-07-01

    Full Text Available Alcohol abuse causes progressive toxicity and degeneration in liver and brain due to insulin resistance, which exacerbates oxidative stress and pro-inflammatory cytokine activation. Alcohol-induced steatohepatitis promotes synthesis and accumulation of ceramides and other toxic lipids that cause insulin resistance. Ceramides can readily cross the blood-brain barrier, and ceramide exposure causes neurodegeneration with insulin resistance and oxidative stress, similar to the effects of alcohol. Therefore, in addition to its direct neurotoxic effects, alcohol misuse establishes a liver-brain axis of neurodegeneration mediated by toxic lipid trafficking across the blood-brain barrier, leading to progressive white matter degeneration and cognitive impairment.

  13. Striatal dopamine transporter binding correlates with serum BDNF levels in patients with striatal dopaminergic neurodegeneration

    DEFF Research Database (Denmark)

    Ziebell, Morten; Khalid, Usman; Klein, Anders B

    2012-01-01

    Compelling evidence has shown, that neurotrophins responsible for the regulation of neuronal growth, survival, and differentiation are involved in neurodegenerative diseases. Whereas lower serum levels of brain derived neurotrophic factor (BDNF) have been observed in patients with Parkinson......'s disease, no studies have directly related the degree of striatal neurodegeneration of dopaminergic neurons (DA) with serum BDNF levels. In this study we examined the relationship between striatal neurodegeneration as determined with (123)I-PE2I-single photon emission computer tomography (SPECT) and serum...

  14. Interleukin-33 drives activation of alveolar macrophages and airway inflammation in a mouse model of acute exacerbation of chronic asthma.

    Science.gov (United States)

    Bunting, Melissa M; Shadie, Alexander M; Flesher, Rylie P; Nikiforova, Valentina; Garthwaite, Linda; Tedla, Nicodemus; Herbert, Cristan; Kumar, Rakesh K

    2013-01-01

    We investigated the role of interleukin-33 (IL-33) in airway inflammation in an experimental model of an acute exacerbation of chronic asthma, which reproduces many of the features of the human disease. Systemically sensitized female BALB/c mice were challenged with a low mass concentration of aerosolized ovalbumin for 4 weeks to induce chronic asthmatic inflammation and then received a single moderate-level challenge to trigger acute airway inflammation simulating an asthmatic exacerbation. The inflammatory response and expression of cytokines and activation markers by alveolar macrophages (AM) were assessed, as was the effect of pretreatment with a neutralizing antibody to IL-33. Compared to chronically challenged mice, AM from an acute exacerbation exhibited significantly enhanced expression of markers of alternative activation, together with enhanced expression of proinflammatory cytokines and of cell surface proteins associated with antigen presentation. In parallel, there was markedly increased expression of both mRNA and immunoreactivity for IL-33 in the airways. Neutralization of IL-33 significantly decreased both airway inflammation and the expression of proinflammatory cytokines by AM. Collectively, these data indicate that in this model of an acute exacerbation of chronic asthma, IL-33 drives activation of AM and has an important role in the pathogenesis of airway inflammation.

  15. Interleukin-33 Drives Activation of Alveolar Macrophages and Airway Inflammation in a Mouse Model of Acute Exacerbation of Chronic Asthma

    Directory of Open Access Journals (Sweden)

