Effect of MK-801 on methamphetamine-induced dopaminergic neurotoxicity: long-term attenuation of methamphetamine-induced dopamine release

International Nuclear Information System (INIS)

Kim, Sang Eun; Kim, Yu Ri; Hwang, Se Hwan

2001-01-01

Repeated administration of methamphetamine (METH) produces high extracellular levels of dopamine (DA) and subsequent striatal DA terminal damage. The effect of MK-801, a noncompetitive N-methyl-D-aspartate receptor antagonist, on METH-induced changes in DA transporter (DAT) and DA release evoked by an acute METH challenge was evaluated in rodent striatum using [ 3 H] WIN 38,428 ex vivo auto-radiography and in vivo microdialysis. Four injections of METH (10 mg/kg, i.p.), each given 2 h apart, produced 71% decrease in DAT levels in mouse striatum 3 d after administration. Pretreatment with MK-801 (2.5 g/kg, i.p.) 15 min before each of the four METH injections protected completely against striatal DAT depletions. Four injections of MK-801 alone did not significantly change striatal DAT levels. Striatal DA release evoked by an acute METH challenge (4mg/kg, i.p.) at 3 d after repeated administration of METH in rats was decreased but significant compared with controls, which was attenuated by repeated pretreatment with MK-801. Also, repeated injections of MK-801 alone attenuated acute METH-induced striatal DA release 3 d after administration. These results suggest that repeated administration of MK-801 may exert a preventive effect against METH-induced DA terminal injury through long-term attenuation of DA release induced by METH and other stimuli

Effect of MK-801 on the development of nicotine sensitization of nucleus accumbens dopamine release

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Hong, Soo Kyung; Choung, In Soon; Kim, Sang Eun [Seoul National University College of Medicine, Seoul (Korea, Republic of)

2005-07-01

We have previously found that MK-801, a noncompetitive NMDA receptor antagonist, prevents behavioral sensitization to nicotine. This study aimed to investigate the effect of MK-801 on a neurochemical component of nicotine sensitization by evaluating the effect of the drug on nicotine sensitization of nucleus accumbens dopamine (DA) release. Sprague-Dawley rats were pretreated with MK-801 (0.3 mg/kg, i.p.) or saline 30 min before injection of nicotine (0.4 mg/kg, s.c., once daily) for 7 consecutive days. Twenty-four hours after the last drug injection, animals were challenged with local perfusion of 5 mM nicotine into the shell of nucleus accumbens and DA release was monitored using in vivo microdialysis. In rats pretreated with chronic nicotine, local nicotine challenge induced a greater increase of accumbal DA release than in saline-treated animals (maximal DA response 969 {+-} 235% (mean {+-} SEM) of basal level vs. 520 {+-} 93%, P < 0.05). Co-administration of MK-801 with nicotine attenuated an increase of DA release elicited by local nicotine challenge, compared with nicotine alone (maximal DA response 427 {+-} 83% of basal level vs. 969 {+-} 235%, P < 0.01). These results suggest that MK-801 blocks the development of nicotine sensitization of nucleus accumbens DA release, further supporting the involvement of NMDA receptors in the development of behavioral sensitization to nicotine.

Olanzapine Reverses MK-801-Induced Cognitive Deficits and Region-Specific Alterations of NMDA Receptor Subunits

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Liu, Xiao; Li, Jitao; Guo, Chunmei; Wang, Hongli; Sun, Yaxin; Wang, Han; Su, Yun-Ai; Li, Keqing; Si, Tianmei

2018-01-01

Cognitive dysfunction constitutes an essential component in schizophrenia for its early presence in the pathophysiology of the disease and close relatedness to life quality of patients. To develop effective treatment of cognitive deficits, it is important to understand their neurobiological causes and to identify potential therapeutic targets. In this study, adopting repeated MK-801 treatment as an animal model of schizophrenia, we investigated whether antipsychotic drugs, olanzapine and haloperidol, can reverse MK-801-induced cognitive deficits and how the reversal processes recruited proteins involved in glutamate neurotransmission in rat medial prefrontal cortex (mPFC) and hippocampus. We found that low-dose chronic MK-801 treatment impaired object-in-context recognition memory and reversal learning in the Morris water maze, leaving reference memory relatively unaffected, and that these cognitive deficits can be partially reversed by olanzapine, not haloperidol, treatment. At the molecular level, chronic MK-801 treatment resulted in the reduction of multiple N-methyl-D-aspartate (NMDA) receptor subunits in rat mPFC and olanzapine, not haloperidol, treatment restored the levels of GluN1 and phosphorylated GluN2B in this region. Taken together, MK-801-induced cognitive deficits may be associated with region-specific changes in NMDA receptor subunits and the reversal of specific NMDA receptor subunits may underlie the cognition-enhancing effects of olanzapine. PMID:29375333

Effect of MK-801 on the development of nicotine sensitization of nucleus accumbens dopamine release

International Nuclear Information System (INIS)

Hong, Soo Kyung; Choung, In Soon; Kim, Sang Eun

2005-01-01

We have previously found that MK-801, a noncompetitive NMDA receptor antagonist, prevents behavioral sensitization to nicotine. This study aimed to investigate the effect of MK-801 on a neurochemical component of nicotine sensitization by evaluating the effect of the drug on nicotine sensitization of nucleus accumbens dopamine (DA) release. Sprague-Dawley rats were pretreated with MK-801 (0.3 mg/kg, i.p.) or saline 30 min before injection of nicotine (0.4 mg/kg, s.c., once daily) for 7 consecutive days. Twenty-four hours after the last drug injection, animals were challenged with local perfusion of 5 mM nicotine into the shell of nucleus accumbens and DA release was monitored using in vivo microdialysis. In rats pretreated with chronic nicotine, local nicotine challenge induced a greater increase of accumbal DA release than in saline-treated animals (maximal DA response 969 ± 235% (mean ± SEM) of basal level vs. 520 ± 93%, P < 0.05). Co-administration of MK-801 with nicotine attenuated an increase of DA release elicited by local nicotine challenge, compared with nicotine alone (maximal DA response 427 ± 83% of basal level vs. 969 ± 235%, P < 0.01). These results suggest that MK-801 blocks the development of nicotine sensitization of nucleus accumbens DA release, further supporting the involvement of NMDA receptors in the development of behavioral sensitization to nicotine

Developmental vitamin D deficiency alters MK-801-induced behaviours in adult offspring.

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Kesby, James P; O'Loan, Jonathan C; Alexander, Suzanne; Deng, Chao; Huang, Xu-Feng; McGrath, John J; Eyles, Darryl W; Burne, Thomas H J

2012-04-01

Developmental vitamin D (DVD) deficiency is a candidate risk factor for developing schizophrenia in humans. In rodents DVD deficiency induces subtle changes in the way the brain develops. This early developmental insult leads to select behavioural changes in the adult, such as an enhanced response to amphetamine-induced locomotion in female DVD-deficient rats but not in male DVD-deficient rats and an enhanced locomotor response to the N-methyl-D: -aspartate (NMDA) receptor antagonist, MK-801, in male DVD-deficient rats. However, the response to MK-801-induced locomotion in female DVD-deficient rats is unknown. Therefore, the aim of the current study was to further examine this behavioural finding in male and female rats and assess NMDA receptor density. DVD-deficient Sprague Dawley rats were assessed for locomotion, ataxia, acoustic startle response (ASR) and prepulse inhibition (PPI) of the ASR to multiple doses of MK-801. The NMDA receptor density in relevant brain regions was assessed in a drug-naive cohort. DVD deficiency increased locomotion in response to MK-801 in both sexes. DVD-deficient rats also showed an enhanced ASR compared with control rats, but PPI was normal. Moreover, DVD deficiency decreased NMDA receptor density in the caudate putamen of both sexes. These results suggest that a transient prenatal vitamin D deficiency has a long-lasting effect on NMDA-mediated signalling in the rodent brain and may be a plausible candidate risk factor for schizophrenia and other neuropsychiatric disorders.

Psychotomimetic effects of different doses of MK-801 and the underlying mechanisms in a selective memory impairment model.

Science.gov (United States)

Liu, Weiqing; Wang, Dong; Hong, Wenjuan; Yu, Yi; Tang, Jinsong; Wang, Jicai; Liu, Fang; Xu, Xiufeng; Tan, Liwen; Chen, Xiaogang

2017-03-01

Although N-methyl-d-aspartate receptor antagonists-induced hypoglutamate rodent models are the most well-established models for preclinical studies of schizophrenia-related deficits, they also evoke a wide spectrum of psychotomimetic side effects. It is significant to increase the specificity of hypoglutamate rodent models. In this study, the recognition memory was evaluated in rats by object recognition test (ORT), sensorimotor gating was evaluated by prepulse inhibition of the startle reflex (PPI), and locomotor activity was measured using open field test. High-performance liquid chromatography was used to measure neurotransmitters content in the medial prefrontal cortex (mPFC) and thalamus (THA). Total Akt and phospho-Akt protein was measured by Western blots. Results showed that 0.3mg/kg of MK-801 was most effective in inducing locomotion. 0.3mg/kg of MK-801 was most effective in decreasing PPI. 0.03mg/kg of MK-801 was most effective in decreasing object memory while not affecting exploration manners in the training session. 0.03mg/kg of MK-801 significantly increased HVA and Glu content in the mPFC. 0.1mg/kg of MK-801 significantly decreased GABA content in the THA. 0.03mg/kg of MK-801 significantly decreased Akt phosphorylation in the mPFC, which was related to the ORT index. In conclusion, a dose of 0.03mg/kg MK-801 can establish a "pure" memory impairment model without contaminations of sensorimotor gating and locomotor activity. MK-801-induced cognitive deficits is associated with increased DA metabolites and glutamate content in the mPFC and decreased GABA content in the THA as well as decrease in Akt phosphorylation in the mPFC. Copyright © 2016. Published by Elsevier B.V.

The neuroprotective efficacy of MK-801 in focal cerebral ischemia varies with rat strain and vendor.

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Oliff, H S; Marek, P; Miyazaki, B; Weber, E

1996-08-26

The present study was designed to evaluate whether the neuroprotective efficacy of MK-801 in focal cerebral ischemia was dependent on strain and/or vendor differences. MK-801 (0.12 mg/kg i.v. bolus followed by 0.108 mg/kg/h infusion or 0.60 mg/kg i.v. bolus followed by 0.540 mg/kg/h infusion) or saline was administered just after intraluminal middle cerebral artery occlusion. Administration of 0.540 mg/kg/h MK-801 provided strain/line-dependent neuroprotection in the following rank order: Simonsen Laboratories Sprague-Dawley rats > Simonsen Laboratories Wistar rats > Taconic Laboratories Sprague-Dawley rats. After 0.108 mg/kg/h MK-801 treatment, Simonsen Laboratories Wistar rats were the only strain/line that were significantly neuroprotected. These results indicate that the neuroprotective effect of an experimental drug may be influenced by rat strain and vendor differences.

FOXO/TXNIP pathway is involved in the suppression of hepatocellular carcinoma growth by glutamate antagonist MK-801

International Nuclear Information System (INIS)

Yamaguchi, Fuminori; Hirata, Yuko; Akram, Hossain; Kamitori, Kazuyo; Dong, Youyi; Sui, Li; Tokuda, Masaaki

2013-01-01

Accumulating evidence has suggested the importance of glutamate signaling in cancer growth, yet the signaling pathway has not been fully elucidated. N-methyl-D-aspartic acid (NMDA) receptor activates intracellular signaling pathways such as the extracellular-signal-regulated kinase (ERK) and forkhead box, class O (FOXO). Suppression of lung carcinoma growth by NMDA receptor antagonists via the ERK pathway has been reported. However, series of evidences suggested the importance of FOXO pathways for the regulation of normal and cancer cell growth. In the liver, FOXO1 play important roles for the cell proliferation such as hepatic stellate cells as well as liver metabolism. Our aim was to investigate the involvement of the FOXO pathway and the target genes in the growth inhibitory effects of NMDA receptor antagonist MK-801 in human hepatocellular carcinoma. Expression of NMDAR1 in cancer cell lines from different tissues was examined by Western blot. NMDA receptor subunits in HepG2, HuH-7, and HLF were examined by reverse transcriptase polymerase chain reaction (RT-PCR), and growth inhibition by MK-801 and NBQX was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of MK-801 on the cell cycle were examined by flow cytometry and Western blot analysis. Expression of thioredoxin-interacting protein (TXNIP) and p27 was determined by real-time PCR and Western blotting. Activation of the FOXO pathway and TXNIP induction were examined by Western blotting, fluorescence microscopy, Chromatin immunoprecipitation (ChIP) assay, and reporter gene assay. The effects of TXNIP on growth inhibition were examined using the gene silencing technique. NMDA receptor subunits were expressed in all cell lines examined, and MK-801, but not NBQX, inhibited cell growth of hepatocellular carcinomas. Cell cycle analysis showed that MK-801 induced G1 cell cycle arrest by down-regulating cyclin D1 and up-regulating p27. MK-801 dephosphorylated

The effect of hippocampal NMDA receptor blockade by MK-801 on cued fear extinction.

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Zhang, Bo; Li, Chuan-Yu; Wang, Xiu-Song

2017-08-14

Extinction of conditioned fear has been suggested to be a new form of learning instead of erasure of what was originally learned, and the process is NMDA (N-methyl d-aspartate) receptor (NMDAR) dependent. Most of studies have so far revealed the important roles of NMDARs in the amygdala and medial prefrontal cortex (mPFC) in cued fear extinction. Although the ventral hippocampus has intimately reciprocal connections with the amygdala and mPFC, the role of its NMDARs in cued fear extinction remains unclear. The present experiment explored the issue by bilateral pre-extinction microinjection of the noncompetitive NMDAR antagonist MK-801 into the ventral hippocampus. Four groups of rats were given habituation, tone cued fear conditioning, fear extinction training and extinction test. Prior to extinction training, rats received bilateral infusions of either MK-801 (1.5, 3, or 6μg/0.5μl) or saline. Our results showed that MK-801 reduced freezing on the first trial of extinction training with no impact on within-session acquisition of extinction, and that the lower doses of MK-801 resulted in increased freezing on the extinction retrieval test. These findings suggest that ventral hippocampal NMDARs are necessary for the consolidation of tone cued fear extinction. Copyright © 2017 Elsevier B.V. All rights reserved.

The excitatory amino acid receptor antagonist MK-801 prevents the hypersensitivity induced by spinal cord ischemia in the rat

International Nuclear Information System (INIS)

Hao, J.X.; Xu, X.J.; Aldskogius, H.; Seiger, A.; Wiesenfeld-Hallin, Z.

1991-01-01

Protection by the NMDA receptor antagonist MK-801 against transient spinal cord ischemia-induced hypersensitivity was studied in rats. The spinal ischemia was initiated by vascular occlusion resulting from the interaction between the photosensitizing dye Erythrosin B and an argon laser beam. The hypersensitivity, termed allodynia, where the animals reacted by vocalization to nonnoxious mechanical stimuli in the flank area, was consistently observed during several days after induction of the ischemia. Pretreatment with MK-801 (0.1-0.5 mg/kg, iv) 10 min before laser irradiation dose dependently prevented the occurrence of allodynia. The neuroprotective effect of MK-801 was not reduced by maintaining normal body temperature during and after irradiation. There was a significant negative correlation between the delay in the administration of MK-801 after irradiation and the protective effect of the drug. Histological examination revealed slight morphological damage in the spinal cord in 38% of control rats after 1 min of laser irradiation without pretreatment with MK-801. No morphological abnormalities were observed in rats after pretreatment with MK-801 (0.5 mg/kg). The present results provide further evidence for the involvement of excitatory amino acids, through activation of the NMDA receptor, in the development of dysfunction following ischemic trauma to the spinal cord

Effect of subchronic caffeine treatment on MK-801-induced changes in locomotion, cognition and ataxia in mice.

Science.gov (United States)

de Oliveira, R V; Dall'Igna, O P; Tort, A B L; Schuh, J F; Neto, P F; Santos Gomes, M W; Souza, D O; Lara, D R

2005-03-01

N-Methyl-D-aspartate (NMDA) receptor antagonists cause hyperlocomotion and cognitive deficits in rodents, and caffeine-tolerant mice show diminished locomotor response to NMDA receptor antagonists. The aim of this study was to evaluate the effect of subchronic caffeine treatment on MK-801-induced hyperlocomotion, ataxia and cognitive deficits, as well as amphetamine-induced hyperlocomotion in mice. Mice were treated subchronically with caffeine (0, 0.1, 0.3 and 1 mg/ml and 1, 3 and 7 days) and evaluated for locomotor activity, working memory (delayed alternation test), long-term memory (inhibitory avoidance task) and ataxia. Hyperlocomotion induced by MK-801 (0.25 mg/kg i.p.) was diminished after 3 days and almost abolished after 7 days of caffeine treatment at the 1 mg/ml dose, and this effect was also dose-dependent. Ataxia induced by 0.5 mg/kg MK-801 was not affected by caffeine treatment, but a short-lived hyperlocomotor effect was observed. Performance deficit in the inhibitory avoidance task induced by MK-801 (0.01 mg/kg) was prevented in mice treated with caffeine for 7 days at 1 mg/ml, and perseverative errors in the T-maze by MK-801 (0.4 mg/kg) were attenuated. The locomotor effect of amphetamine (5 mg/kg) was unaffected by subchronic caffeine treatment. The findings that hyperlocomotion and cognitive effects induced by MK-801 can be specifically influenced by reduced adenosinergic activity agree with a model of adenosine hypofunction in schizophrenia, since NMDA receptor antagonists are pharmacological models for this disorder.

Recovery of NMDA receptor currents from MK-801 blockade is accelerated by Mg2+ and memantine under conditions of agonist exposure

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McKay, Sean; Bengtson, C. Peter; Bading, Hilmar; Wyllie, David J.A.; Hardingham, Giles E.

2013-01-01

MK-801 is a use-dependent NMDA receptor open channel blocker with a very slow off-rate. These properties can be exploited to ‘pre-block’ a population of NMDARs, such as synaptic ones, enabling the selective activation of a different population, such as extrasynaptic NMDARs. However, the usefulness of this approach is dependent on the stability of MK-801 blockade after washout. We have revisited this issue, and confirm that recovery of NMDAR currents from MK-801 blockade is enhanced by channel opening by NMDA, and find that it is further increased when Mg2+ is also present. In the presence of Mg2+, 50% recovery from MK-801 blockade is achieved after 10′ of 100 μM NMDA, or 30′ of 15 μM NMDA exposure. In Mg2+-free medium, NMDA-induced MK-801 dissociation was found to be much slower. Memantine, another PCP-site antagonist, could substitute for Mg2+ in accelerating the unblock of MK-801 in the presence of NMDA. This suggests a model whereby, upon dissociation from its binding site in the pore, MK-801 is able to re-bind in a process antagonized by Mg2+ or another PCP-site antagonist. Finally we show that even when all NMDARs are pre-blocked by MK-801, incubation of neurons with 100 μM NMDA in the presence of Mg2+ for 2.5 h triggers sufficient unblocking to kill >80% of neurons. We conclude that while synaptic MK-801 ‘pre-block’ protocols are useful for pharmacologically assessing synaptic vs. extrasynaptic contributions to NMDAR currents, or studying short-term effects, it is problematic to use this technique to attempt to study the effects of long-term selective extrasynaptic NMDAR activation. This article is part of the Special Issue entitled ‘Glutamate Receptor-Dependent Synaptic Plasticity’. PMID:23402996

Hippocampal serotonin depletion unmasks differences in the hyperlocomotor effects of phencyclidine and MK-801: quantitative versus qualitative analyses

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Wendy K Adams

2013-08-01

Full Text Available Antagonism of N-methyl-D-aspartate (NMDA receptors by phencyclidine is thought to underlie its ability to induce a schizophrenia-like syndrome in humans, yet evidence indicates it has a broader pharmacological profile. Our previous lesion studies highlighted a role for serotonergic projections from the median, but not dorsal, raphe nucleus in mediating the hyperlocomotor effects of phencyclidine, without changing the action of the more selective NMDA receptor antagonist, MK-801. Here we compared locomotor responses to phencyclidine and MK 801 in rats that were administered 5,7 dihydroxytryptamine (5,7-DHT into either the dorsal or ventral hippocampus, which are preferentially innervated by median and dorsal raphe, respectively. Dorsal hippocampus lesions potentiated phencyclidine-induced hyperlocomotion (0.5, 2.5 mg/kg, but not the effect of MK-801 (0.1 mg/kg. Ventral hippocampus lesions did not alter the hyperlocomotion elicited by either compound. Given that phencyclidine and MK-801 may induce different spatiotemporal patterns of locomotor behavior, together with the known role of the dorsal hippocampus in spatial processing, we also assessed whether the 5,7-DHT-lesions caused any qualitative differences in locomotor responses. Treatment with phencyclidine or MK-801 increased the smoothness of the path travelled (reduced spatial d and decreased the predictability of locomotor patterns within the chambers (increased entropy. 5,7-DHT-lesions of the dorsal hippocampus did not alter the effects of phencyclidine on spatial d or entropy—despite potentiating total distance moved—but caused a slight reduction in levels of MK-801-induced entropy. Taken together, serotonergic lesions targeting the dorsal hippocampus unmask a functional differentiation of the hyperlocomotor effects of phencyclidine and MK 801. These findings have implications for studies utilising NMDA receptor antagonists in modeling glutamatergic dysfunction in schizophrenia.

Kindling-induced potentiation of excitatory and inhibitory inputs to hippocampal dentate granule cells. II. Effects of the NMDA antagonist MK-801.

LENUS (Irish Health Repository)

Robinson, G B

1991-10-18

The effect of the non-competitive N-methyl-D-aspartate antagonist MK-801 on the early development of kindling-induced potentiation was examined in the rabbit hippocampal dentate gyrus. MK-801 (0.5 mg\\/kg) was administered 2 h before each daily kindling stimulation was applied to the perforant path. This treatment continued for the first 10 days of kindling. MK-801 depressed the growth of the afterdischarge duration and suppressed development of behavioral seizures. MK-801 did not block kindling-induced potentiation of either the perforant path-dentate granule cell population spike or excitatory postsynaptic potential. Random impulse train stimulation and non-linear systems analytic techniques were used to examine kindling-induced potentiation of presumed GABAergic recurrent inhibitory circuits. Both the magnitude and duration of kindling-induced response inhibition, to the second of each pair of impulses within the train, were reduced in rabbits pretreated with MK-801. These results suggest that MK-801 differentially affects kindling-induced potentiation of excitatory and inhibitory circuits within the rabbit hippocampal dentate gyrus.

FOXO/TXNIP pathway is involved in the suppression of hepatocellular carcinoma growth by glutamate antagonist MK-801

Science.gov (United States)

2013-01-01

Background Accumulating evidence has suggested the importance of glutamate signaling in cancer growth, yet the signaling pathway has not been fully elucidated. N-methyl-D-aspartic acid (NMDA) receptor activates intracellular signaling pathways such as the extracellular-signal-regulated kinase (ERK) and forkhead box, class O (FOXO). Suppression of lung carcinoma growth by NMDA receptor antagonists via the ERK pathway has been reported. However, series of evidences suggested the importance of FOXO pathways for the regulation of normal and cancer cell growth. In the liver, FOXO1 play important roles for the cell proliferation such as hepatic stellate cells as well as liver metabolism. Our aim was to investigate the involvement of the FOXO pathway and the target genes in the growth inhibitory effects of NMDA receptor antagonist MK-801 in human hepatocellular carcinoma. Methods Expression of NMDAR1 in cancer cell lines from different tissues was examined by Western blot. NMDA receptor subunits in HepG2, HuH-7, and HLF were examined by reverse transcriptase polymerase chain reaction (RT-PCR), and growth inhibition by MK-801 and NBQX was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of MK-801 on the cell cycle were examined by flow cytometry and Western blot analysis. Expression of thioredoxin-interacting protein (TXNIP) and p27 was determined by real-time PCR and Western blotting. Activation of the FOXO pathway and TXNIP induction were examined by Western blotting, fluorescence microscopy, Chromatin immunoprecipitation (ChIP) assay, and reporter gene assay. The effects of TXNIP on growth inhibition were examined using the gene silencing technique. Results NMDA receptor subunits were expressed in all cell lines examined, and MK-801, but not NBQX, inhibited cell growth of hepatocellular carcinomas. Cell cycle analysis showed that MK-801 induced G1 cell cycle arrest by down-regulating cyclin D1 and up-regulating p

Altered 13C glucose metabolism in the cortico-striato-thalamo-cortical loop in the MK-801 rat model of schizophrenia

DEFF Research Database (Denmark)

Eyjolfsson, Elvar M; Nilsen, Linn Hege; Kondziella, Daniel

2011-01-01

Using a modified MK-801 (dizocilpine) N-methyl-D-aspartic acid (NMDA) receptor hypofunction model for schizophrenia, we analyzed glycolysis, as well as glutamatergic, GABAergic, and monoaminergic neurotransmitter synthesis and degradation. Rats received an injection of MK-801 daily for 6 days...... in all regions. In conclusion, neurotransmitter metabolism in the cortico-striato-thalamo-cortical loop is severely impaired in the MK-801 (dizocilpine) NMDA receptor hypofunction animal model for schizophrenia....

AC-3933, a benzodiazepine partial inverse agonist, improves memory performance in MK-801-induced amnesia mouse model.

Science.gov (United States)

Hashimoto, Takashi; Iwamura, Yoshihiro

2016-05-01

AC-3933, a novel benzodiazepine receptor partial inverse agonist, is a drug candidate for cognitive disorders including Alzheimer's disease. We have previously reported that AC-3933 enhances acetylcholine release in the rat hippocampus and ameliorates scopolamine-induced memory impairment and age-related cognitive decline in both rats and mice. In this study, we further evaluated the procognitive effect of AC-3933 on memory impairment induced by MK-801, an N-methyl-d-aspartate receptor antagonist, in mice. Unlike the acetylcholinesterase inhibitor donepezil and the benzodiazepine receptor inverse agonist FG-7142, oral administration of AC-3933 significantly ameliorated MK-801-induced memory impairment in the Y-maze test and in the object location test. Interestingly, the procognitive effects of AC-3933 on MK-801-induced memory impairment were not affected by the benzodiazepine receptor antagonist flumazenil, although this was not the case for the beneficial effects of AC-3933 on scopolamine-induced memory deficit. Moreover, the onset of AC-3933 ameliorating effect on scopolamine- or MK-801-induced memory impairment was different in the Y-maze test. Taken together, these results indicate that AC-3933 improves memory deficits caused by both cholinergic and glutamatergic hypofunction and suggest that the ameliorating effect of AC-3933 on MK-801-induced memory impairment is mediated by a mechanism other than inverse activation of the benzodiazepine receptor. Copyright © 2016 Elsevier Inc. All rights reserved.

Competitive (AP7) and non-competitive (MK-801) NMDA receptor antagonists differentially alter glucose utilization in rat cortex

International Nuclear Information System (INIS)

Clow, D.W.; Lee, S.J.; Hammer, R.P. Jr.

1991-01-01

The effects of D,L-2-amino-7-phosphonoheptanoic acid (AP7), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, and MK-801, a non-competitive NMDA receptor antagonist, on regional brain metabolism were studied in unanesthetized, freely moving rats by using the quantitative 14 C2-deoxyglucose autoradiographic procedure. AP7 (338 or 901 mg/kg) produced a dose-dependent decrease of metabolic activity throughout most of the regions studied including sensory, motor, and limbic cortices. In contrast, MK-801 (0.1 or 1.0 mg/kg) resulted in a dose-dependent decrease of metabolic activity in sensory cortices, and an increase in limbic regions such as the hippocampal stratum lacunosum moleculare and entorhinal cortex. MK-801 also produced a biphasic response in agranular motor cortex, whereby the low dose increased while the high dose decreased labeling. In addition, MK-801 produced heterogeneous effects on regional cerebral metabolism in sensory cortices. Metabolic activity decreased in layer IV relative to layer Va following MK-801 treatment in primary somatosensory (SI) and visual (VI) cortices, suggesting a shift in activity from afferent fibers innervating layer IV to those innervating layer Va. MK-801 administration also decreased metabolic activity in granular SI relative to dysgranular SI, and in VI relative to secondary visual cortex (VII), thus providing a relative sparing of activity in dysgranular SI and VII. Thus, the non-competitive NMDA receptor antagonist suppressed activity from extrinsic neocortical sources, enhancing relative intracortical activity and stimulating limbic regions, while the competitive NMDA antagonist depressed metabolic activity in all cortical regions

Dopamine D2/D3 receptor binding of [123I]epidepride in risperidone-treatment chronic MK-801-induced rat schizophrenia model using nanoSPECT/CT neuroimaging

International Nuclear Information System (INIS)

Huang, Y.R.; Pai, C.W.; Cheng, K.H.; Kuo, W.I.; Chen, M.W.; Chang, K.W.

2014-01-01

Introduction: Epidepride is a compound with an affinity in picomolar range for D 2 /D 3 receptors. The aim of this work was designed to investigate the diagnostic possibility of [ 123 I]epidepride imaging platform for risperidone-treatment chronic MK-801-induced rat schizophrenia model. Methods: Rats received repeated administration of MK-801 (dissolved in saline, i.p., 0.3 mg/kg/day) or saline for 4 weeks. After 1-week administration of MK-801, rats in MK-801 + risperidone group received risperidone (0.5 mg/kg/day) intraperitoneally 15 min prior to MK-801 administration for the rest of 3-week treatment. We obtained serial [ 123 I]epidepride neuroimages from nanoSPECT/CT and evaluated the alteration of specific binding in striatum and midbrain. Results: Risperidone reversed chronic MK-801-induced decrease in social interaction duration. IHC and ELISA analysis showed consistent results that chronic MK-801 treatment significantly decreased striatal and midbrain D 2 R expression but repeated risperidone administration reversed the effect of MK-801 treatment. In addition, [ 123 I]epidepride nanoSPECT/CT neuroimaging revealed that low specific [ 123 I]epidepride binding ratios caused by MK-801 in striatum and midbrain were statistically alleviated after 1- and 2-week risperidone administration, respectively. Conclusions: We established a rat schizophrenia model by chronic MK-801 administration for 4 weeks. [ 123 I]Epidepride nanoSPECT neuroimaging can trace the progressive alteration of D 2 R expression in striatum and midbrain caused by long-lasting MK-801 treatment. Besides diagnosing illness stage of disease, [ 123 I]epidepride can be a useful tool to evaluate therapeutic effects of antipsychotic drug in chronic MK-801-induced rat schizophrenia model

The Histamine H3 Receptor Antagonist DL77 Ameliorates MK801-Induced Memory Deficits in Rats

Directory of Open Access Journals (Sweden)

Nermin Eissa

2018-02-01

Full Text Available The role of Histamine H3 receptors (H3Rs in memory, and the prospective of H3R antagonists in pharmacological control of neurodegenerative disorders, e.g., Alzheimer disease (AD is well-accepted. For that reason, the procognitive effects of the H3R antagonist DL77 on cognitive impairments induced with MK801 were tested in an inhibitory passive avoidance paradigm (PAP and novel object recognition (NOR task in adult male rats, using donepezil (DOZ as a standard drug. Acute systemic pretreatment with DL77 (2.5, 5, and 10 mg/kg, i.p. significantly ameliorated memory deficits induced with MK801 in PAP (all P < 0.05, n = 7. The ameliorative effect of most promising dose of DL77 (5 mg/kg, i.p. was reversed when rats were co-injected with the H3R agonist R-(α-methylhistamine (RAMH, 10 mg/kg, i.p. (p = 0.701 for MK801-amnesic group vs. MK801+DL77+RAMH group, n = 6. In the NOR paradigm, DL77 (5 mg/kg, i.p. counteracted long-term memory (LTM deficits induced with MK801 (P < 0.05, n = 6–8, and the DL77-provided effect was similar to that of DOZ (p = 0.788, n = 6–8, and was reversed when rats were co-injected with RAMH (10 mg/kg, i.p. (p = 0.877, n = 6, as compared to the (MK801-amnesic group. However, DL77 (5 mg/kg, i.p. did not alter short-term memory (STM impairment in NOR test (p = 0.772, n = 6–8, as compared to (MK801-amnesic group. Moreover, DL77 (5 mg/kg failed to modify anxiety and locomotor behaviors of animals innate to elevated-plus maze (EPM (p = 0.67 for percentage of time spent exploring the open arms, p = 0.52 for number of entries into the open arms, p = 0.76 for percentage of entries into the open arms, and p = 0.73 number of closed arm entries as compared to saline-treated groups, all n = 6, demonstrating that the procognitive effects observed in PAP or NOR tests were unconnected to alterations in emotions or in natural locomotion of tested animals. These results signify the potential involvement of H3Rs in modulating

MK-801 treatment affects glycolysis in oligodendrocytes more than in astrocytes and neuronal cells: insights for schizophrenia

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Guest, Paul C.; Iwata, Keiko; Kato, Takahiro A.; Steiner, Johann; Schmitt, Andrea; Turck, Christoph W.; Martins-de-Souza, Daniel

2015-01-01

Schizophrenia is a debilitating mental disorder, affecting more than 30 million people worldwide. As a multifactorial disease, the underlying causes of schizophrenia require analysis by multiplex methods such as proteomics to allow identification of whole protein networks. Previous post-mortem proteomic studies on brain tissues from schizophrenia patients have demonstrated changes in activation of glycolytic and energy metabolism pathways. However, it is not known whether these changes occur in neurons or in glial cells. To address this question, we treated neuronal, astrocyte, and oligodendrocyte cell lines with the NMDA receptor antagonist MK-801 and measured the levels of six glycolytic enzymes by Western blot analysis. MK-801 acts on the glutamatergic system and has been proposed as a pharmacological means of modeling schizophrenia. Treatment with MK-801 resulted in significant changes in the levels of glycolytic enzymes in all cell types. Most of the differences were found in oligodendrocytes, which had altered levels of hexokinase 1 (HK1), enolase 2 (ENO2), phosphoglycerate kinase (PGK), and phosphoglycerate mutase 1 after acute MK-801 treatment (8 h), and HK1, ENO2, PGK, and triosephosphate isomerase (TPI) following long term treatment (72 h). Addition of the antipsychotic clozapine to the cultures resulted in counter-regulatory effects to the MK-801 treatment by normalizing the levels of ENO2 and PGK in both the acute and long term cultures. In astrocytes, MK-801 affected only aldolase C (ALDOC) under both acute conditions and HK1 and ALDOC following long term treatment, and TPI was the only enzyme affected under long term conditions in the neuronal cells. In conclusion, MK-801 affects glycolysis in oligodendrocytes to a larger extent than neuronal cells and this may be modulated by antipsychotic treatment. Although cell culture studies do not necessarily reflect the in vivo pathophysiology and drug effects within the brain, these results suggest that

Minocycline exacerbates apoptotic neurodegeneration induced by the NMDA receptor antagonist MK-801 in the early postnatal mouse brain.

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Inta, Ioana; Vogt, Miriam A; Vogel, Anne S; Bettendorf, Markus; Gass, Peter; Inta, Dragos

2016-10-01

NMDA receptor (NMDAR) antagonists induce in perinatal rodent cortical apoptosis and protracted schizophrenia-like alterations ameliorated by antipsychotic treatment. The broad-spectrum antibiotic minocycline elicits antipsychotic and neuroprotective effects. Here we tested, if minocycline protects also against apoptosis triggered by the NMDAR antagonist MK-801 at postnatal day 7. Surprisingly, minocycline induced widespread cortical apoptosis and exacerbated MK-801-triggered cell death. In some areas such as the subiculum, the pro-apoptotic effect of minocycline was even more pronounced than that elicited by MK-801. These data reveal among antipsychotics unique pro-apoptotic properties of minocycline, raising concerns regarding consequences for brain development and the use in children.

(/sup 3/H)MK-801 labels a site on the N-methyl-D-aspartate receptor channel complex in rat brain membranes

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Wong, E H; Knight, A R; Woodruff, G N

1988-01-01

The potent noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist (/sup 3/H)MK-801 bound with nanomolar affinity to rat brain membranes in a reversible, saturable, and stereospecific manner. The affinity of (/sup 3/H)MK-801 was considerably higher in 5 mM Tris-HCl (pH 7.4) than in previous studies using Krebs-Henseleit buffer. (/sup 3/H)MK-801 labels a homogeneous population of sites in rat cerebral cortical membranes with KD of 6.3 nM and Bmax of 2.37 pmol/mg of protein. This binding was unevenly distributed among brain regions, with hippocampus greater than cortex greater than olfactory bulb = striatum greater than medulla-pons, and the cerebellum failing to show significant binding. Detailed pharmacological characterization indicated (/sup 3/H)MK-801 binding to a site which was competitively and potently inhibited by known noncompetitive NMDA receptor antagonists, such as phencyclidine, thienylcyclohexylpiperidine (TCP), ketamine, N-allylnormetazocine (SKF 10,047), cyclazocine, and etoxadrol, a specificity similar to sites labelled by (/sup 3/H)TCP. These sites were distinct from the high-affinity sites labelled by the sigma receptor ligand (+)-(/sup 3/H)SKF 10,047. (/sup 3/H)MK-801 binding was allosterically modulated by the endogenous NMDA receptor antagonist Mg2+ and by other active divalent cations. These data suggest that (/sup 3/H)MK-801 labels a high-affinity site on the NMDA receptor channel complex, distinct from the NMDA recognition site, which is responsible for the blocking action of MK-801 and other noncompetitive NMDA receptor antagonists.

Knockout of NMDA-receptors from parvalbumin interneurons sensitizes to schizophrenia-related deficits induced by MK-801

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Bygrave, A M; Masiulis, S; Nicholson, E; Berkemann, M; Barkus, C; Sprengel, R; Harrison, P J; Kullmann, D M; Bannerman, D M; Kätzel, D

2016-01-01

It has been suggested that a functional deficit in NMDA-receptors (NMDARs) on parvalbumin (PV)-positive interneurons (PV-NMDARs) is central to the pathophysiology of schizophrenia. Supportive evidence come from examination of genetically modified mice where the obligatory NMDAR-subunit GluN1 (also known as NR1) has been deleted from PV interneurons by Cre-mediated knockout of the corresponding gene Grin1 (Grin1ΔPV mice). Notably, such PV-specific GluN1 ablation has been reported to blunt the induction of hyperlocomotion (a surrogate for psychosis) by pharmacological NMDAR blockade with the non-competitive antagonist MK-801. This suggests PV-NMDARs as the site of the psychosis-inducing action of MK-801. In contrast to this hypothesis, we show here that Grin1ΔPV mice are not protected against the effects of MK-801, but are in fact sensitized to many of them. Compared with control animals, Grin1ΔPVmice injected with MK-801 show increased stereotypy and pronounced catalepsy, which confound the locomotor readout. Furthermore, in Grin1ΔPVmice, MK-801 induced medial-prefrontal delta (4 Hz) oscillations, and impaired performance on tests of motor coordination, working memory and sucrose preference, even at lower doses than in wild-type controls. We also found that untreated Grin1ΔPVmice are largely normal across a wide range of cognitive functions, including attention, cognitive flexibility and various forms of short-term memory. Taken together these results argue against PV-specific NMDAR hypofunction as a key starting point of schizophrenia pathophysiology, but support a model where NMDAR hypofunction in multiple cell types contribute to the disease. PMID:27070406

The combination of glutamate receptor antagonist MK-801 with tamoxifen and its active metabolites potentiates their antiproliferative activity in mouse melanoma K1735-M2 cells

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Ribeiro, Mariana P.C.; Nunes-Correia, Isabel; Santos, Armanda E.; Custódio, José B.A.