    Melissa M. Bunting

    2013-01-01

    Full Text Available We investigated the role of interleukin-33 (IL-33 in airway inflammation in an experimental model of an acute exacerbation of chronic asthma, which reproduces many of the features of the human disease. Systemically sensitized female BALB/c mice were challenged with a low mass concentration of aerosolized ovalbumin for 4 weeks to induce chronic asthmatic inflammation and then received a single moderate-level challenge to trigger acute airway inflammation simulating an asthmatic exacerbation. The inflammatory response and expression of cytokines and activation markers by alveolar macrophages (AM were assessed, as was the effect of pretreatment with a neutralizing antibody to IL-33. Compared to chronically challenged mice, AM from an acute exacerbation exhibited significantly enhanced expression of markers of alternative activation, together with enhanced expression of proinflammatory cytokines and of cell surface proteins associated with antigen presentation. In parallel, there was markedly increased expression of both mRNA and immunoreactivity for IL-33 in the airways. Neutralization of IL-33 significantly decreased both airway inflammation and the expression of proinflammatory cytokines by AM. Collectively, these data indicate that in this model of an acute exacerbation of chronic asthma, IL-33 drives activation of AM and has an important role in the pathogenesis of airway inflammation.

  16. Behavioral Abnormalities in a Mouse Model of Chronic Toxoplasmosis Are Associated with MAG1 Antibody Levels and Cyst Burden.

    Science.gov (United States)

    Xiao, Jianchun; Li, Ye; Prandovszky, Emese; Kannan, Geetha; Viscidi, Raphael P; Pletnikov, Mikhail V; Yolken, Robert H

    2016-04-01

    There is marked variation in the human response to Toxoplasma gondii infection. Epidemiological studies indicate associations between strain virulence and severity of toxoplasmosis. Animal studies on the pathogenic effect of chronic infection focused on relatively avirulent strains (e.g. type II) because they can easily establish latent infections in mice, defined by the presence of bradyzoite-containing cysts. To provide insight into virulent strain-related severity of human toxoplasmosis, we established a chronic model of the virulent type I strain using outbred mice. We found that type I-exposed mice displayed variable outcomes ranging from aborted to severe infections. According to antibody profiles, we found that most of mice generated antibodies against T. gondii organism but varied greatly in the production of antibodies against matrix antigen MAG1. There was a strong correlation between MAG1 antibody level and brain cyst burden in chronically infected mice (r = 0.82, p = 0.0021). We found that mice with high MAG1 antibody level displayed lower weight, behavioral changes, altered levels of gene expression and immune activation. The most striking change in behavior we discovered was a blunted response to amphetamine-trigged locomotor activity. The extent of most changes was directly correlated with levels of MAG1 antibody. These changes were not found in mice with less cyst burden or mice that were acutely but not chronically infected. Our finding highlights the critical role of cyst burden in a range of disease severity during chronic infection, the predictive value of MAG1 antibody level to brain cyst burden and to changes in behavior or other pathology in chronically infected mice. Our finding may have important implications for understanding the heterogeneous effects of T. gondii infections in human.

  17. Complement C3-Deficiency Leads to Accelerated Aβ Plaque Deposition and Neurodegeneration, and Modulation of the Microglia/Macrophage Phenotype in APP Transgenic Mice

    OpenAIRE

    Maier, Marcel; Peng, Ying; Jiang, Liying; Seabrook, Timothy J.; Carroll, Michael C.; Lemere, Cynthia A.

    2008-01-01

    Complement factor C3 is the central component of the complement system and a key inflammatory protein activated in Alzheimer's disease (AD). Previous studies demonstrated that inhibition of C3 by overexpression of sCrry in an AD mouse model led to reduced microgliosis, increased Aβ plaque burden and neurodegeneration. To further address the role of C3 in AD pathology, we generated a complement C3-deficient APP transgenic AD mouse model (APP;C3−/−). Brains were analyzed at 8, 12 and 17 months ...

  18. Scale-dependent approaches to modeling spatial epidemiology of chronic wasting disease.

    Science.gov (United States)

    Conner, Mary M.; Gross, John E.; Cross, Paul C.; Michael R, Ebinger; Gillies, Robert; Samuel, Michael D.; Miller, Michael W.