2014-01-01

Recent reports suggest that N-methyl-D-aspartate receptor (NMDAR) blockade by MK-801 decreases tumor growth. Thus, we investigated whether other ionotropic glutamate receptor (iGluR) antagonists were also able to modulate the proliferation of melanoma cells. On the other hand, the antiestrogen tamoxifen (TAM) decreases the proliferation of melanoma cells, and is included in combined therapies for melanoma. As the efficacy of TAM is limited by its metabolism, we investigated the effects of the NMDAR antagonist MK-801 in combination with TAM and its active metabolites, 4-hydroxytamoxifen (OHTAM) and endoxifen (EDX). The NMDAR blockers MK-801 and memantine decreased mouse melanoma K1735-M2 cell proliferation. In contrast, the NMDAR competitive antagonist APV and the AMPA and kainate receptor antagonist NBQX did not affect cell proliferation, suggesting that among the iGluR antagonists only the NMDAR channel blockers inhibit melanoma cell proliferation. The combination of antiestrogens with MK-801 potentiated their individual effects on cell biomass due to diminished cell proliferation, since it decreased the cell number and DNA synthesis without increasing cell death. Importantly, TAM metabolites combined with MK-801 promoted cell cycle arrest in G1. Therefore, the data obtained suggest that the activity of MK-801 and antiestrogens in K1735-M2 cells is greatly enhanced when used in combination. - Highlights: • MK-801 and memantine decrease melanoma cell proliferation. • The combination of MK-801 with antiestrogens inhibits melanoma cell proliferation. • These combinations greatly enhance the effects of the compounds individually. • MK-801 combined with tamoxifen active metabolites induces cell cycle arrest in G1. • The combination of MK-801 and antiestrogens is an innovative strategy for melanoma

mGluR5 positive allosteric modulation and its effects on MK-801 induced set-shifting impairments in a rat operant delayed matching/non-matching-to-sample task

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LaCrosse, Amber L.; Burrows, Brian T.; Angulo, Rachel M.; Conrad, Phoebe R.; Himes, Sarah M.; Mathews, Nordia; Wegner, Scott A.; Taylor, Sara B.; Olive, M. Foster

2014-01-01

Rationale Positive allosteric modulators (PAMs) of type 5 metabotropic glutamate receptors (mGluR5) exert pro-cognitive effects in animal models of various neuropsychiatric diseases. However, few studies to date have examined ability of mGluR5 PAMs to reverse cognitive deficits in operant delayed matching/non-matching-to-sample (DMS/DNMS) tasks. Objectives To determine the ability of the mGluR5 PAM 3-cyano-N-1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) to reverse set-shifting deficits induced by the NMDA receptor antagonist MK-801. Methods Male Sprague-Dawley rats were initially trained to lever press for sucrose reinforcement under either DMS or DNMS conditions. Following successful acquisition of the task, reinforcement conditions were reversed (DNMS→DMS or DMS→DNMS). In Experiment 1, rats were treated daily prior to each session with either vehicle/vehicle, vehicle/MK-801 (0.06 mg/kg) simultaneously, CDPPB (20 mg/kg)/MK-801 simultaneously, or CDPPB 30 min prior to MK-801. In Experiment 2, rats were treated with either vehicle/vehicle, vehicle/MK-801, or CDPPB 30 min prior to MK-801 only prior to sessions that followed task reversal. Results In Experiment 1, no group differences in initial task acquisition were observed. Rats treated with vehicle+MK−801 showed significant set-shifting impairments following task reversal, which were partially attenuated by simultaneous administration of CDPPB/MK-801, and completely precluded by administration of CDPPB 30 min prior to MK-801. In Experiment 2, MK-801 did not impair reversal learning and no other group differences were observed. Conclusions MK-801 induced deficits in operant set-shifting ability were prevented by pretreatment with CDPPB. MK-801 did not produce deficits in initial task learning or when treatment was initiated following task reversal. PMID:24973895

Histamine ameliorates spatial memory deficits induced by MK-801 infusion into ventral hippocampus as evaluated by radial maze task in rats

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Li-sha XU; Li-xia YANG; Wei-wei HU; Xiao YU; Li MA; Lu-ying LIU; Er-qing WEI; Zhong CHEN

2005-01-01

Aim: To investigate the role of histamine in memory deficits induced by MK-801 infusion into the ventral hippocampus in rats. Methods: An 8-arm radial maze (4arms baited) was used to assess spatial memory. Results: Bilateral ventral intrahippocampal (ih) infusion of MK-801 (0.3 μg/site), an N-methyl-D-aspartate (NMDA) antagonist, impaired the retrieval process in both working memory and reference memory. Intrahippocampal injection of histamine (25 or 50 ng/site) or intraperitoneal (ip) injection of histidine (25, 50 or 100 mg/kg) markedly ameliorated the spatial memory deficits induced by MK-801. Both the histamine H1 antagonist pyrilamine (0.5 or 1.0 μg/site, ih) and the H2 antagonist cimetidine (2.5 μg/site,ih) abolished the ameliorating effect of histidine (100 mg/kg, ip) on reference memory deficits, but not that on working memory deficits induced by MK-801. Conclusion:The results indicate that histamine in the ventral hippocampus can ameliorate MK-801-induced spatial memory deficits, and that histamine's effect on reference memory is mediated by postsynaptic histamine H1 and H2 receptors.

Effects of MK-801 on vicarious trial-and-error and reversal of olfactory discrimination learning in weanling rats.

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Griesbach, G S; Hu, D; Amsel, A

1998-12-01

The effects of dizocilpine maleate (MK-801) on vicarious trial-and-error (VTE), and on simultaneous olfactory discrimination learning and its reversal, were observed in weanling rats. The term VTE was used by Tolman (The determiners of behavior at a choice point. Psychol. Rev. 1938;46:318-336), who described it as conflict-like behavior at a choice-point in simultaneous discrimination learning. It takes the form of head movements from one stimulus to the other, and has recently been proposed by Amsel (Hippocampal function in the rat: cognitive mapping or vicarious trial-and-error? Hippocampus, 1993;3:251-256) as related to hippocampal, nonspatial function during this learning. Weanling male rats received systemic MK-801 either 30 min before the onset of olfactory discrimination training and its reversal, or only before its reversal. The MK-801-treated animals needed significantly more sessions to acquire the discrimination and showed significantly fewer VTEs in the acquisition phase of learning. Impaired reversal learning was shown only when MK-801 was administered during the reversal-learning phase, itself, and not when it was administered throughout both phases.

MK-801 induced amnesia for the elevated plus-maze in mice

Czech Academy of Sciences Publication Activity Database

Hliňák, Zdeněk; Krejčí, I.

2002-01-01

Roč. 131, 1-2 (2002), s. 221-225 ISSN 0166-4328 R&D Projects: GA ČR GA309/00/1644 Institutional research plan: CEZ:AV0Z5011922 Keywords : amnesia * elevated plus-maze * MK-801 Subject RIV: FH - Neurology Impact factor: 2.791, year: 2002

N-methyl-D-aspartate receptor antagonist MK-801 impairs learning but not memory fixation or expression of classical fear conditioning in goldfish (Carassius auratus).

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Xu, X; Davis, R E

1992-04-01

The amnestic effects of the noncompetitive antagonist MK-801 on visually mediated, classic fear conditioning in goldfish (Carassius auratus) was examined in 5 experiments. MK-801 was administered 30 min before the training session on Day 1 to look for anterograde amnestic effects, immediately after training to look for retrograde amnestic effects, and before the training or test session, or both, to look for state-dependence effects. The results showed that MK-801 produced anterograde amnesia at doses that did not produce retrograde amnesia or state dependency and did not impair the expression of conditioned or unconditioned branchial suppression responses (BSRs) to the conditioned stimulus. The results indicate that MK-801 disrupts the mechanism of learning of the conditioned stimulus-unconditioned stimulus relation. Evidence is also presented that the learning processes that are disrupted by MK-801 occur during the initial stage of BSR conditioning.

Superior effects of quetiapine compared with aripiprazole and iloperidone on MK-801-induced olfactory memory impairment in female mice.

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Mutlu, Ahmet; Mutlu, Oguz; Ulak, Guner; Akar, Furuzan; Kaya, Havva; Erden, Faruk; Tanyeri, Pelin

2017-05-01

Cognitive dysfunction is commonly observed in schizophrenic patients and the administration of antipsychotic treatments results in different outcomes. Although the typical antipsychotic treatments, such as haloperidol, appear to be unable to improve cognition dysfunction, the atypical antipsychotic drugs (quetiapine, aripiprazole and iloperidone) exert a beneficial effect. The purpose of the current study was to investigate the effects of atypical antipsychotics on olfactory memory in mice, utilizing the social transmission of food preference (STFP) tests to evaluate the effects of drugs on MK-801-induced cognitive dysfunction. Female BALB/c mice were treated with quetiapine (5 and 10 mg/kg), aripiprazole (3 and 6 mg/kg), iloperidone (0.5 and 1 mg/kg) or MK-801 (0.1 mg/kg) alone or concurrently prior to retention sessions of STFP tests. In the STFP tests, quetiapine (10 mg/kg; P<0.05), aripiprazole (3 and 6 mg/kg; P<0.01 and P<0.001, respectively), iloperidone (0.5 and 1 mg/kg; P<0.01 and P<0.001, respectively) and MK-801 (P<0.001) significantly decreased cued/total food eaten (%). Quetiapine (5 mg/kg; P<0.05) significantly increased MK-801-induced decreases in cued/total food eaten (%), while aripiprazole and iloperidone demonstrated no significant effects. The results revealed that all of the drugs disturbed olfactory memory in the naive mice; however, only quetiapine reversed MK-801-induced memory impairment in the STFP test.

Risperidone reverses the spatial object recognition impairment and hippocampal BDNF-TrkB signalling system alterations induced by acute MK-801 treatment

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Chen, Guangdong; Lin, Xiaodong; Li, Gongying; Jiang, Diego; Lib, Zhiruo; Jiang, Ronghuan; Zhuo, Chuanjun

2017-01-01

The aim of the present study was to investigate the effects of a commonly-used atypical antipsychotic, risperidone, on alterations in spatial learning and in the hippocampal brain-derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) signalling system caused by acute dizocilpine maleate (MK-801) treatment. In experiment 1, adult male Sprague-Dawley rats subjected to acute treatment of either low-dose MK801 (0.1 mg/kg) or normal saline (vehicle) were tested for spatial object recognition and hippocampal expression levels of BDNF, TrkB and the phophorylation of TrkB (p-TrkB). We found that compared to the vehicle, MK-801 treatment impaired spatial object recognition of animals and downregulated the expression levels of p-TrkB. In experiment 2, MK-801- or vehicle-treated animals were further injected with risperidone (0.1 mg/kg) or vehicle before behavioural testing and sacrifice. Of note, we found that risperidone successfully reversed the deleterious effects of MK-801 on spatial object recognition and upregulated the hippocampal BDNF-TrkB signalling system. Collectively, the findings suggest that cognitive deficits from acute N-methyl-D-aspartate receptor blockade may be associated with the hypofunction of hippocampal BDNF-TrkB signalling system and that risperidone was able to reverse these alterations. PMID:28451387

Effects of chronic prenatal MK-801 treatment on object recognition, cognitive flexibility, and drug-induced locomotor activity in juvenile and adult rat offspring.

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Gallant, S; Welch, L; Martone, P; Shalev, U

2017-06-15

Patients with schizophrenia display impaired cognitive functioning and increased sensitivity to psychomimetic drugs. The neurodevelopmental hypothesis of schizophrenia posits that disruption of the developing brain predisposes neural networks to lasting structural and functional abnormalities resulting in the emergence of such symptoms in adulthood. Given the critical role of the glutamatergic system in early brain development, we investigated whether chronic prenatal exposure to the glutamate NMDA receptor antagonist, MK-801, induces schizophrenia-like behavioural and neurochemical changes in juvenile and adult rats. Pregnant Long-Evans rats were administered saline or MK-801 (0.1mg/kg; s.c.) at gestation day 7-19. Object recognition memory and cognitive flexibility were assessed in the male offspring using a novel object preference task and a maze-based set-shifting procedure, respectively. Locomotor-activating effects of acute amphetamine and MK-801 were also assessed. Adult, but not juvenile, prenatally MK-801-treated rats failed to show novel object preference after a 90min delay, suggesting that object recognition memory may have been impaired. In addition, the set-shifting task revealed impaired acquisition of a new rule in adult prenatally MK-801-treated rats compared to controls. This deficit appeared to be driven by regression to the previously learned behaviour. There were no significant differences in drug-induced locomotor activity in juvenile offspring or in adult offspring following acute amphetamine challenges. Unexpectedly, MK-801-induced locomotor activity in adult prenatally MK-801-treated rats was lower compared to controls. Glutamate transmission dysfunction during early development may modify behavioural parameters in adulthood, though these parameters do not appear to model deficits observed in schizophrenia. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of scallop shell extract on scopolamine-induced memory impairment and MK801-induced locomotor activity.

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Hasegawa, Yasushi; Inoue, Tatsuro; Kawaminami, Satoshi; Fujita, Miho

2016-07-01

To evaluate the neuroprotective effects of the organic components of scallop shells (scallop shell extract) on memory impairment and locomotor activity induced by scopolamine or 5-methyl-10,11-dihydro-5H-dibenzo (a,d) cyclohepten-5,10-imine (MK801). Effect of the scallop shell extract on memory impairment and locomotor activity was investigated using the Y-maze test, the Morris water maze test, and the open field test. Scallop shell extract significantly reduced scopolamine-induced short-term memory impairment and partially reduced scopolamine-induced spatial memory impairment in the Morris water maze test. Scallop shell extract suppressed scopolamine-induced elevation of acetylcholine esterase activity in the cerebral cortex. Treatment with scallop shell extract reversed the increase in locomotor activity induced by scopolamine. Scallop shell extract also suppressed the increase in locomotor activity induced by MK801. Our results provide initial evidence that scallop shell extract reduces scopolamine-induced memory impairment and suppresses MK-801-induced hyperlocomotion. Copyright © 2016 Hainan Medical College. Production and hosting by Elsevier B.V. All rights reserved.

Neuroprotection by Combined Administration with Maslinic Acid, a Natural Product from Olea europaea, and MK-801 in the Cerebral Ischemia Model

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Yisong Qian

2016-08-01

Full Text Available Glutamate-mediated excitotoxicity is a major cause of ischemic brain damage. MK-801 confers neuroprotection by attenuating the activation of the N-methyl-d-aspartate (NMDA receptor, but it failed in clinical use due to the short therapeutic window. Here we aim to investigate the effects of maslinic acid, a natural product from Olea europaea, on the therapeutic time window and dose range for the neuroprotection of MK-801. Rats were administered with maslinic acid intracerebroventricularly and cerebral ischemia was induced by middle cerebral artery occlusion (MCAO followed by reperfusion. MK-801 was administered at 1 h, 2 h, 3 h and 4 h after ischemia, respectively. The cerebral infarct volume was determined by 2,3,5-Triphenyltetrazolium chloride (TTC staining, neuronal damage was assessed by Haematoxylin Eosin (H&E staining, and the expression of glial glutamate transporters and glial fibrillary acidic protein (GFAP was evaluated by immunohistochemistry and Western blot post-ischemia. Results showed that the presence of maslinic acid extended the therapeutic time window for MK-801 from 1 h to 3 h. Co-treatment of maslinic acid and MK-801 at a subthreshold dosage obviously induced neuroprotection after ischemia. The combination of these two compounds improved the outcome in ischemic rats. Moreover, maslinic acid treatment promoted the expression of GLT-1 and GFAP post-ischemia. These data suggest that the synergistic effect of maslinic acid on neurological protection might be associated with the improvement of glial function, especially with the increased expression of GLT-1. The combination therapy of maslinic acid and MK-801 may prove to be a potential strategy for treating acute ischemic stroke.

Neuroprotection by Combined Administration with Maslinic Acid, a Natural Product from Olea europaea, and MK-801 in the Cerebral Ischemia Model.

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Qian, Yisong; Tang, Xuzhen; Guan, Teng; Li, Yunman; Sun, Hongbin

2016-08-19

Glutamate-mediated excitotoxicity is a major cause of ischemic brain damage. MK-801 confers neuroprotection by attenuating the activation of the N-methyl-d-aspartate (NMDA) receptor, but it failed in clinical use due to the short therapeutic window. Here we aim to investigate the effects of maslinic acid, a natural product from Olea europaea, on the therapeutic time window and dose range for the neuroprotection of MK-801. Rats were administered with maslinic acid intracerebroventricularly and cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) followed by reperfusion. MK-801 was administered at 1 h, 2 h, 3 h and 4 h after ischemia, respectively. The cerebral infarct volume was determined by 2,3,5-Triphenyltetrazolium chloride (TTC) staining, neuronal damage was assessed by Haematoxylin Eosin (H&E) staining, and the expression of glial glutamate transporters and glial fibrillary acidic protein (GFAP) was evaluated by immunohistochemistry and Western blot post-ischemia. Results showed that the presence of maslinic acid extended the therapeutic time window for MK-801 from 1 h to 3 h. Co-treatment of maslinic acid and MK-801 at a subthreshold dosage obviously induced neuroprotection after ischemia. The combination of these two compounds improved the outcome in ischemic rats. Moreover, maslinic acid treatment promoted the expression of GLT-1 and GFAP post-ischemia. These data suggest that the synergistic effect of maslinic acid on neurological protection might be associated with the improvement of glial function, especially with the increased expression of GLT-1. The combination therapy of maslinic acid and MK-801 may prove to be a potential strategy for treating acute ischemic stroke.

MK-801 protection against methamphetamine-induced striatal dopamine terminal injury is associated with attenuated dopamine overflow.

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Weihmuller, F B; O'Dell, S J; Marshall, J F

1992-06-01

Repeated administrations of methamphetamine (m-AMPH) produce high extracellular levels of dopamine (DA) and subsequent striatal DA terminal damage. Pharmacological blockade of N-methyl-D-aspartate (NMDA) receptors has been shown previously to prevent m-AMPH-induced striatal DA terminal injury, but the mechanism for this protection is unclear. In the present study, in vivo microdialysis was used to determine the effects of blockade of NMDA receptors with the noncompetitive antagonist MK-801 on m-AMPH-induced striatal DA overflow. Four injections of MK-801 (0.5 mg/kg, ip) alone did not significantly change extracellular striatal DA concentrations from pretreatment values. Four treatments with m-AMPH (4.0 mg/kg, sc at 2-hr intervals) increased striatal DA overflow, and the overflow was particularly extensive following the fourth injection. This m-AMPH regimen produced a 40% reduction in striatal DA tissue content 1 week later. Treatment with MK-801 15 min before each of the four m-AMPH injections or prior to only the last two m-AMPH administrations attenuated the m-AMPH-induced increase in striatal DA overflow and protected completely against striatal DA depletions. Other MK-801 treatment regimens less effectively reduced the m-AMPH-induced striatal DA efflux and were ineffective in protecting against striatal DA depletions. Linear regression analysis indicated that cumulative DA overflow was strongly predictive (r = -.68) of striatal DA tissue levels measured one week later. These findings suggest that the extensive DA overflow seen during a neurotoxic regimen of m-AMPH is a crucial component of the subsequent neurotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Anticonvulsant Effects of Memantine and MK-801 in Guinea Pig Hippocampal Neurons.

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investigation we compared the anticonvulsant properties of Mem to those of MK-801 in guinea pig hippocampal slices. Extracellular recordings were...obtained from area CA1 of guinea pig hippocampal slices in a total submersion chamber at 32 deg C in normal oxygenated artificial cerebrospinal fluid (ACSF

Kynurenic acid prevented social recognition deficits induced by MK-801 in rats

Czech Academy of Sciences Publication Activity Database

Hliňák, Zdeněk; Krejčí, I.

2003-01-01

Roč. 52, č. 6 (2003), s. 805-808 ISSN 0862-8408 R&D Projects: GA ČR GA309/00/1644 Institutional research plan: CEZ:AV0Z5011922 Keywords : amnesia * kynurenic acid * MK-801 Subject RIV: FH - Neurology Impact factor: 0.939, year: 2003

In vivo binding and autoradiographic imaging of (+)-3-[125I]Iodo-MK-801 to the NMDA receptor-channel complex in rat brain

International Nuclear Information System (INIS)

Gibson, R.E.; Burns, H.D.; Thorpe, H.H.; Waisi Eng; Ransom, R.; Solomon, H.

1992-01-01

Radioiodinated (+)-3-Iodo-MK-801 is a high affinity radioligand for the N-methyl-D-aspartate (NMDA) receptor-channel complex. We have demonstrated in vivo localization in the CNS of rat which is stereoselective and blocked by coinjection of unlabeled MK-801. Autoradiography indicates localization in vivo which is in concordance with in vitro autoradiographic studies. These results indicate that radioiodinated (+)-3-Iodo-MK-801 is a useful probe for in vitro and in vivo autoradiographic studies and suggest that radioligands for the NMDA receptor may be developed which will provide in vivo images of receptor distribution in man. (author)

Developmental vitamin D deficiency alters MK 801-induced hyperlocomotion in the adult rat: An animal model of schizophrenia.

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Kesby, James P; Burne, Thomas H J; McGrath, John J; Eyles, Darryl W

2006-09-15

Developmental vitamin D (DVD) deficiency has been proposed as a risk factor for schizophrenia. The behavioral phenotype of adult rats subjected to transient low prenatal vitamin D is characterized by spontaneous hyperlocomotion but normal prepulse inhibition of acoustic startle (PPI). The aim of this study was to examine the impact of selected psychotropic agents and one well-known antipsychotic agent on the behavioral phenotype of DVD deplete rats. Control versus DVD deplete adult rats were assessed on holeboard, open field and PPI. In the open field, animals were given MK-801 and/or haloperidol. For PPI, the animals were given apomorphine or MK-801. DVD deplete rats had increased baseline locomotion on the holeboard task and increased locomotion in response to MK-801 compared to control rats. At low doses, haloperidol antagonized the MK-801 hyperactivity of DVD deplete rats preferentially and, at a high dose, resulted in a more pronounced reduction in spontaneous locomotion in DVD deplete rats. DVD depletion did not affect either baseline or drug-mediated PPI response. These results suggest that DVD deficiency is associated with a persistent alteration in neuronal systems associated with motor function but not those associated with sensory motor gating. In light of the putative association between low prenatal vitamin D and schizophrenia, the discrete behavioral differences associated with the DVD model may help elucidate the neurobiological correlates of schizophrenia.

Effect of acute and chronic MK-801 administration on extracellular glutamate and ascorbic acid release in the prefrontal cortex of freely moving mice on line with open-field behavior.

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Zuo, Dai-Ying; Zhang, Ya-Hong; Cao, Yue; Wu, Chun-Fu; Tanaka, Masatoshi; Wu, Ying-Liang

2006-04-04

The present study was designed to investigate the effects of acute and chronic administration of MK-801 (0.6 mg/kg), a noncompetitive NMDA-receptor antagonist on extracellular glutamate (Glu) and ascorbic acid (AA) release in the prefrontal cortex (PFC) of freely moving mice using in vivo microdialysis with open-field behavior. In line with earlier studies, acute administration of MK-801 induced an increase of Glu in the PFC. We also observed single MK-801 treatment increased AA release in the PFC. In addition, our results indicated that the basal AA levels in the PFC after MK-801 administration for 7 consecutive days were significantly decreased, and basal Glu levels also had a decreased tendency. After chronic administration (0.6 mg/kg, 7 days), MK-801 (0.6 mg/kg) challenge significantly decreased dialysate levels of AA and Glu. Our study also found that both acute and chronic administration of MK-801 induced hyperactivity in mice, but the intensity of acute administration was more than that of chronic administration. Furthermore, in all acute treatment mice, individual changes in Glu dialysate concentrations and the numbers of locomotion were positively correlated. In conclusion, this study may provide new evidence that a single MK-801 administration induces increases of dialysate AA and Glu concentrations in the PFC of freely moving mice, which are opposite to those induced by repeated MK-801 administration, with an unknown mechanism. Our results suggested that redox-response might play an important role in the model of schizophrenic symptoms induced by MK-801.

Buspirone Counteracts MK-801-Induced Schizophrenia-Like Phenotypes through Dopamine D3 Receptor Blockade

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Torrisi, Sebastiano Alfio; Salomone, Salvatore; Geraci, Federica; Caraci, Filippo; Bucolo, Claudio; Drago, Filippo; Leggio, Gian Marco

2017-01-01

Background: Several efforts have been made to develop effective antipsychotic drugs. Currently, available antipsychotics are effective on positive symptoms, less on negative symptoms, but not on cognitive impairment, a clinically relevant dimension of schizophrenia. Drug repurposing offers great advantages over the long-lasting, risky and expensive, de novo drug discovery strategy. To our knowledge, the possible antipsychotic properties of buspirone, an azapirone anxiolytic drug marketed in 1986 as serotonin 5-HT1A receptor (5-HT1AR) partial agonist, have not been extensively investigated despite its intriguing pharmacodynamic profile, which includes dopamine D3 (D3R) and D4 receptor (D4R) antagonist activity. Multiple lines of evidence point to D3R as a valid therapeutic target for the treatment of several neuropsychiatric disorders including schizophrenia. In the present study, we tested the hypothesis that buspirone, behaving as dopamine D3R antagonist, may have antipsychotic-like activity. Materials and Methods: Effects of acute administration of buspirone was assessed on a wide-range of schizophrenia-relevant abnormalities induced by a single administration of the non-competitive NMDAR antagonist MK-801, in both wild-type mice (WT) and D3R-null mutant mice (D3R-/-). Results: Buspirone (3 mg⋅kg-1, i.p.) was devoid of cataleptogenic activity in itself, but resulted effective in counteracting disruption of prepulse inhibition (PPI), hyperlocomotion and deficit of temporal order recognition memory (TOR) induced by MK-801 (0.1 mg⋅kg-1, i.p.) in WT mice. Conversely, in D3R-/- mice, buspirone was ineffective in preventing MK-801-induced TOR deficit and it was only partially effective in blocking MK-801-stimulated hyperlocomotion. Conclusion: Taken together, these results indicate, for the first time, that buspirone, might be a potential therapeutic medication for the treatment of schizophrenia. In particular, buspirone, through its D3R antagonist activity, may be

Different MK-801 administration schedules induce mild to severe learning impairments in an operant conditioning task: role of buspirone and risperidone in ameliorating these cognitive deficits.

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Rapanelli, Maximiliano; Frick, Luciana Romina; Bernardez-Vidal, Micaela; Zanutto, Bonifacio Silvano

2013-11-15

Blockade of N-methyl-d-aspartate receptor (NMDA) by the noncompetitive NMDA receptor (NMDAR) antagonist MK-801 produces behavioral abnormalities and alterations in prefrontal cortex (PFC) functioning. Due to the critical role of the PFC in operant conditioning task learning, we evaluated the effects of acute, repeated postnatal injections of MK-801 (0.1mg/kg) on learning performance. We injected Long-Evans rats i.p. with MK-801 (0.1mg/kg) using three different administration schedules: injection 40 min before beginning the task (during) (n=12); injection twice daily for six consecutive days prior to beginning the experimental procedures (prior) (n=12); or twice daily subcutaneous injections from postnatal day 7 to 11 (postnatal) (n=12). Next, we orally administered risperidone (serotonin receptor 2A and dopamine receptor 2 antagonist, 1mg/kg) or buspirone (serotonin receptor 1A partial agonist, 10mg/kg) to animals treated with the MK-801 schedule described above. The postnatal and prior administration schedules produced severe learning deficits, whereas injection of MK-801 just before training sessions had only mild effects on acquisition of an operant conditioning. Risperidone was able to reverse the detrimental effect of MK-801 in the animals that were treated with MK-801 during and prior training sessions. In contrast, buspirone was only effective at mitigating the cognitive deficits induced by MK-801 when administered during the training procedures. The data demonstrates that NMDA antagonism disrupts basic mechanisms of learning in a simple PFC-mediated operant conditioning task, and that buspirone and risperidone failed to attenuate the learning deficits when NMDA neurotransmission was blocked in the early stages of the postnatal period. Copyright © 2013 Elsevier B.V. All rights reserved.

Effect of clozapine on locomotor activity and anxiety-related behavior in the neonatal mice administered MK-801.

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Pınar, Neslihan; Akillioglu, Kubra; Sefil, Fatih; Alp, Harun; Sagir, Mustafa; Acet, Ahmet

2015-08-11

Atypical antipsychotics have been used to treat fear and anxiety disturbance that are highly common in schizophrenic patients. It is suggested that disruptions of N-methyl-d-aspartate (NMDA)-mediated transmission of glutamate may underlie the pathophysiology of schizophrenia. The present study was conducted to analyze the effectiveness of clozapine on the anxiety-related behavior and locomotor function of the adult brain, which had previously undergone NMDA receptor blockade during a developmental period. In order to block the NMDA receptor, male mice were administered 0.25 mg/kg of MK-801 on days 7 to 10 postnatal. In adulthood, they were administered intraperitoneally 0.5 mg/kg of clozapine and tested with open-field and elevated plus maze test, to assess their emotional behavior and locomotor activity. In the group receiving MK-801 in the early developmental period the elevated plus maze test revealed a reduction in the anxiety-related behavior (ptest indicated a decrease in locomotor activity (plocomotor activity and anxiety-related behavior, induced by administration of the MK-801 in neonatal period.

Differential effects of MK-801 on cerebrocortical neuronal injury in C57BL/6J, NSA, and ICR mice.

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Brosnan-Watters, G; Ogimi, T; Ford, D; Tatekawa, L; Gilliam, D; Bilsky, E J; Nash, D

2000-08-01

1. Antagonists of the N-methyl-D-aspartate (NMDA) glutamate (Glu) receptor, including [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate], dizocilpine maleate (MK-801), injure pyramidal neurons in the posterior cingulate/retrosplenial (PC/RS) cortex when administered systemically to adult rats and mice. 2. These results have, to our knowledge, only been reported previously in Harlan Sprague Dawley albino rats and International Cancer Research (ICR) mice, an outbred albino strain. 3. Male Non-Swiss Albino (NSA) mice, an albino outbred strain, and male C57BL/6J (B6) mice, a pigmented inbred strain, were injected systemically with 1 mg/kg of MK-801 in the first experiment. This dose of MK-801 reliably produces cytoplasmic vacuoles in neurons in layers III and IV of the PC/RS cortex in 100% of ICR mice treated 4. There was a significant difference in the number of vacuolated neurons in B6 and NSA mice, as assessed by ANOVA. The NSA were not significantly different than previously examined ICR mice, but the B6 had fewer vacuolated neurons than either of the two outbred strains. 5. In the second experiment, male NSA, ICR, and B6 mice were injected systemically with a high dose, 10 mg/kg, of MK-801. This dose has been demonstrated to result in necrosis in the same population of neurons injured by lower doses of MK-801. 6. An ANOVA indicated that there was a significant difference among the three strains of mice, and a Fisher's protected t revealed that the B6 mice were significantly different from both the NSA and ICR, but that, with our test, those two strains were indistinguishable. 7. Male ICR, NSA, and B6 mice were tested in the holeboard food search task 5 hours after 1 mg/kg of MK-801. There were significant differences between the strains in performance both pre and posttreatment. The effect of the drug was not statistically significant. 8. These results suggest that there may be a genetically mediated difference in the reaction to NMDA

Establishment of a schizophrenic animal model through chronic administration of MK-801 in infancy and social isolation in childhood.

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Liu, Weiqing; Wang, Xiuyan; Hong, Wenjuan; Wang, Dong; Chen, Xiaogang

2017-02-01

Although an increasing amount of evidence supports a "two-hit" hypothesis for the neurodevelopmental model of schizophrenia, there has been no development in animal models to test this hypothesis. An animal model was established by chronic administration of 0.1, 0.3, and 0.5mg/kg MK-801 in P7-P21 rats followed by four weeks of social isolation in childhood and then five days of social housing. Animal behaviors were measured by the open field (OF) test, the novel object recognition (NOR) test, the prepulse inhibition (PPI) test, and the elevated plus maze (EPM) test. We found a significant decrease in the NOR index in adolescent rats compared to saline control rats when administering 0.5mg/kg of MK-801 (P=0.02). We found that social isolation had no significant effect on NOR index, though social isolation significantly increased the total distance traveled and significantly decreased the resting time in adolescent rats in the OF test (Psocial isolation had no significant effect on the percent of PPI and startle amplitudes in adolescent rats. Social isolation significantly reduced the open arm entries in adolescent rats in the EPM test (P=0.023), but it did not reduce the ratio to enter the open arms and the stay time in open arm. Administration of MK-801 showed no significant effect on the indexes of entering the open arms in the EPM test on adolescent rats. MK-801 intervention in infancy is associated with the damage of long-term visual memory, whereas social isolation in childhood is associated with the increased spontaneous activity and anxiety levels. Administration of MK-801 in infancy and social isolation in childhood are two independent factors on the neurodevelopmental defects. Copyright © 2017 Elsevier Inc. All rights reserved.

Combined Diazepam and MK-801 Therapy Provides Synergistic Protection from Tetramethylenedisulfotetramine-induced Tonic-Clonic Seizures and Lethality in Mice

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Shakarjian, Michael P.; Ali, Mahil S.; Velíšková, Jana; Stanton, Patric K.; Heck, Diane E.; Velíšek, Libor

2015-01-01

The synthetic rodenticide, tetramethylenedisulfotetramine (TMDT), is a persistent and highly lethal GABA-gated Cl− channel blocker. TMDT is clandestinely produced, remains popular in mainland China, and causes numerous unintentional and deliberate poisonings worldwide. TMDT is odorless, tasteless, and easy to manufacture, features that make it a potential weapon of terrorism. There is no effective treatment. We previously characterized the effects of TMDT in C57BL/6 mice and surveyed efficacies of GABAergic and glutamatergic anticonvulsant treatments. At 0.4 mg/kg i.p., TMDT produced neurotoxic symptomatology consisting of twitches, clonic and tonic-clonic seizures, often progressing to status epilepticus and death. If administered immediately after the occurrence of the first clonic seizure, the benzodiazepine diazepam (DZP) effectively prevented all subsequent seizure symptoms, whereas the NMDA receptor antagonist dizocilpine (MK-801) primarily prevented tonic-clonic seizures. The latter agent, however, appeared to be more effective at preventing delayed death. The present study further explored these phenomena, and characterized the therapeutic actions of DZP and MK-801 as combinations. Joint treatment with both DZP and MK-801 displayed synergistic protection against tonic-clonic seizures and 24 hour lethality as determined by isobolographic analysis. Clonic seizures, however, remained poorly controlled. A modification of the treatment regimen, where DZP was followed 10 min later by MK-801, yielded a reduction in both types of seizures and improved overall outcome. Simultaneous monitoring of subjects via EEG and videography confirmed effectiveness of this sequential regimen. We conclude that TMDT blockage at GABAA receptors involves early activation of NMDA receptors, which contribute to persistent ictogenic activity. Our data predict that a sequential combination treatment with DZP followed by MK-801 will be superior to either individual therapy with, or

Impairment of Fos protein formation in the rat infarct borderzone by MK-801, but not by NBQX

DEFF Research Database (Denmark)

Christensen, Thomas; Jørgensen, M B; Diemer, Nils Henrik

1993-01-01

or a glutamate receptor antagonist; the non-competitive NMDA receptor antagonist MK-801 or the AMPA receptor antagonist NBQX which are known to be able to reduce infarct size in MCA occluded rats. The saline treated rats showed presence of Fos protein in nerve cell nuclei throughout the cortical and striatal...... infarct borderzone, but no staining in the infarct core or contralateral hemisphere. MK-801 almost totally abolished this expression of Fos protein whereas NBQX had no significant effect on Fos protein expression. It is suggested that the Fos protein induction is due to repeated spreading depressions...

N-methyl-D-aspartate prevented memory deficits induced by MK-801 in mice

Czech Academy of Sciences Publication Activity Database

Hliňák, Zdeněk; Krejčí, I.

2003-01-01

Roč. 52, č. 6 (2003), s. 809-812 ISSN 0862-8408 R&D Projects: GA ČR GA309/00/1644 Institutional research plan: CEZ:AV0Z5011922 Keywords : N-methyl-D-aspartate * MK-801 * spatial memory Subject RIV: FH - Neurology Impact factor: 0.939, year: 2003

A NMDA receptor antagonist, MK-801 impairs consolidating extinction of auditory conditioned fear responses in a Pavlovian model.

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Jun-Li Liu

Full Text Available BACKGROUND: In auditory fear conditioning, repeated presentation of the tone in the absence of shock leads to extinction of the acquired fear responses. The glutamate N-methyl-D-aspartate receptor (NMDAR is thought to be involved in the extinction of the conditioned fear responses, but its detailed role in initiating and consolidating or maintaining the fear extinction memory is unclear. Here we investigated this issue by using a NMDAR antagonist, MK-801. METHODS/MAIN FINDINGS: The effects of immediate (beginning at 10 min after the conditioning and delayed (beginning at 24 h after conditioning extinctions were first compared with the finding that delayed extinction caused a better and long-lasting (still significant on the 20(th day after extinction depression on the conditioned fear responses. In a second experiment, MK-801 was intraperitoneally (i.p. injected at 40 min before, 4 h or 12 h after the delayed extinction, corresponding to critical time points for initiating, consolidating or maintaining the fear extinction memory. i.p. injection of MK-801 at either 40 min before or 4 h after delayed extinction resulted in an impairment of initiating and consolidating fear extinction memory, which caused a long lasting increased freezing score that was still significant on the 7th day after extinction, compared with extinction group. However, MK-801 administered at 12 h after the delayed extinction, when robust consolidation has been occurred and stabilized, did not affect the established extinction memory. Furthermore, the changed freezing behaviors was not due to an alteration in general anxiety levels, since MK-801 treatment had no effect on the percentage of open-arm time or open-arm entries in an Elevated Plus Maze (EPM task. CONCLUSIONS/SIGNIFICANCE: Our data suggested that the activation of NMDARs plays important role in initiation and consolidation but not maintenance of fear extinction memory. Together with the fact that NMDA receptor is

Selective activation of M4 muscarinic acetylcholine receptors reverses MK-801-induced behavioral impairments and enhances associative learning in rodents

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Bubser, Michael; Bridges, Thomas M; Dencker, Ditte

2014-01-01

PAMs, enabling a more extensive characterization of M4 actions in rodent models. We used VU0467154 to test the hypothesis that selective potentiation of M4 receptor signaling could ameliorate the behavioral, cognitive, and neurochemical impairments induced by the noncompetitive NMDAR antagonist MK-801....... VU0467154 produced a robust dose-dependent reversal of MK-801-induced hyperlocomotion and deficits in preclinical models of associative learning and memory functions, including the touchscreen pairwise visual discrimination task in wild-type mice, but failed to reverse these stimulant...

Vitamin A depletion alters sensitivity of motor behavior to MK-801 in C57BL/6J mice

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Zhu Hui

2010-01-01

Full Text Available Abstract Background Vitamin A and its derivatives (retinoids are crucial for the development, maintenance and morphogenesis of the central nervous system (CNS. Although motor impairment has been reported in postnatal vitamin A depletion rodents, the effect of vitamin A depletion on homeostasis maintaining capability in response to external interference is not clear. Methods In the current study, we measured the effect of vitamin A depletion on motor ability and pain sensitivity under two different conditions: 1. prior to any injection and 2. after the injection of an N-methyl-D-aspartate (NMDA receptor antagonist (MK-801. Results Vitamin A depletion mice showed decreased body weight, enhanced locomotor activity, increased rearing and less tail flick latency. Vitamin A depletion also induced hypersensitivity of stereotypy, ataxia, rearing, and tail flick latency to MK-801, but hyposensitivity of locomotion to MK-801. Conclusions These findings suggest that vitamin A depletion affect broad basal behavior and disrupt homeostasis maintaining capability in response to glutamate perturbation. We provide a useful animal model for assessing the role of vitamin A depletion in regulating animal behavior, and for detecting how neurotransmitter pathways might be involved in vitamin A depletion related behavioral abnormalities.

Interactions of MK-801 with glutamate-, glutamine- and methamphetamine-evoked release of [3H]dopamine from striatal slices

International Nuclear Information System (INIS)

Bowyer, J.F.; Scallet, A.C.; Holson, R.R.; Lipe, G.W.; Slikker, W. Jr.; Ali, S.F.

1991-01-01

The interactions of MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine], glutamate and glutamine with methamphetamine (METH)-evoked release of [ 3 H]dopamine were assessed in vitro to determine whether MK-801 inhibition of METH neurotoxicity might be mediated presynaptically, and to evaluate the effects of glutamatergic stimulation on METH-evoked dopamine release. MK-801 inhibition of glutamate- or METH-evoked dopamine release might reduce synaptic dopamine levels during METH exposure and decrease the formation of 6-hydroxydopamine or other related neurotoxins. Without Mg 2+ present, 40 microM and 1 mM glutamate evoked a N-methyl-D-aspartate receptor-mediated [ 3 H]dopamine and [ 3 H]metabolite (tritium) release of 3 to 6 and 12 to 16% of total tritium stores, respectively, from striatal slices. With 1.50 mM Mg 2+ present, 10 mM glutamate alone or in combination with the dopamine uptake blocker nomifensine released only 2.1 or 4.2%, respectively, of total tritium stores, and release was only partially dependent on N-methyl-D-aspartate-type glutamate receptors. With or without 1.50 mM Mg 2+ present, 0.5 or 5 microM METH evoked a substantial release of tritium (5-8 or 12-21% of total stores, respectively). METH-evoked dopamine release was not affected by 5 microM MK-801 but METH-evoked release was additive with glutamate-evoked release. Without Mg 2+ present, 1 mM glutamine increased glutamate release and induced the release of [ 3 H]dopamine and metabolites. Both 0.5 and 5 microM METH also increased tritium release with 1 mM glutamine present. When striatal slices were exposed to 5 microM METH this glutamine-evoked release of glutamate was increased more than 50%

MK-801-induced deficits in social recognition in rats: reversal by aripiprazole, but not olanzapine, risperidone, or cannabidiol.

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Deiana, Serena; Watanabe, Akihito; Yamasaki, Yuki; Amada, Naoki; Kikuchi, Tetsuro; Stott, Colin; Riedel, Gernot

2015-12-01

Deficiencies in social activities are hallmarks of numerous brain disorders. With respect to schizophrenia, social withdrawal belongs to the category of negative symptoms and is associated with deficits in the cognitive domain. Here, we used the N-methyl-D-aspartate receptor antagonist dizocilpine (MK-801) for induction of social withdrawal in rats and assessed the efficacy of several atypical antipsychotics with different pharmacological profiles as putative treatment. In addition, we reasoned that the marijuana constituent cannabidiol (CBD) may provide benefit or could be proposed as an adjunct treatment in combination with antipsychotics. Hooded Lister rats were tested in the three-chamber version for social interaction, with an initial novelty phase, followed after 3 min by a short-term recognition memory phase. No drug treatment affected sociability. However, distinct effects on social recognition were revealed. MK-801 reduced social recognition memory at all doses (>0.03 mg/kg). Predosing with aripiprazole dose-dependently (2 or 10 mg/kg) prevented the memory decline, but doses of 0.1 mg/kg risperidone or 1 mg/kg olanzapine did not. Intriguingly, CBD impaired social recognition memory (12 and 30 mg/kg) but did not rescue the MK-801-induced deficits. When CBD was combined with protective doses of aripiprazole (CBD-aripiprazole at 12 :  or 5 : 2 mg/kg) the benefit of the antipsychotic was lost. At the same time, activity-related changes in behaviour were excluded as underlying reasons for these pharmacological effects. Collectively, the combined activity of aripiprazole on dopamine D2 and serotonin 5HT1A receptors appears to provide a significant advantage over risperidone and olanzapine with respect to the rescue of cognitive deficits reminiscent of schizophrenia. The differential pharmacological properties of CBD, which are seemingly beneficial in human patients, did not back-translate and rescue the MK-801-induced social memory deficit.

The N-Methyl-d-Aspartate Receptor Antagonist MK-801 Prevents Thallium-Induced Behavioral and Biochemical Alterations in the Rat Brain.

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Osorio-Rico, Laura; Villeda-Hernández, Juana; Santamaría, Abel; Königsberg, Mina; Galván-Arzate, Sonia

2015-01-01

Thallium (Tl(+)) is a toxic heavy metal capable of increasing oxidative damage and disrupting antioxidant defense systems. Thallium invades the brain cells through potassium channels, increasing neuronal excitability, although until now the possible role of glutamatergic transmission in this event has not been investigated. Here, we explored the possible involvement of a glutamatergic component in the Tl(+)-induced toxicity through the N-methyl-d-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) in rats. The effects of MK-801 (1 mg/kg, intraperitoneally [ip]) on early (24 hours) motor alterations, lipid peroxidation, reduced glutathione (GSH) levels, and GSH peroxidase activity induced by Tl(+) acetate (32 mg/kg, ip) were evaluated in adult rats. MK-801 attenuated the Tl(+)-induced hyperactivity and lipid peroxidation in the rat striatum, hippocampus and midbrain, and produced mild effects on other end points. Our findings suggest that glutamatergic transmission via NMDA receptors might be involved in the Tl(+)-induced altered regional brain redox activity and motor performance in rats. © The Author(s) 2015.

Effects of a glycine transporter-1 inhibitor and D-serine on MK-801-induced immobility in the forced swimming test in rats.

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Kawaura, Kazuaki; Koike, Hiroyuki; Kinoshita, Kohnosuke; Kambe, Daiji; Kaku, Ayaka; Karasawa, Jun-ichi; Chaki, Shigeyuki; Hikichi, Hirohiko

2015-02-01

Glutamatergic dysfunction, particularly the hypofunction of N-methyl-D-aspartate (NMDA) receptors, is involved in the pathophysiology of schizophrenia. The positive modulation of the glycine site on the NMDA receptor has been proposed as a novel therapeutic approach for schizophrenia. However, its efficacy against negative symptoms, which are poorly managed by current medications, has not been fully addressed. In the present study, the effects of the positive modulation of the glycine site on the NMDA receptor were investigated in an animal model of negative symptoms of schizophrenia. The subchronic administration of MK-801 increased immobility in the forced swimming test in rats without affecting spontaneous locomotor activity. The increased immobility induced by MK-801 was attenuated by the atypical antipsychotic clozapine but not by either the typical antipsychotic haloperidol or the antidepressant imipramine, indicating that the increased immobility induced by subchronic treatment with MK-801 in the forced swimming test may represent a negative symptom of schizophrenia. Likewise, positive modulation of the glycine sites on the NMDA receptor using an agonist for the glycine site, D-serine, and a glycine transporter-1 inhibitor, N-[(3R)-3-([1,1'-biphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine hydrochloride (NFPS), significantly reversed the increase in immobility in MK-801-treated rats without reducing the immobility time in vehicle-treated rats. The present results show that the stimulation of the NMDA receptor through the glycine site on the receptor either directly with D-serine or by blocking glycine transporter-1 attenuates the immobility elicited by the subchronic administration of MK-801 and may be potentially useful for the treatment of negative symptoms of schizophrenia. Copyright © 2014 Elsevier B.V. All rights reserved.

Stimulation of the metabotropic glutamate (mGlu) 2 receptor attenuates the MK-801-induced increase in the immobility time in the forced swimming test in rats.

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Kawaura, Kazuaki; Karasawa, Jun-Ichi; Hikichi, Hirohiko

2016-02-01

Negative symptoms of schizophrenia are poorly managed using the currently available antipsychotics. Previous studies indicate that agonists of the metabotropic glutamate (mGlu) 2/3 receptors may provide a novel approach for the treatment of schizophrenia. However, the effects of mGlu2/3 receptor agonists or mGlu2 receptor positive allosteric modulators have not yet been clearly elucidated in animal models of the negative symptoms of schizophrenia. Recently, we reported that the forced swimming test in rats treated with subchronic MK-801, an NMDA receptor antagonist, may be regarded as a useful test to evaluate the activities of drugs against the negative symptoms of schizophrenia. We evaluated the effects of LY379268, an mGlu2/3 receptor agonist, and BINA, an mGlu2 receptor positive allosteric modulator, on the hyperlocomotion induced by acute administration of MK-801 (0.15mg/kg, sc) and on the increase in the immobility time in the forced swimming test induced by subchronic treatment with MK-801 (0.5mg/kg, sc, twice a day for 7 days) in rats. Both LY379268 (3mg/kg, sc) and BINA (100mg/kg, ip) attenuated the increase in the immobility time induced by subchronic treatment with MK-801 at the same doses at which they attenuated the MK-801-induced increase in locomotor activity, but had no effect on the immobility time in saline-treated rats. The present results suggest that stimulation of the mGlu2 receptor attenuates the increase in the immobility time in the forced swimming test elicited by subchronic administration of MK-801, and may be potentially useful for treatment of the negative symptoms of schizophrenia. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

[MK-801 or DNQX reduces electroconvulsive shock-induced impairment of learning-memory and hyperphosphorylation of Tau in rats].

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Liu, Chao; Min, Su; Wei, Ke; Liu, Dong; Dong, Jun; Luo, Jie; Liu, Xiao-Bin

2012-08-25

This study explored the effect of the excitatory amino acid receptor antagonists on the impairment of learning-memory and the hyperphosphorylation of Tau protein induced by electroconvulsive shock (ECT) in depressed rats, in order to provide experimental evidence for the study on neuropsychological mechanisms improving learning and memory impairment and the clinical intervention treatment. The analysis of variance of factorial design set up two intervention factors which were the electroconvulsive shock (two level: no disposition; a course of ECT) and the excitatory amino acid receptor antagonists (three level: iv saline; iv NMDA receptor antagonist MK-801; iv AMPA receptor antagonist DNQX). Forty-eight adult Wistar-Kyoto (WKY) rats (an animal model for depressive behavior) were randomly divided into six experimental groups (n = 8 in each group): saline (iv 2 mL saline through the tail veins of WKY rats ); MK-801 (iv 2 mL 5 mg/kg MK-801 through the tail veins of WKY rats) ; DNQX (iv 2 mL 5 mg/kg DNQX through the tail veins of WKY rats ); saline + ECT (iv 2 mL saline through the tail veins of WKY rats and giving a course of ECT); MK-801 + ECT (iv 2 mL 5 mg/kg MK-801 through the tail veins of WKY rats and giving a course of ECT); DNQX + ECT (iv 2 mL 5 mg/kg DNQX through the tail veins of WKY rats and giving a course of ECT). The Morris water maze test started within 1 day after the finish of the course of ECT to evaluate learning and memory. The hippocampus was removed from rats within 1 day after the finish of Morris water maze test. The content of glutamate in the hippocampus of rats was detected by high performance liquid chromatography. The contents of Tau protein which included Tau5 (total Tau protein), p-PHF1(Ser396/404), p-AT8(Ser199/202) and p-12E8(Ser262) in the hippocampus of rats were detected by immunohistochemistry staining (SP) and Western blot. The results showed that ECT and the glutamate ionic receptor blockers (NMDA receptor antagonist MK-801 and

[123I]Epidepride neuroimaging of dopamine D2/D3 receptor in chronic MK-801-induced rat schizophrenia model

International Nuclear Information System (INIS)

Huang, Yuan-Ruei; Shih, Jun-Ming; Chang, Kang-Wei; Huang, Chieh; Wu, Yu-Lung; Chen, Chia-Chieh

2012-01-01

Purpose: [ 123 I]Epidepride is a radio-tracer with very high affinity for dopamine D 2 /D 3 receptors in brain. The importance of alteration in dopamine D 2 /D 3 receptor binding condition has been wildly verified in schizophrenia. In the present study we set up a rat schizophrenia model by chronic injection of a non-competitive NMDA receptor antagonist, MK-801, to examine if [ 123 I]epidepride could be used to evaluate the alterations of dopamine D 2 /D 3 receptor binding condition in specific brain regions. Method: Rats were given repeated injection of MK-801 (dissolved in saline, 0.3 mg/kg) or saline for 1 month. Afterwards, total distance traveled (cm) and social interaction changes were recorded. Radiochemical purity of [ 123 I]epidepride was analyzed by Radio-Thin-Layer Chromatography (chloroform: methanol, 9:1, v/v) and [ 123 I]epidepride neuroimages were obtained by ex vivo autoradiography and small animal SPECT/CT. Data obtained were then analyzed to determine the changes of specific binding ratio. Result: Chronic MK-801 treatment for a month caused significantly increased local motor activity and induced an inhibition of social interaction. As shown in [ 123 I]epidepride ex vivo autoradiographs, MK-801 induced a decrease of specific binding ratio in the striatum (24.01%), hypothalamus (35.43%), midbrain (41.73%) and substantia nigra (37.93%). In addition, [ 123 I]epidepride small animal SPECT/CT neuroimaging was performed in the striatum and midbrain. There were statistically significant decreases in specific binding ratio in both the striatum (P 123 I]epidepride is a useful radio-tracer to reveal the alterations of dopamine D 2 /D 3 receptor binding in a rat schizophrenia model and is also helpful to evaluate therapeutic effects of schizophrenia in the future.

The effect of combined treatment with risperidone and antidepressants on the MK-801-induced deficits in the social interaction test in rats.

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Kamińska, Katarzyna; Rogóż, Zofia

2015-12-01

Several clinical reports have suggested that augmentation of atypical antipsychotics' activity by antidepressants may efficiently improve the treatment of negative and some cognitive symptoms of schizophrenia. The aim of the present study was to investigate the effect of antidepressant mirtazapine or escitalopram and risperidone (an atypical antipsychotic), given separately or jointly, on the MK-801-induced deficits in the social interaction test in rats. Antidepressants and risperidone were given 60 and 30 min before the test, respectively. The social interaction of male Wistar rats was measured for 10 min, starting 4 h after MK-801 (0.1 mg/kg) administration. In the social interaction test, MK-801-induced deficits in the parameters studied, i.e. the number of episodes and the time of interactions. Risperidone at a higher dose (0.1 mg/kg) reversed that effect. Co-treatment with an ineffective dose of risperidone (0.01 mg/kg) and mirtazapine (2.5 or 5 mg/kg) or escitalopram only at a dose of 5 mg/kg (but not 2.5 and 10 mg/kg) abolished the deficits evoked by MK-801. The obtained results suggest that especially mirtazapine, and to a smaller degree escitalopram may enhance the antipsychotic-like effect of risperidone in the animal test modeling some negative symptoms of schizophrenia. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Clozapine blockade of MK-801-induced learning/memory impairment in the mEPM: Role of 5-HT1A receptors and hippocampal BDNF levels.

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López Hill, Ximena; Richeri, Analía; Scorza, María Cecilia

2017-10-01

Cognitive impairment associated with schizophrenia (CIAS) is highly prevalent and affects the overall functioning of patients. Clozapine (Clz), an atypical antipsychotic drug, significantly improves CIAS although the underlying mechanisms remain under study. The role of the 5-HT 1A receptor (5-HT 1A -R) in the ability of Clz to prevent the learning/memory impairment induced by MK-801 was investigated using the modified elevated plus-maze (mEPM) considering the Transfer latency (TL) as an index of spatial memory. We also investigated if changes in hippocampal brain-derived neurotrophic factor (BDNF) levels underlie the behavioral prevention induced by Clz. Clz (0.5 and 1mg/kg)- or vehicle-pretreated Wistar rats were injected with MK-801 (0.05mg/kg) or saline. TL was evaluated 35min later (TL1, acquisition session) while learning/memory performance was measured 24h (TL2, retention session) and 48h later (TL3, long-lasting effect). WAY-100635, a 5-HT 1A -R antagonist, was pre-injected (0.3mg/kg) to examine the presumed 5-HT 1A -R involvement in Clz action. At TL2, another experimental group treated with Clz and MK-801 and its respective control groups were added to measure BDNF protein levels by ELISA. TL1 and TL3 were not significantly modified by the different treatments. MK-801 increased TL2 compared to control group leading a disruption of spatial memory processing which was markedly attenuated by Clz. WAY-100635 suppressed this action supporting a relevant role of 5-HT 1A -R in the Clz mechanism of action to improve spatial memory dysfunction. Although a significant decrease of hippocampal BDNF levels underlies the learning/memory impairment induced by MK-801, this effect was not significantly prevented by Clz. Copyright © 2017 Elsevier Inc. All rights reserved.

Pharmacological or genetic orexin 1 receptor inhibition attenuates MK-801 induced glutamate release in mouse cortex

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Leah eAluisio

2014-05-01

Full Text Available The orexin/hypocretin neuropeptides are produced by a cluster of neurons within the lateral posterior hypothalamus and participate in neuronal regulation by activating their receptors (OX1 and OX2 receptors. The orexin system projects widely through the brain and functions as an interface between multiple regulatory systems including wakefulness, energy balance, stress, reward and emotion. Recent studies have demonstrated that orexins and glutamate interact at the synaptic level and that orexins facilitate glutamate actions. We tested the hypothesis that orexins modulate glutamate signaling via OX1 receptors by monitoring levels of glutamate in frontal cortex of freely moving mice using enzyme coated biosensors under inhibited OX1 receptor conditions. MK-801, an NMDA receptor antagonist, was administered subcutaneously (0.178 mg/kg to indirectly disinhibit pyramidal neurons and therefore increase cortical glutamate release. In wild-type mice, pretreatment with the OX1 receptor antagonist GSK-1059865 (10 mg/kg S.C. which had no effect by itself, significantly attenuated the cortical glutamate release elicited by MK-801. OX1 receptor knockout mice had a blunted glutamate release response to MK-801 and exhibited about half of the glutamate release observed in wild-type mice in agreement with the data obtained with transient blockade of OX1 receptors. These results indicate that pharmacological (transient or genetic (permanent inhibition of the OX1 receptor similarly interfere with glutamatergic function in the cortex. Selectively targeting the OX1 receptor with an antagonist may normalize hyperglutamatergic states and thus may represent a novel therapeutic strategy for the treatment of various psychiatric disorders associated with hyperactive states.

Early Adolescent MK-801 Exposure Impairs the Maturation of Ventral Hippocampal Control of Basolateral Amygdala Drive in the Adult Prefrontal Cortex

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Thomases, Daniel R.; Cass, Daryn K.; Meyer, Jacqueline D.; Caballero, Adriana

2014-01-01

The adolescent susceptibility to the onset of psychiatric disorders is only beginning to be understood when factoring in the development of the prefrontal cortex (PFC). The functional maturation of the PFC is dependent upon proper integration of glutamatergic inputs from the ventral hippocampus (vHipp) and the basolateral amygdala (BLA). Here we assessed how transient NMDAR blockade during adolescence alters the functional interaction of vHipp–BLA inputs in regulating PFC plasticity. Local field potential recordings were used to determine changes in long-term depression (LTD) and long-term potentiation (LTP) of PFC responses resulting from vHipp and BLA high-frequency stimulation in adult rats that received repeated injections of saline or the NMDAR antagonist MK-801 from postnatal day 35 (P35) to P40. We found that early adolescent MK-801 exposure elicited an age- and input-specific dysregulation of vHipp–PFC plasticity, characterized by a shift from LTD to LTP without altering the BLA-induced LTP. Data also showed that the vHipp normally resets the LTP state of BLA transmission; however, this inhibitory regulation is absent following early adolescent MK-801 treatment. This deficit was reminiscent of PFC responses seen in drug-naive juveniles. Notably, local prefrontal upregulation of GABAAα1 function completely restored vHipp functionality and its regulation of BLA plasticity in MK-801-treated rats. Thus, NMDAR signaling is critical for the periadolescent acquisition of a GABA-dependent hippocampal control of PFC plasticity, which enables the inhibitory control of the prefrontal output by the vHipp. A dysregulation of this pathway can alter PFC processing of other converging afferents such as those from the BLA. PMID:24990926

Effect of antemortem and postmortem factors on [3H]MK-801 binding in the human brain: Transient elevation during early childhood

International Nuclear Information System (INIS)

Kornhuber, J.; Mack-Burkhardt, F.; Konradi, C.; Fritze, J.; Riederer, P.

1989-01-01

The effect of a number of antemortem and postmortem factors on [ 3 H]MK-801 binding was investigated under equilibrium conditions in the frontal cortex of human brains of 38 controls. Binding values transiently increased during the early postnatal period reaching a maximum at the age of about 2 years. After age 10 years [ 3 H]MK-801 binding sites disappeared at 5.7% per decade. The storage time of brain tissue had a reducing effect on these binding sites. There was no effect of gender, brain weight or postmortem time interval and the binding sites were bilaterally symmetrically distributed in the frontal cortex

"Interaction of different doses of Aspartame with Morphine-induced antinociception in the presence of MK-801, a NMDA antagonist "

Directory of Open Access Journals (Sweden)

Abdollahi M

2002-07-01

Full Text Available This study was designed to investigate the relative role of sweetness and comparative effects of different taste sensation of the non - caloric sweetener , aspartame on pain and its interaction with MK - 80] as a non - selective MMDA antagonist by formalin - test in mice. The formalin - test was chosen because it measures the response to a long - lasting nociceptive stimulus and closely resembles to the clinical pain. Morphine induced a dose dependent antinociception in the early and late phases of formalin test. Twelve days pretreatment of animals by aspartame ( 0.08% , 0.16% , 0.32% significantly potentiated morphine - induced (1.5-9 mg/kg analgesia in the early phase but significantly antagonized its analgesic effect in the late phase, dose dependently. Aspartame (0.16% alone showed a reduction in pain response . Naloxone (0.4 mg/kg significantly antagonized the antinociceptive effect of morphine in the presence of aspartame (0-0.32% in the early phase. Increasing the dose of aspartame decreased effects of naloxone. MK-801 (0.1 mg/kg as an N- Methyl - D - Aspartate (NMDA antagonist significantly potentiated the effect of aspartame on morphine - induced antinociception in the early phase. In the late phase, naloxone (0.4 mg/kg increased pain response but MK- 801 (0.1 mg/kg induced anti-inflammatory effect significantly. Treatment of animals with MK- 801 alone, significantly induced analgesia in both phases of formalin - test. This effect was potentiated with aspartame dose - dependently. Possible interaction of aspartame with NMDA receptors and its role to facilitate endogenous opioid system are proposed mechanisms of aspartame in modulating morphine - induced antinociception. Furthermore, the resulting association between morphine and aspartame chronic consumption may be explained as an interactive action rather than simple dose combination of both drugs.

Effects of the noncompetitive N-methyl-d-aspartate receptor antagonists ketamine and MK-801 on pain-stimulated and pain-depressed behaviour in rats.

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Hillhouse, T M; Negus, S S

2016-09-01

Pain is a significant public health concern, and current pharmacological treatments have problematic side effects and limited effectiveness. N-methyl-d-aspartate (NMDA) glutamate receptor antagonists have emerged as one class of candidate treatments for pain because of the significant contribution of glutamate signalling in nociceptive processing. This study compared effects of the NMDA receptor antagonists ketamine and MK-801 in assays of pain-stimulated and pain-depressed behaviour in rats. The nonsteroidal anti-inflammatory drug ketoprofen was examined for comparison as a positive control. Intraperitoneal injection of dilute acid served as an acute visceral noxious stimulus to stimulate a stretching response or depress intracranial self-stimulation (ICSS) in male Sprague-Dawley rats. Ketamine (1.0-10.0 mg/kg) blocked acid-stimulated stretching but failed to block acid-induced depression of ICSS, whereas MK-801 (0.01-0.1 mg/kg) blocked both acid-stimulated stretching and acid-induced depression of ICSS. These doses of ketamine and MK-801 did not alter control ICSS in the absence of the noxious stimulus; however, higher doses of ketamine (10 mg/kg) and MK-801 (0.32 mg/kg) depressed all behaviour. Ketoprofen (1.0 mg/kg) blocked both acid-induced stimulation of stretching and depression of ICSS without altering control ICSS. These results support further consideration of NMDA receptor antagonists as analgesics; however, some NMDA receptor antagonists are more efficacious at attenuating pain-depressed behaviours. NMDA receptor antagonists produce dissociable effects on pain-depressed behaviour. Provides evidence that pain-depressed behaviours should be considered and evaluated when determining the antinociceptive effects of NMDA receptor antagonists. © 2016 European Pain Federation - EFIC®

GluN2C/GluN2D subunit-selective NMDA receptor potentiator CIQ reverses MK-801-induced impairment in prepulse inhibition and working memory in Y-maze test in mice

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Suryavanshi, P S; Ugale, R R; Yilmazer-Hanke, D; Stairs, D J; Dravid, S M

2014-01-01

Background and Purpose Despite ample evidence supporting the N-methyl-d-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia, progress in the development of effective therapeutics based on this hypothesis has been limited. Facilitation of NMDA receptor function by co-agonists (d-serine or glycine) only partially alleviates the symptoms in schizophrenia; other means to facilitate NMDA receptors are required. NMDA receptor sub-types differ in their subunit composition, with varied GluN2 subunits (GluN2A-GluN2D) imparting different physiological, biochemical and pharmacological properties. CIQ is a positive allosteric modulator that is selective for GluN2C/GluN2D-containing NMDA receptors (Mullasseril et al.). Experimental Approach The effect of systemic administration of CIQ was tested on impairment in prepulse inhibition (PPI), hyperlocomotion and stereotypy induced by i.p. administration of MK-801 and methamphetamine. The effect of CIQ was also tested on MK-801-induced impairment in working memory in Y-maze spontaneous alternation test. Key Results We found that systemic administration of CIQ (20 mg·kg−1, i.p.) in mice reversed MK-801 (0.15 mg·kg−1, i.p.)-induced, but not methamphetamine (3 mg·kg−1, i.p.)-induced, deficit in PPI. MK-801 increased the startle amplitude to pulse alone, which was not reversed by CIQ. In contrast, methamphetamine reduced the startle amplitude to pulse alone, which was reversed by CIQ. CIQ also partially attenuated MK-801- and methamphetamine-induced hyperlocomotion and stereotyped behaviours. Additionally, CIQ reversed the MK-801-induced working memory deficit in spontaneous alternation in a Y-maze. Conclusion and Implications Together, these results suggest that facilitation of GluN2C/GluN2D-containing receptors may serve as an important therapeutic strategy for treating positive and cognitive symptoms in schizophrenia. PMID:24236947

A neuroligin-1-derived peptide stimulates phosphorylation of the NMDA receptor NR1 subunit and rescues MK-801-induced decrease in long-term potentiation and memory impairment

DEFF Research Database (Denmark)

Korshunova, Irina; Gjørlund, Michelle D; Jacobsen, Sylwia Owczarek

2015-01-01

neurolide-1 effects on short- and long-term social and spatial memory in social recognition, Morris water-maze, and Y-maze tests. We found that subcutaneous neurolide-1 administration, restored hippocampal LTP compromised by NMDA receptor inhibitor MK-801. It counteracted MK-801-induced memory deficit...... in the water-maze and Y-maze tests after long-term treatment (24 h and 1-2 h before the test), but not after short-term exposure (1-2 h). Long-term exposure to neurolide-1 also facilitated social recognition memory. In addition, neurolide-1-induced phosphorylation of the NMDA receptor NR1 subunit on a site...... receptor phosphorylation after treatment with NL1 or a mimetic peptide, neurolide-1, was quantified by immunoblotting. Subsequently, we investigated effects of neurolide-1 on long-term potentiation (LTP) induction in hippocampal slices compromised by NMDA receptor inhibitor MK-801. Finally, we investigated...

Effect of the MK 801 and (-) nicotine intracerebral administration on Glu and Gaba extracellular concentration in the pedunculopontine nucleus from rats

International Nuclear Information System (INIS)

Blanco Lezcano, Lisette; Lorigados Pedre, Lourdes del Carmen; Gonzalez Fraguela, Maria Elena and others

2011-01-01

Although the pharmacological manipulation of the glutamatergic and cholinergic systems have been studied in animal models of Parkinson's Disease (PD), only some authors have done work on this topic at the pedunculopontine nucleus (PPN). The present work studied the changes in glutamate (Glu) and δ-aminobutyric acid (GABA) extracellular concentrations (EC) in the PPN from hemiparkinsonian rats by 6hydroxydopamine injection. The rats were locally perfused by MK-801 (10 μ mol/l) or (-) nicotine (10 mm) solutions by cerebral microdialysis. The biochemical studies were carried out through high performance liquid chromatography coupled to fluorescence detection. Mk-801 infusion induced a significant decrease of Glu (p< 0.01) and GABA (p< 0.01) EC in PPN. On the other hand (-) nicotine infusion induced a significant increase of Glu (p< 0.001) and GABA (p< 0.001) EC in PPN from hemiparkinsonian rats. The local blockade of NMDA receptors by MK-801 infusion facilitates the interaction between Glu and their metabotropic receptors that take part in presynaptic inhibition mechanisms and interfere with neurotransmitters release. Meanwhile, the nicotine infusion sums the effects of nicotinic receptor activation with the glutamatergic and gabaergic neurotransmission changes produced in the PPN in the parkinsonian condition. The cholinergic and glutamergic drug infusion in PPN impose a new adjustment to the neurotransmission at this level that is added to the neurochemical changes associated to dopaminergic denervation.

Effects of hypoxia-ischemia and MK-801 treatment on the binding of a phencyclidine analogue in the developing rat brain

International Nuclear Information System (INIS)

Silverstein, F.S.; McDonald, J.W. III; Bommarito, M.; Johnston, M.V.

1990-01-01

The phencyclidine analogue [ 3 H](1-[2-thienyl]cyclohexyl)piperidine ( 3 H-TCP) binds to the ion channel associated with the N-methyl-D-aspartate receptor channel complex. In vitro autoradiography indicates that the distribution of 3 H-TCP binding in brain closely parallels that of [ 3 H]glutamate binding to the N-methyl-D-aspartate receptor. In nine 7-day-old rats, an acute focal hypoxic-ischemic insult produced by unilateral carotid artery ligation and subsequent exposure to 8% oxygen acutely reduced 3 H-TCP binding ipsilateral to the ligation by 30% in the CA1, by 27% in the CA3, by 26% in the dentate gyrus, and by 17% in the striatum compared with values from the contralateral hemisphere. In 10 littermates that received 1 mg/kg of the neuroprotective noncompetitive N-methyl-D-aspartate antagonist MK-801 immediately before hypoxic exposure, the regional distribution of 3 H-TCP binding in hypoxic-ischemic brain was relatively preserved and there were no interhemispheric asymmetries in 3 H-TCP binding densities. In addition, in three unoperated rats decapitated 24 hours after MK-801 treatment, 3 H-TCP binding was reduced by 15-35%; similar bilateral suppression of 3 H-TCP binding was detected in MK-801-treated ligates. Our data indicate that 3 H-TCP autoradiography can be used to assay the efficacy of neuroprotective agents in this experimental model of perinatal stroke

MK-801 and memantine act differently on short-term memory tested with different time-intervals in the Morris water maze test.

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Duda, Weronika; Wesierska, Malgorzata; Ostaszewski, Pawel; Vales, Karel; Nekovarova, Tereza; Stuchlik, Ales

2016-09-15

N-methyl-d-aspartate receptors (NMDARs) play a crucial role in spatial memory formation. In neuropharmacological studies their functioning strongly depends on testing conditions and the dosage of NMDAR antagonists. The aim of this study was to assess the immediate effects of NMDAR block by (+)MK-801 or memantine on short-term allothetic memory. Memory was tested in a working memory version of the Morris water maze test. In our version of the test, rats underwent one day of training with 8 trials, and then three experimental days when rats were injected intraperitoneally with low- 5 (MeL), high - 20 (MeH) mg/kg memantine, 0.1mg/kg MK-801 or 1ml/kg saline (SAL) 30min before testing, for three consecutive days. On each experimental day there was just one acquisition and one test trial, with an inter-trial interval of 5 or 15min. During training the hidden platform was relocated after each trial and during the experiment after each day. The follow-up effect was assessed on day 9. Intact rats improved their spatial memory across the one training day. With a 5min interval MeH rats had longer latency then all rats during retrieval. With a 15min interval the MeH rats presented worse working memory measured as retrieval minus acquisition trial for path than SAL and MeL and for latency than MeL rats. MK-801 rats had longer latency than SAL during retrieval. Thus, the high dose of memantine, contrary to low dose of MK-801 disrupts short-term memory independent on the time interval between acquisition and retrieval. This shows that short-term memory tested in a working memory version of water maze is sensitive to several parameters: i.e., NMDA receptor antagonist type, dosage and the time interval between learning and testing. Copyright © 2016. Published by Elsevier B.V.

Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics.

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Bradford, Andrea M; Savage, Kevin M; Jones, Declan N C; Kalinichev, Mikhail

2010-10-01

We evaluated locomotor hyperactivity induced in BALB/C mice by an N-methyl-D-aspartate receptor antagonist MK-801 as an assay for the detection of antipsychotic drugs. We assessed the effects of antipsychotic drugs to validate the assay (study 1), selective dopamine and serotonin ligands for pharmacological characterisation of the model (study 2) and a number of compounds with efficacy in models of schizophrenia to understand the predictive validity of the model (study 3). Adult males (n  = 9/group) were pretreated with a test compound, habituated to locomotor activity cages before receiving MK-801 (0.32 mg/kg) and activity recorded for a further 75 or 120 min. In study 1, we tested haloperidol, clozapine, olanzapine, risperidone, ziprasidone, aripiprazole, sertindole and quetiapine. In study 2, we tested SCH23390 (D(1) antagonist), sulpiride (D(2)/D(3) antagonist), raclopride (D(2)/D(3) antagonist), SB-277011 (D(3) antagonist), L-745,870 (D(4) antagonist), WAY100635 (5-HT(1A) antagonist), 8-OH-DPAT (5-HT(1A) agonist), ketanserin (5-HT(2A)/5-HT(2C) antagonist) and SB-242084 (5-HT(2C) antagonist). In study 3, we tested xanomeline (M(1)/M(4) receptor agonist), LY379268 (mGluR2/3 receptor agonist), diazepam (GABA(A) modulator) and thioperamide (H(3) receptor antagonist). All antipsychotics suppressed MK-801-induced hyperactivity in a dose-dependent and specific manner. The effects of antipsychotics appear to be mediated via dopamine D(1), D(2) and 5-HT(2) receptors. Xanomeline, LY379268 and diazepam were active in this assay while thioperamide was not. MK-801-induced hyperactivity in BALB/C mice model of positive symptoms has shown predictive validity with novel compounds acing at M(1)/M(4), mGluR2/3 and GABA(A) receptors and can be used as a screening assay for detection of novel pharmacotherapies targeting those receptors.

Effects of scallop shell extract on scopolamine-induced memory impairment and MK801-induced locomotor activity

OpenAIRE

HASEGAWA, Yasushi; INOUE, Tatsuro; KAWAMINAMI, Satoshi; FUJITA, Miho

2016-01-01

ObjectiveTo evaluate the neuroprotective effects of the organic components of scallop shells (scallop shell extract) on memory impairment and locomotor activity induced by scopolamine or 5-methyl-10,11-dihydro-5H-dibenzo (a,d) cyclohepten-5,10-imine (MK801).MethodsEffect of the scallop shell extract on memory impairment and locomotor activity was investigated using the Y-maze test, the Morris water maze test, and the open field test.ResultsScallop shell extract significantly reduced scopolami...

Therapy with radiolabelled somatostatin analogs in neuroendocrine tumors

International Nuclear Information System (INIS)

Kunikowska, J.; Krolicki, L.