    2007-01-01

    This e-book is the product of a second workshop that was funded and promoted by the United States Geological Survey to enhance cooperation between states for the management of chronic wasting disease (CWD). The first workshop addressed issues surrounding the statistical design and collection of surveillance data for CWD. The second workshop, from which this document arose, followed logically from the first workshop and focused on appropriate methods for analysis, interpretation, and use of CWD surveillance and related epidemiology data. Consequently, the emphasis of this e-book is on modeling approaches to describe and gain insight of the spatial epidemiology of CWD. We designed this e-book for wildlife managers and biologists who are responsible for the surveillance of CWD in their state or agency. We chose spatial methods that are popular or common in the spatial epidemiology literature and evaluated them for their relevance to modeling CWD. Our opinion of the usefulness and relevance of each method was based on the type of field data commonly collected as part of CWD surveillance programs and what we know about CWD biology, ecology, and epidemiology. Specifically, we expected the field data to consist primarily of the infection status of a harvested or culled sample along with its date of collection (not date of infection), location, and demographic status. We evaluated methods in light of the fact that CWD does not appear to spread rapidly through wild populations, relative to more highly contagious viruses, and can be spread directly from animal to animal or indirectly through environmental contamination.

  19. The chronic care model versus disease management programs: a transaction cost analysis approach.

    Science.gov (United States)

    Leeman, Jennifer; Mark, Barbara

    2006-01-01

    The present article applies transaction cost analysis as a framework for better understanding health plans' decisions to improve chronic illness management by using disease management programs versus redesigning care within physician practices.

  20. Different susceptibility to neurodegeneration of dorsal and ventral hippocampal dentate gyrus: a study with transgenic mice overexpressing GSK3β.

    Directory of Open Access Journals (Sweden)

    Almudena Fuster-Matanzo

    Full Text Available Dorsal hippocampal regions are involved in memory and learning processes, while ventral areas are related to emotional and anxiety processes. Hippocampal dependent memory and behaviour alterations do not always come out in neurodegenerative diseases at the same time. In this study we have tested the hypothesis that dorsal and ventral dentate gyrus (DG regions respond in a different manner to increased glycogen synthase kinase-3β (GSK3β levels in GSK3β transgenic mice, a genetic model of neurodegeneration. Reactive astrocytosis indicate tissue stress in dorsal DG, while ventral area does not show that marker. These changes occurred with a significant reduction of total cell number and with a significantly higher level of cell death in dorsal area than in ventral one as measured by fractin-positive cells. Biochemistry analysis showed higher levels of phosphorylated GSK3β in those residues that inactivate the enzyme in hippocampal ventral areas compared with dorsal area suggesting that the observed susceptibility is in part due to different GSK3 regulation. Previous studies carried out with this animal model had demonstrated impairment in Morris Water Maze and Object recognition tests point out to dorsal hippocampal atrophy. Here, we show that two tests used to evaluate emotional status, the light-dark box and the novelty suppressed feeding test, suggest that GSK3β mice do not show any anxiety-related disorder. Thus, our results demonstrate that in vivo overexpression of GSK3β results in dorsal but not ventral hippocampal DG neurodegeneration and suggest that both areas do not behave in a similar manner in neurodegenerative processes.

  1. Interleukin-4 Protects Dopaminergic Neurons In vitro but Is Dispensable for MPTP-Induced Neurodegeneration In vivo

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    Hühner, Laura; Rilka, Jennifer; Gilsbach, Ralf; Zhou, Xiaolai; Machado, Venissa; Spittau, Björn