2007-01-01

In the 80's the discovery of somatostatin receptors expression on NET cells enabled the application of somatostatin analogues in diagnosis and therapy. Initially, 'cold' somatostatin analogs were used for therapeutical purpose, with overall good clinical response, but with minimal anti-proliferation effect. Furthermore, radiolabelled receptor-binding peptides have been shown to be an important class of radiopharmaceuticals for tumor diagnosis and therapy with minimal side-effects. Specific binding between receptor on tumor cell and peptide with beta emitting radionuclide act not only on tumor related symptoms but also on tumor cell via radiotoxic effect of beta radiation. Discoveries of next receptor combinations, allow the work over synthesis and applications of next receptors' analogs both in diagnosis and in therapy. Due to complex characteristics of NET's, the use therapeutic 'cocktail' containing the variety analogs may be of great importance. (author)

GLYX-13 Ameliorates Schizophrenia-Like Phenotype Induced by MK-801 in Mice: Role of Hippocampal NR2B and DISC1

Science.gov (United States)

Zhou, Dongsheng; Lv, Dan; Wang, Zhen; Zhang, Yanhua; Chen, Zhongming; Wang, Chuang

2018-01-01

Background: Evidence supports that the hypofunction of N-methyl-D-aspartate receptor (NMDAR) and downregulation of disrupted-in-schizophrenia 1 (DISC1) contribute to the pathophysiology of schizophrenia. N-Methyl D-aspartate receptor subtype 2B (NR2B)-containing NMDAR are associated with cognitive dysfunction in schizophrenia. GLYX-13 is an NMDAR glycine-site functional partial agonist and cognitive enhancer that does not induce psychotomimetic side effects. However, it remains unclear whether NR2B plays a critical role in the GLYX-13-induced alleviation of schizophrenia-like behaviors in mice. Methods: The effect of GLYX-13 was tested by observing changes in locomotor activity, novel object recognition ability, and prepulse inhibition (PPI) induced by dizocilpine (known as MK-801) in mice. Lentivirus-mediated NR2B knockdown in the hippocampus was assessed to confirm the role of NR2B in GLYX-13 pathophysiology, using Western blots and immunohistochemistry. Results: The systemic administration of GLYX-13 (0.5 and 1 mg/kg, i.p.) ameliorates MK-801 (0.5 mg/kg, i.p.)-induced hyperlocomotion, deficits in memory, and PPI in mice. Additionally, GLYX-13 normalized the MK-801-induced alterations in signaling molecules, including NR2B and DISC1 in the hippocampus. Furthermore, we found that NR2B knockdown produced memory and PPI deficits without any changes in locomotor activity. Notably, DISC1 levels significantly decreased by NR2B knockdown. However, the effective dose of GLYX-13 did not alleviate the memory and PPI dysfunctions or downregulation of DISC1 induced by NR2B knockdown. Conclusion: Our results suggest GLYX-13 as a candidate for schizophrenia treatment, and NR2B and DISC1 in the hippocampus may account for the molecular mechanisms of GLYX-13. PMID:29695955

Postnatal BDNF Expression Profiles in Prefrontal Cortex and Hippocampus of a Rat Schizophrenia Model Induced by MK-801 Administration

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Chunmei Guo

2010-01-01

Full Text Available Neonatal blockade of N-methyl-D-aspartic acid (NMDA receptors represents one of experimental animal models for schizophrenia. This study is to investigate the long-term brain-derived neurotrophic factor (BDNF expression profiles in different regions and correlation with “schizophrenia-like” behaviors in the adolescence and adult of this rat model. The NMDA receptor antagonist MK801 was administered to female Sprague-Dawley rats on postnatal days (PND 5 through 14. Open-field test was performed on PND 42, and PND 77 to examine the validity of the current model. BDNF protein levels in hippocampus and prefrontal cortex (PFC were analyzed on PND 15, PND 42, and PND 77. Results showed that neonatal challenge with MK-801 persistently elevated locomotor activity as well as BDNF expression; the alterations in BDNF expression varied at different developing stages and among brain regions. However, these findings provide neurochemical evidence that the blockade of NMDA receptors during brain development results in long-lasting alterations in BDNF expression and might contribute to neurobehavioral pathology of the present animal model for schizophrenia. Further study in the mechanisms and roles of the BDNF may lead to better understanding of the pathophysiology of schizophrenia.

Effect of alpha1-adrenergic antagonist prazosin on behavioral alterations induced by MK-801 in a spatial memory task in Long-Evans rats

Czech Academy of Sciences Publication Activity Database

Stuchlík, Aleš; Petrásek, Tomáš; Valeš, Karel

2009-01-01

Roč. 58, č. 5 (2009), s. 733-740 ISSN 0862-8408 R&D Projects: GA ČR(CZ) GA309/09/0286; GA ČR(CZ) GA309/07/0341 Institutional research plan: CEZ:AV0Z50110509 Keywords : prazosin * MK-801 * learning Subject RIV: FH - Neuro logy Impact factor: 1.430, year: 2009

Antagonista NMDA-receptorů MK-801 narušuje rozeznávání pozice vzdáleného objektu

Czech Academy of Sciences Publication Activity Database

Levčík, David; Klement, Daniel; Nekovářová, Tereza; Valeš, Karel; Stuchlík, Aleš

2010-01-01

Roč. 14, Suppl.2 (2010), s. 15-18 ISSN 1211-7579 R&D Projects: GA MŠk(CZ) 1M0517; GA ČR(CZ) GA309/09/0286; GA MZd(CZ) NR9178; GA MŠk(CZ) LC554 Institutional research plan: CEZ:AV0Z50110509 Keywords : recognition of position * MK-801 * CHPG * mGluR Subject RIV: FH - Neurology

Combined administration of MK-801 and cycloheximide produces a delayed potentiation of fear discrimination memory extinction.

Science.gov (United States)

Kochli, Daniel E; Campbell, Tiffany L; Hollingsworth, Ethan W; Lab, Rain S; Postle, Abagail F; Perry, Megan M; Mordzinski, Victoria M; Quinn, Jennifer J

2018-04-01

Mixed evidence exists regarding the role of N-methyl-D-aspartate (NMDA) receptors in memory reconsolidation. We provide no evidence that NMDA receptors are involved with memory reconsolidation, but instead demonstrate that prereactivation systemic MK-801 injection, combined with postreactivation intrabasolateral amygdala (BLA) cycloheximide infusion, produces a delayed potentiation of extinction learning. These data suggest that an interaction between NMDA antagonism and protein synthesis inhibition may enhance extinction by exerting effects outside of the intended reconsolidation manipulation window. The present work demonstrates a novel pharmacological enhancement of extinction, and underscores the importance of employing proper control procedures in reconsolidation research. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

DEVELOPMENTAL LEAD (PB) EXPOSURE REDUCES THE ABILITY OF THE NNDA ANTAGONIST MK801 TO SUPPRESS LONG-TERM POTENTIATION (LTP) IN THE RAT DENTATE GYRUS, IN VIVO

Science.gov (United States)

Chronic developmental lead (Pb) exposure increases the threshold and enhances decay of long-term potentiation (LTP) in the dentate gyrus of the hippocampal formation. MK-801 and other antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor subtype impair induction of LT...

UCCB01-125, a dimeric inhibitor of PSD-95, reduces inflammatory pain without disrupting cognitive or motor performance: Comparison with the NMDA receptor antagonist MK-801

DEFF Research Database (Denmark)

Andreasen, Jesper T.; Bach, Anders; Gynther, Mikko

2013-01-01

Excessive N-Methyl-d-aspartate receptor (NMDAR)-dependent production of nitric oxide (NO) is involved in the development and maintenance of chronic pain states, and is mediated by postsynaptic density protein-95 (PSD-95). By binding to both the NMDAR and neuronal NO synthase (nNOS), PSD-95 mediates...... a specific coupling between NMDAR activation and NO production. NMDAR antagonism shows anti-nociceptive action in humans and animal models of chronic pain but is associated with severe disturbances of cognitive and motor functions. An alternative approach to modulate the NMDAR-related activity is to perturb......'s adjuvant (CFA) model of inflammatory pain. To examine side-effect profiles we also compared the effects of UCCB01-125 and MK-801 in tests of attention, long-term memory, and motor performance. When administered concurrently with CFA, both MK-801 and UCCB01-125 prevented the development of CFA...

Preclinical evaluation of neurotensin(8-13) analog radiolabeled with 99mTc: in vitro and in vivo characterization

International Nuclear Information System (INIS)

Teodoro, Rodrigo

2010-01-01

The radiolabeling of receptor specific biomolecules with 99m Tc using bifunctional chelator agents represents a growing field in Nuclear Medicine, specially, regarding regulatory peptides, such as Neurotensin, which are important in several essential physiological functions, particularly in tumor growth. The aim of the study was the comparative radiolabeling evaluation of the double-stabilized NT(8-13) analog with 99m Tc, via the bifunctional chelating agents 6- hydrazinonicotinamide (HYNIC) and S-acetyl-mercaptoacetyltriglycine (MAG3) in MDA-MB-231 breast cancer cell line. High radiochemical yields (> 97%) and stability toward transchelant agents was observed for both radiolabeled analogs. Also, comparable in vitro behaviour regarding the percentage of plasma protein binding (nearby 22%), metabolic stability, receptor binding affinity (nM range), and internalization/externalization rates were obtained. The greater lipophilicity found for the analog radiolabeled via MAG 3 , reflected in the major differences in biodistribution studies. The in vivo metabolic stability studies suggested that the degradation observed in the later time point (90 min) for the conjugate radiolabeled via HYNIC, leads not only to lower tumor uptake accumulation (0,44±0,02% ID/g), but also to lower tumor-to-non-tumor ratios ( 3 had been confirmed in the present study, a structural re-design aiming the reduction of the high gastrointestinal uptake must be done in order to guarantee the potential applicability of MAG 3 -radio complex. (author)

Neuropeptide S ameliorates olfactory spatial memory impairment induced by scopolamine and MK801 through activation of cognate receptor-expressing neurons in the subiculum complex.

Science.gov (United States)

Shao, Yu-Feng; Wang, Can; Xie, Jun-Fan; Kong, Xiang-Pan; Xin, Le; Dong, Chao-Yu; Li, Jing; Ren, Wen-Ting; Hou, Yi-Ping

2016-07-01

Our previous studies have demonstrated that neuropeptide S (NPS), via selective activation of the neurons bearing NPS receptor (NPSR) in the olfactory cortex, facilitates olfactory function. High level expression of NPSR mRNA in the subiculum complex of hippocampal formation suggests that NPS-NPSR system might be involved in the regulation of olfactory spatial memory. The present study was undertaken to investigate effects of NPS on the scopolamine- or MK801-induced impairment of olfactory spatial memory using computer-assisted 4-hole-board spatial memory test, and by monitoring Fos expression in the subiculum complex in mice. In addition, dual-immunofluorescence microscopy was employed to identify NPS-induced Fos-immunereactive (-ir) neurons that also bear NPSR. Intracerebroventricular administration of NPS (0.5 nmol) significantly increased the number of visits to switched odorants in recall trial in mice suffering from odor-discriminating inability induced by scopolamine, a selective muscarinic cholinergic receptor antagonist, or MK801, a N-methyl-D-aspartate receptor antagonist, after training trials. The improvement of olfactory spatial memory by NPS was abolished by the NPSR antagonist [D-Val(5)]NPS (40 nmol). Ex vivo c-Fos and NPSR immunohistochemistry revealed that, as compared with vehicle-treated mice, NPS markedly enhanced Fos expression in the subiculum complex encompassing the subiculum (S), presubiculum (PrS) and parasubiculum (PaS). The percentages of Fos-ir neurons that also express NPSR were 91.3, 86.5 and 90.0 % in the S, PrS and PaS, respectively. The present findings demonstrate that NPS, via selective activation of the neurons bearing NPSR in the subiculum complex, ameliorates olfactory spatial memory impairment induced by scopolamine and MK801 in mice.

Higher Doses of (+)MK-801 (Dizocilpine) Induced Mortality and Procedural but Not Cognitive Deficits in Delayed Testing in the Active Place Avoidance With Reversal on the Carousel

Czech Academy of Sciences Publication Activity Database

Lobellová, Veronika; Brichtová, Eva; Petrásek, Tomáš; Valeš, Karel; Stuchlík, Aleš

2015-01-01

Roč. 64, č. 2 (2015), s. 269-275 ISSN 0862-8408 R&D Projects: GA MZd(CZ) NT13386 Institutional support: RVO:67985823 Keywords : Dizocilpine * (+)MK-801 * active place avoidance * Carousel * Long-Evans rats Subject RIV: FH - Neurology Impact factor: 1.643, year: 2015

MK-801 impairs cognitive coordination on a rotating arena (Carousel and contextual specificity of hippocampal immediate-early gene expression in a rat model of psychosis

Directory of Open Access Journals (Sweden)

Štěpán eKubík

2014-03-01

Full Text Available Flexible behavior in dynamic, real-world environments requires more than static spatial learning and memory. Discordant and unstable cues must be organized in coherent subsets to give rise to meaningful spatial representations. We model this form of cognitive coordination on a rotating arena - Carousel where arena- and room-bound spatial cues are dissociated. Hippocampal neuronal ensemble activity can repeatedly switch between multiple representations of such an environment. Injection of tetrodotoxin into one hippocampus prevents cognitive coordination during avoidance of a stationary room-defined place on the Carousel and increases coactivity of previously unrelated neurons in the uninjected hippocampus. Place avoidance on the Carousel is impaired after systemic administration of non-competitive NMDAr blockers (MK-801 used to model schizophrenia in animals and people. We tested if this effect is due to cognitive disorganization or other effect of NMDAr antagonism such as hyperlocomotion, spatial memory impairment, or general learning deficit. We also examined if the same dose of MK-801 alters patterns of immediate-early gene (IEG expression in the hippocampus. IEG expression is triggered in neuronal nuclei in a context-specific manner after behavioral exploration and it is used to map activity in neuronal populations. IEG expression is critical for maintenance of synaptic plasticity and memory consolidation. We show that the same dose of MK-801 that impairs spatial coordination of rats on the Carousel also eliminates contextual specificity of IEG expression in hippocampal CA1 ensembles. This effect is due to increased similarity between ensembles activated in different environments, consistent with the idea that it is caused by increased coactivity between neurons, which did not fire together before. Our data support the proposition of the Hypersynchrony theory that cognitive disorganization in psychosis is due to increased coactivity between

MK-801 Impairs Cognitive Coordination on a Rotating Arena (Carousel) and Contextual Specificity of Hippocampal Immediate-Early Gene Expression in a Rat Model of Psychosis.

Science.gov (United States)

Kubík, Stěpán; Buchtová, Helena; Valeš, Karel; Stuchlík, Aleš

2014-01-01

Flexible behavior in dynamic, real-world environments requires more than static spatial learning and memory. Discordant and unstable cues must be organized in coherent subsets to give rise to meaningful spatial representations. We model this form of cognitive coordination on a rotating arena - Carousel where arena- and room-bound spatial cues are dissociated. Hippocampal neuronal ensemble activity can repeatedly switch between multiple representations of such an environment. Injection of tetrodotoxin into one hippocampus prevents cognitive coordination during avoidance of a stationary room-defined place on the Carousel and increases coactivity of previously unrelated neurons in the uninjected hippocampus. Place avoidance on the Carousel is impaired after systemic administration of non-competitive NMDAr blockers (MK-801) used to model schizophrenia in animals and people. We tested if this effect is due to cognitive disorganization or other effect of NMDAr antagonism such as hyperlocomotion, spatial memory impairment, or general learning deficit. We also examined if the same dose of MK-801 alters patterns of immediate-early gene (IEG) expression in the hippocampus. IEG expression is triggered in neuronal nuclei in a context-specific manner after behavioral exploration and it is used to map activity in neuronal populations. IEG expression is critical for maintenance of synaptic plasticity and memory consolidation. We show that the same dose of MK-801 that impairs spatial coordination of rats on the Carousel also eliminates contextual specificity of IEG expression in hippocampal CA1 ensembles. This effect is due to increased similarity between ensembles activated in different environments, consistent with the idea that it is caused by increased coactivity between neurons, which did not previously fire together. Our data support the proposition of the Hypersynchrony theory that cognitive disorganization in psychosis is due to increased coactivity between unrelated

MK-801 Impairs Cognitive Coordination on a Rotating Arena (Carousel) and Contextual Specificity of Hippocampal Immediate-Early Gene Expression in a Rat Model of Psychosis

Science.gov (United States)

Kubík, Štěpán; Buchtová, Helena; Valeš, Karel; Stuchlík, Aleš

2014-01-01

Flexible behavior in dynamic, real-world environments requires more than static spatial learning and memory. Discordant and unstable cues must be organized in coherent subsets to give rise to meaningful spatial representations. We model this form of cognitive coordination on a rotating arena – Carousel where arena- and room-bound spatial cues are dissociated. Hippocampal neuronal ensemble activity can repeatedly switch between multiple representations of such an environment. Injection of tetrodotoxin into one hippocampus prevents cognitive coordination during avoidance of a stationary room-defined place on the Carousel and increases coactivity of previously unrelated neurons in the uninjected hippocampus. Place avoidance on the Carousel is impaired after systemic administration of non-competitive NMDAr blockers (MK-801) used to model schizophrenia in animals and people. We tested if this effect is due to cognitive disorganization or other effect of NMDAr antagonism such as hyperlocomotion, spatial memory impairment, or general learning deficit. We also examined if the same dose of MK-801 alters patterns of immediate-early gene (IEG) expression in the hippocampus. IEG expression is triggered in neuronal nuclei in a context-specific manner after behavioral exploration and it is used to map activity in neuronal populations. IEG expression is critical for maintenance of synaptic plasticity and memory consolidation. We show that the same dose of MK-801 that impairs spatial coordination of rats on the Carousel also eliminates contextual specificity of IEG expression in hippocampal CA1 ensembles. This effect is due to increased similarity between ensembles activated in different environments, consistent with the idea that it is caused by increased coactivity between neurons, which did not previously fire together. Our data support the proposition of the Hypersynchrony theory that cognitive disorganization in psychosis is due to increased coactivity between unrelated

EFECTO DE LA ADMINISTRACIÓN INTRACEREBRAL DE MK-801 Y (- NICOTINA EN LAS CONCENTRACIONES EXTRACELULARES DE GLU Y GABA EN EL NÚCLEO PEDUNCULOPONTINO DE RATAS.

Directory of Open Access Journals (Sweden)

Lisette Blanco

2011-01-01

Full Text Available Aunque la manipulación farmacológica de los sistemas glutamatérgico y colinérgico se ha tratado en modelos experimentales de enfermedad de Parkinson (EP, pocos autores han realizado estudios de esta temática a nivel del núcleo pedunculopontino (NPP. El presente trabajo aborda los cambios en las concentraciones extracelulares (CE de glutamato (Glu y ácido δ-amino butírico (GABA en el NPP de ratas hemiparkinsonizadas por inyección de 6-hidroxidopamina (6-OHDA y sometidas a la infusión local de MK-801 (10 mol/L o (- nicotina (10mM. La infusión se realizó mediante microdiálisis cerebral y la determinación de las CE de los neurotransmisores se realizó a través de cromatografía líquida de alta resolución acoplada a detección de fluorescencia. La infusión de MK-801 en el NPP produjo una disminución significativa de las CE de Glu (p

A novel photoaffinity ligand for the phencyclidine site of the N-methyl-D-aspartate receptor labels a Mr 120,000 polypeptide

International Nuclear Information System (INIS)

Sonders, M.S.; Barmettler, P.; Lee, J.A.; Kitahara, Y.; Keana, J.F.; Weber, E.

1990-01-01

A radiolabeled photoaffinity ligand has been developed for the N-methyl-D-aspartate (NMDA)-preferring excitatory amino acid receptor complex. [3H]3-Azido-(5S, 10R)(+)-5-methyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imine [3H]3-azido-MK-801 demonstrated nearly identical affinity, density of binding sites, selectivity, pH sensitivity, and pharmacological profile in reversible binding assays with guinea pig brain homogenates to those displayed by its parent compound, MK-801. When employed in a photo-labeling protocol designed to optimize specific incorporation, [3H]3-azido-MK-801 labeled a single protein band which migrated in sodium dodecyl sulfate-polyacrylamide gels with Mr = 120,000. Incorporation of tritium into this band was completely inhibited when homogenates and [3H]3-azido-MK-801 were coincubated with 10 microM phencyclidine. These data suggest that the phencyclidine site of the NMDA receptor complex is at least in part comprised of a Mr = 120,000 polypeptide

Selective Activation of M4 Muscarinic Acetylcholine Receptors Reverses MK-801-Induced Behavioral Impairments and Enhances Associative Learning in Rodents

Science.gov (United States)

2015-01-01

Positive allosteric modulators (PAMs) of the M4 muscarinic acetylcholine receptor (mAChR) represent a novel approach for the treatment of psychotic symptoms associated with schizophrenia and other neuropsychiatric disorders. We recently reported that the selective M4 PAM VU0152100 produced an antipsychotic drug-like profile in rodents after amphetamine challenge. Previous studies suggest that enhanced cholinergic activity may also improve cognitive function and reverse deficits observed with reduced signaling through the N-methyl-d-aspartate subtype of the glutamate receptor (NMDAR) in the central nervous system. Prior to this study, the M1 mAChR subtype was viewed as the primary candidate for these actions relative to the other mAChR subtypes. Here we describe the discovery of a novel M4 PAM, VU0467154, with enhanced in vitro potency and improved pharmacokinetic properties relative to other M4 PAMs, enabling a more extensive characterization of M4 actions in rodent models. We used VU0467154 to test the hypothesis that selective potentiation of M4 receptor signaling could ameliorate the behavioral, cognitive, and neurochemical impairments induced by the noncompetitive NMDAR antagonist MK-801. VU0467154 produced a robust dose-dependent reversal of MK-801-induced hyperlocomotion and deficits in preclinical models of associative learning and memory functions, including the touchscreen pairwise visual discrimination task in wild-type mice, but failed to reverse these stimulant-induced deficits in M4 KO mice. VU0467154 also enhanced the acquisition of both contextual and cue-mediated fear conditioning when administered alone in wild-type mice. These novel findings suggest that M4 PAMs may provide a strategy for addressing the more complex affective and cognitive disruptions associated with schizophrenia and other neuropsychiatric disorders. PMID:25137629

NMDA receptor antagonism by repetitive MK801 administration induces schizophrenia-like structural changes in the rat brain as revealed by voxel-based morphometry and diffusion tensor imaging.

Science.gov (United States)

Wu, H; Wang, X; Gao, Y; Lin, F; Song, T; Zou, Y; Xu, L; Lei, H

2016-05-13

Animal models of N-methyl-d-aspartate receptor (NMDAR) antagonism have been widely used for schizophrenia research. Less is known whether these models are associated with macroscopic brain structural changes that resemble those in clinical schizophrenia. Magnetic resonance imaging (MRI) was used to measure brain structural changes in rats subjected to repeated administration of MK801 in a regimen (daily dose of 0.2mg/kg for 14 consecutive days) known to be able to induce schizophrenia-like cognitive impairments. Voxel-based morphometry (VBM) revealed significant gray matter (GM) atrophy in the hippocampus, ventral striatum (vStr) and cortex. Diffusion tensor imaging (DTI) demonstrated microstructural impairments in the corpus callosum (cc). Histopathological results corroborated the MRI findings. Treatment-induced behavioral abnormalities were not measured such that correlation between the brain structural changes observed and schizophrenia-like behaviors could not be established. Chronic MK801 administration induces MRI-observable brain structural changes that are comparable to those observed in schizophrenia patients, supporting the notion that NMDAR hypofunction contributes to the pathology of schizophrenia. Imaging-derived brain structural changes in animal models of NMDAR antagonism may be useful measurements for studying the effects of treatments and interventions targeting schizophrenia. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Blockade of MK-801-induced heat shock protein 72/73 in rat brain by antipsychotic and monoaminergic agents targeting D2, 5-HT1A, 5-HT2A and α1-adrenergic receptors.

Science.gov (United States)

Romón, Tamara; Planas, Anna M; Adell, Albert

2014-02-01

Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists can produce positive and negative symptomatology as well as impairment of cognitive function that closely resemble those present in schizophrenia. In rats, these drugs induce a behavioral syndrome (characterized by hyperlocomotion and stereotypies), an enhanced glutamatergic transmission in the medial prefrontal cortex, and damage to retrosplenial cortical neurons in adult rats, which was measured as the induction of the stress protein 72/73 kDa heat shock protein (Hsp72/73). In the present work, we have examined the existence of possible differences among different antipsychotic drugs in their capacity to block immunolabeling of Hsp72/73 in the retrosplenial cortex of the rat induced by the potent NMDA receptor antagonist, MK- 801. In addition, the effects of selective monoaminergic agents were also studied to delineate the particular receptors responsible for the actions of antipsychotic drugs. Pretreatment with clozapine, chlorpromazine, olanzapine, ziprasidone--and to a lesser extent haloperidol-reduced the formation of Hsp72/73 protein in the rat retrosplenial cortex after the administration of MK-801. In addition, antagonism at dopamine D2 (raclopride), 5-HT2 (M100907) and α1- adrenoceptors (prazosin) as well as agonism at 5-HT1A receptors (BAY x 3702) also diminished the MK-801-induced number of cells labeled with Hsp72/73. Each of these effects may contribute to antipsychotic action. The results suggest that the efficacy of atypical antipsychotic drugs in the clinic may result from a combined effect on 5-HT2, 5-HT1A and α1-adrenergic receptors added to the classical dopamine D2 receptor antagonism.

Prenatal exposure to an NMDA receptor antagonist, MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to methamphetamine in postpubertal rats.

Science.gov (United States)

Abekawa, Tomohiro; Ito, Koki; Nakagawa, Shin; Koyama, Tsukasa

2007-06-01

Neurodevelopmental deficits of parvalbumin-immunoreactive gamma-aminobutyric acid (GABA)ergic interneurons in prefrontal cortex have been reported in schizophrenia. Glutamate influences the proliferation of this type of interneuron by an N-methyl-D-aspartate (NMDA)-receptor-mediated mechanism. The present study hypothesized that prenatal blockade of NMDA receptors would disrupt GABAergic neurodevelopment, resulting in differences in effects on behavioral responses to a noncompetitive NMDA antagonist, phencyclidine (PCP), and a dopamine releaser, methamphetamine (METH). GABAergic neurons were immunohistochemically stained with parvalbumin antibody. Psychostimulant-induced hyperlocomotion was measured using an infrared sensor. Prenatal exposure (E15-E18) to the NMDA receptor antagonist MK-801 reduced the density of parvalbumin-immunoreactive neurons in rat medial prefrontal cortex on postnatal day 63 (P63) and enhanced PCP-induced hyperlocomotion but not the acute effects of METH on P63 or the development of behavioral sensitization. Prenatal exposure to MK-801 reduced the number of parvalbumin-immunoreactive neurons even on postnatal day 35 (P35) and did not enhance PCP-induced hyperlocomotion, the acute effects of METH on P35, or the development of behavioral sensitization to METH. These findings suggest that prenatal blockade of NMDA receptors disrupts GABAergic neurodevelopment in medial prefrontal cortex, and that this disruption of GABAergic development may be related to the enhancement of the locomotion-inducing effect of PCP in postpubertal but not juvenile offspring. GABAergic deficit is unrelated to the effects of METH. This GABAergic neurodevelopmental disruption and the enhanced PCP-induced hyperlocomotion in adult offspring prenatally exposed to MK-801 may prove useful as a new model of the neurodevelopmental process of pathogenesis of treatment-resistant schizophrenia via an NMDA-receptor-mediated hypoglutamatergic mechanism.

MK-801, but not drugs acting at strychnine-insensitive glycine receptors, attenuate methamphetamine nigrostriatal toxicity.

Science.gov (United States)

Layer, R T; Bland, L R; Skolnick, P

1993-10-15

Repeated administration of methamphetamine (METH) results in damage to nigrostriatal dopaminergic neurons. Both competitive N-methyl-D-aspartate (NMDA) receptor antagonists and use-dependent cation channel blockers attenuate METH-induced damage. The objectives of the present study were to examine whether comparable reductions in METH-induced damage could be obtained by compounds acting at strychnine-insensitive glycine receptors on the NMDA receptor complex. Four injections of METH (5 mg/kg i.p.) resulted in a approximately 70.9% depletion of striatal dopamine (DA) and approximately 62.7% depletion of dihydroxyphenylacetic acid (DOPAC) content, respectively. A significant protection against METH-induced DA and DOPAC depletion was afforded by the use-dependent channel blocker, MK-801. The competitive glycine antagonist 7-chlorokynurenic acid (7-Cl-KA), the low efficacy glycine partial agonist (+)-3-amino-1-hydroxy-2-pyrrolidone ((+)-HA-966), and the high efficacy partial glycine agonist 1-aminocyclopropane-carboxylic acid (ACPC) were ineffective against METH-induced toxicity despite their abilities to attenuate glutamate-induced neurotoxicity under both in vivo and in vitro conditions. These results indicate that glycinergic ligands do not possess the same broad neuroprotective spectrum as other classes of NMDA antagonists.

Development of a novel bombesin analog radiolabeled with Lutetium-177: in vivo evaluation of the biological properties in Balb-C mice

International Nuclear Information System (INIS)

Pujatti, Priscilla Brunelli; Barrio, Ofelia; Santos, Josefina da Silva; Mengatti, Jair; Araujo, Elaine Bortoleti de

2008-01-01

Bombesin (BBN), a 14-aminoacid amphibian peptide homologue of mammalian gastrin-releasing peptide (GRP), has demonstrated the ability to bind with high affinity and specificity to GRP receptor, which are overexpressed on a variety of human cancers. A large number of BBN analogs were synthesized for this purpose and have shown to reduce tumor growth in mice. However, most of the studied analogs exhibit high abdominal accumulation, specially in pancreas. This abdominal accumulation may represent a problem in clinical use of radiolabeled bombesin analogs probably due to serious side effects to patients. In this study we describe the results of radiolabeling with lutetium-177 ( 177 Lu) and in vivo biodistribution and pharmacokinetics studies in normal Balb-C mice of a novel bombesin analog (BBNp4) - DOTA-X-BBN(6-14), where X is a spacer of four aminoacids. This spacer was inserted between the chelator and the binding sequence in order to improve bombesin in vivo properties. BBNp4 was successfully labeled with high yield and kept stable for more than 96 hours at 4 deg C and 4 hours in human plasma. Data analysis obtained from the in vivo studies showed that the amount of BBNp4 present in plasma decreased rapidly and became almost undetectable at 60 min p.i., indicating rapid peptide excretion, which is performed mainly by renal pathway. In addition, biodistribution and single photon emission tomography showed low abdominal accumulation of 177 Lu-DOTA-X-BBN(6-14), indicating that this analog is a potential candidate for tumors target therapy. (author)

Synthesis of an 125I analog of MK-0591 and characterization of a 5-lipoxygenase activating protein binding assay

International Nuclear Information System (INIS)

Eggler, J.F.; Cheng, J.B.; Cooper, K.; Hanak, L.M.; Pillar, J.S.

1994-01-01

The 125 I analog of MK-0591,1, has been prepared for use as a radioligand for developing a 5-lipoxygenase activating protein (FLAP) binding assay. The radiosynthesis involves a two step oxidative iododestannylation-saponification procedure. A FLAP binding assay has been developed in human neutrophil membranes. The binding of 1 to human neutrophil FLAP is rapid, reversible, of high affinity, saturable and selective for FLAP inhibitors. (author)

Analysis of sensitivity to MK-801 treatment in a novel active allothetic place avoidance task and in the working memory version of the Morris water maze reveals differences between Long-Evans and Wistar rats

Czech Academy of Sciences Publication Activity Database

Valeš, Karel; Bubeníková-Valešová, V.; Klement, Daniel; Stuchlík, Aleš

2006-01-01

Roč. 55, č. 4 (2006), s. 383-388 ISSN 0168-0102 R&D Projects: GA MZd(CZ) NL7684; GA MŠk(CZ) 1M0517; GA MŠk(CZ) LC554; GA ČR(CZ) GP309/03/P126; GA ČR(CZ) GA309/06/1231 Institutional research plan: CEZ:AV0Z50110509 Keywords : Wistar/Long-Evans rats * MK-801 * cognition Subject RIV: FH - Neurology Impact factor: 1.953, year: 2006

Free thyroxin by radioimmunoassay: evaluation of a new direct method involving a radiolabeled thyroxin analog

International Nuclear Information System (INIS)

Kubasik, N.P.; Lundberg, P.A.; Brodows, R.G.; Hallauer, G.D.; Same, D.G.; Lindstedt, G.; Bengtsson, C.; Nystroem, E.

1983-01-01

The first performance evaluation of a new direct method for free thyroxin (T4) in serum by radioimmunoassay, with use of coated tubes and a radioiodinated T4 analog (Diagnostic Products Corp.) is presented. The assay is precise and robust: within-run imprecision (CV), 3.1-6.6%; between-run imprecision, 4.0-7.9%; no demonstrable variation between technologists irrespective of experience with the method. No outliers were observed when we compared the free T4 results with serum total T4. Reference values are reported for a total of 1243 euthyroid subjects; there was no significant age effect on serum free T4 in women 26 to 72 years old. The biological variation was about +/- 35% of the mean (2 SD). Free T4 results are the same for serum and plasma. The assay performs well in hypothyroidism and hyperthyroidism, and distinguishes individuals with thyroid disease from normal individuals. Free T4 values in women taking oral contraceptives are normal. Depressed results were often observed in acute nonthyroidal illness and continuing pregnancy. These results were directly comparable with those of another commercial direct radiolabeled-T4 analog kit for free T4

Dizocilpine and reduced body temperature do not prevent methamphetamine-induced neurotoxicity in the vervet monkey: [11C]WIN 35,428 - positron emission tomography studies.

Science.gov (United States)

Melega, W P; Lacan, G; Harvey, D C; Huang, S C; Phelps, M E

1998-12-11

[11C]WIN 35,428 (WIN), a cocaine analog that binds to the dopamine transporter (DAT), and positron emission tomography (PET) were used to evaluate the potential neuroprotective effects of dizocilpine (MK-801) on methamphetamine (MeAmp) induced neurotoxicity in the striatal dopamine system of the vervet monkey. MK-801 (1 mg/kg, i.m.) was administered 30 min prior to a neurotoxic MeAmp dosage for this species (2 x 2 mg/kg, 4 h apart); control subjects received MeAmp. MK-801 treated subjects were anesthetized by the drug for 6-8 h; throughout that period, a 2-3 degrees C decrease in body temperature was measured. At 1-2 weeks post-MeAmp, decreases of approximately 75% in striatal WIN binding were observed for both MK-801/MeAmp and MeAmp subjects. Thus, in this non-human primate species, the combination of MK-801 pretreatment and reduced body temperature did not provide protection from the MeAmp-induced loss of DAT. Further, the absence of an elevated body temperature during the acute MeAmp exposure period indicated that hyperthermia, per se, was not a necessary concomitant of the MeAmp neurotoxicity profile as has been previously demonstrated in rodents. These results provide evidence that different regulatory factors maintain the integrity of the rodent and primate striatal dopamine systems.

Concentration change of DA, DOPAC, Glu and GABA in brain tissues in schizophrenia developmental model rats induced by MK-801.

Science.gov (United States)

Liu, Yong; Tang, Yamei; Pu, Weidan; Zhang, Xianghui; Zhao, Jingping

2011-08-01

To explore the related neurobiochemical mechanism by comparing the concentration change of dopamine (DA), dihydroxy-phenyl acetic acid (DOPAC), glutamate (Glu), and γ-aminobutyric acid (GABA) in the brain tissues in schizophrenia (SZ) developmental model rats and chronic medication model rats. A total of 60 neonatal male Spragur-Dawley (SD) rats were randomly assigned to 3 groups at the postnatal day 6: an SZ developmental rat model group (subcutaneous injection with MK-801 at the postnatal day 7-10, 0.1 mg/kg, Bid), a chronic medication model group (intraperitoneal injection at the postnatal day 47-60, 0.2 mg/kg,Qd), and a normal control group (injection with 0.9% normal saline during the corresponding periods). DA, DOPAC, Glu, and GABA of the tissue homogenate from the medial prefrontal cortex (mPFC) and hippocampus were examined with Coularray electrochemic detection by high performance liquid chromatogram technique. The utilization rate of DA and Glu was calculated. Compared with the normal control group, the concentration of DA and DOPAC in the mPFC and the hippocampus in the SZ developmental model group significantly decreased (PGABA concentration and Glu utilization rate in the mPFC also decreased (PGABA system decrease in the mPFC and the DA system function reduces in the hippocampus of SZ developmental rats.

Chronic MK-801 Application in Adolescence and Early Adulthood: A Spatial Working Memory Deficit in Adult Long-Evans Rats But No Changes in the Hippocampal NMDA Receptor Subunits

Science.gov (United States)

Uttl, Libor; Petrasek, Tomas; Sengul, Hilal; Svojanovska, Marketa; Lobellova, Veronika; Vales, Karel; Radostova, Dominika; Tsenov, Grygoriy; Kubova, Hana; Mikulecka, Anna; Svoboda, Jan; Stuchlik, Ales

2018-01-01

The role of NMDA receptors in learning, memory and hippocampal function has long been recognized. Post-mortem studies have indicated that the expression or subunit composition of the NMDA glutamate receptor subtype might be related to the impaired cognitive functions found in schizophrenia patients. NMDA receptor antagonists have been used to develop animal models of this disorder. There is accumulating evidence showing that not only the acute but also the chronic application of NMDA receptor antagonists may induce schizophrenia-like alterations in behavior and brain functions. However, limited evidence is available regarding the consequences of NMDA receptor blockage during periods of adolescence and early adulthood. This study tested the hypothesis that a 2-week treatment of male Long-Evans and Wistar rats with dizocilpine (MK-801; 0.5 mg/kg daily) starting at postnatal days (PD) 30 and 60 would cause a long-term cognitive deficit and changes in the levels of NMDA receptor subunits. The working memory version of the Morris water maze (MWM) and active place avoidance with reversal on a rotating arena (Carousel) requiring cognitive coordination and flexibility probed cognitive functions and an elevated-plus maze (EPM) was used to measure anxiety-like behavior. The western blot method was used to determine changes in NMDA receptor subunit levels in the hippocampus. Our results showed no significant changes in behaviors in Wistar rats. Slightly elevated anxiety-like behavior was observed in the EPM in Long-Evans rats with the onset of treatment on PD 30. Furthermore, Long-Evans rats treated from PD 60 displayed impaired working memory in the MWM. There were; however, no significant changes in the levels of NMDA receptor subunits because of MK-801 administration. These findings suggest that a 2-week treatment starting on PD 60 in Long-Evans rats leads to long-term changes in working memory, but this deficit is not paralleled by changes in NMDA receptor subunits. These

Optimised labeling, preclinical and initial clinical aspects of CCK-2 receptor-targeting with 3 radiolabeled peptides

International Nuclear Information System (INIS)

Breeman, Wouter A.P.; Froeberg, A.C.; Blois, E. de; Gameren, A. van; Melis, M.; Jong, M. de; Maina, T.; Nock, B.A.; Erion, J.L.; Maecke, H.R.; Krenning, E.P.

2008-01-01

Medullary thyroid carcinoma (MTC) expresses CCK-2 receptors. 111 In-labeled DOTA-DGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH 2 (DOTA-MG11), DOTA-DAsp-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH 2 (DOTA-CCK), and 99m Tc-labeled N 4 -Gly-DGlu-(Glu) 5 -Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH 2 ( 99m Tc-Demogastrin 2) are analogs developed for CCK-2 receptor-targeted scintigraphy. All 3 radiolabeled analogs were selected on the basis of their high CCK-2 receptor affinity and their good in vitro serum stability, with in vitro serum t 1/2 values of several hours. Radiolabeling of DOTA-peptides with 111 In requires a heating procedure, typically in the range of 80 deg. - 100 deg. C up to 30 min. Following this procedure with DOTA-MG11 resulted in a >98 % incorporation of 111 In, however, with a radiochemical purity (RCP) of 111 In involved 5 min heating at 80 deg. C and led to an incorporation of 111 In of >98 %. In addition, all analogs were radiolabeled in the presence of quenchers to prevent radiolysis and oxidation resulting in a RCP of >90 %. All 3 radiolabeled analogs were i.v. administered to 6 MTC patients: radioactivity cleared rapidly by the kidneys, with no significant differences in the excretion pattern of the 3 radiotracers. All 3 radiolabeled analogs exhibited a low in vivo stability in patients, as revealed during analysis of blood samples, with the respective t 1/2 found in the order of minutes. In patient blood, the rank of radiopeptide in vivo stability was: 99m Tc-Demogastrin 2 (t 1/2 10-15 min)> 111 In-DOTA-CCK (t 1/2 ∼5-10 min)> 111 In-DOTA-MG11 (t 1/2 <5 min)

MK-801, but not naloxone, attenuates high-dose dextromethorphan-induced convulsive behavior: Possible involvement of the GluN2B receptor.

Science.gov (United States)

Tran, Hai-Quyen; Chung, Yoon Hee; Shin, Eun-Joo; Tran, The-Vinh; Jeong, Ji Hoon; Jang, Choon-Gon; Nah, Seung-Yeol; Yamada, Kiyofumi; Nabeshima, Toshitaka; Kim, Hyoung-Chun

2017-11-01

Dextromethorphan (DM) is a dextrorotatory isomer of levorphanol, a typical morphine-like opioid. When administered at supra-antitussive doses, DM produces psychotoxic and neurotoxic effects in humans. Although DM abuse has been well-documented, few studies have examined the effects of high-dose DM. The present study aimed to explore the effects of a single high dose of DM on mortality and seizure occurrence. After intraperitoneal administration with a high dose of DM (80mg/kg), Sprague-Dawley rats showed increased seizure occurrence and intensity. Hippocampal expression levels of N-methyl-d-aspartate (NMDA) receptor subunits (GluN1MK-801, attenuated these effects of high-dose DM, whereas an opioid antagonist, naloxone, did not affect DM-induced neurotoxicity. Moreover, pretreatment with a highly specific GluN2B subunit inhibitor, traxoprodil, was selectively effective in preventing DM-induced c-Fos expression and apoptotic changes. These results suggest that high-dose DM produces convulsive behaviors by activating GluN2B/NMDA signaling that leads to pro-apoptotic changes. Copyright © 2017. Published by Elsevier Inc.

Radiopharmaceutical development of radiolabelled peptides

Energy Technology Data Exchange (ETDEWEB)

Fani, Melpomeni; Maecke, Helmut R. [University Hospital Freiburg, Department of Nuclear Medicine, Freiburg (Germany)

2012-02-15

Receptor targeting with radiolabelled peptides has become very important in nuclear medicine and oncology in the past few years. The overexpression of many peptide receptors in numerous cancers, compared to their relatively low density in physiological organs, represents the molecular basis for in vivo imaging and targeted radionuclide therapy with radiolabelled peptide-based probes. The prototypes are analogs of somatostatin which are routinely used in the clinic. More recent developments include somatostatin analogs with a broader receptor subtype profile or with antagonistic properties. Many other peptide families such as bombesin, cholecystokinin/gastrin, glucagon-like peptide-1 (GLP-1)/exendin, arginine-glycine-aspartic acid (RGD) etc. have been explored during the last few years and quite a number of potential radiolabelled probes have been derived from them. On the other hand, a variety of strategies and optimized protocols for efficient labelling of peptides with clinically relevant radionuclides such as {sup 99m}Tc, M{sup 3+} radiometals ({sup 111}In, {sup 86/90}Y, {sup 177}Lu, {sup 67/68}Ga), {sup 64/67}Cu, {sup 18}F or radioisotopes of iodine have been developed. The labelling approaches include direct labelling, the use of bifunctional chelators or prosthetic groups. The choice of the labelling approach is driven by the nature and the chemical properties of the radionuclide. Additionally, chemical strategies, including modification of the amino acid sequence and introduction of linkers/spacers with different characteristics, have been explored for the improvement of the overall performance of the radiopeptides, e.g. metabolic stability and pharmacokinetics. Herein, we discuss the development of peptides as radiopharmaceuticals starting from the choice of the labelling method and the conditions to the design and optimization of the peptide probe, as well as some recent developments, focusing on a selected list of peptide families, including somatostatin

Effects of the metabotropic glutamate receptor 5 positive allosteric modulator CDPPB on rats tested with the paired associates learning task in touchscreen-equipped operant conditioning chambers.

Science.gov (United States)

Lins, Brittney R; Howland, John G

2016-03-15

Effective treatments for the cognitive symptoms of schizophrenia are critically needed. Positive allosteric modulation (PAM) of metabotropic glutamate receptor subtype 5 (mGluR5) is one strategy currently under investigation to improve these symptoms. Examining cognition using touchscreen-equipped operant chambers may increase translation between preclinical and clinical research through analogous behavioral testing paradigms in rodents and humans. We used acute CDPPB (1-30mg/kg) treatment to examine the effects of mGluR5 PAM in the touchscreen paired associates learning (PAL) task using well-trained rats with and without co-administration of acute MK-801 (0.15mg/kg). CDPPB had no consistent effects on task performance when administered alone and failed to reverse the MK-801 induced impairments at any of the examined doses. Overall, the disruptive effects of MK-801 on PAL were consistent with previous research but increasing mGluR5 signaling is not beneficial in the PAL task. Future research should test whether administration of CDPPB during PAL acquisition increases performance. Copyright © 2015 Elsevier B.V. All rights reserved.

Optimised labeling, preclinical and initial clinical aspects of CCK-2 receptor-targeting with 3 radiolabeled peptides

Energy Technology Data Exchange (ETDEWEB)

Breeman, Wouter A.P. [Department of Nuclear Medicine, Erasmus MC Rotterdam' s 3015 CE Rotterdam (Netherlands)], E-mail: w.a.p.breeman@erasmusmc.nl; Froeberg, A.C.; Blois, E. de; Gameren, A. van; Melis, M.; Jong, M. de [Department of Nuclear Medicine, Erasmus MC Rotterdam' s 3015 CE Rotterdam (Netherlands); Maina, T.; Nock, B.A. [Molecular Radiopharmacy Section, I/R-RP, NCSR ' Demokritos' , Athens (Greece); Erion, J.L. [BioSynthema Inc., St. Louis, MO (United States); Maecke, H.R. [Radiological Chemistry, University Hospital Basel (Switzerland); Krenning, E.P. [Department of Nuclear Medicine, Erasmus MC Rotterdam' s 3015 CE Rotterdam (Netherlands); Department of Internal Medicine, Erasmus MC, Rotterdam (Netherlands)

2008-11-15

Medullary thyroid carcinoma (MTC) expresses CCK-2 receptors. {sup 111}In-labeled DOTA-DGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH{sub 2} (DOTA-MG11), DOTA-DAsp-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH{sub 2} (DOTA-CCK), and {sup 99m}Tc-labeled N{sub 4}-Gly-DGlu-(Glu){sub 5}-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH{sub 2} ({sup 99m}Tc-Demogastrin 2) are analogs developed for CCK-2 receptor-targeted scintigraphy. All 3 radiolabeled analogs were selected on the basis of their high CCK-2 receptor affinity and their good in vitro serum stability, with in vitro serum t{sub 1/2} values of several hours. Radiolabeling of DOTA-peptides with {sup 111}In requires a heating procedure, typically in the range of 80 deg. - 100 deg. C up to 30 min. Following this procedure with DOTA-MG11 resulted in a >98 % incorporation of {sup 111}In, however, with a radiochemical purity (RCP) of <50 %. The decrease in RCP was found to be due to oxidation of the methionine residue in the molecule. Moreover, this oxidized compound lost its CCK-2 receptor affinity. Therefore, conditions during radiolabeling were optimised: labeling of DOTA-MG11 and DOTA-CCK with {sup 111}In involved 5 min heating at 80 deg. C and led to an incorporation of {sup 111}In of >98 %. In addition, all analogs were radiolabeled in the presence of quenchers to prevent radiolysis and oxidation resulting in a RCP of >90 %. All 3 radiolabeled analogs were i.v. administered to 6 MTC patients: radioactivity cleared rapidly by the kidneys, with no significant differences in the excretion pattern of the 3 radiotracers. All 3 radiolabeled analogs exhibited a low in vivo stability in patients, as revealed during analysis of blood samples, with the respective t{sub 1/2} found in the order of minutes. In patient blood, the rank of radiopeptide in vivo stability was: {sup 99m}Tc-Demogastrin 2 (t{sub 1/2} 10-15 min)>{sup 111}In-DOTA-CCK (t{sub 1/2}{approx}5-10 min)>{sup 111}In-DOTA-MG11 (t{sub 1/2}<5 min)

18 CFR 385.801 - Waiver of hearing (Rule 801).

Science.gov (United States)

2010-04-01

... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Waiver of hearing (Rule 801). 385.801 Section 385.801 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY....801 Waiver of hearing (Rule 801). In any proceeding in which the Commission is authorized to act after...

Application of single-vial ready-for-use formulation of 111In- or 177Lu-labelled somatostatin analogs.

Science.gov (United States)

de Blois, Erik; Chan, Ho Sze; de Zanger, Rory; Konijnenberg, Mark; Breeman, Wouter A P

2014-02-01

For the sake of safety it would be desirable to store and transport the ready-for-use liquid formulation (diagnostics and therapeutics) of radiolabelled peptides. The use of ethanol, in combination with a mixture of gentisic- and ascorbic acid, has superior effects on stabilizing radiolabelled somatostatin analogs. As a consequence, (111)In- and (177)Lu-labelled somatostatin analogs can be stored and transported in a single-vial ready-for-use liquid formulation up to 7 days after radiolabelling. © 2013 Published by Elsevier Ltd.

Effects of a dragonfly (Anax i.) homeopathic remedy on learning, memory and cell morphology in mice.

Science.gov (United States)

Mutlu, Oguz; Ulak, Guner; Kokturk, Sibel; Komsuoglu Celikyurt, Ipek; Tanyeri, Pelin; Akar, Furuzan; Erden, Faruk

2016-02-01

Homeopathy is a form of alternative medicine in which uses highly diluted preparations that are believed to cause healthy people to exhibit symptoms similar to those exhibited by patients. The aim of this study was to investigate the effects of dragonfly (Anax imperator, Anax i.) on learning and memory in naive mice using the Morris water maze (MWM) test; moreover, the effects of dragonfly on MK-801-induced cognitive dysfunction were evaluated. Male balb-c mice were treated with dragonfly (30C and 200C) or MK-801 (0.2 mg/kg) alone or concurrently (n = 10). Dragonfly (D) and MK-801 were administered subchronically for 6 days intraperitoneally 60 min and 30 min, respectively, before the daily performance of the MWM test. This study revealed that in the familiarization session and first session of the MWM test, Anax i. D30 significantly decreased escape latency compared to the control group, although MK-801, D30 and D200 significantly increased escape latency at the end of five acquisition sessions. Anax i. combined with dizocilpine maleate (MK-801) also significantly decreased escape latency in the familiarization session and first session of the MWM test, although this combination increased escape latency compared to the MK-801 alone group at the end of the test. Time spent in escape platform's quadrant in the probe trial significantly decreased while mean distance to platform significantly increased in MK-801, D30 and D200 groups. In the MWM test, Anax i. combined with MK-801 significantly decreased speed of the animals compared to the MK-801 alone group. General cell morphology was disturbed in the MK-801 group while D30 and D200 seemed to improve cell damage in the MK-801 group. These results suggest that the homeopathic Anax i. can impair learning acquisition and reference memory, and it has beneficial effects on disturbed cell morphology. Copyright © 2015 The Faculty of Homeopathy. Published by Elsevier Ltd. All rights reserved.

Effect of NMDA Receptor Antagonist on Local Cerebral Glucose Metabolic Rate in Focal Cerebral Ischemia

International Nuclear Information System (INIS)

Kim, Sang Eun; Hong, Seung Bong; Yoon, Byung Woo

1995-01-01

There has recently been increasing interest in the use of NMDA receptor antagonists as potential neuroprotective agents for the treatment of ischemic stroke. To evaluate the neuroprotective effect of the selective non-competitive NMDA receptor antagonist MK-801 in focal cerebral ischemia, local cerebral glucose utilization (1CGU) was examined in 15 neuroanatomically discrete regions of the conscious rat brain using the 2-deoxy-D[14C]glucose quantitative autoradiographic technique 24 hr after left middle cerebral artery occlusion (MCAO). Animals received MK-801 (5 mg/kg i.v.) or saline vehicle before (20-30 min) or after (30 min) MCAO. Both pretreatment and posttreatment of MK-801 increased occluded/non-occluded 1CGU ratio in 7 and 5 of the 15 regions measured, respectively(most notably in cortical structures). Following MK-801 pretreatment, there was evidence of widespread increases in 1CCPU not only in the non-occluded hemisphere (12 of the 15 areas studied) but also in the occluded hemisphere (13 of the 15 areas studied), while MK-801 posttreatment did not significantly increase 1CGU both in the normal and occluded hemispheres. These data indicate that MK-801 has a neuroprotective effect in focal cerebral ischemia and demonstrate that MK-801 provides widespread alterations of glucose utilization in conscious animals.

Chronic dietary chlorpyrifos causes long-term spatial memory impairment and thigmotaxic behavior.

Science.gov (United States)

López-Granero, Caridad; Ruiz-Muñoz, Ana M; Nieto-Escámez, Francisco A; Colomina, María T; Aschner, Michael; Sánchez-Santed, Fernando

2016-03-01

Little is known about the long-term effects of chronic exposure to low-level organophosphate (OP) pesticides, and the role of neurotransmitter systems, other than the cholinergic system, in mediating OP neurotoxicity. In this study, rats were administered 5mg/kg/day of chlorpyrifos (CPF) for 6 months commencing at 3-months-of-age. The animals were examined 7 months later (at 16-months-of-age) for spatial learning and memory in the Morris water maze (MWM) and locomotor activity. In addition, we assessed the chronic effects of CPF on glutamatergic and gamma-aminobutyric acid (GABAergic) function using pharmacological challenges with dizocilpine (MK801) and diazepam. Impaired performance related to altered search patterns, including thigmotaxis and long-term spatial memory was noted in the MWM in animals exposed to CPF, pointing to dietary CPF-induced behavioral disturbances, such as anxiety. Twenty-four hours after the 31st session of repeated acquisition task, 0.1mg/kg MK801, an N-methyl-d-aspartate (NMDA) antagonist was intraperitoneally (i.p.) injected for 4 consecutive days. Decreased latencies in the MWM in the control group were noted after two sessions with MK801 treatment. Once the MWM assessment was completed, animals were administered 0.1 or 0.2mg/kg of MK801 and 1 or 3mg/kg of diazepam i.p., and tested for locomotor activity. Both groups, the CPF dietary and control, displayed analogous performance in motor activity. In conclusion, our data point to a connection between the long-term spatial memory, thigmotaxic response and CPF long after the exposure ended. Copyright © 2015 Elsevier Inc. All rights reserved.

Dizocilpine (MK-801) impairs learning in the active place avoidance task but has no effect on the performance during task/context alternation.

Science.gov (United States)

Vojtechova, Iveta; Petrasek, Tomas; Hatalova, Hana; Pistikova, Adela; Vales, Karel; Stuchlik, Ales

2016-05-15

The prevention of engram interference, pattern separation, flexibility, cognitive coordination and spatial navigation are usually studied separately at the behavioral level. Impairment in executive functions is often observed in patients suffering from schizophrenia. We have designed a protocol for assessing these functions all together as behavioral separation. This protocol is based on alternated or sequential training in two tasks testing different hippocampal functions (the Morris water maze and active place avoidance), and alternated or sequential training in two similar environments of the active place avoidance task. In Experiment 1, we tested, in adult rats, whether the performance in two different spatial tasks was affected by their order in sequential learning, or by their day-to-day alternation. In Experiment 2, rats learned to solve the active place avoidance task in two environments either alternately or sequentially. We found that rats are able to acquire both tasks and to discriminate both similar contexts without obvious problems regardless of the order or the alternation. We used two groups of rats, controls and a rat model of psychosis induced by a subchronic intraperitoneal application of 0.08mg/kg of dizocilpine (MK-801), a non-competitive antagonist of NMDA receptors. Dizocilpine had no selective effect on parallel/sequential learning of tasks/contexts. However, it caused hyperlocomotion and a significant deficit in learning in the active place avoidance task regardless of the task alternation. Cognitive coordination tested by this task is probably more sensitive to dizocilpine than spatial orientation because no hyperactivity or learning impairment was observed in the Morris water maze. Copyright © 2016 Elsevier B.V. All rights reserved.

The effect of infectious brain edema on NMDA receptor binding in rat's brain

International Nuclear Information System (INIS)

Cheng Guansheng; Chen Jianfang; Chen Xiang

1997-01-01

PURPOSE: The effect of the infectious brain edema (IBE) induced by Bordetella Pertussis (BP) on the specific binding of 3 H MK-801 in rat's brain in vivo was determined. METHODS: BP was injected via left internal carotid artery in rat model of infectious brain edema. Male SD rats were divided into three groups: 1) Group control (NS, n = 11); 2) Group IBF (BP, n = 12); 3) Group pretreatment of MK-801 + PB (MK-801, n = 4). Normal saline or BP 0.2 ml/kg was injected into left internal carotid artery in NS and BP group respectively. MK-801 0.5 mg/kg per day was injected i.p. two days before injection of BP in group MK-801. Rats were killed by decapitation at 24 hours after injection of BP. The specific binding of N-methyl-D-aspartate (NMDA) receptor were measured with 3 H-MK-801 in the neuronal membrane of cerebral cortex. The Scatchard plots were performed. RESULTS: The B max values were 0.623 +- 0.082 and 0.606 +- 0.087 pmol/mg protein in group NS and BP respectively (t = 0.48, P>0.05). The Kd values were 43.1 +- 4.2 and 30.5 +- 3.0 nmol/L in group NS and BP respectively (t = 7.8, P<0.05). The specific binding of NMDA receptor was decreased by pretreatment of MK-801. CONCLUSIONS: The total number of NMDA receptor had not changed, whereas its affinity increased significantly in the model of brain edema induced by pertussis bacilli in rat. The increase of affinity of NMDA receptor can be blockaded by MK-801 pretreatment in vivo

Radiolabeled antibodies in cancer. Oncology Overview

International Nuclear Information System (INIS)

1984-11-01

Oncology Overviews are a service of the International Cancer Research Data Bank (ICRDB) Program of the National Cancer Institute, intended to facilitate and promote the exchange of information between cancer scientists by keeping them aware of literature related to their research being published by other laboratories through the world. Each Oncology Overview represents a survey of the literature associated with a selected area of cancer research. It contains abstracts of articles which have been selected and organized by researchers associated with the field. Contents: Radiolabeled antibodies--labeling and imaging techniques; Radiolabeled antibodies--carcinoembryonic antigen; Radiolabeled antibodies--alpha-fetoprotein; Radiolabeled antibodies--human chorionic gonadotropin; Radiolabeled antibodies--ferritin; Radiolabeled antibodies--imaging of colorectal tumors; Radiolabeled antibodies--imaging of malignant melanoma; Radiolabeled antibodies--imaging of urogenital tumors; Radiolabeled antibodies--imaging of thyroid tumors; Radiolabeled antibodies--other clinical studies; Radiolabeled antibodies--selected preclinical studies; Radiolabeled antibodies--reviews

7 CFR 801.1 - Applicability.

Science.gov (United States)

2010-01-01

... 7 Agriculture 7 2010-01-01 2010-01-01 false Applicability. 801.1 Section 801.1 Agriculture Regulations of the Department of Agriculture (Continued) GRAIN INSPECTION, PACKERS AND STOCKYARD... FOR GRAIN INSPECTION EQUIPMENT § 801.1 Applicability. The requirements set forth in this part 801...

Crucial roles of the protein kinases MK2 and MK3 in a mouse model of glomerulonephritis.

Directory of Open Access Journals (Sweden)

Adam J Guess

Full Text Available Elevated mitogen-activated protein kinase p38 (p38 MAPK signaling has been implicated in various experimental and human glomerulopathies, and its inhibition has proven beneficial in animal models of these diseases. p38 MAPK signaling is partially mediated through MK2 and MK3, two phylogenetically related protein kinases that are its direct substrates. The current study was designed to determine the specific roles of MK2 and MK3 in a mouse model of acute proliferative glomerulonephritis, using mice with disrupted MK2 and/or MK3 genes. We found that the absence of MK3 alone worsened the disease course and increased mortality slightly compared to wild-type mice, whereas the absence of MK2 alone exhibited no significant effect. However, in an MK3-free background, the disease course depended on the presence of MK2 in a gene dosage-dependent manner, with double knock-out mice being most susceptible to disease induction. Histological and renal functional analyses confirmed kidney damage following disease induction. Because the renal stress response plays a crucial role in kidney physiology and disease, we analyzed the stress response pattern in this disease model. We found that renal cortices of diseased mice exhibited a pronounced and specific pattern of expression and/or phosphorylation of stress proteins and other indicators of the stress response (HSPB1, HSPB6, HSPB8, CHOP, eIF2α, partially in a MK2/MK3 genotype-specific manner, and without induction of a general stress response. Similarly, the expression and activation patterns of other protein kinases downstream of p38 MAPK (MNK1, MSK1 depended partially on the MK2/MK3 genotype in this disease model. In conclusion, MK2 and MK3 together play crucial roles in the regulation of the renal stress response and in the development of glomerulonephritis, which can potentially be exploited to develop novel therapeutic approaches to treat glomerular disease.

Radiolabelled peptides: New radiopharmaceuticals for targeted therapy

International Nuclear Information System (INIS)

Chinol, M.

2001-01-01

Radiolabelled peptides have been the focus of an increasing interest by the nuclear medicine community within the last few years. This has mainly been due to successful development of one of these peptides, somatostatin, as a tool to visualise various pathologic conditions known to express a high number of somatostatin receptors. Somatostatin receptors have been identified in different tumours such as neuroendocrine tumours, tumours of the central nervous system, breast, lung and lymphatic tissue. These observations served as the biomolecular basis for the clinical use of radiolabelled somatostatin analogs, which are at present of great interest for diagnostic and therapeutic applications. A promising somatostatin analogue, DOTA-D-Phe 1 -Ty 3 -octreotide, named DOTATOC, has shown favourable biodistribution and high affinity binding to SSTR2 and SSTR5, high hydrophilicity and ease of labelling and stability with 111 In and 90 Y. A clinical trial aimed at evaluating the biodistribution and dosimetry of DOTATOC radiolabelled with 111 In, in anticipation of therapy trials with 90 Y-DOTATOC in patients was undertaken. 111 In-DOTATOC showed favourable pharmacokinetics (fast blood clearance and urinary excretion) and biodistribution, and high affinity to tumours expressing somatostatin receptors (thus, a high residence time in tumour). These results are promising for therapy trials with 90 Y-DOTAOC, for which radiation dosimetry appears acceptable for normal organs (including the red marrow). Moreover, labelling conditions of DOTATOC with 90 Y has been optimised in order to achieve labelling yields of more than 98% and specific activities of greater than 60 GBq (1.6 Ci)/μmol. (author)

Development and preclinical evaluation of radiolabelled somatostatin receptor agonists and αvβ3-integrin antagonists

International Nuclear Information System (INIS)

Stoecklin, G.; Wester, H.J.; Haubner, R.; Schottelius, M.

2002-01-01

Tumours express specific receptors for peptide ligands. This can be exploited for tumour targeting. New bioactive peptides are available, in particular new somatostatin analogs and RGD-Peptides for targeting the α V β 3 -integrin. The design and optimization of radiolabelled peptides with respect to their receptor affinity, tumour uptake, biodistribution, pharmacokinetics and stability may provide better tracers for tumour imaging and therapy. Based on two basic structures, new radioiodinated and carbohydrated somatostatin analogs and cyclic RGD-peptides were developed and evaluated. (author)

Sex pheromone receptor proteins. Visualization using a radiolabeled photoaffinity analog

International Nuclear Information System (INIS)

Vogt, R.G.; Prestwich, G.D.; Riddiford, L.M.

1988-01-01

A tritium-labeled photoaffinity analog of a moth pheromone was used to covalently modify pheromone-selective binding proteins in the antennal sensillum lymph and sensory dendritic membranes of the male silk moth, Antheraea polyphemus. This analog, (E,Z)-6,11-[ 3 H]hexadecadienyl diazoacetate, allowed visualization of a 15-kilodalton soluble protein and a 69-kilodalton membrane protein in fluorescence autoradiograms of electrophoretically separated antennal proteins. Covalent modification of these proteins was specifically reduced when incubation and UV irradiation were conducted in the presence of excess unlabeled pheromone, (E,Z)-6,11-hexadecadienyl acetate. These experiments constitute the first direct evidence for a membrane protein of a chemosensory neuron interacting in a specific fashion with a biologically relevant odorant

Maslinic acid ameliorates NMDA receptor blockade-induced schizophrenia-like behaviors in mice.

Science.gov (United States)

Jeon, Se Jin; Kim, Eunji; Lee, Jin Su; Oh, Hee Kyong; Zhang, Jiabao; Kwon, Yubeen; Jang, Dae Sik; Ryu, Jong Hoon

2017-11-01

Schizophrenia is a chronic psychotic disorder characterized by positive, negative, and cognitive symptoms. Primary treatments for schizophrenia relieve the positive symptoms but are less effective against the negative and cognitive symptoms. In the present study, we investigated whether maslinic acid, isolated from Syzygium aromaticum (clove), can ameliorate schizophrenia-like behaviors in mice induced by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist. After maslinic acid treatment in the MK-801 model, we examined the behavioral alteration and signaling pathways in the prefrontal cortex. Mice were treated with maslinic acid (30 mg/kg), and their behaviors were evaluated through an array of behavioral tests. The effects of maslinic acid were also examined in the signaling pathways in the prefrontal cortex. A single administration of maslinic acid blocked the MK-801-induced hyperlocomotion and reversed the MK-801-induced sensorimotor gating deficit in the acoustic startle response test. In the social novelty preference test, maslinic acid ameliorated the social behavior deficits induced by MK-801. The MK-801-induced attention and recognition memory impairments were also alleviated by a single administration of maslinic acid. Furthermore, maslinic acid normalized the phosphorylation levels of Akt-GSK-3β and ERK-CREB in the prefrontal cortex. Overall, maslinic acid ameliorated the schizophrenia-like symptoms induced by MK-801, and these effects may be partly mediated through Akt-GSK-3β and ERK-CREB activation. These findings suggest that maslinic acid could be a candidate for the treatment of several symptoms of schizophrenia, including positive symptoms, sensorimotor gating disruption, social interaction deficits, and cognitive impairments. Copyright © 2017 Elsevier Ltd. All rights reserved.

7 CFR 801.10 - [Reserved

Science.gov (United States)

2010-01-01

... 7 Agriculture 7 2010-01-01 2010-01-01 false [Reserved] 801.10 Section 801.10 Agriculture Regulations of the Department of Agriculture (Continued) GRAIN INSPECTION, PACKERS AND STOCKYARD... FOR GRAIN INSPECTION EQUIPMENT § 801.10 [Reserved] ...

Radiolabeled cypoxic cell sensitizers: tracer for assessment of ischemia

International Nuclear Information System (INIS)

Mathias, C.J.; Welch, M.J.; Kilbourn, M.R.; Jerabek, P.A.; Patrick, T.B.; Raichle, M.E.; Krohn, K.A.; Rasey, J.S.; Shaw, D.W.

1987-01-01

Hypoxic, non-functional, but viable, tissue may exist in heart and brain following an arterial occlusion. Identification of such tissue in vivo is crucial to the development of effective treatment strategies. It has been suggested that certain compounds capable of sensitizing hypoxic tumor cells to killing by x-rays (i.e., misonidazole) might serve as in vivo markers of hypoxic tissue in ischemic myocardium or brain if properly radiolabeled. To this end the authors have radiolabeled two fluorinated analogs of nitroimidazole based hypoxic cell sensitizers with the 110 minute half-lived positron-emitting fluorine-18. The ability of these tracers to quantitate the presence of hypoxic tissue has been studied in a gerbil stroke model. The in vivo uptake of one of these tracers [F-18]-fluoronormethyoxymisonidazole is dependent on the extent of tissue hypoxia, and thus, appears to have potential as a diagnostic indicator of non-functional but viable tissue when the tracer is used in conjunction with positron emission tomography. 80 references, 2 figures, 1 table

48 CFR 25.801 - General.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false General. 25.801 Section 25.801 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION SOCIOECONOMIC PROGRAMS FOREIGN ACQUISITION Other International Agreements and Coordination 25.801 General. Treaties and...

48 CFR 22.801 - Definitions.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Definitions. 22.801 Section 22.801 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION SOCIOECONOMIC PROGRAMS APPLICATION OF LABOR LAWS TO GOVERNMENT ACQUISITIONS Equal Employment Opportunity 22.801...

36 CFR 801.3 - Applicant responsibilities.

Science.gov (United States)

2010-07-01

.... 801.3 Section 801.3 Parks, Forests, and Public Property ADVISORY COUNCIL ON HISTORIC PRESERVATION HISTORIC PRESERVATION REQUIREMENTS OF THE URBAN DEVELOPMENT ACTION GRANT PROGRAM § 801.3 Applicant... responsibility of the applicant to provide the information specified in § 801.7, to make an informed and...

48 CFR 8.801 - Definitions.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Definitions. 8.801 Section 8.801 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION ACQUISITION PLANNING REQUIRED SOURCES OF SUPPLIES AND SERVICES Acquisition of Printing and Related Supplies 8.801 Definitions...

48 CFR 32.801 - Definitions.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Definitions. 32.801 Section 32.801 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION GENERAL CONTRACTING REQUIREMENTS CONTRACT FINANCING Assignment of Claims 32.801 Definitions. Designated agency, as used in this...

14 CFR 27.801 - Ditching.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Ditching. 27.801 Section 27.801 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS STANDARDS: NORMAL CATEGORY ROTORCRAFT Design and Construction Personnel and Cargo Accommodations § 27.801...

48 CFR 19.801 - [Reserved

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false [Reserved] 19.801 Section 19.801 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION SOCIOECONOMIC PROGRAMS SMALL BUSINESS PROGRAMS Contracting With the Small Business Administration (the 8(a) Program) 19.801...

48 CFR 4.801 - General.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false General. 4.801 Section 4.801 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION GENERAL ADMINISTRATIVE MATTERS Government Contract Files 4.801 General. (a) The head of each office performing contracting...

14 CFR 29.801 - Ditching.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Ditching. 29.801 Section 29.801 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Design and Construction Personnel and Cargo Accommodations § 29.801...

14 CFR 25.801 - Ditching.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Ditching. 25.801 Section 25.801 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS STANDARDS: TRANSPORT CATEGORY AIRPLANES Design and Construction Emergency Provisions § 25.801 Ditching. (a...

The pre-ischaemic neuroprotective effect of a novel polyamine antagonist, N1-dansyl-spermine in a permanent focal cerebral ischaemia model in mice.

Science.gov (United States)

Li, Jun; Henman, Martin C; Doyle, Karen M; Strbian, Daniel; Kirby, Brian P; Tatlisumak, Turgut; Shaw, Graham G

2004-12-10

The polyamine sites on the NMDA receptor complex offer a therapeutic target for focal ischaemia, potentially devoid of most side effects associated with NMDA antagonists. In this study, we investigated the effect of a novel polyamine antagonist, N(1)-dansyl-spermine (0.5-10 mg kg(-1)) in a permanent focal cerebral ischaemia model in mice, and compared its effect to that of MK-801 (0.3-3 mg kg(-1)) following administration 30 min prior to ischaemia. A battery of histological and behavioural tests was employed following permanent middle cerebral artery occlusion to assess any neuroprotective effect. Following middle cerebral artery occlusion, N(1)-dansyl-spermine (1-5 mg kg(-1)) and MK-801 (1 or 3 mg kg(-1)) caused a comparable and significant reduction in the percentage hemisphere lesion volume. Similarly, both drugs significantly reduced oedema and neurological deficit score to a similar extent. Locomotor activity in MCAO mice was not significantly improved by MK-801 or N(1)-dansyl-spermine, although N(1)-dansyl-spermine induced a trend towards significant improvement. Significant improvement in rotarod performance was observed at neuroprotective doses with both drugs. Upon comparison of the profile of effects, N(1)-dansyl-spermine at least matched the effectiveness of MK-801 as a neuroprotective agent in this model. In addition, in sham-operated control mice, N(1)-dansyl-spermine was well tolerated, in contrast to the pronounced adverse effects of MK-801 on locomotor activity and rotarod performance. In conclusion, this study has shown that N(1)-dansyl-spermine is as effective a neuroprotective drug as MK-801 in this model. Moreover, in contrast to MK-801, N(1)-dansyl-spermine could be a promising therapeutic candidate for stroke as it is well tolerated at neuroprotective doses in sham-operated animals.

Contribution of N-methyl-D-aspartate receptors to attention and episodic spatial memory during senescence.

Science.gov (United States)

Guidi, Michael; Rani, Asha; Karic, Semir; Severance, Barrett; Kumar, Ashok; Foster, Thomas C

2015-11-01

A decrease in N-methyl-D-aspartate receptor (NMDAR) function is associated with age-related cognitive impairments. However, NMDAR antagonists are prescribed for cognitive decline associated with age-related neurodegenerative disease, raising questions as to the role of NMDAR activity in cognitive function during aging. The current studies examined effects of NMDAR blockade on cognitive task that are sensitive to aging. Young and middle-age rats were trained on the five-choice serial reaction time task (5-CSRTT) and challenged with MK-801 (0.025, 0.05, and 0.1mg/kg or vehicle). Attention deficits were apparent in middle-age and performance of young and middle-age rats was enhanced for low doses of MK-801 (0.025 and 0.05). The beneficial effects on attention were reversed by the highest dose of MK-801. Older animals exhibited a delay-dependent impairment of episodic spatial memory examined on a delayed-matching to place water maze task. Similarly, a low dose of MK-801 (0.05mg/kg) impaired performance with increasing delay and aged animals were more susceptible to disruption by NMDAR blockade. Despite MK-801 impairment of episodic spatial memory, MK-801 had minimal effects on spatial reference memory. Our results confirm that NMDARs contribute to rapidly acquired and flexible spatial memory and support the idea that a decline in NMDAR function contributes to the age-related impairments in cognition. Copyright © 2015 Elsevier Inc. All rights reserved.

The pre-ischaemic neuroprotective effects of N1-dansyl-spermine in a transient focal cerebral ischaemia model in mice.

Science.gov (United States)

Li, Jun; Henman, Martin C; Tatlisumak, Turgut; Shaw, Graham G; Doyle, Karen M

2005-09-07

The pre-ischaemic neuroprotective potential of a novel polyamine/NMDA antagonist N1-dansyl-spermine (1-5 mg kg(-1)) was studied in a transient focal cerebral ischaemia model in mice in comparison to a reference compound, MK-801 (1 or 3 mg kg(-1)). The intraluminal suture transient middle cerebral artery occlusion (MCAO) model was used. N1-dansyl-spermine and MK-801 were administered (i.p.) 30 min prior to ischaemia. A range of histological and behavioural assessments was employed. N1-dansyl-spermine had a comparable effect to MK-801 at reducing the percentage hemisphere lesion volume (%HLV) at the doses tested. Furthermore, N1-dansyl-spermine reduced the ischaemic brain oedema, which MK-801 did not. N1-dansyl-spermine significantly reversed the decrease of locomotor activity (LMA) caused by the MCAO and showed a significant effect at improving the rotarod performance impaired by MCAO. In contrast, MK-801 had no beneficial effect on sensorimotor function and even worsened the LMA. These results clearly demonstrate the pre-ischaemic neuroprotective effect of N1-dansyl-spermine in a transient focal cerebral ischaemia model.

Radiolabelled sucralfate compositions

International Nuclear Information System (INIS)

Vasquez, T.E.; Bridges, R.L.; Braunstein, P.; Jansholt, A.

1984-01-01

A novel radiopharmaceutical composition comprising an aqueous solution or suspension containing a radiolabelled sucralfate or sucralfate derivative or precursor is claimed. The composition is effective for in vivo scintigraphic imaging of the gastrointestinal muscosal areas in humans. The sucralfate is combined with a radiolabelled albumin or other protein or protein derivative under acidic conditions

Differential effect of NMDA and AMPA receptor blockade on protein synthesis in the rat infarct borderzone

DEFF Research Database (Denmark)

Christensen, Thomas; Bruhn, T; Frank, L

1996-01-01

treated with either saline, MK-801 (5 mg/kg i.p.) or NBQX (30 mg/kg i.p. x 3) were subjected to permanent MCAO. Regional CPSR and volumes of gray matter structures displaying normal CPSR were measured in coronal cryosections of the brain by quantitative autoradiography following an i.v. bolus injection....... Treatment with MK-801 significantly increased the volume of tissue with normal CPSR in the ischemic hemisphere compared to controls, whereas this was not seen with NBQX treatment. The results suggest that MK-801 and NBQX have different effects on peri-infarct protein synthesis after MCAO. Since both......We investigated whether the known neuroprotective effects of two selective glutamate receptor antagonists, the NMDA antagonist MK-801 and the AMPA antagonist NBQX, are reflected in the regional cerebral protein synthesis rates (CPSR) in rats with middle cerebral artery occlusion (MCAO). Rats...

5 CFR 890.801 - Introduction.

Science.gov (United States)

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Introduction. 890.801 Section 890.801 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Benefits for Former Spouses § 890.801 Introduction. This subpart sets...

7 CFR 760.801 - Administration.

Science.gov (United States)

2010-01-01

... 7 Agriculture 7 2010-01-01 2010-01-01 false Administration. 760.801 Section 760.801 Agriculture Regulations of the Department of Agriculture (Continued) FARM SERVICE AGENCY, DEPARTMENT OF AGRICULTURE SPECIAL PROGRAMS INDEMNITY PAYMENT PROGRAMS 2005-2007 Crop Disaster Program § 760.801 Administration. (a...

9 CFR 93.801 - Prohibitions.

Science.gov (United States)

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Prohibitions. 93.801 Section 93.801 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... CONVEYANCE AND SHIPPING CONTAINERS Elephants, Hippopotami, Rhinoceroses, and Tapirs § 93.801 Prohibitions...

48 CFR 46.801 - Applicability.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Applicability. 46.801 Section 46.801 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION CONTRACT MANAGEMENT QUALITY ASSURANCE Contractor Liability for Loss of or Damage to Property of the Government 46.801...

33 CFR 183.801 - Applicability.

Science.gov (United States)

2010-07-01

... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Applicability. 183.801 Section 183.801 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) BOATING SAFETY BOATS AND ASSOCIATED EQUIPMENT Navigation Lights § 183.801 Applicability. This subpart...

48 CFR 23.801 - Authorities.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Authorities. 23.801 Section 23.801 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION SOCIOECONOMIC... DRUG-FREE WORKPLACE Ozone-Depleting Substances 23.801 Authorities. (a) Title VI of the Clean Air Act...

47 CFR 27.801 - Scope.

Science.gov (United States)

2010-10-01

... 47 Telecommunication 2 2010-10-01 2010-10-01 false Scope. 27.801 Section 27.801 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES MISCELLANEOUS WIRELESS COMMUNICATIONS SERVICES 1.4 GHz Band § 27.801 Scope. This subpart sets out the regulations governing service in...

5 CFR 2634.801 - Scope.

Science.gov (United States)

2010-01-01

... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Scope. 2634.801 Section 2634.801 Administrative Personnel OFFICE OF GOVERNMENT ETHICS GOVERNMENT ETHICS EXECUTIVE BRANCH FINANCIAL DISCLOSURE, QUALIFIED TRUSTS, AND CERTIFICATES OF DIVESTITURE Ethics Agreements § 2634.801 Scope. This subpart applies...