    2017-01-01

    Microglia are involved in physiological as well as neuropathological processes in the central nervous system (CNS). Their functional states are often referred to as M1-like and M2-like activation, and are believed to contribute to neuroinflammation-mediated neurodegeneration or neuroprotection, respectively. Parkinson’s disease (PD) is one the most common neurodegenerative disease and is characterized by the progressive loss of midbrain dopaminergic (mDA) neurons in the substantia nigra resulting in bradykinesia, tremor, and rigidity. Interleukin 4 (IL4)-mediated M2-like activation of microglia, which is characterized by upregulation of alternative markers Arginase 1 (Arg1) and Chitinase 3 like 3 (Ym1) has been well studied in vitro but the role of endogenous IL4 during CNS pathologies in vivo is not well understood. Interestingly, microglia activation by IL4 has been described to promote neuroprotective and neurorestorative effects, which might be important to slow the progression of neurodegenerative diseases. In the present study, we addressed the role of endogenous and exogenous IL4 during MPP+-induced degeneration of mDA neurons in vitro and further addressed the impact of IL4-deficiency on neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD in vivo. Our results clearly demonstrate that exogenous IL4 is important to protect mDA neurons in vitro, but endogenous IL4 seems to be dispensable for development and maintenance of the nigrostriatal system as well as MPTP-induced loss of TH+ neurons in vivo. These results underline the importance of IL4 in promoting a neuroprotective microglia activation state and strengthen the therapeutic potential of exogenous IL4 for protection of mDA neurons in PD models. PMID:28337124

  2. Protective effects of isolated polyphenolic and alkaloid fractions of Ruta graveolens L. on acute and chronic models of inflammation.

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    Ratheesh, M; Shyni, G L; Sindhu, G; Helen, A

    2010-02-01

    Ruta graveolens L. (Rutaceae) are traditionally used for the treatment of rheumatism, arthritis and other inflammatory conditions in the traditional medicine of India, were evaluated for their protective effect in acute and chronic models of inflammation. Carrageenan induced rat paw edema and adjuvant induced arthritis were employed as the experimental models of acute and chronic inflammation respectively. Isolated polyphenolic and alkaloid fraction (AFR) from Ruta graveolens and evaluated its anti inflammatory activity in carrageenan induced acute model. AFR with a dose 10 mg/kg showed higher anti inflammatory effect than polyphenols and standard drug diclofenec. AFR significantly decreased the paw edema in arthritic rats. TBARS, COX-2, 5-LOX and MPO level were decreased and the levels of antioxidant enzymes and GSH level were increased on treatment with AFR. The increment in CRP level and ceruloplasmin level observed in arthritic animals were also found to be significantly restored in AFR treated rats. The results demonstrated the potential beneficiary effect of isolated polyphenolic and alkaloid fraction of Ruta graveolens L. on acute and chronic models of inflammation in rats.

  3. Quantitative Modeling of Microbial Population Responses to Chronic Irradiation Combined with Other Stressors.

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    Igor Shuryak

    Full Text Available Microbial population responses to combined effects of chronic irradiation and other stressors (chemical contaminants, other sub-optimal conditions are important for ecosystem functioning and bioremediation in radionuclide-contaminated areas. Quantitative mathematical modeling can improve our understanding of these phenomena. To identify general patterns of microbial responses to multiple stressors in radioactive environments, we analyzed three data sets on: (1 bacteria isolated from soil contaminated by nuclear waste at the Hanford site (USA; (2 fungi isolated from the Chernobyl nuclear-power plant (Ukraine buildings after the accident; (3 yeast subjected to continuous γ-irradiation in the laboratory, where radiation dose rate and cell removal rate were independently varied. We applied generalized linear mixed-effects models to describe the first two data sets, whereas the third data set was amenable to mechanistic modeling using differential equations. Machine learning and information-theoretic approaches were used to select the best-supported formalism(s among biologically-plausible alternatives. Our analysis suggests the following: (1 Both radionuclides and co-occurring chemical contaminants (e.g. NO2 are important for explaining microbial responses to radioactive contamination. (2 Radionuclides may produce non-monotonic dose responses: stimulation of microbial growth at low concentrations vs. inhibition at higher ones. (3 The extinction-defining critical radiation dose rate is dramatically lowered by additional stressors. (4 Reproduction suppression by radiation can be more important for determining the critical dose rate, than radiation-induced cell mortality. In conclusion, the modeling approaches used here on three diverse data sets provide insight into explaining and predicting multi-stressor effects on microbial communities: (1 the most severe effects (e.g. extinction on microbial populations may occur when unfavorable environmental