5 CFR 2635.801 - Overview.

Science.gov (United States)

2010-01-01

... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Overview. 2635.801 Section 2635.801 Administrative Personnel OFFICE OF GOVERNMENT ETHICS GOVERNMENT ETHICS STANDARDS OF ETHICAL CONDUCT FOR EMPLOYEES OF THE EXECUTIVE BRANCH Outside Activities § 2635.801 Overview. (a) This subpart contains provisions...

38 CFR 17.801 - Definitions.

Science.gov (United States)

2010-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 1 2010-07-01 2010-07-01 false Definitions. 17.801 Section 17.801 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS MEDICAL Transitional Housing Loan Program § 17.801 Definitions. (a) Applicant: A non-profit organization making application for...

36 CFR 801.2 - Definitions.

Science.gov (United States)

2010-07-01

... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Definitions. 801.2 Section 801.2 Parks, Forests, and Public Property ADVISORY COUNCIL ON HISTORIC PRESERVATION HISTORIC PRESERVATION REQUIREMENTS OF THE URBAN DEVELOPMENT ACTION GRANT PROGRAM § 801.2 Definitions. The terms defined...

26 CFR 801.8 - Effective/applicability dates.

Science.gov (United States)

2010-04-01

... 26 Internal Revenue 20 2010-04-01 2010-04-01 false Effective/applicability dates. 801.8 Section 801.8 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INTERNAL... REVENUE SERVICE § 801.8 Effective/applicability dates. The provisions of §§ 801.1 through 801.7 apply on...

7 CFR 801.11 - Related design requirements.

Science.gov (United States)

2010-01-01

... 7 Agriculture 7 2010-01-01 2010-01-01 false Related design requirements. 801.11 Section 801.11... FOR GRAIN INSPECTION EQUIPMENT § 801.11 Related design requirements. (a) Suitability. The design... tolerances prescribed in §§ 801.3 through 801.10, be capable of repeating its results when the equipment is...

29 CFR 1926.801 - Caissons.

Science.gov (United States)

2010-07-01

... 29 Labor 8 2010-07-01 2010-07-01 false Caissons. 1926.801 Section 1926.801 Labor Regulations...) SAFETY AND HEALTH REGULATIONS FOR CONSTRUCTION Underground Construction, Caissons, Cofferdams and Compressed Air § 1926.801 Caissons. (a) Wherever, in caisson work in which compressed air is used, and the...

33 CFR 20.801 - General.

Science.gov (United States)

2010-07-01

... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false General. 20.801 Section 20.801 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY GENERAL RULES OF PRACTICE, PROCEDURE, AND EVIDENCE FOR FORMAL ADMINISTRATIVE PROCEEDINGS OF THE COAST GUARD Evidence § 20.801 General...

47 CFR 22.801 - Scope.

Science.gov (United States)

2010-10-01

... 47 Telecommunication 2 2010-10-01 2010-10-01 false Scope. 22.801 Section 22.801 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES PUBLIC MOBILE SERVICES Air-Ground Radiotelephone Service § 22.801 Scope. The rules in this subpart govern the licensing and operation of air-ground...

38 CFR 14.801 - Applicability.

Science.gov (United States)

2010-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 1 2010-07-01 2010-07-01 false Applicability. 14.801 Section 14.801 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS LEGAL SERVICES... Records in Legal Proceedings § 14.801 Applicability. (a) Sections 14.800 through 14.810 apply to: (1...

33 CFR 25.801 - Scope.

Science.gov (United States)

2010-07-01

... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Scope. 25.801 Section 25.801 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY GENERAL CLAIMS Pollution Removal Damage Claims § 25.801 Scope. This subpart prescribes the requirements for the administrative settlement...

29 CFR 801.40 - General.

Science.gov (United States)

2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false General. 801.40 Section 801.40 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR OTHER LAWS APPLICATION OF THE EMPLOYEE POLYGRAPH PROTECTION ACT OF 1988 Enforcement § 801.40 General. (a) Whenever the Secretary believes...

2 CFR 801.1100 - General.

Science.gov (United States)

2010-01-01

... 2 Grants and Agreements 1 2010-01-01 2010-01-01 false General. 801.1100 Section 801.1100 Grants and Agreements Federal Agency Regulations for Grants and Agreements DEPARTMENT OF VETERANS AFFAIRS... Subpart for OMB Guidance at 2 CFR Part 180). § 801.1100 General. Field facility directors are authorized...

18 CFR 801.0 - Introduction.

Science.gov (United States)

2010-04-01

... 18 Conservation of Power and Water Resources 2 2010-04-01 2010-04-01 false Introduction. 801.0 Section 801.0 Conservation of Power and Water Resources SUSQUEHANNA RIVER BASIN COMMISSION GENERAL POLICIES § 801.0 Introduction. (a) The Governors of the States of New York, Pennsylvania, and Maryland, and...

29 CFR 801.3 - Coverage.

Science.gov (United States)

2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Coverage. 801.3 Section 801.3 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR OTHER LAWS APPLICATION OF THE EMPLOYEE POLYGRAPH PROTECTION ACT OF 1988 General § 801.3 Coverage. (a) The coverage of the Act extends to “any...

Investigation of antidepressant-like and anxiolytic-like actions and cognitive and motor side effects of four N-methyl-D-aspartate receptor antagonists in mice

DEFF Research Database (Denmark)

Refsgaard, Louise Konradsen; Pickering, Darryl S; Andreasen T., Jesper

2017-01-01

antagonists. MK-801, ketamine, S-ketamine, RO 25-6981 and the positive control, citalopram, were tested for antidepressant-like and anxiolytic-like effects in mice using the forced-swim test, the elevated zero maze and the novelty-induced hypophagia test. Side effects were assessed using a locomotor activity...... test, the modified Y-maze and the rotarod test. All compounds increased swim distance in the forced-swim test. In the elevated zero maze, the GluN2B subtype-selective RO 25-6981 affected none of the measured parameters, whereas all other compounds showed anxiolytic-like effects. In the novelty......-induced hypophagia test, citalopram and MK-801 showed anxiogenic-like action. All NMDAR antagonists induced hyperactivity. The high doses of ketamine and MK-801 impaired performance in the modified Y-maze test, whereas S-ketamine and RO 25-6891 showed no effects in this test. Only MK-801 impaired rotarod performance...

18 CFR 801.13 - Proviso.

Science.gov (United States)

2010-04-01

... 18 Conservation of Power and Water Resources 2 2010-04-01 2010-04-01 false Proviso. 801.13 Section 801.13 Conservation of Power and Water Resources SUSQUEHANNA RIVER BASIN COMMISSION GENERAL POLICIES § 801.13 Proviso. (a) This part is promulgated pursuant to sections 3.1, 3.5(1), and 15.2 of the Compact...

Mono(pyridine-N-oxide) DOTA analog and its G1/G4-PAMAM dendrimer conjugates labeled with 177Lu: Radiolabeling and biodistribution studies

International Nuclear Information System (INIS)

Laznickova, A.; Biricova, V.; Laznicek, M.; Hermann, P.

2014-01-01

177 Lu radiolabeling of the first (G1-) or fourth (G4-) generation polyaminoamide (PAMAM) dendrimer conjugates with DOTA-like bifunctional chelator with one methylenepyridine-N-oxide pendant arm (DO3A-py NO-C ) stability of the radiolabeled species and their pharmacokinetic characteristics were evaluated in preclinical experiments. The results showed that the G1- and G4-dendrimer conjugates, modified in average with 7.5 or 57 DO3A-py NO-C chelating units, respectively, can also be labeled with 177 Lu with a high specific activity and radiochemical purity even at 37 °C. The radiolabeled species were stable for at least 24 h. Distribution profile of G1-dendrimer conjugate in organs and tissues of rats was more favorable than that of G4 one. On the other hand, the later dendrimer conjugate bears a substantially higher number of metal chelators per molecule enabling binding of a considerably larger number of radiometals. Our results indicate that an employment of dendrimer-chelate conjugates with bound radiometals might represent a prospective way for radiolabeling of biologically active target-specific macromolecules to obtain markedly high specific activity. - Highlights: • Chelation of DOTA-like ligands suitable for biomacromolecules modification. • Radiolabeling of modified PAMAM-dendrimers with 177 Lu. • Determination of stability of the labeled conjugates. • Pharmacokinetic characteristics evaluated in preclinical experiments

49 CFR 236.801 - Shoe, latch.

Science.gov (United States)

2010-10-01

... 49 Transportation 4 2010-10-01 2010-10-01 false Shoe, latch. 236.801 Section 236.801 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION..., MAINTENANCE, AND REPAIR OF SIGNAL AND TRAIN CONTROL SYSTEMS, DEVICES, AND APPLIANCES Definitions § 236.801...

Methods to obtain radiolabelled monocrotaline

International Nuclear Information System (INIS)

Lame, M.W.; Morin, D.; Wilson, D.W.; Segall, H.J.

1996-01-01

Crotalaria spectabilis, a plant found in many areas of the world is associated with the pyrrolizidine alkaloid monocrotaline. Monocrotaline when injected subcutaneously in Sprague Dawley rats has been utilized for years to create a condition known to mimic pulmonary hypertension in humans. We attempted to determine the optimum conditions for the biosynthesis of radiolabelled monocrotaline. Our work describes the plant growth conditions and the time periods associated with the production of radiolabelled monocrotaline. In addition, the incorporation of 14 CO 2 or [2,3- 3 H]-putrescine dihydrochloride and the specific activity plus the amount(s) of recovered radiolabelled monocrotaline are discussed. We conclude that the most efficient and cost effective method for the biosynthesis of radiolabelled monocrotaline is still the utilization of 14 CO 2 . (author)

Radiolabelled cellular blood elements

International Nuclear Information System (INIS)

Sinzinger, H.

1990-01-01

This book reports on radiolabelled cellular blood elements, covering new advances made during the past several years, in particular the use of Tc-99 as a tracer for blood elements. Coverage extends to several radiolabelled monoclonal antibodies that are specific for blood components and may label blood elements in vivo

36 CFR 801.7 - Information requirements.

Science.gov (United States)

2010-07-01

... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Information requirements. 801.7 Section 801.7 Parks, Forests, and Public Property ADVISORY COUNCIL ON HISTORIC PRESERVATION HISTORIC PRESERVATION REQUIREMENTS OF THE URBAN DEVELOPMENT ACTION GRANT PROGRAM § 801.7 Information...

14 CFR 36.801 - Noise measurement.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Noise measurement. 36.801 Section 36.801 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT NOISE STANDARDS: AIRCRAFT TYPE AND AIRWORTHINESS CERTIFICATION Helicopters § 36.801 Noise measurement. For primary, normal...

7 CFR 801.2 - Meaning of terms.

Science.gov (United States)

2010-01-01

... 7 Agriculture 7 2010-01-01 2010-01-01 false Meaning of terms. 801.2 Section 801.2 Agriculture... FOR GRAIN INSPECTION EQUIPMENT § 801.2 Meaning of terms. (a) Construction. Words used in the singular... used in this part 801. For the purposes of this part, the following terms shall have the meanings given...

30 CFR 75.801 - Grounding resistors.

Science.gov (United States)

2010-07-01

... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Grounding resistors. 75.801 Section 75.801 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR COAL MINE SAFETY AND HEALTH MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Underground High-Voltage Distribution § 75.801 Grounding...

Secretory phospholipase A2-mediated neuronal cell death involves glutamate ionotropic receptors

DEFF Research Database (Denmark)

Kolko, Miriam; de Turco, Elena B; Diemer, Nils Henrik

2002-01-01

To define the significance of glutamate ionotropic receptors in sPLA -mediated neuronal cell death we used the NMDA receptor antagonist MK-801 and the AMPA receptor antagonist PNQX. In primary neuronal cell cultures both MK-801 and PNQX inhibited sPLA - and glutamate-induced neuronal death. [ H...

26 CFR 1.801-7 - Variable annuities.

Science.gov (United States)

2010-04-01

... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Variable annuities. 1.801-7 Section 1.801-7...) INCOME TAXES Life Insurance Companies § 1.801-7 Variable annuities. (a) In general. (1) Section 801(g)(1) provides that for purposes of part I, subchapter L, chapter 1 of the Code, an annuity contract includes a...

Inducible nitric oxide inhibitors block NMDA antagonist-stimulated motoric behaviors and medial prefrontal cortical glutamate efflux

Directory of Open Access Journals (Sweden)

Hadley C Bergstrom

2015-12-01

Full Text Available Nitric oxide (NO plays a critical role in the motoric and glutamate releasing action of N-methyl-D-aspartate (NMDA-antagonist stimulants. Earlier studies utilized neuronal nitric oxide synthase inhibitors (nNOS for studying the neurobehavioral effects of noncompetitive NMDA-antagonist stimulants such as dizocilpine (MK-801 and phencyclidine (PCP. This study explores the role of the inducible nitric oxide synthase inhibitors (iNOS aminoguanidine (AG and (--epigallocatechin-3-gallate (EGCG in NMDA-antagonist induced motoric behavior and prefrontal cortical glutamate efflux. Adult male rats were administered a dose range of AG, EGCG or vehicle prior to receiving NMDA antagonists MK-801, PCP or a conventional psychostimulant (cocaine and tested for motoric behavior in an open arena. Glutamate in the medial prefrontal cortex was measured using in vivo microdialysis after a combination of AG or EGCG prior to MK-801. Acute administration of AG or EGCG dose-dependently attenuated the locomotor and ataxic properties of MK-801 and PCP. Both AG and EGCG were unable to block the motoric effects of cocaine, indicating the acute pharmacologic action of AG and EGCG is specific to NMDA antagonism and not generalizable to all stimulant class drugs. AG and EGCG normalized MK-801-stimulated medial prefrontal cortical glutamate efflux. These data demonstrate that AG and EGCG attenuates NMDA antagonist-stimulated motoric behavior and cortical glutamate efflux. Our results suggest that EGCG-like polyphenol nutraceuticals (contained in green tea and chocolate may be clinically useful in protecting against the adverse behavioral dissociative and cortical glutamate stimulating effects of NMDA antagonists. Medications that interfere with NMDA antagonists such as MK-801 and PCP have been proposed as treatments for schizophrenia.

49 CFR 801.59 - Geological records.

Science.gov (United States)

2010-10-01

... 49 Transportation 7 2010-10-01 2010-10-01 false Geological records. 801.59 Section 801.59... PUBLIC AVAILABILITY OF INFORMATION Exemption From Public Disclosure § 801.59 Geological records. Pursuant to 5 U.S.C. 552(b)(9), records concerning geological wells are exempt from public disclosure. ...

20 CFR 638.801 - Staff training.

Science.gov (United States)

2010-04-01

... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Staff training. 638.801 Section 638.801 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR JOB CORPS PROGRAM UNDER TITLE IV-B OF THE JOB TRAINING PARTNERSHIP ACT Administrative Provisions § 638.801 Staff training. The...

38 CFR 3.801 - Special acts.

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2010-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 1 2010-07-01 2010-07-01 false Special acts. 3.801 Section 3.801 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS ADJUDICATION Pension, Compensation, and Dependency and Indemnity Compensation Special Benefits § 3.801 Special acts. (a) General. A...

36 CFR 801.4 - Council comments.

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2010-07-01

... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Council comments. 801.4 Section 801.4 Parks, Forests, and Public Property ADVISORY COUNCIL ON HISTORIC PRESERVATION HISTORIC PRESERVATION REQUIREMENTS OF THE URBAN DEVELOPMENT ACTION GRANT PROGRAM § 801.4 Council comments. The following...

18 CFR 801.1 - Standard definitions.

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2010-04-01

... 18 Conservation of Power and Water Resources 2 2010-04-01 2010-04-01 false Standard definitions. 801.1 Section 801.1 Conservation of Power and Water Resources SUSQUEHANNA RIVER BASIN COMMISSION GENERAL POLICIES § 801.1 Standard definitions. (a) Many terms that will be used in official Commission...

36 CFR 801.8 - Public participation.

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2010-07-01

... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Public participation. 801.8 Section 801.8 Parks, Forests, and Public Property ADVISORY COUNCIL ON HISTORIC PRESERVATION HISTORIC PRESERVATION REQUIREMENTS OF THE URBAN DEVELOPMENT ACTION GRANT PROGRAM § 801.8 Public participation. (a) The...

30 CFR 77.801 - Grounding resistors.

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2010-07-01

... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Grounding resistors. 77.801 Section 77.801 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR COAL MINE SAFETY AND HEALTH...-Voltage Distribution § 77.801 Grounding resistors. The grounding resistor, where required, shall be of the...

Methods to obtain radiolabelled monocrotaline

Energy Technology Data Exchange (ETDEWEB)

Lame, M.W.; Morin, D.; Wilson, D.W.; Segall, H.J. [University of California, Davis, CA (United States)

1996-12-01

Crotalaria spectabilis, a plant found in many areas of the world is associated with the pyrrolizidine alkaloid monocrotaline. Monocrotaline when injected subcutaneously in Sprague Dawley rats has been utilized for years to create a condition known to mimic pulmonary hypertension in humans. We attempted to determine the optimum conditions for the biosynthesis of radiolabelled monocrotaline. Our work describes the plant growth conditions and the time periods associated with the production of radiolabelled monocrotaline. In addition, the incorporation of {sup 14}CO{sub 2} or [2,3-{sup 3}H]-putrescine dihydrochloride and the specific activity plus the amount(s) of recovered radiolabelled monocrotaline are discussed. We conclude that the most efficient and cost effective method for the biosynthesis of radiolabelled monocrotaline is still the utilization of {sup 14}CO{sub 2}. (author).

Dicty_cDB: SFJ801 [Dicty_cDB

Lifescience Database Archive (English)

Full Text Available SF (Link to library) SFJ801 (Link to dictyBase) - - - - SFJ801P (Link to Original s...ite) SFJ801F 633 SFJ801Z 345 SFJ801P 978 - - Show SFJ801 Library SF (Link to library) Clone ID SFJ801 (Link to dict...yBase) Atlas ID - NBRP ID - dictyBase ID - Link to Contig - Original site URL http://dictycdb.biol.ts...t alignments: (bits) Value N U36937 |U36937.1 Dictyostelium discoideum calreticulin mRNA, complete cds. 1021...IpTrk_27_j08 Trunk kidney cDNA library Ictalurus punctatus cDNA 5' similar to ER-resident chaperone calretic

18 CFR 801.4 - Project review.

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2010-04-01

... 18 Conservation of Power and Water Resources 2 2010-04-01 2010-04-01 false Project review. 801.4 Section 801.4 Conservation of Power and Water Resources SUSQUEHANNA RIVER BASIN COMMISSION GENERAL POLICIES § 801.4 Project review. (a) The Compact provides generally that no project affecting the water...

Irreversible amnesia in rats and edible snails under conditions of associative memory reconsolidation disturbance caused by NMDA-glutamate receptor antagonist.

Science.gov (United States)

Storozheva, Z I; Solntseva, S V; Nikitin, V P; Proshin, A T; Sherstnev, V V

2011-01-01

The effect of MK-801, an antagonist to NMDA-glutamate receptors, on reconsolidation of olfactory discrimination task in rats and taste discrimination in edible snails was examined. Twenty-four hours after conditioning, the animals received a single systemic injection of MK-801 followed by a reminding conditional stimulus. Disturbances in retrieval of the acquired task were observed 10 days after injection followed by a reminding procedure. Repeated conditioning of these animals did not restore the task. Injection of MK-801 without reminding stimulation had no effect on task retention. Thus, disturbances of NMDA-dependent reconsolidation of the associative memory in animals of different taxonomic groups irreversibly eliminated long-term memory.

26 CFR 1.801-1 - Definitions.

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2010-04-01

... TAXES Life Insurance Companies § 1.801-1 Definitions. (a) Life insurance company. The term life.... For the definition of an “insurance company”, see paragraph (b) of this section. In determining... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Definitions. 1.801-1 Section 1.801-1 Internal...

20 CFR 801.304 - Business hours.

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2010-04-01

... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Business hours. 801.304 Section 801.304 Employees' Benefits BENEFITS REVIEW BOARD, DEPARTMENT OF LABOR ESTABLISHMENT AND OPERATION OF THE BOARD Action by the Board § 801.304 Business hours. The office of the Clerk of the Board at Washington, DC...

Radiolabeled derivatives of folic acid

International Nuclear Information System (INIS)

1980-01-01

Derivatives of folic acid are described, in which the α-carboxyl group is substituted with an amino compound having an aromatic or heterocyclic ring substituent which is capable of being radiolabelled. Particularly mentioned as a radiolabel is 125 I. (author)

Reference design (MK-I and MK-II) for experimental multi-purpose VHTR

International Nuclear Information System (INIS)

Miyamoto, Yoshiaki; Suzuki, Kunihiko; Sato, Sadao

1975-10-01

This report summarizes the results of a study on thermal and mechanical performances of the core, which are obtained in course of reference design (Mk-I and Mk-II) for the experimental multi-purpose VHTR: (1) Design criteria, design methods and design data. These bases are also discussed in order to refer in the case of proceeding a next design work. (2) The results of performance analysis such as the initial core and its prediction for the irradiated core. (auth.)

Role of thalamic projection in NMDA receptor-induced disruption of cortical slow oscillation and short-term plasticity

Directory of Open Access Journals (Sweden)

Tamás eKiss

2011-04-01

Full Text Available NMDA receptor (NMDAR antagonists, such as phencyclidine, ketamine or dizocilpine (MK-801 are commonly used in psychiatric drug discovery in order to model several symptoms of schizophrenia, including psychosis and impairments in working memory. In spite of the widespread use of NMDAR antagonists in preclinical and clinical studies, our understanding of the mode of action of these drugs on brain circuits and neuronal networks is still limited. In the present study spontaneous local field potential (LFP, multi- (MUA and single unit activity, and evoked potential, including paired-pulse facilitation (PPF in response to electrical stimulation of the ipsilateral subiculum were carried out in the medial prefrontal cortex (mPFC in urethane anesthetized rats. Systemic administration of MK-801 (0.05~mg/kg, i.v. decreased overall MUA, with a diverse effect on single unit activity, including increased, decreased or unchanged firing, and in line with our previous findings shifted delta frequency power of the LFP and disrupted PPF (Kiss et al., Int J Neuropsychopharmacol. 2010. In order to provide further insight to the mechanisms of action of NMDAR antagonists, MK-801 was administered intracranially into the mPFC and mediodorsal nucleus of the thalamus (MD. Microinjections of MK-801, but not physiological saline, localized into the MD evoked changes in both LFP parameters and PPF similar to the effects of systemically administered MK-801. Local microinjection of MK-801 into the mPFC was without effect on these parameters. Our findings indicate that the primary site of the action of systemic administration of NMDA receptor antagonists is unlikely to be the cortex. We presume that multiple neuronal networks, involving thalamic nuclei contribute to disrupted behavior and cognition following NMDA receptor blockade.

Arcaine uncovers dual interactions of polyamines with the N-methyl-D-aspartate receptor

Energy Technology Data Exchange (ETDEWEB)

Reynolds, I.J. (Univ. of Pittsburgh, PA (USA))

1990-12-01

This study investigated the interaction between the polyamines spermine and spermidine and the N-methyl-D-aspartate (NMDA) receptor by using (+)-(3H)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-im ine maleate ((3H)MK801) binding to well washed rat brain membranes. The actions of arcaine, agmatine, diethylenetriamine and 1,8-octanediamine as polyamine antagonists were compared to use as tools in this study. Arcaine was found to be the antagonist of choice due to its greater potency. Several divalent cations, including Ba++, Ca++ and Sr++, but not Zn++, decreased the apparent potency of arcaine. These cations enhance (3H)MK801 binding in a similar fashion to spermidine and spermine suggesting that they may share a common site and mechanism of action. Moreover, arcaine competitively reduced the enhancement of (3H)MK801 binding produced by Sr++ did not alter the inhibition produced by higher concentrations of this cation, a phenomenon that also occurs with spermidine. The distinct arcaine sensitivity of the two separate phases of the concentration-response curves of both spermidine and Sr++ suggests two separate mechanisms underlying the action of spermidine-like drugs on the NMDA receptor. Further investigation of the increase in (3H)MK801 binding produced by spermidine revealed that spermidine increased the equilibrium affinity of this ligand by 2-fold without significantly altering the density of binding sites. In contrast, polyamine induced increases in the dissociation of (3H)MK801 required higher polyamine concentrations than necessary to increase ligand binding and were relatively insensitive to arcaine. These findings suggest that polyamines do not activate or promote the activation of the NMDA receptor, but instead enhance (3H)MK801 binding by allosterically increasing ligand affinity.

Arcaine uncovers dual interactions of polyamines with the N-methyl-D-aspartate receptor

International Nuclear Information System (INIS)

Reynolds, I.J.

1990-01-01

This study investigated the interaction between the polyamines spermine and spermidine and the N-methyl-D-aspartate (NMDA) receptor by using (+)-[3H]-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-im ine maleate ([3H]MK801) binding to well washed rat brain membranes. The actions of arcaine, agmatine, diethylenetriamine and 1,8-octanediamine as polyamine antagonists were compared to use as tools in this study. Arcaine was found to be the antagonist of choice due to its greater potency. Several divalent cations, including Ba++, Ca++ and Sr++, but not Zn++, decreased the apparent potency of arcaine. These cations enhance [3H]MK801 binding in a similar fashion to spermidine and spermine suggesting that they may share a common site and mechanism of action. Moreover, arcaine competitively reduced the enhancement of [3H]MK801 binding produced by Sr++ did not alter the inhibition produced by higher concentrations of this cation, a phenomenon that also occurs with spermidine. The distinct arcaine sensitivity of the two separate phases of the concentration-response curves of both spermidine and Sr++ suggests two separate mechanisms underlying the action of spermidine-like drugs on the NMDA receptor. Further investigation of the increase in [3H]MK801 binding produced by spermidine revealed that spermidine increased the equilibrium affinity of this ligand by 2-fold without significantly altering the density of binding sites. In contrast, polyamine induced increases in the dissociation of [3H]MK801 required higher polyamine concentrations than necessary to increase ligand binding and were relatively insensitive to arcaine. These findings suggest that polyamines do not activate or promote the activation of the NMDA receptor, but instead enhance [3H]MK801 binding by allosterically increasing ligand affinity

Facilitating effect of histamine on spatial memory deficits induced by dizocilpine as evaluated by 8-arm radial maze in SD rats%组胺对地佐环平诱发的SD大鼠八臂迷宫空间记忆障碍的改善作用

Institute of Scientific and Technical Information of China (English)

黄育文; 陈忠; 胡薇薇; 张力三; 吴炜; 应力阳; 魏尔清

2003-01-01

AIM: To investigate whether or not histamine is involved in spatial memory deficits induced by dizocilpine (MK 801) as evaluated by 8-arm radial maze of rats. METHODS: 8-Arm (4-arm baited) radial maze was used to measure spatial memory in rats. RESULTS: Bilaterally intrahippocampal (ih) injection of MK-801 (0.3 μg/site) impaired working memory and reference memory in rats. Both histamine (50, 100 ng/site, ih) and intraperitoneal (ip) injection of histidine (100, 200 mg/kg) markedly improved the spatial memory deficits induced by MK-801. On the other hand, the ameliorating effect of histidine (100 mg/kg, ip) was completely antagonized by αfluoromethylhistidine (α-FMH, 5 μg/site, ih), a potent and selective histidine decarboxylase (HDC) inhibitor, and H1-antagonist pyrilamine (1 μg/site, ih), but not by H2-antagonist cimetidine, even at a high dose (2.5 μg/site, ih).CONCLUSION: The hippocampal histamine plays an important role in the ameliorating effect on MK-801-induced spatial memory deficits, and its action is mediated through postsynaptic H1-receptor.

24 CFR 220.801 - Initial insurance endorsement.

Science.gov (United States)

2010-04-01

... 24 Housing and Urban Development 2 2010-04-01 2010-04-01 false Initial insurance endorsement. 220.801 Section 220.801 Housing and Urban Development Regulations Relating to Housing and Urban... AREAS Contract Rights and Obligations-Projects Insured Project Improvement Loans § 220.801 Initial...

26 CFR 801.2 - Measuring organizational performance.

Science.gov (United States)

2010-04-01

... 26 Internal Revenue 20 2010-04-01 2010-04-01 false Measuring organizational performance. 801.2 Section 801.2 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INTERNAL... REVENUE SERVICE § 801.2 Measuring organizational performance. The performance measures that comprise the...

A 20mK temperature sensor

International Nuclear Information System (INIS)

Wang, N.; Sadoulet, B.; Shutt, T.

1987-11-01

We are developing a 20mK temperature sensor made of neutron transmutation doped (NTD) germanium for use as a phonon detector in a dark matter search. We find that NTD germanium thermistors around 20mK have resistances which are a strong function of temperature, and have sufficient sensitivity to eventually reach a base line rms energy fluctuation of 6eV at 25mK. Further work is needed to understand the extreme sensitivity of the thermistors to bias power. 13 refs., 18 figs

12 CFR 1805.801 - Notice of Award.

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2010-01-01

... 12 Banks and Banking 7 2010-01-01 2010-01-01 false Notice of Award. 1805.801 Section 1805.801 Banks and Banking COMMUNITY DEVELOPMENT FINANCIAL INSTITUTIONS FUND, DEPARTMENT OF THE TREASURY COMMUNITY DEVELOPMENT FINANCIAL INSTITUTIONS PROGRAM Terms and Conditions of Assistance § 1805.801 Notice of...

7 CFR 801.8 - Tolerances for sieves.

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2010-01-01

... 7 Agriculture 7 2010-01-01 2010-01-01 false Tolerances for sieves. 801.8 Section 801.8 Agriculture Regulations of the Department of Agriculture (Continued) GRAIN INSPECTION, PACKERS AND STOCKYARD... FOR GRAIN INSPECTION EQUIPMENT § 801.8 Tolerances for sieves. The maintenance tolerances for sieves...

36 CFR 801.1 - Purpose and authorities.

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2010-07-01

... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Purpose and authorities. 801.1 Section 801.1 Parks, Forests, and Public Property ADVISORY COUNCIL ON HISTORIC PRESERVATION HISTORIC PRESERVATION REQUIREMENTS OF THE URBAN DEVELOPMENT ACTION GRANT PROGRAM § 801.1 Purpose and...

14 CFR 1203.801 - Redelegation.

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2010-01-01

... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Redelegation. 1203.801 Section 1203.801 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM Delegation of... TOP SECRET, SECRET, or CONFIDENTIAL original classification authority or declassification authority is...

40 CFR 57.801 - Purpose and scope.

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2010-07-01

... 40 Protection of Environment 5 2010-07-01 2010-07-01 false Purpose and scope. 57.801 Section 57.801 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED... Technology § 57.801 Purpose and scope. (a) This subpart shall govern all proceedings for the waiver of the...

18 CFR 801.12 - Electric power generation.

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2010-04-01

... 18 Conservation of Power and Water Resources 2 2010-04-01 2010-04-01 false Electric power generation. 801.12 Section 801.12 Conservation of Power and Water Resources SUSQUEHANNA RIVER BASIN COMMISSION GENERAL POLICIES § 801.12 Electric power generation. (a) Significant uses are presently being made...

10 CFR 2.801 - Initiation of rulemaking.

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2010-01-01

... 10 Energy 1 2010-01-01 2010-01-01 false Initiation of rulemaking. 2.801 Section 2.801 Energy NUCLEAR REGULATORY COMMISSION RULES OF PRACTICE FOR DOMESTIC LICENSING PROCEEDINGS AND ISSUANCE OF ORDERS Rulemaking § 2.801 Initiation of rulemaking. Rulemaking may be initiated by the Commission at its own...

49 CFR 801.41 - Reports to Congress.

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2010-10-01

... 49 Transportation 7 2010-10-01 2010-10-01 false Reports to Congress. 801.41 Section 801.41... PUBLIC AVAILABILITY OF INFORMATION Other Board Documents § 801.41 Reports to Congress. The NTSB submits its annual report to Congress each year, in accordance with 49 U.S.C. 1117. The report will be...

29 CFR 801.6 - Notice of protection.

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2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Notice of protection. 801.6 Section 801.6 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR OTHER LAWS APPLICATION OF THE EMPLOYEE POLYGRAPH PROTECTION ACT OF 1988 General § 801.6 Notice of protection. Every employer subject to...

29 CFR 801.71 - Filing and service.

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2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Filing and service. 801.71 Section 801.71 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR OTHER LAWS APPLICATION OF THE... and Order of Administrative Law Judge § 801.71 Filing and service. (a) Filing. All documents submitted...

21 CFR 801.61 - Statement of identity.

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2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Statement of identity. 801.61 Section 801.61 Food... DEVICES LABELING Labeling Requirements for Over-the-Counter Devices § 801.61 Statement of identity. (a... principal features a statement of the identity of the commodity. (b) Such statement of identity shall be in...

46 CFR 154.801 - Pressure relief systems.

Science.gov (United States)

2010-10-01

... 46 Shipping 5 2010-10-01 2010-10-01 false Pressure relief systems. 154.801 Section 154.801 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CERTAIN BULK DANGEROUS CARGOES SAFETY... Vent Systems § 154.801 Pressure relief systems. (a) Each cargo tank that has a volume of 20m3 (706 ft.3...

20 CFR 404.801 - Introduction.

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2010-04-01

... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false Introduction. 404.801 Section 404.801 Employees' Benefits SOCIAL SECURITY ADMINISTRATION FEDERAL OLD-AGE, SURVIVORS AND DISABILITY INSURANCE (1950... health insurance program. This subpart tells what is evidence of earnings, how you can find out what the...

48 CFR 3.801 - Definitions.

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2010-10-01

... consistent with the amount normally paid for such services in the private sector. Recipient includes the... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Definitions. 3.801 Section... Federal Transactions 3.801 Definitions. As used in this subpart— Agency means executive agency as defined...

36 CFR 801.5 - State Historic Preservation Officer responsibilities.

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2010-07-01

... Officer responsibilities. 801.5 Section 801.5 Parks, Forests, and Public Property ADVISORY COUNCIL ON... § 801.5 State Historic Preservation Officer responsibilities. (a) The State Historic Preservation... § 801.3(b); responding, within 45 days, to submittal of a determination by the applicant under section...

48 CFR 801.103 - Authority.

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2010-10-01

... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Authority. 801.103 Section... VETERANS AFFAIRS ACQUISITION REGULATION SYSTEM Purpose, Authority, Issuance 801.103 Authority. The Secretary issues the VAAR under the authority of 40 U.S.C. 121(c), Title 48 of the Code of Federal...

Dicty_cDB: CFE801 [Dicty_cDB

Lifescience Database Archive (English)

Full Text Available CF (Link to library) CFE801 (Link to dictyBase) - - - Contig-U12894-1 CFE801Z (Link... to Original site) - - CFE801Z 690 - - - - Show CFE801 Library CF (Link to library) Clone ID CFE801 (Link to dict...yBase) Atlas ID - NBRP ID - dictyBase ID - Link to Contig Contig-U12894-1 Original site URL http://dict...6e1 5', mRNA sequence. 36 5.4 2 CK426247 |CK426247.1 AUF_IpTes_24_l09 Testis cDNA library Ict...A26838 )prestalk protein precursor - slime mold (Dictyoste... 66 9e-10 AC117072_6

29 CFR 801.2 - Definitions.

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2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Definitions. 801.2 Section 801.2 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR OTHER LAWS APPLICATION OF THE.... 2001-2009). (b) (1) The term commerce has the meaning provided in section 3(b) of the Fair Labor...

Radiolabeled peptides: experimental and clinical applications

International Nuclear Information System (INIS)

Thakur, M.L.; Pallela, V.R.

1998-01-01

Radiolabeled receptor specific biomolecules hold unlimited potential in nuclear medicine. During the past few years much attention has been drawn to the development radiolabeled peptides for a variety of diagnostic applications, as well as for therapy of malignant tumors. Although only one peptide, In-111-DTPA-(D)-Phe 1 -octreotide, is available commercially for oncologic imaging, many more have been examined in humans with hematological disorders, and the early results appear to be promising. Impetus generated by these results have prompted investigators to label peptides with such radionuclides as Tc-99m, I-123, F-18, Cu-64, and Y-90. This review is intended to highlight the qualities of peptides, summarize the clinical results, and address some important issues associated with radiolabeling of highly potent peptides. While doing so, various methods of radiolabeling have been described, and their strengths and weaknesses have also been discussed. (author)

48 CFR 801.670 - Special and limited delegation.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Special and limited delegation. 801.670 Section 801.670 Federal Acquisition Regulations System DEPARTMENT OF VETERANS AFFAIRS... Authority, and Responsibilities 801.670 Special and limited delegation. The authority vested in the...

48 CFR 11.801 - Preaward in-use evaluation.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Preaward in-use evaluation. 11.801 Section 11.801 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION ACQUISITION PLANNING DESCRIBING AGENCY NEEDS Testing 11.801 Preaward in-use evaluation. Supplies may be...

Parabrachial complex glutamate receptors modulate the cardiorespiratory response evoked from hypothalamic defense area.

Science.gov (United States)

Díaz-Casares, A; López-González, M V; Peinado-Aragonés, C A; González-Barón, S; Dawid-Milner, M S

2012-08-16

To characterize the possible role of glutamate in the interaction between Hypothalamic Defense Area (HDA) and Parabrachial complex (PBc) nuclei, cardiorespiratory changes were analyzed in response to electrical stimulation of the HDA (1 ms pulses, 30-50 μA given at 100 Hz for 5s) before and after the microinjection of the nonspecific glutamate receptor antagonist kynurenic acid (50 nl, 5 nmol), NMDA receptor antagonist MK-801 (50 nl, 50 nmol), non-NMDA receptor antagonist CNQX (50 nl, 50 nmol) or metabotropic glutamate receptor antagonist MCPG (50 nl, 5 nmol) within the PBc. HDA stimulation evoked an inspiratory facilitatory response, consisting of an increase in respiratory rate (pHDA stimulation. Similarly, the magnitude of the tachycardia and the pressor response was decreased after the microinjection of MK-801 (pHDA stimulation but the respiratory response persisted unchanged after MK-801 or CNQX microinjection into the lPB. Kynurenic acid within the medial parabrachial region (mPB) abolished the tachycardia (pHDA stimulation. MK-801 and CNQX microinjection in this region decreased the magnitude of the tachycardia (pHDA stimulation was not changed after the microinjection of kynurenic acid, MK-801 or CNQX within the mPB. No changes were observed in the cardiorespiratory response evoked to HDA stimulation after MCPG microinjection within lPB and mPB. These results indicate that glutamate PBc receptors are involved in the cardiorespiratory response evoked from the HDA. The possible mechanisms involved in these interactions are discussed. Copyright © 2012 Elsevier B.V. All rights reserved.

7 CFR 801.4 - Tolerances for dockage testers.

Science.gov (United States)

2010-01-01

... 7 Agriculture 7 2010-01-01 2010-01-01 false Tolerances for dockage testers. 801.4 Section 801.4 Agriculture Regulations of the Department of Agriculture (Continued) GRAIN INSPECTION, PACKERS AND STOCKYARD... FOR GRAIN INSPECTION EQUIPMENT § 801.4 Tolerances for dockage testers. The maintenance tolerances for...

33 CFR 147.801 - Boxer Platform safety zone.

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2010-07-01

... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Boxer Platform safety zone. 147.801 Section 147.801 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OUTER CONTINENTAL SHELF ACTIVITIES SAFETY ZONES § 147.801 Boxer Platform safety zone. (a...

7 CFR 801.6 - Tolerances for moisture meters.

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2010-01-01

... 7 Agriculture 7 2010-01-01 2010-01-01 false Tolerances for moisture meters. 801.6 Section 801.6 Agriculture Regulations of the Department of Agriculture (Continued) GRAIN INSPECTION, PACKERS AND STOCKYARD... FOR GRAIN INSPECTION EQUIPMENT § 801.6 Tolerances for moisture meters. (a) The maintenance tolerances...

26 CFR 601.801 - Purpose and statutory authority.

Science.gov (United States)

2010-04-01

... 26 Internal Revenue 20 2010-04-01 2010-04-01 false Purpose and statutory authority. 601.801 Section 601.801 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INTERNAL REVENUE PRACTICE STATEMENT OF PROCEDURAL RULES Tax Counseling for the Elderly § 601.801 Purpose and...

7 CFR 801.3 - Tolerances for barley pearlers.

Science.gov (United States)

2010-01-01

... 7 Agriculture 7 2010-01-01 2010-01-01 false Tolerances for barley pearlers. 801.3 Section 801.3 Agriculture Regulations of the Department of Agriculture (Continued) GRAIN INSPECTION, PACKERS AND STOCKYARD... FOR GRAIN INSPECTION EQUIPMENT § 801.3 Tolerances for barley pearlers. The maintenance tolerances for...

2 CFR 801.30 - What policies and procedures must I follow?

Science.gov (United States)

2010-01-01

...? 801.30 Section 801.30 Grants and Agreements Federal Agency Regulations for Grants and Agreements DEPARTMENT OF VETERANS AFFAIRS NONPROCUREMENT DEBARMENT AND SUSPENSION § 801.30 What policies and procedures... § 801.220 in this part (2 CFR 801.220). ...

7 CFR 810.801 - Definition of mixed grain.

Science.gov (United States)

2010-01-01

... 7 Agriculture 7 2010-01-01 2010-01-01 false Definition of mixed grain. 810.801 Section 810.801 Agriculture Regulations of the Department of Agriculture (Continued) GRAIN INSPECTION, PACKERS AND STOCKYARD... GRAIN United States Standards for Mixed Grain Terms Defined § 810.801 Definition of mixed grain. Any...

Ketamine displaces the novel NMDA receptor SPET probe [123I]CNS-1261 in humans in vivo

International Nuclear Information System (INIS)

Stone, James M.; Erlandsson, Kjell; Arstad, Erik; Bressan, Rodrigo A.; Squassante, Lisa; Teneggi, Vincenza; Ell, Peter J.; Pilowsky, Lyn S.

2006-01-01

[ 123 I]CNS-1261 [N-(1-naphthyl)-N'-(3-iodophenyl)-N-methylguanidine] is a high-affinity SPET ligand with selectivity for the intrachannel PCP/ketamine/MK-801 site of the N-methyl-D-aspartate (NMDA) receptor. This study evaluated the effects of ketamine (a specific competitor for the intrachannel PCP/ketamine/MK-801 site) on [ 123 I]CNS-1261 binding to NMDA receptors in vivo. Ten healthy volunteers underwent 2 bolus-plus-infusion [ 123 I]CNS-1261 scans, one during placebo and the other during a ketamine challenge. Ketamine administration led to a significant decrease in [ 123 I]CNS-1261 V T in most of the brain regions examined (P 123 I]CNS-1261 appears to be a specific ligand in vivo for the intrachannel PCP/ketamine/MK-801 NMDA binding site

29 CFR 801.69 - Procedures for initiating review.

Science.gov (United States)

2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Procedures for initiating review. 801.69 Section 801.69 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR OTHER LAWS... Vacation of Decision and Order of Administrative Law Judge § 801.69 Procedures for initiating review. (a...

29 CFR 801.70 - Implementation by the Secretary.

Science.gov (United States)

2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Implementation by the Secretary. 801.70 Section 801.70 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR OTHER LAWS... Vacation of Decision and Order of Administrative Law Judge § 801.70 Implementation by the Secretary. (a...

21 CFR 801.4 - Meaning of intended uses.

Science.gov (United States)

2010-04-01

... may be shown by the circumstances surrounding the distribution of the article. This objective intent... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL... words of similar import in §§ 801.5, 801.119, and 801.122 refer to the objective intent of the persons...

Evaluation of tricine and EDDA as Co-ligands for 99mTc-labeled HYNIC-MSH analogs for melanoma imaging.

Science.gov (United States)

Garcia, Maria Fernanda; Zhang, Xiuli; Gallazzi, Fabio; Fernandez, Marcelo; Moreno, Maria; Gambini, Juan Pablo; Porcal, Williams; Cabral, Pablo; Quinn, Thomas P

2015-01-01

Several radiolabeled alpha-melanocyte stimulating hormone (α-MSH) analogs have been studied for their abilities to target melanoma tumor cells through specific recognition and binding to the melanocortin receptor 1 (MCR1). In this work, a lactam bridgecyclized α-MSH analog was labeled with (99m) via the hydrazinonicotinamide (HYNIC) chelator and characterized for its melanoma tumor targeting properties. The bifunctional chelating agent HYNIC-Boc was attached to the N-terminus of the MSH peptide followed by the lactam cyclization, resulting in the HYNIC-cyc-MSH analog. The lactam cyclized peptide displayed high affinity and specificity for MC1-receptors present on B16/F1 melanoma tumor cells, exhibiting an IC50 of 6.48 nM. HYNIC-cyc-MSH was radiolabeled with (99m)Tc using two common co-ligands, tricine and EDDA. In vitro, the radiochemical stability, cell binding and efflux properties were similar between the peptides radiolabeled with tricine and EDDA as co-ligands. In vivo, biodistribution studies (n=4) demonstrated that (99m)Tc- HYNIC-cyc-MSH/tricine had superior tumor to muscle and tumor to blood ratios than (99m)Tc-HYNIC-cyc-MSH/EDDA at early time points. Planar gamma imaging of melanoma bearing mice showed that 99mTc-HYNIC-cyc-MSH/tricine was able to clearly visualize tumors, underscoring the potential utility of (99m)Tc labeled lactam cyclized MSH molecules as melanoma imaging agents.

21 CFR 801.119 - In vitro diagnostic products.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false In vitro diagnostic products. 801.119 Section 801...) MEDICAL DEVICES LABELING Exemptions From Adequate Directions for Use § 801.119 In vitro diagnostic products. A product intended for use in the diagnosis of disease and which is an in vitro diagnostic...

29 CFR 801.68 - Authority of the Secretary.

Science.gov (United States)

2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Authority of the Secretary. 801.68 Section 801.68 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR OTHER LAWS APPLICATION... of Decision and Order of Administrative Law Judge § 801.68 Authority of the Secretary. (a) The...

Radiolabeled antibody imaging

International Nuclear Information System (INIS)

Wahl, R.L.

1987-01-01

Radiolabeled antibodies, in particular monoclonal antibodies, offer the potential for the specific nuclear imaging of malignant and benign diseases in man. If this imaging potential is realized, they may also have a large role in cancer treatment. This paper reviews: (1) what monoclonal antibodies are and how they differ from polyclonal antibodies, (2) how they are produced and radiolabeled, (3) the results of preclinical and clinical trials in cancer imaging, including the utility of SPECT and antibody fragments, (4) the role of antibodies in the diagnosis of benign diseases, (5) alternate routes of antibody delivery, (6) the role of these agents in therapy, and (7) whether this technology ''revolutionizes'' the practice of nuclear radiology, or has a more limited complementary role in the imaging department

29 CFR 801.42 - Civil money penalties-assessment.

Science.gov (United States)

2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Civil money penalties-assessment. 801.42 Section 801.42... APPLICATION OF THE EMPLOYEE POLYGRAPH PROTECTION ACT OF 1988 Enforcement § 801.42 Civil money penalties—assessment. (a) A civil money penalty in an amount not to exceed $10,000 for any violation may be assessed...

26 CFR 801.1 - Balanced performance measurement system; in general.

Science.gov (United States)

2010-04-01

... general. 801.1 Section 801.1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... WITHIN THE INTERNAL REVENUE SERVICE § 801.1 Balanced performance measurement system; in general. (a) In general. (1) The regulations in this part 801 implement the provisions of sections 1201 and 1204 of the...

29 CFR 801.8 - Employment relationship.

Science.gov (United States)

2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Employment relationship. 801.8 Section 801.8 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR OTHER LAWS APPLICATION... files a complaint, institutes a proceeding, testifies in a proceeding, or exercises any right under EPPA. ...

A review: radiolabeled synthesis of pesticides

International Nuclear Information System (INIS)

Li Juying; Han Ailiang; Wang Haiyan; Wang Wei; Ye Qingfu

2010-01-01

Isotope tracer technique has been widely applied in studies of metabolism, mode action, fate and environmental behavior of pesticides. In such studies, the key point is to obtain suitable radiolabelled compounds. However, the radiotracers, especially the labelled pesticides which are novel compounds with complex structures and longer synthesis routes, are usually unavailable from domestic and /or foreign markets. Therefore, it is essential to explore the synthesis methods of radiolabelled pesticides, which are quite different from the conventional nonradiosynthesis, and are requested to obtain higher yield. This article is a review on current status of choosing the available radionuclide and labelled position, the main synthesis methods and problems in the process of preparing radiolabelled pesticides. (authors)

Quantitative imaging with radiolabeled monoclonal antibodies

International Nuclear Information System (INIS)

Moldofsky, P.J.; Hammond, N.D.

1988-01-01

The ability to image tumor by using radiolabeled monoclonal antibody products has been widely demonstrated. The questions of safety and efficacy remain open and require further experience, but at least in some clinical situations radioimmunoimaging has provided clinically useful information. Imaging tumor with radiolabeled monoclonal and polyclonal antibodies has been widely reported, and several summaries have recently appeared. For extensive review of recent clinical imaging the reader is referred to these excellent sources. Having demonstrated the possibility of imaging tumor with radiolabeled antibody, the question now apparent is: will the imaging modality provide information new and different from the already available with established techniques in computed tomography, magnetic resonance imaging, and standard nuclear medicine?

7 CFR 801.12 - Design requirements incorporated by reference.

Science.gov (United States)

2010-01-01

... 7 Agriculture 7 2010-01-01 2010-01-01 false Design requirements incorporated by reference. 801.12 Section 801.12 Agriculture Regulations of the Department of Agriculture (Continued) GRAIN INSPECTION... OFFICIAL PERFORMANCE REQUIREMENTS FOR GRAIN INSPECTION EQUIPMENT § 801.12 Design requirements incorporated...

37 CFR 1.801 - Biological material.

Science.gov (United States)

2010-07-01

... 37 Patents, Trademarks, and Copyrights 1 2010-07-01 2010-07-01 false Biological material. 1.801... Biological Material § 1.801 Biological material. For the purposes of these regulations pertaining to the deposit of biological material for purposes of patents for inventions under 35 U.S.C. 101, the term...

Neurotoxicity of cholinesterase inhibitors: Mechanism, prophylaxis, and therapy (organophosphates). Midterm report, 1 December 1991-30 June 1993

Energy Technology Data Exchange (ETDEWEB)

De Groot, D.M.; Bierman, E.P.; Van Huygevoort, A.H.; Bruijnzeel, P.L.

1993-09-30

The effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist N-L(2-thienyl)cyclohexylpiperidine (TCP) on soman-induced convulsions and brain damage were studied in rats. For comparison, the effects of another non-competitive NMDA receptor antagonist MK801 were investigated in a pilot study. We were unable to provide hard evidence that TCP without additional drug treatment has therapeutic effects on soman-induced convulsions and/or brain damage, either when injected intracerebrally, or when injected systemically. In contrast, MK801 was effective, but only when an additional dose of MK801 was administered 5 minutes prior to the soman injection and not when seizures had been going on for 30 minutes. The results suggest that interference with the mechanisms leading to brain damage after soman at the level of the NMDA receptor only, is not sufficient to prevent this damage. However, in combination with drugs that interfere at an earlier stage in the sequence of events leading to convulsions and brain damage after soman, TCP and analogues appear as promising drugs for further treatment of soman-intoxicated individuals. Non-Competitive NMDA antagonists, TCP, MK801, Convulsions, Neuropathology, Intracerebral injections, NMDA receptors, RA V, Lab animals, Rats, Amino acids.

Ketamine displaces the novel NMDA receptor SPET probe [{sup 123}I]CNS-1261 in humans in vivo

Energy Technology Data Exchange (ETDEWEB)

Stone, James M. [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom)]. E-mail: j.stone@iop.kcl.ac.uk; Erlandsson, Kjell [Institute of Nuclear Medicine, University College London, London, W1N 8AA (United Kingdom); Arstad, Erik [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom); Bressan, Rodrigo A. [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom); Squassante, Lisa [GlaxoSmithKline (GSK), Verona 37135 (Italy); Teneggi, Vincenza [GlaxoSmithKline (GSK), Verona 37135 (Italy); Ell, Peter J. [Institute of Nuclear Medicine, University College London, London, W1N 8AA (United Kingdom); Pilowsky, Lyn S. [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom); Institute of Nuclear Medicine, University College London, London, W1N 8AA (United Kingdom)

2006-02-15

[{sup 123}I]CNS-1261 [N-(1-naphthyl)-N'-(3-iodophenyl)-N-methylguanidine] is a high-affinity SPET ligand with selectivity for the intrachannel PCP/ketamine/MK-801 site of the N-methyl-D-aspartate (NMDA) receptor. This study evaluated the effects of ketamine (a specific competitor for the intrachannel PCP/ketamine/MK-801 site) on [{sup 123}I]CNS-1261 binding to NMDA receptors in vivo. Ten healthy volunteers underwent 2 bolus-plus-infusion [{sup 123}I]CNS-1261 scans, one during placebo and the other during a ketamine challenge. Ketamine administration led to a significant decrease in [{sup 123}I]CNS-1261 V {sub T} in most of the brain regions examined (P<.05). [{sup 123}I]CNS-1261 appears to be a specific ligand in vivo for the intrachannel PCP/ketamine/MK-801 NMDA binding site.

5 CFR 950.801 - Campaign schedule.

Science.gov (United States)

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Campaign schedule. 950.801 Section 950... VOLUNTARY ORGANIZATIONS CFC Timetable § 950.801 Campaign schedule. (a) The Combined Federal Campaign will be.../International and International parts of the Charity List to all local campaigns by a date to be determined by...

18 CFR 801.6 - Water supply.

Science.gov (United States)

2010-04-01

... 18 Conservation of Power and Water Resources 2 2010-04-01 2010-04-01 false Water supply. 801.6... POLICIES § 801.6 Water supply. (a) The Susquehanna River Basin is rich in water resources. With proper... forth in the comprehensive plan. (c) The Commission shall study the basin's water supply needs, the...

18 CFR 801.7 - Water quality.

Science.gov (United States)

2010-04-01

... 18 Conservation of Power and Water Resources 2 2010-04-01 2010-04-01 false Water quality. 801.7... POLICIES § 801.7 Water quality. (a) The signatory States have the primary responsibility in the basin for water quality management and control. However, protection of the water resources of the basin from...

Recent developments in monoclonal antibody radiolabeling techniques

International Nuclear Information System (INIS)

Srivastava, S.C.; Mease, R.C.

1989-01-01

Monoclonal antibodies (MAbs) have shown the potential to serve as selective carriers of radionuclides to specific in vivo antigens. Accordingly, there has been an intense surge of research activity in an effort to develop and evaluate MAb-based radiopharmaceuticals for tumor imaging (radioimmunoscintigraphy) and therapy (radioimmunotherapy), as well as for diagnosing nonmalignant diseases. A number of problems have recently been identified, related to the MAbs themselves and to radiolabeling techniques, that comprise both the selectivity and the specificity of the in vivo distribution of radiolabeled MAbs. This paper will address some of these issues and primarily discuss recent developments in the techniques for radiolabeling monoclonal antibodies that may help resolve problems related to the poor in vivo stability of the radiolabel and may thus produce improved biodistribution. Even though many issues are identical with therapeutic radionuclides, the discussion will focus mainly on radioimmunoscintigraphic labels. 78 refs., 6 tabs

Recent developments in monoclonal antibody radiolabeling techniques

Energy Technology Data Exchange (ETDEWEB)

Srivastava, S.C.; Mease, R.C.

1989-01-01

Monoclonal antibodies (MAbs) have shown the potential to serve as selective carriers of radionuclides to specific in vivo antigens. Accordingly, there has been an intense surge of research activity in an effort to develop and evaluate MAb-based radiopharmaceuticals for tumor imaging (radioimmunoscintigraphy) and therapy (radioimmunotherapy), as well as for diagnosing nonmalignant diseases. A number of problems have recently been identified, related to the MAbs themselves and to radiolabeling techniques, that comprise both the selectivity and the specificity of the in vivo distribution of radiolabeled MAbs. This paper will address some of these issues and primarily discuss recent developments in the techniques for radiolabeling monoclonal antibodies that may help resolve problems related to the poor in vivo stability of the radiolabel and may thus produce improved biodistribution. Even though many issues are identical with therapeutic radionuclides, the discussion will focus mainly on radioimmunoscintigraphic labels. 78 refs., 6 tabs.

7 CFR 801.9 - Tolerances for test weight apparatuses.

Science.gov (United States)

2010-01-01

... 7 Agriculture 7 2010-01-01 2010-01-01 false Tolerances for test weight apparatuses. 801.9 Section 801.9 Agriculture Regulations of the Department of Agriculture (Continued) GRAIN INSPECTION, PACKERS... PERFORMANCE REQUIREMENTS FOR GRAIN INSPECTION EQUIPMENT § 801.9 Tolerances for test weight apparatuses. The...

18 CFR 801.11 - Public values.

Science.gov (United States)

2010-04-01

... 18 Conservation of Power and Water Resources 2 2010-04-01 2010-04-01 false Public values. 801.11... POLICIES § 801.11 Public values. (a) The basin has many points of archeological and historic interest, and... value of these areas cannot be measured simply in economic terms and will strive to preserve and promote...

18 CFR 801.5 - Comprehensive plan.

Science.gov (United States)

2010-04-01

... 18 Conservation of Power and Water Resources 2 2010-04-01 2010-04-01 false Comprehensive plan. 801... POLICIES § 801.5 Comprehensive plan. (a) The Compact requires that the Commission formulate and adopt a comprehensive plan for the immediate and long-range development and use of the water resources of the basin. (1...

26 CFR 1.801-3 - Definitions.

Science.gov (United States)

2010-04-01

... elects to revalue such reserves on a net level premium basis under section 818(c), such revalued basis... life insurance reserves (as defined in section 801(b) and § 1.801-4), plus unearned premiums, and... which a reserve in addition to the unearned premiums (as defined in paragraph (e) of this section) must...

JOYO MK-II core characteristics database

International Nuclear Information System (INIS)

Tabuchi, Shiro; Aoyama, Takafumi; Nagasaki, Hideaki; Kato, Yuichi

1998-12-01

The experimental fast reactor JOYO served as the MK-II irradiation bed core for testing fuel and material for FBR development for 15 years from 1982 to 1997. During the MK-II operation, extensive data were accumulated from the core characteristics tests conducted in thirty-one duty operations and thirteen special test operations. These core management data and core characteristics data were compiled into a database. The code system MAGI has been developed and used for core management of JOYO MK-II, and the core characteristics and the irradiation test conditions were calculated using MAGI on the basis of three dimensional diffusion theory with seven neutron energy groups. The core management data include extensive data, which were recorded on CD-ROM for user convenience. The data are specifications and configurations of the core, and for about 300 driver fuel subassemblies and about 60 uninstrumented irradiation subassemblies are core composition before and after irradiation, neutron flux, neutron fluences, fuel and control rod burn-up, and temperature and power distributions. MK-II core characteristics and test conditions were stored in the database for post analysis. Core characteristics data include excess reactivities, control rod worths, and reactivity coefficients, e.g., temperature, power and burn-up. Test conditions include both measured and calculated data for irradiation conditions. (author)

18 CFR 801.8 - Flood plain management and protection.

Science.gov (United States)

2010-04-01

... 18 Conservation of Power and Water Resources 2 2010-04-01 2010-04-01 false Flood plain management and protection. 801.8 Section 801.8 Conservation of Power and Water Resources SUSQUEHANNA RIVER BASIN COMMISSION GENERAL POLICIES § 801.8 Flood plain management and protection. (a) Periodic inundation of lands...

49 CFR 801.50 - Exemptions from disclosure.

Science.gov (United States)

2010-10-01

... be inconsistent with the purpose of the exemption concerned. Examples of records given in §§ 801.51... stated in § 801.2 of this title, the NTSB may choose to make a discretionary release of a record that is...

29 CFR 801.73 - Final decision of the Secretary.

Science.gov (United States)

2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Final decision of the Secretary. 801.73 Section 801.73 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR OTHER LAWS... Vacation of Decision and Order of Administrative Law Judge § 801.73 Final decision of the Secretary. The...

2 CFR 801.10 - What does this part do?

Science.gov (United States)

2010-01-01

... 2 Grants and Agreements 1 2010-01-01 2010-01-01 false What does this part do? 801.10 Section 801.10 Grants and Agreements Federal Agency Regulations for Grants and Agreements DEPARTMENT OF VETERANS AFFAIRS NONPROCUREMENT DEBARMENT AND SUSPENSION § 801.10 What does this part do? This part adopts the...

26 CFR 801.4 - Customer satisfaction measures.

Science.gov (United States)

2010-04-01

... 26 Internal Revenue 20 2010-04-01 2010-04-01 false Customer satisfaction measures. 801.4 Section... REVENUE SERVICE § 801.4 Customer satisfaction measures. The customer satisfaction goals and... may be employed to gather data regarding customer satisfaction. Information to measure customer...

Propofol can Protect Against the Impairment of Learning-memory Induced by Electroconvulsive Shock via Tau Protein Hyperphosphorylation in Depressed Rats

Institute of Scientific and Technical Information of China (English)

Wan-fu Liu; Chao Liu

2015-01-01

Objective To explore the possible neurophysiologic mechanisms of propofol and N-methyl-D-aspartate (NMDA) receptor antagonist against learning-memory impairment of depressed rats without olfactory bulbs. Methods Models of depressed rats without olfactory bulbs were established. For the factorial design in analysis of variance, two intervention factors were included: electroconvulsive shock groups (with and without a course of electroconvulsive shock) and drug intervention groups [intraperotoneal (ip) injection of saline, NMDA receptor antagonist MK-801 and propofol. A total of 60 adult depressed rats without olfactory bulbs were randomly divided into 6 experimental groups (n=10 per group):ip injection of 5 ml saline;ip injection of 5 ml of 10 mg/kg MK-801;ip injection of 5 ml of 10 mg/kg MK-801 and a course of electroconvulsive shock;ip injection of 5 ml of 200 mg/kg propofol;ip injection of 5 ml of 200 mg/kg propofol and a course of electroconvulsive shock;and ip injection of 5 ml saline and a course of electroconvulsive shock. The learning-memory abilities of the rats was evaluated by the Morris water maze test. The content of glutamic acid in the hippocampus was detected by high-performance liquid chromatography. The expressions of p-AT8Ser202 in the hippocampus were determined by Western blot analysis. Results Propofol, MK-801 or electroconvulsive shock alone induced learning-memory impairment in depressed rats, as proven by extended evasive latency time and shortened space probe time. Glutamic acid content in the hippocampus of depressed rats was significantly up-regulated by electroconvulsive shock and down-regulated by propofol, but MK-801 had no significant effect on glutamic acid content. Levels of phosphorylated Tau protein p-AT8Ser202 in the hippocampus was up-regulated by electroconvulsive shock but was reduced by propofol and MK-801 alone. Propofol prevented learning-memory impairment and reduced glutamic acid content and p-AT8Ser202 levels induced by

Spermine modulation of the glutamateNMDA receptors is differentially responsive to conantokins in normal and alzheimer disease human cortex

International Nuclear Information System (INIS)

Ragnarsson, L.; Dodd, P.R.; Lewis, R.; University of Queensland, QLD

1998-01-01

Full text: The pharmacological characteristics of human N-methyl-D-aspartate (NMDA) receptors were examined in 12 control and 6 pathologically confirmed Alzheimer disease (AD) cases in six different brain areas, by studying their responses to MK-801, glutamate, spermine, and the NMDA receptor antagonists Ala(7)-conantokinG and Lys(7)-conantokinG. [ 3 H]MK801 binding assays performed by standard protocols on well-washed synoptic plasma membranes showed little variation in k D in all six brain areas, including comparisons between control and matched AD cases. b MAX values showed regional differences within control and AD cases, but there was no significant difference between groups in any of the brain regions. Maximal glutamate-enhanced [ 3 H]MK801 binding did not vary much between the brain regions or between control and AD cases, whereas maximal spermine-enhanced [ 3 H]MK-801 binding differed significantly between certain brain regions and between control and AD cases. In absolute terms in the control cases, the activation values were much lower in the spared regions, occipital and motor cortex, than in other areas; further, areas which are susceptible to damage showed reduced spermine activation in AD cases. These regional differences in the efficacy of spermine activation might be the result of local variations in the subunit composition of the NMDA receptor. Ala(7)-conantokinG and Lys(7)-conantokinG showed slight differences in potency, with the Ala(7) compound as the more potent. Both peptides produced 100% inhibition of spermine-enhanced [ 3 H]MK-801 binding in all brain areas, ana both gave lower IC 50 values in AD cases than in control cases. The significant differences in the inhibition of spermine-enhanced [ 3 H]MK-801 binding by the peptides between control and AD cases suggest that AD cases have a particular receptor subunit composition that is responsive to polyamines and which might make them more susceptible to excitotoxic damage. The spermine site

26 CFR 801.5 - Employee satisfaction measures.

Science.gov (United States)

2010-04-01

... 26 Internal Revenue 20 2010-04-01 2010-04-01 false Employee satisfaction measures. 801.5 Section... REVENUE SERVICE § 801.5 Employee satisfaction measures. The employee satisfaction numerical ratings to be... employed to gather data regarding satisfaction. The information gathered will be used to measure, among...

JOYO MK-II core characteristics database

International Nuclear Information System (INIS)

Ohkawachi, Yasushi; Maeda, Shigetaka; Sekine, Takashi; Aoyama, Takafumi

2003-04-01

The 'JOYO' MK-II core characteristics database was compiled and published in 1998. Comments and requests from many users led to the creation of a revised edition. The revisions include changes to the MAGI calculation code system to use the 70 group JFS-3-J3.2 constant set processed from the JENDL-3.2 library. Total control rod worth, reactor kinetic parameters and the MK-II core performance test results were included per user's requests. The core characteristics obtained from the 32 nd to 35 th operational cycles, which were conducted in the MK-III transition core, were newly added in this revised version. The MK-II core management data and core characteristics data were recorded to CD-ROM for user convenience. The Configuration Data' include the core arrangement and refueling record for each operational cycle. The 'Subassembly Library Data' include the atomic number density, neutron fluence, burn-up, integral power of 362 driver fuel subassemblies and 69 irradiation test subassemblies. The 'Output Data' contain the calculated neutron flux, gamma flux, power density, linear heat rate, coolant and fuel temperature distribution of all the fuel subassemblies at the beginning and end of each operational cycle. The 'Core Characteristics Data' include the measured excess reactivity, control rod worth calibration curve, and reactivity coefficients of temperature, power and burn-up. (author)

Preparation and biodistribution of radiolabeled fullerene C60 nanocrystals

International Nuclear Information System (INIS)

Nikolic, Nadezda; Vranjes-Duric, Sanja; Jankovic, Drina; Dokic, Divna; Mirkovic, Marija; Bibic, Natasa; Trajkovic, Vladimir

2009-01-01

The present study describes for the first time a procedure for the radiolabeling of fullerene (C 60 ) nanocrystals (nanoC 60 ) with Na 125 I, as well as the biodistribution of radiolabeled nanoC 60 ( 125 I-nanoC 60 ). The solvent exchange method with tetrahydrofuran was used to make colloidal water suspensions of radiolabeled nanoC 60 particles. The radiolabeling procedure with the addition of Na 125 I to tetrahydrofuran during dissolution of C 60 gave a higher radiochemical yield of radiolabeled nanoC 60 particles in comparison to the second option, in which Na 125 I was added after C 60 was dissolved. Using photon correlation spectroscopy and transmission electron microscopy, 125 I-nanoC 60 particles were found to have a crystalline structure and a mean diameter of 200-250 nm. The 125 I-nanoC 60 had a particularly high affinity for human serum albumin, displaying 95% binding efficiency after 1 h. Biodistribution studies of 125 I-nanoC 60 in rats indicated significant differences in tissue accumulation of 125 I-nanoC 60 and the radioactive tracer Na 125 I. The higher accumulation of radiolabeled nanoC 60 was observed in liver and spleen, while accumulation in thyroid, stomach, lungs and intestines was significantly lower in comparison to Na 125 I. In addition to being useful for testing the biological distribution of nanoC 60 , the described radiolabeling procedure might have possible applications in cancer radiotherapy.

Assessing the Frequency and Material Consequences of Collisions with Vessels Lying at an Anchorage in Line with IALA iWrap MkII

Directory of Open Access Journals (Sweden)

Hans-Christoph Burmeister

2014-03-01

Full Text Available This paper proposes a collision model for ships underway and temporary objects as an extension to state-of-the-art maritime risk assessment like IALA iWrap MkII. It gives a brief review of frequency modeling's and consequence calculation theory as well as its applications, before it analogously derives a model to assess the risk of anchorage areas. Subsequently, its benefit is demonstrated by an example scenario.

48 CFR 42.801 - Notice of intent to disallow costs.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Notice of intent to disallow costs. 42.801 Section 42.801 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION CONTRACT MANAGEMENT CONTRACT ADMINISTRATION AND AUDIT SERVICES Disallowance of Costs 42.801 Notice of...

7 CFR 801.5 - Tolerance for diverter-type mechanical samplers.

Science.gov (United States)

2010-01-01

... 7 Agriculture 7 2010-01-01 2010-01-01 false Tolerance for diverter-type mechanical samplers. 801.5 Section 801.5 Agriculture Regulations of the Department of Agriculture (Continued) GRAIN INSPECTION... OFFICIAL PERFORMANCE REQUIREMENTS FOR GRAIN INSPECTION EQUIPMENT § 801.5 Tolerance for diverter-type...

Disruption of long-term alcohol-related memory reconsolidation: Role of β-adrenoceptors and NMDA receptors

Directory of Open Access Journals (Sweden)

Jelte A Wouda

2010-11-01

Full Text Available Disrupting reconsolidation of drug-related memories may be effective in reducing the incidence of relapse. In the current study we examine whether alcohol- related memories are prone to disruption by the β -adrenergicreceptor antagonist propranolol (10 mg/kg and the NMDA receptor antagonist MK801 (0.1 mg/kg following their reactivation. In operant chambers, male Wistar rats were trained to self-administer a 12% alcohol solution. After 3 weeks of abstinence, the animals were placed in the self-administration cages and were reexposed to the alcohol-associated cues for a 20-min retrieval period, immediately followed by a systemic injection of either propranolol, MK801 or saline. Rats were tested for cue-induced alcohol seeking on the following day. Retrieval session, injection and test were repeated on 2 further occasions at weekly intervals. Both propranolol and MK801 administration upon reactivation did not reduce alcohol seeking after the first reactivation test. However, a significant reduction of alcohol seeking was observed over three post-training tests in propranolol treated animals, and MK801 treated animals showed a strong tendency towards reduced alcohol seeking (p=0.06. Our data indicate that reconsolidation of alcohol-related memories can be disrupted after a long post-training interval and that particularly β-adrenergic receptors may represent novel targets for pharmacotherapy of alcoholism, in combination with cue-exposure therapies.

47 CFR 2.801 - Radiofrequency device defined.

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2010-10-01

... 47 Telecommunication 1 2010-10-01 2010-10-01 false Radiofrequency device defined. 2.801 Section 2... MATTERS; GENERAL RULES AND REGULATIONS Marketing of Radio-frequency Devices § 2.801 Radiofrequency device defined. As used in this part, a radiofrequency device is any device which in its operation is capable of...

Development of Radiolabeled compounds using reactor-produced radionuclides

International Nuclear Information System (INIS)

Choi, Sun Ju; Park, K. B.; Park, S. H.

2007-06-01

To establish a robust technology for radiopharmaceutical development, we focused on the configuration of fundamental development of radiolabeled compounds for radioimmunotherapy and drug delivery as well as the development of bifunctional chelating agents and radiolabeling methods for the radiopharmaceuticals with highly specific activity to deliver sufficient number of radionuclides to the target site. In this project, we aim to improve the quality of life and the public welfare by fostering the medical application of radioisotopes for the effective treatment of malignant diseases and by developing efficient radiolabeling methods of specific bio-active materials with radioisotopes and new candidates for radiopharmaceutical application. We have established the procedure for the preparation of radiolabeled antibody and biotin with radioisotopes such as 166 Ho, 131 I, 90 Y and 111 In for tumour targeting. In the future, these technologies will be applicable to development of radioimmunotherapeutic drug. The combination treatment of radioisotope with anti-cancer agents or chemotherapeutic agents may produce a synergistic static effects in the tumour and this synergism would be exerted via gene level through the activation of a cell death pathway. The combination therapy may be very beneficial for cancer treatment and this can overcome not only the hazards of unnecessary exposure to high radiation level during therapy, but also the tendency for drug resistance caused by chemotherapy. To develop new drug delivery system suitable for CT imaging agent, a chitosan derivative and radiolabed Folate-targeted polymer with 131 I were synthesized. We also carried out the development of DTPA derivatives for CT imaging agent, radiolabeled precursor, and established a highly efficient radiolabeling methodology with lanthanide nuclide. In order to develop neuroreceptor targeting compounds, we synthesized WAY-100635 compound and 99m Tc(CO) 3 precursor from Chrysamine G derivatives

MK3 modulation affects BMI1-dependent and independent cell cycle check-points.

Directory of Open Access Journals (Sweden)

Peggy Prickaerts

Full Text Available Although the MK3 gene was originally found deleted in some cancers, it is highly expressed in others. The relevance of MK3 for oncogenesis is currently not clear. We recently reported that MK3 controls ERK activity via a negative feedback mechanism. This prompted us to investigate a potential role for MK3 in cell proliferation. We here show that overexpression of MK3 induces a proliferative arrest in normal diploid human fibroblasts, characterized by enhanced expression of replication stress- and senescence-associated markers. Surprisingly, MK3 depletion evokes similar senescence characteristics in the fibroblast model. We previously identified MK3 as a binding partner of Polycomb Repressive Complex 1 (PRC1 proteins. In the current study we show that MK3 overexpression results in reduced cellular EZH2 levels and concomitant loss of epigenetic H3K27me3-marking and PRC1/chromatin-occupation at the CDKN2A/INK4A locus. In agreement with this, the PRC1 oncoprotein BMI1, but not the PCR2 protein EZH2, bypasses MK3-induced senescence in fibroblasts and suppresses P16INK4A expression. In contrast, BMI1 does not rescue the MK3 loss-of-function phenotype, suggesting the involvement of multiple different checkpoints in gain and loss of MK3 function. Notably, MK3 ablation enhances proliferation in two different cancer cells. Finally, the fibroblast model was used to evaluate the effect of potential tumorigenic MK3 driver-mutations on cell proliferation and M/SAPK signaling imbalance. Taken together, our findings support a role for MK3 in control of proliferation and replicative life-span, in part through concerted action with BMI1, and suggest that the effect of MK3 modulation or mutation on M/SAPK signaling and, ultimately, proliferation, is cell context-dependent.

29 CFR 801.1 - Purpose and scope.

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2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Purpose and scope. 801.1 Section 801.1 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR OTHER LAWS APPLICATION OF THE... section 10 of the Act on other laws or collective bargaining agreements. Subpart B sets forth rules...

Targeting of human glioma xenografts in vivo utilizing radiolabeled antibodies

International Nuclear Information System (INIS)

Williams, J.A.; Wessels, B.W.; Wharam, M.D.; Order, S.E.; Wanek, P.M.; Poggenburg, J.K.; Klein, J.L.

1990-01-01

Radiolabeled antibodies provide a potential basis for selective radiotherapy of human gliomas. We have measured tumor targeting by radiolabeled monoclonal and polyclonal antibodies directed against neuroectodermal and tumor-associated antigens in nude mice bearing human glioma xenografts. Monoclonal P96.5, a mouse IgG2a immunoglobulin, defines an epitope of a human melanoma cell surface protein, and specifically binds the U-251 human glioma as measured by immunoperoxidase histochemistry. 111In-radiolabeled P96.5 specifically targets the U-251 human glioma xenograft and yields 87.0 microCuries (microCi) of tumor activity per gram per 100 microCi injected activity compared to 4.5 microCi following administration of radiolabeled irrelevant monoclonal antibody. Calculations of targeting ratios demonstrate deposited dose to be 11.6 times greater with radiolabeled P96.5 administration compared to irrelevant monoclonal antibody. The proportion of tumor dose found in normal organs is less than 10%, further supporting specific targeting of the human glioma xenograft by this antibody. Monoclonal antibody ZME018, which defines a second melanoma-associated antigen, and polyclonal rabbit antiferritin, which defines a tumor-associated antigen, demonstrate positive immunoperoxidase staining of the tumor, but comparatively decreased targeting. When compared to the 111In-radiolabeled antibody, 90Y-radiolabeled P96.5 demonstrates comparable tumor targeting and percentages of tumor dose found in normal organs. To test the therapeutic potential of 90Y-radiolabeled P96.5, tumors and normal sites were implanted with miniature thermoluminescent dosimeters (TLD). Seven days following administration of 100 microCi 90Y-radiolabeled P96.5, average absorbed doses of 3770, 980, 353, and 274 cGy were observed in tumor, liver, contralateral control site, and total body, respectively

Effects of Electroacupuncture on N-Methyl-D-aspartate Receptor-Related Signaling Pathway in the Spinal Cord of Normal Rats

Directory of Open Access Journals (Sweden)

Ha-Neui Kim

2012-01-01

rats. Bilateral 2 Hz EA stimulations (1-2-3.0 mA were delivered at acupoints corresponding to Zusanli (ST36 and Sanyinjiao (SP6 in men for 30 min. Thermal sensitization was strongly inhibited by EA, but this analgesia was reduced by preintrathecal injection of the NMDAR antagonist, MK801. Phosphorylation of the NMDAR NR2B subunit, cAMP response element-binding protein (CREB, and especially phosphatidylinositol 3-kinase (PI3K were significantly induced by EA. However, these marked phosphorylations were not observed in MK801-pretreated rats. EA analgesia was reduced by preintrathecal injection with the calcium chelators Quin2 and TMB8, similar to the results evident using MK801. Phosphorylation of PI3K and CREB induced by EA was also inhibited by TMB8. Calcium influx by NMDAR activation may play an important role in EA analgesia of normal rats through the modulation of the phosphorylation of spinal PI3K and CREB.