  4. Chronic leucine supplementation improves glycemic control in etiologically distinct mouse models of obesity and diabetes mellitus

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    Hou Jue

    2010-07-01

    Full Text Available Abstract Background Leucine may function as a signaling molecule to regulate metabolism. We have previously shown that dietary leucine supplementation significantly improves glucose and energy metabolism in diet-induced obese mice, suggesting that leucine supplementation could potentially be a useful adjuvant therapy for obesity and type 2 diabetes. Since the underlying cause for obesity and type 2 diabetes is multifold, we further investigated metabolic effects of leucine supplementation in obese/diabetes mouse models with different etiologies, and explored the underlying molecular mechanisms. Methods Leucine supplementation was carried out in NONcNZO10/LtJ (RCS10 - a polygenic model predisposed to beta cell failure and type 2 diabetes, and in B6.Cg-Ay/J (Ay - a monogenic model for impaired central melanocortin receptor signaling, obesity, and severe insulin resistance. Mice in the treatment group received the drinking water containing 1.5% leucine for up to 8 months; control mice received the tap water. Body weight, body composition, blood HbA1c levels, and plasma glucose and insulin levels were monitored throughout and/or at the end of the study period. Indirect calorimetry, skeletal muscle gene expression, and adipose tissue inflammation were also assessed in Ay mice. Results Leucine supplementation significantly reduced HbA1c levels throughout the study period in both RCS10 and Ay mice. However, the treatment had no long term effect on body weight or adiposity. The improvement in glycemic control was associated with an increased insulin response to food challenge in RCS10 mice and decreased plasma insulin levels in Ay mice. In leucine-treated Ay mice, energy expenditure was increased by ~10% (p y mice whereas the expression levels of MCP-1 and TNF-alpha and macrophage infiltration in adipose tissue were significantly reduced. Conclusions Chronic leucine supplementation significantly improves glycemic control in multiple mouse models of

  5. Modelling Estimates of Norovirus Disease in Patients with Chronic Medical Conditions

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    Thomas Verstraeten; Baoguo Jiang; John G Weil; Lin, Jennifer H.

    2016-01-01

    Background The burden of disease due to norovirus infection has been well described in the general United States population, but studies of norovirus occurrence among persons with chronic medical conditions have been limited mostly to the immunocompromised. We assessed the impact of norovirus gastroenteritis on health care utilization in US subjects with a range of chronic medical conditions. Methods We performed a retrospective cohort study using MarketScan data from July 2002 to December 20...

  6. Multivariate profiling of neurodegeneration-associated changes in a subcellular compartment of neurons via image processing

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    Kumarasamy Saravana K

    2008-11-01

    differentiates all three bchs phenotypes (loss of function as well as overexpression from the wild type. Conclusion Our model demonstrates that neurodegeneration-associated endolysosomal defects can be detected, analyzed, and classified rapidly and accurately as a diagnostic imaging-based screening tool.

  7. Reciprocal learning and chronic care model implementation in primary care: results from a new scale of learning in primary care

    Directory of Open Access Journals (Sweden)

    Noël Polly H

    2011-02-01

    Full Text Available Abstract Background Efforts to improve the care of patients with chronic disease in primary care settings have been mixed. Application of a complex adaptive systems framework suggests that this may be because implementation efforts often focus on education or decision support of individual providers, and not on the dynamic system as a whole. We believe that learning among clinic group members is a particularly important attribute of a primary care clinic that has not yet been well-studied in the health care literature, but may be related to the ability of primary care practices to improve the care they deliver. To better understand learning in primary care settings by developing a scale of learning in primary care clinics based on the literature related to learning across disciplines, and to examine the association between scale responses and chronic care model implementation as measured by the Asses