2 CFR 801.20 - Does this part apply to me?

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2010-01-01

... 2 Grants and Agreements 1 2010-01-01 2010-01-01 false Does this part apply to me? 801.20 Section 801.20 Grants and Agreements Federal Agency Regulations for Grants and Agreements DEPARTMENT OF VETERANS AFFAIRS NONPROCUREMENT DEBARMENT AND SUSPENSION § 801.20 Does this part apply to me? This part and...

13 CFR 120.801 - How a 504 Project is financed.

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2010-01-01

... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false How a 504 Project is financed. 120.801 Section 120.801 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION BUSINESS LOANS Development Company Loan Program (504) § 120.801 How a 504 Project is financed. (a) One or more small...

29 CFR 801.5 - Effect on other laws or agreements.

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2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Effect on other laws or agreements. 801.5 Section 801.5 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR OTHER LAWS APPLICATION OF THE EMPLOYEE POLYGRAPH PROTECTION ACT OF 1988 General § 801.5 Effect on other laws or...

Radiolabelled monoclonal antibodies: magic bullets for colorectal carcinoma

International Nuclear Information System (INIS)

Slade, Linda

1997-01-01

Radiolabelled monoclonal antibodies (MoAbs) have been heralded as highly specific detection agents for many types of tumours. However, because of the many problems that have been associated with the use of these agents, their development and successes did not meet expectations. This paper discusses the use of radiolabelled MoAbs in the diagnosis and staging of colorectal cancer, the type of antibodies and radionuclides investigated over the past thirty years, and the advantages and disadvantages of each. An attempt is made to define the role of radioimmunoscintigraphy (RIS) in the investigation and management of patients with colorectal cancer. It appears that this technique can improve tumour detection, especially when used in conjunction with other imaging modalities. High sensitivities and specificities have been found using radio-labelled MoAbs for investigation of colorectal carcinoma. However, the author estimates there are a number of areas that require further research and improvement before naming radiolabelled MoAbs as 'magic bullets' for colorectal cancer. 8 refs., 3 tabs

Radiolabeled antibodies and RGD-peptides for the treatment of ovarian cancer.

NARCIS (Netherlands)

Janssen, M.L.H.

2004-01-01

In this thesis, preclinical studies on new treatment modalities for ovarian cancer are descibed, applying radiolabeled antibodies and radiolabeled RGD-peptides. In chapter 2 a study is described comparing the therapeutic efficacy of the antibody HMFG1 radiolabeled with several beta-emitting

Preparation of radiolabeled bioactive asbestos fibers

Energy Technology Data Exchange (ETDEWEB)

Tewson, T J; Francsechini, M P; Scheule, R K; Holian, A [Texas Univ., Houston, TX (USA). Health Science Center

1991-01-01

We have developed an efficient procedure to radiolabel asbestos fibers while retaining the bioactivity of the fibers. The fibers are labeled with {sup 68}Ge. The {sup 68}Ge decays into {sup 68}Ga, which then can be detected by its characteristic positron emission. Both chrysotile and crocidolite asbestos, a serpentine and an amphibole, respectively, were radiolabeled successfully. Mild reaction conditions and short reaction times were found under which {similar to}90% of the added {sup 68}Ge and {sup 68}Ga bound to the fibers. The radiolabel was retained even after washing the fibers extensively with physiologic buffers. The effects of the labeling on the bioactivity of the fibers were evaluated in an in vitro assay using guinea pig alveolar macrophages as a target cell. Labeled chrysotile fibers were found to retain >95% of their ability to stimulate these cells. The labeling procedure described in this study should be useful in preparing labeled fibers to investigate both in vitro and in vivo phenomena. (author).

Microfluidic radiolabeling of biomolecules with PET radiometals

International Nuclear Information System (INIS)

Zeng Dexing; Desai, Amit V.; Ranganathan, David; Wheeler, Tobias D.; Kenis, Paul J.A.; Reichert, David E.

2013-01-01

Introduction: A robust, versatile and compact microreactor has been designed, fabricated and tested for the labeling of bifunctional chelate conjugated biomolecules (BFC-BM) with PET radiometals. Methods: The developed microreactor was used to radiolabel a chelate, either 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) that had been conjugated to cyclo(Arg-Gly-Asp-DPhe-Lys) peptide, with both 64 Cu and 68 Ga respectively. The microreactor radiolabeling conditions were optimized by varying temperature, concentration and residence time. Results: Direct comparisons between the microreactor approach and conventional methods showed improved labeling yields and increased reproducibility with the microreactor under identical labeling conditions, due to enhanced mass and heat transfer at the microscale. More importantly, over 90% radiolabeling yields (incorporation of radiometal) were achieved with a 1:1 stoichiometry of bifunctional chelate biomolecule conjugate (BFC-BM) to radiometal in the microreactor, which potentially obviates extensive chromatographic purification that is typically required to remove the large excess of unlabeled biomolecule in radioligands prepared using conventional methods. Moreover, higher yields for radiolabeling of DOTA-functionalized BSA protein (Bovine Serum Albumin) were observed with 64 Cu/ 68 Ga using the microreactor, which demonstrates the ability to label both small and large molecules. Conclusions: A robust, reliable, compact microreactor capable of chelating radiometals with common chelates has been developed and validated. Based on our radiolabeling results, the reported microfluidic approach overall outperforms conventional radiosynthetic methods, and is a promising technology for the radiometal labeling of commonly utilized BFC-BM in aqueous solutions.

MK classification of evolved blue stars in the halo

International Nuclear Information System (INIS)

Garrison, R.F.

1987-01-01

The problem of the masses and origin of the evolved blue stars is very complex. No single approach can give all the answers unambiguously; it would be naive to suppose otherwise. The MK process and the MK system give a perspective which complements photometric, kinematic, high dispersion and other quantitative data. It is useful to know which stars are similar (or not) in spectral morphology, so that interesting candidates can be selected for further study. In many cases, the gross physical characteristics can be fairly well determined by use of the MK System. 8 references

The effect of high curing temperature on the reaction kinetics in MK/lime and MK-blended cement matrices at 60 deg. C

International Nuclear Information System (INIS)

Rojas, Moises Frias; Sanchez de Rojas, M.I.

2003-01-01

It is well known that the pozzolanic reaction between metakaolin (MK) and calcium hydroxide produces CSH, C 2 ASH 8 (stratlingite), C 4 AH 13 and C 3 ASH 6 (hydrogarnet). However, the presence or absence of these hydrated phases depends on different parameters, such as curing temperature, matrix used, etc. This paper shows the results of a study in order to know the effect of high curing temperature (60 deg. C) on the kinetics of the pozzolanic reaction in different matrices. MK/lime (calcium hydroxide) and MK-blended cement matrices were studied in samples stored and cured at 60 deg. C and up to 123 days of hydration. The nature, sequence and crystallinity of the hydrated phases were analysed using differential thermal analysis (DTA) and X-ray diffraction (XRD) techniques. Results showed that the sequence and formation of the hydrated phases was different in both matrices cured at 60 deg. C. In an MK/lime matrix, C 2 ASH 8 , C 4 AH 13 and C 3 ASH 6 were the main hydrated phases; while in an MK-blended cement, stratlingite was the sole hydrated phase issued from pozzolanic reaction. The DTA and XRD data also reveal an important fact: there is no evidence of the presence of hydrogarnet in blended cements

System for exposing animals to radiolabeled diesel exhaust

International Nuclear Information System (INIS)

Lopez, J.A.; Wolf, I.; Wolff, R.K.; Sun, J.D.; Mokler, B.V.

1981-01-01

One approach to determining the deposition and fate of inhaled diesel particles is the conduct of inhalation exposure studies with radiolabeled diesel fuel. A system was designed, constructed and tested for the simultaneous exposure of animals to radiolabeled diesel exhaust and collection of large quantities of radiolabeled diesel exhaust particles from a single cylinder diesel engine. The system performance was characterized and evaluated over a range of operating conditions: 0 to 1800 watts of engine load, 1000 to 2500 rpm and dilution air rates of 1:2 and 1:10. The exposure system met required design and operating criteria for safety, portability, space and flexibility

7 CFR 1494.801 - Enforcement and termination of agreements with CCC.

Science.gov (United States)

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Enforcement and termination of agreements with CCC. 1494.801 Section 1494.801 Agriculture Regulations of the Department of Agriculture (Continued... PROGRAMS Export Enhancement Program Operations § 1494.801 Enforcement and termination of agreements with...

SAFARI engineering model 50 mK cooler

Science.gov (United States)

Duband, L.; Duval, J. M.; Luchier, N.

2014-11-01

SAFARI is an infrared instrument developed by a European based consortium to be flown in SPICA, a Japanese led mission. The SAFARI detectors are transition edge sensors (TES) and require temperatures down to 50 mK for their operation. For that purpose we have developed a hybrid architecture based on the combination of a 300 mK sorption stage and a small adiabatic demagnetization stage. An engineering model has been designed to provide net heat lifts of 0.4 and 14 μW respectively at 50 and 300 mK, with an overall cycle duration of 48 h and a duty cycle objective of over 75%. The cooler is self-contained, fits in a volume of 156 × 312 × 182 mm and is expected to weigh 5.1 kg. It has been designed to withstand static loads of 120 g and a random vibration level of 21 g RMS.

NMDA antagonists exert distinct effects in experimental organophosphate or carbamate poisoning in mice

International Nuclear Information System (INIS)

Dekundy, Andrzej; Kaminski, Rafal M.; Zielinska, Elzbieta; Turski, Waldemar A.

2007-01-01

Organophosphate (OP) and carbamate acetylcholinesterase (AChE) inhibitors produce seizures and lethality in mammals. Anticonvulsant and neuroprotective properties of N-methyl-D-aspartate (NMDA) antagonists encourage the investigation of their effects in AChE inhibitor-induced poisonings. In the present study, the effects of dizocilpine (MK-801, 1 mg/kg) or 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP, 10 mg/kg), alone or combined with muscarinic antagonist atropine (1.8 mg/kg), on convulsant and lethal properties of an OP pesticide dichlorvos or a carbamate drug physostigmine, were studied in mice. Both dichlorvos and physostigmine induced dose-dependent seizure activity and lethality. Atropine did not prevent the occurrence of convulsions but decreased the lethal effects of both dichlorvos and physostigmine. MK-801 or CPP blocked or attenuated, respectively, dichlorvos-induced convulsions. Contrariwise, NMDA antagonists had no effect in physostigmine-induced seizures or lethality produced by dichlorvos or physostigmine. Concurrent pretreatment with atropine and either MK-801 or CPP blocked or alleviated seizures produced by dichlorvos, but not by physostigmine. Both MK-801 and CPP co-administered with atropine enhanced its antilethal effects in both dichlorvos and physostigmine poisoning. In both saline- and AChE inhibitor-treated mice, no interaction of the investigated antidotes with brain cholinesterase was found. The data indicate that both muscarinic ACh and NMDA receptor-mediated mechanisms contribute to the acute toxicity of AChE inhibitors, and NMDA receptors seem critical to OP-induced seizures

Microfluidic radiolabeling of biomolecules with PET radiometals.

Science.gov (United States)

Zeng, Dexing; Desai, Amit V; Ranganathan, David; Wheeler, Tobias D; Kenis, Paul J A; Reichert, David E

2013-01-01

A robust, versatile and compact microreactor has been designed, fabricated and tested for the labeling of bifunctional chelate conjugated biomolecules (BFC-BM) with PET radiometals. The developed microreactor was used to radiolabel a chelate, either 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) that had been conjugated to cyclo(Arg-Gly-Asp-DPhe-Lys) peptide, with both ⁶⁴Cu and ⁶⁸Ga respectively. The microreactor radiolabeling conditions were optimized by varying temperature, concentration and residence time. Direct comparisons between the microreactor approach and conventional methods showed improved labeling yields and increased reproducibility with the microreactor under identical labeling conditions, due to enhanced mass and heat transfer at the microscale. More importantly, over 90% radiolabeling yields (incorporation of radiometal) were achieved with a 1:1 stoichiometry of bifunctional chelate biomolecule conjugate (BFC-BM) to radiometal in the microreactor, which potentially obviates extensive chromatographic purification that is typically required to remove the large excess of unlabeled biomolecule in radioligands prepared using conventional methods. Moreover, higher yields for radiolabeling of DOTA-functionalized BSA protein (Bovine Serum Albumin) were observed with ⁶⁴Cu/⁶⁸Ga using the microreactor, which demonstrates the ability to label both small and large molecules. A robust, reliable, compact microreactor capable of chelating radiometals with common chelates has been developed and validated. Based on our radiolabeling results, the reported microfluidic approach overall outperforms conventional radiosynthetic methods, and is a promising technology for the radiometal labeling of commonly utilized BFC-BM in aqueous solutions. Copyright © 2013 Elsevier Inc. All rights reserved.

48 CFR 801.602-85 - Results of review.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Results of review. 801.602... DEPARTMENT OF VETERANS AFFAIRS ACQUISITION REGULATION SYSTEM Career Development, Contracting Authority, and Responsibilities 801.602-85 Results of review. (a) When the review is complete, the reviewing office will advise...

29 CFR 801.7 - Authority of the Secretary.

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2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Authority of the Secretary. 801.7 Section 801.7 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR OTHER LAWS APPLICATION... other agencies, and cooperate with and furnish technical assistance to employers, labor organizations...

29 CFR 801.75 - Certification of official record.

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2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Certification of official record. 801.75 Section 801.75 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR OTHER LAWS... Decision and Order issued under this part, the Chief Administrative Law Judge shall promptly certify and...

29 CFR 801.41 - Representation of the Secretary.

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2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Representation of the Secretary. 801.41 Section 801.41 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR OTHER LAWS... the Supreme Court, the Solicitor of Labor may appear for and represent the Secretary in any civil...

Biodistribution of radiolabeled lymphocytes

International Nuclear Information System (INIS)

Fawwaz, R.A.; Oluwole, S.; Wang, T.S.; Kuromoto, N.; Iga, C.; Hardy, M.A.; Alderson, P.O.

1985-01-01

Factors that might affect the biodistribution and clinical utility of radiolabeled lymphocytes were evaluated in experimental animals. Indium-111 (In-111) labeled lymphocytes obtained from peripheral blood, lymph node, or spleen were found in significant amounts in the lymphoid tissues of Lewis rats as early as 3 hours after infusion. A progressive increase in nodal activity with concomitant fall of activity in other organs followed, indicating active recirculation of the lymphocytes. In vitro irradiation of the In-111 labeled lymphocytes resulted in no detectable lymphocyte recirculation and/or reduced localization in lymphoid tissue. Splenectomized animals and those sensitized to an organ allograft before cell infusion showed increased activity in their bone marrow. These results suggest that the source of the injected cells, cell irradiation dose level and host sensitization should be considered when radiolabeled lymphocytes are being prepared for use in clinical diagnosis and therapy

Positron Emission Tomography Imaging Using Radiolabeled Inorganic Nanomaterials

Science.gov (United States)

Sun, Xiaolian; Cai, Weibo; Chen, Xiaoyuan

2015-01-01

CONSPECTUS Positron emission tomography (PET) is a radionuclide imaging technology that plays an important role in preclinical and clinical research. With administration of a small amount of radiotracer, PET imaging can provide a noninvasive, highly sensitive, and quantitative readout of its organ/tissue targeting efficiency and pharmacokinetics. Various radiotracers have been designed to target specific molecular events. Compared with antibodies, proteins, peptides, and other biologically relevant molecules, nanoparticles represent a new frontier in molecular imaging probe design, enabling the attachment of different imaging modalities, targeting ligands, and therapeutic payloads in a single vector. We introduce the radiolabeled nanoparticle platforms that we and others have developed. Due to the fundamental differences in the various nanoparticles and radioisotopes, most radiolabeling methods are designed case-by-case. We focus on some general rules about selecting appropriate isotopes for given types of nanoparticles, as well as adjusting the labeling strategies according to specific applications. We classified these radiolabeling methods into four categories: (1) complexation reaction of radiometal ions with chelators via coordination chemistry; (2) direct bombardment of nanoparticles via hadronic projectiles; (3) synthesis of nanoparticles using a mixture of radioactive and nonradioactive precursors; (4) chelator-free postsynthetic radiolabeling. Method 1 is generally applicable to different nanomaterials as long as the surface chemistry is well-designed. However, the addition of chelators brings concerns of possible changes to the physicochemical properties of nanomaterials and detachment of the radiometal. Methods 2 and 3 have improved radiochemical stability. The applications are, however, limited by the possible damage to the nanocomponent caused by the proton beams (method 2) and harsh synthetic conditions (method 3). Method 4 is still in its infancy

29 CFR 801.74 - Retention of official record.

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2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Retention of official record. 801.74 Section 801.74 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR OTHER LAWS APPLICATION... part shall be maintained and filed under the custody and control of the Chief Administrative Law Judge. ...

2 CFR 801.1105 - Cause for a limited denial of participation.

Science.gov (United States)

2010-01-01

... 2 Grants and Agreements 1 2010-01-01 2010-01-01 false Cause for a limited denial of participation. 801.1105 Section 801.1105 Grants and Agreements Federal Agency Regulations for Grants and Agreements... (Department of Veterans Affairs Optional Subpart for OMB Guidance at 2 CFR Part 180). § 801.1105 Cause for a...

Radiolabelled RGD peptides for imaging and therapy

Energy Technology Data Exchange (ETDEWEB)

Gaertner, F.C.; Schwaiger, M.; Beer, A.J. [Technische Universitaet Muenchen, Department of Nuclear Medicine, Klinikum rechts der Isar, Munich (Germany); Kessler, H. [Technische Universitaet Muenchen, Institute for Advanced Study and Center of Integrated Protein Science, Department of Chemistry, Garching (Germany); King Abdulaziz University, Chemistry Department, Faculty of Science, Jeddah (Saudi Arabia); Wester, H.-J. [Institute for Pharmaceutical Radiochemistry, Garching (Germany)

2012-02-15

Imaging of angiogenesis has become increasingly important with the rising use of targeted antiangiogenic therapies like bevacizumab (Avastin). Non-invasive assessment of angiogenic activity is in this respect interesting, e.g. for response assessment of such targeted antiangiogenic therapies. One promising approach of angiogenesis imaging is imaging of specific molecular markers of the angiogenic cascade like the integrin {alpha}{sub v}{beta}{sub 3}. For molecular imaging of integrin expression, the use of radiolabelled peptides is still the only approach that has been successfully translated into the clinic. In this review we will summarize the current data on imaging of {alpha}{sub v}{beta}{sub 3} expression using radiolabelled RGD peptides with a focus on tracers already in clinical use. A perspective will be presented on the future clinical use of radiolabelled RGD peptides including an outlook on potential applications for radionuclide therapy. (orig.)

Composition and method for stabilizing radiolabelled compounds using thiocarbonylated diethylenetriamines

International Nuclear Information System (INIS)

Tzodikov, N.R.

1984-01-01

Radiolabelled compounds, such as amino acids, nucleosides, vitamins and drugs, are stabilised against radiolytic decomposition by adding a solution of a thiocarbonylated diethylenetriamine to a solution of the radiolabelled compound. (author)

29 CFR 801.66 - Consent findings and order.

Science.gov (United States)

2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Consent findings and order. 801.66 Section 801.66 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR OTHER LAWS APPLICATION... Administrative Law Judge; and (4) A waiver of any right to challenge or contest the validity of the findings and...

Analysis of excess reactivity of JOYO MK-III performance test core

International Nuclear Information System (INIS)

Maeda, Shigetaka; Yokoyama, Kenji

2003-10-01

JOYO is currently being upgraded to the high performance irradiation bed JOYO MK-III core'. The MK-III core is divided into two fuel regions with different plutonium contents. To obtain a higher neutron flux, the active core height was reduced from 55 cm to 50 cm. The reflector subassemblies were replaced by shielding subassemblies in the outer two rows. Twenty of the MK-III outer core fuel subassemblies in the performance test core were partially burned in the transition core. Four irradiation test rigs, which do not contain any fuel material, were loaded in the center of the performance test core. In order to evaluate the excess reactivity of MK-III performance test core accurately, we evaluated it by applying not only the JOYO MK-II core management code system MAGI, but also the MK-III core management code system HESTIA, the JUPITER standard analysis method and the Monte Carlo method with JFS-3-J3.2R content set. The excess reactivity evaluations obtained by the JUPITER standard analysis method were corrected to results based on transport theory with zero mesh-size in space and angle. A bias factor based on the MK-II 35th core, which sensitivity was similar to MK-III performance test core's, was also applied, except in the case where an adjusted nuclear cross-section library was used. Exact three-dimensional, pin-by-pin geometry and continuous-energy cross sections were used in the Monte Carlo calculation. The estimated error components associated with cross-sections, methods correction factors and the bias factor were combined based on Takeda's theory. Those independently calculated values agree well and range from 2.8 to 3.4%Δk/kk'. The calculation result of the MK-III core management code system HESTLA was 3.13% Δk/kk'. The estimated errors for bias method range from 0.1 to 0.2%Δk/kk'. The error in the case using adjusted cross-section was 0.3%Δk/kk'. (author)

Imaging thrombus with radiolabelled monoclonal antibody to platelets

Energy Technology Data Exchange (ETDEWEB)

Peters, A.M.; Lavender, J.P.; Needham, S.G.; Loutfi, I.; Snook, D.; Epenetos, A.A.; Lumley, P.; Keery, R.J.; Hogg, N.

1986-12-13

A study was conducted evaluating a method of imaging thrombus with platelets radiolabelled with a /sup 111/In labelled monoclonal antibody, P256, directed to the platelet surface glycoprotein complex IIb/IIIa. when the number of receptors occupied by P256 was less than 3% of the total available on the platelet surface, platelet function was undisturbed. P256 was radiolabelled with /sup 111/In using diethylenetriaminepenta-acetic acid, which achieved a specific activity of 185 MBq (5 mCi)/mg. No impairment of immunoreactivity was detected at this specific activity. Platelets were labelled with radiolabelled monoclonal antibody in vitro in two patients at a receptor occupancy of 6% and in vivo in six patients at a receptor occupancy of 1%. In vivo recovery and biodistribution kinetics suggested that after in vitro labelling platelets were minimally activated. The /sup 111/In kinetics recorded after intravenous P256 suggested rapid and efficient radiolabelling of platelets and gave no indication of platelet activation. Of the six patients who received intravenous P256, three had documented thrombus, two of whom gave positive results on P256 platelet scintigraphy. The third had chronic deep venous thrombosis and was scintigraphically negative.

Long-term phase reorganization of conditioned food aversion memory in edible snail.

Science.gov (United States)

Kozyrev, S A; Solntseva, S V; Nikitin, V P

2014-08-01

The specific features of memory reconsolidation in edible snails were studied over 30 days after learning of conditioned food aversion. Injections of a NMDA glutamate receptor antagonist MK-801 or protein synthesis inhibitor cycloheximide in combination with the conditioned food stimulus (reminder) on day 2 after learning were followed by the development of amnesia. Repeated training on day 10 after the induction of amnesia did not result in skill formation. Injections of MK-801 or cycloheximide and reminder by the 10th day after training had no effect on memory retention. Injections of MK-801 or cycloheximide and reminder by the 30th day after training were followed by the development of amnesia. In these experiments, memory was recovered after repeated training. Our results indicate that a complex phase reorganization of memory occurs over 30 days after learning. This process includes memory consolidation over the first days after training, stabilization and resistance to adverse factors after 10 days, and newly acquired ability for reconsolidation by the 30th day after training.

Study of the radiolabeling of substance P with Lutetium-177 and analysis of the stability in vitro: development of new radiopharmaceutical for tumor treatment

International Nuclear Information System (INIS)

Lima, Clarice Maria de; Pujatti, Priscilla Brunelli; Mengatti, Jair Mengatti; Araujo, Elaine Bortoleti de

2009-01-01

Substance P (SP) is an 11- amino acid neuropeptide, which is known as an important member of the family of the tachykinins, characterized by the C-terminal sequence Phe-X-Gly-Leu-Met-NH2. Radiolabeled SP has been described and proposal for detection and treatment of diseases such as arthritis and tumors. SP is the most important target of neurokinin 1 (NK-1) receptors, over expressed in malignant gliomas. 177 Lu is commonly used in the production of radiopharmaceuticals for treatment of neuroendocrine tumors and is a radionuclide with favorable properties for endo radiotherapy. The half-life of 177 Lu is 6.75 days and it emits b- particles of 497 keV average energy. Moreover, 177 Lu also emits g radiation of 208 keV average energy, which makes imaging diagnosis possible. There are few studies describing radiolabeled SP analogs in literature and the objective of this work was to study the radiolabeling conditions and the stability of SP complexed to DOTA chelator, using 177 Lu as radionuclide, in order to determine the best radiolabeling methodology. A high radiochemical purity (> 95%) and high specific activity of DOTA-SP was achieved when the reaction time was 30 minutes, the temperature was 90 deg C, the mass of DOTA-SP was 10 mg and 177 Lu activity was 185 MBq. These conditions extrapolate will be used in future experiments with high activity and also in in vitro and in vivo studies involving glioma models. (author)

29 CFR 801.50 - Applicability of procedures and rules.

Science.gov (United States)

2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Applicability of procedures and rules. 801.50 Section 801.50 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR OTHER LAWS APPLICATION OF THE EMPLOYEE POLYGRAPH PROTECTION ACT OF 1988 Administrative Proceedings General...

16 CFR 801.21 - Securities and cash not considered assets when acquired.

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2010-01-01

... 16 Commercial Practices 1 2010-01-01 2010-01-01 false Securities and cash not considered assets when acquired. 801.21 Section 801.21 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS... regularly prepared balance sheet of “A” referred to in § 801.11—the voting securities of X must be reflected...

13 CFR 126.801 - How does one file a HUBZone status protest?

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2010-01-01

... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false How does one file a HUBZone status protest? 126.801 Section 126.801 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION HUBZONE PROGRAM Protests § 126.801 How does one file a HUBZone status protest? (a) General. The protest procedures...

Radiolabeled amino acids : Basic aspects and clinical applications in oncology

NARCIS (Netherlands)

Jager, PL; Vaalburg, W; Pruim, J; de Vries, EGE; Langen, KJ; Piers, DA

As the applications of metabolic imaging are expanding, radiolabeled amino acids may gain increased clinical interest, This review first describes the basic aspects of amino acid metabolism, then continues with basic aspects of radiolabeled amino acids, and finally describes clinical applications,

In vitro and in vivo effects of a novel dimeric inhibitor of PSD-95 on excitotoxicity and functional recovery after experimental traumatic brain injury

DEFF Research Database (Denmark)

Sommer, Jens Bak; Bach, Anders; Rytter, Hana Malá

2017-01-01

weeks post-trauma, spatial learning and memory were assessed in a water maze, and at 3 months, brains were removed for estimation of lesion volumes. Overall, neither treatment with UCCB01-147 nor MK-801 resulted in significant improvements of cognition and histopathology after CCI. Although MK-801......PSD-95 inhibitors have been shown to be neuroprotective in stroke, but have only to a very limited extent been evaluated in the treatment of traumatic brain injury (TBI) that has pathophysiological mechanisms in common with stroke. The aims of the current study were to assess the effects of a novel...

Imaging thrombus with radiolabelled monoclonal antibody to platelets

International Nuclear Information System (INIS)

Loutfi, I.; Peters, A.M.; Lavender, J.P.; Epenetos, A.A.

1988-01-01

Indium-111-hydroxyquinoline labelled platelets, though useful in the detection of thrombus, have not gained widespread use owing to the time and technical skill required for their preparation. A study was therefore conducted evaluating a new method of imaging thrombus with platelets radiolabelled with a 111 In labelled monoclonal antibody, P 256 , directed to the platelet surface glycoprotein complex IIb/IIIa. When the number of receptors occupied by P 256 was less than 3% of the total available on the platelet surface platelet function, as assessed by platelet aggregometry, was undisturbed. P 256 was radiolabelled with 111 In using diethylenetriaminepenta-acetic acid, which achieved a specific activity of 185 MBq (5 mCi)/mg. No impairment of immunoreactivity was detected at this specific activity. Platelets were labelled with radiolabelled monoclonal antibody in vitro in two patients at a receptor occupancy of 6% and in vivo - that is, by direct intravenous injection of P 256 - in six patients at a receptor occupancy of 1%. In vivo recovery and biodistribution kinetics suggested that after in vitro labelling platelets were minimally activated. The 111 In kinetics recorded after intravenous P 256 suggested rapid and efficient radiolabelling of platelets and gave no indication of platelet activation. Of the six patients who received intravenous P 256 , three had documented thrombus, tow of whom gave positive results on P 256 platelet scintigraphy. The third subject had chromic deep venous thrombosis and was scintigraphically negative. Imaging thrombus using a radiolabelled monoclonal antibody directed to platelets appears to offer great potential as a simple, non-invasive approach to the diagnosis of thrombosis. 3 refs. (Author)

20 CFR 801.2 - Definitions and use of terms.

Science.gov (United States)

2010-04-01

... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Definitions and use of terms. 801.2 Section 801.2 Employees' Benefits BENEFITS REVIEW BOARD, DEPARTMENT OF LABOR ESTABLISHMENT AND OPERATION OF... whenever necessary in respect of any claim for benefits or compensation arising under the Acts. (7) Chief...

A new technique for radiolabelling of humic substances

International Nuclear Information System (INIS)

Franke, K.; Patt, J.T.; Patt, M.; Kupsch, H.; Steinbach, J.

2004-01-01

A new method of radiolabelling of humic substances (HS) in the aqueous phase has been developed. Radiolabelling with the short-lived positron-emitter 18 F was carried out via diazonium coupling to electron-rich aromatic residues of the humic substances. Labelling yields of up to 75% were obtained after optimization of the synthetic procedure. Introductory experimental steps were performed for testing the labelling stability of the humic substances with ultrafiltration, electrophoretic and chromatographic methods. (orig.)

Radiolabelled peptides for oncological diagnosis

Energy Technology Data Exchange (ETDEWEB)

Laverman, Peter; Boerman, Otto C.; Oyen, Wim J.G. [Radboud University Nijmegen Medical Centre, Department of Nuclear Medicine, Nijmegen (Netherlands); Sosabowski, Jane K. [Queen Mary University of London, Centre for Molecular Oncology, Barts Cancer Institute, London (United Kingdom)

2012-02-15

Radiolabelled receptor-binding peptides targeting receptors (over)expressed on tumour cells are widely under investigation for tumour diagnosis and therapy. The concept of using radiolabelled receptor-binding peptides to target receptor-expressing tissues in vivo has stimulated a large body of research in nuclear medicine. The {sup 111}In-labelled somatostatin analogue octreotide (OctreoScan trademark) is the most successful radiopeptide for tumour imaging, and was the first to be approved for diagnostic use. Based on the success of these studies, other receptor-targeting peptides such as cholecystokinin/gastrin analogues, glucagon-like peptide-1, bombesin (BN), chemokine receptor CXCR4 targeting peptides, and RGD peptides are currently under development or undergoing clinical trials. In this review, we discuss some of these peptides and their analogues, with regard to their potential for radionuclide imaging of tumours. (orig.)

29 CFR 801.10 - Exclusion for public sector employers.

Science.gov (United States)

2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Exclusion for public sector employers. 801.10 Section 801... public sector employers. (a) Section 7(a) provides an exclusion from the Act's coverage for the United... public officials (i.e., appointed by an elected public official(s) and/or subject to removal procedures...

29 CFR 801.4 - Prohibitions on lie detector use.

Science.gov (United States)

2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Prohibitions on lie detector use. 801.4 Section 801.4 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR OTHER LAWS APPLICATION... complaint, for testifying in any proceeding, or for exercising any rights afforded by the Act. (b) An...

Chitosan Microspheres as Radiolabeled Delivery Devices

International Nuclear Information System (INIS)

Permtermsin, Chalermsin; Ngamprayad, Tippanan; Phumkhem, Sudkanung; Srinuttrakul, Wannee; Kewsuwan, Prartana

2007-08-01

Full text: This study optimized conditions for preparing, characterizing, radiolabeled of chitosan microspheres and the biodistribution of 99mTc-Chitosan microspheres after intravenous administration. Particle size distribution of the microspheres was determined by light scattering. Zeta potential was studied by dynamic light scattering and electrophoresis technique. Biodistribution studies were performed by radiolabeling using 99mTc. The results shown that geometric mean diameter of the microspheres was found to be 77.26?1.96 ?m. Microsphere surface charge of chitosan microspheres was positive charge and zeta potential was 25.80 ? 0.46 mV. The labeling efficiency for this condition was more than 95% and under this condition was stable for at least 6 h. Radioactivity

A new technique for radiolabelling of humic substances

Energy Technology Data Exchange (ETDEWEB)

Franke, K.; Patt, J.T.; Patt, M.; Kupsch, H.; Steinbach, J. [Inst. of Interdisciplinary Isotope Research, Leipzig (Germany)

2004-07-01

A new method of radiolabelling of humic substances (HS) in the aqueous phase has been developed. Radiolabelling with the short-lived positron-emitter {sup 18}F was carried out via diazonium coupling to electron-rich aromatic residues of the humic substances. Labelling yields of up to 75% were obtained after optimization of the synthetic procedure. Introductory experimental steps were performed for testing the labelling stability of the humic substances with ultrafiltration, electrophoretic and chromatographic methods. (orig.)

Kynurenic Acid Inhibits the Electrical Stimulation Induced Elevated Pituitary Adenylate Cyclase-Activating Polypeptide Expression in the TNC

Directory of Open Access Journals (Sweden)

Tamás Körtési

2018-01-01

Full Text Available BackgroundMigraine is a primary headache of imprecisely known mechanism, but activation of the trigeminovascular system (TS appears to be essential during the attack. Intensive research has recently focused on pituitary adenylate cyclase-activating polypeptide (PACAP and the kynurenine systems as potential pathogenic factors.AimWe investigated the link between these important mediators and the effects of kynurenic acid (KYNA and its synthetic analog (KYNA-a on PACAP expression in the rat trigeminal nucleus caudalis (TNC in a TS stimulation model related to migraine mechanisms.MethodsAdult male Sprague-Dawley rats were pretreated with KYNA, KYNA-a, the NMDA receptor antagonist MK-801, or saline (vehicle. Next, the trigeminal ganglion (TRG was electrically stimulated, the animals were transcardially perfused following 180 min, and the TNC was removed. In the TNC samples, 38 amino acid form of PACAP (PACAP1–38-like radioimmunoactivity was measured by radioimmunoassay, the relative optical density of preproPACAP was assessed by Western blot analysis, and PACAP1–38 mRNA was detected by real-time PCR.Results and conclusionElectrical TRG stimulation resulted in significant increases of PACAP1–38-LI, preproPACAP, and PACAP1–38 mRNA in the TNC. These increases were prevented by the pretreatments with KYNA, KYNA-a, and MK-801. This is the first study to provide evidence for a direct link between PACAP and the kynurenine system during TS activation.

33 CFR 117.801 - Newtown Creek, Dutch Kills, English Kills and their tributaries.

Science.gov (United States)

2010-07-01

... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Newtown Creek, Dutch Kills, English Kills and their tributaries. 117.801 Section 117.801 Navigation and Navigable Waters COAST GUARD....801 Newtown Creek, Dutch Kills, English Kills and their tributaries. (a) The following requirements...

Radiolabeling Silica-Based Nanoparticles via Coordination Chemistry: Basic Principles, Strategies, and Applications.

Science.gov (United States)

Ni, Dalong; Jiang, Dawei; Ehlerding, Emily B; Huang, Peng; Cai, Weibo

2018-03-20

As one of the most biocompatible and well-tolerated inorganic nanomaterials, silica-based nanoparticles (SiNPs) have received extensive attention over the last several decades. Recently, positron emission tomography (PET) imaging of radiolabeled SiNPs has provided a highly sensitive, noninvasive, and quantitative readout of the organ/tissue distribution, pharmacokinetics, and tumor targeting efficiency in vivo, which can greatly expedite the clinical translation of these promising NPs. Encouraged by the successful PET imaging of patients with metastatic melanoma using 124 I-labeled ultrasmall SiNPs (known as Cornell dots or C dots) and their approval as an Investigational New Drug (IND) by the United States Food and Drug Administration, different radioisotopes ( 64 Cu, 89 Zr, 18 F, 68 Ga, 124 I, etc.) have been reported to radiolabel a wide variety of SiNPs-based nanostructures, including dense silica (dSiO 2 ), mesoporous silica (MSN), biodegradable mesoporous silica (bMSN), and hollow mesoporous silica nanoparticles (HMSN). With in-depth knowledge of coordination chemistry, abundant silanol groups (-Si-O-) on the silica surface or inside mesoporous channels not only can be directly used for chelator-free radiolabeling but also can be readily modified with the right chelators for chelator-based labeling. However, integrating these labeling strategies for constructing stably radiolabeled SiNPs with high efficiency has proven difficult because of the complexity of the involved key parameters, such as the choice of radioisotopes and chelators, nanostructures, and radiolabeling strategy. In this Account, we present an overview of recent progress in the development of radiolabeled SiNPs for cancer theranostics in the hope of speeding up their biomedical applications and potential translation into the clinic. We first introduce the basic principles and mechanisms for radiolabeling SiNPs via coordination chemistry, including general rules of selecting proper

Localization of tumors by radiolabelled antibodies

International Nuclear Information System (INIS)

Hansen, H.J.; Primus, F.J.

1975-01-01

A method of utilizing radiolabelled antibodies to carcinoembryonic antigens for determining the site of tumors which produce or are associated with carcinoembryonic antigen is disclosed. 3 claims, no drawings

Effects of NMDA receptor antagonists on probability discounting depend on the order of probability presentation.

Science.gov (United States)

Yates, Justin R; Breitenstein, Kerry A; Gunkel, Benjamin T; Hughes, Mallory N; Johnson, Anthony B; Rogers, Katherine K; Shape, Sara M

Risky decision making can be measured using a probability-discounting procedure, in which animals choose between a small, certain reinforcer and a large, uncertain reinforcer. Recent evidence has identified glutamate as a mediator of risky decision making, as blocking the N-methyl-d-aspartate (NMDA) receptor with MK-801 increases preference for a large, uncertain reinforcer. Because the order in which probabilities associated with the large reinforcer can modulate the effects of drugs on choice, the current study determined if NMDA receptor ligands alter probability discounting using ascending and descending schedules. Sixteen rats were trained in a probability-discounting procedure in which the odds against obtaining the large reinforcer increased (n=8) or decreased (n=8) across blocks of trials. Following behavioral training, rats received treatments of the NMDA receptor ligands MK-801 (uncompetitive antagonist; 0, 0.003, 0.01, or 0.03mg/kg), ketamine (uncompetitive antagonist; 0, 1.0, 5.0, or 10.0mg/kg), and ifenprodil (NR2B-selective non-competitive antagonist; 0, 1.0, 3.0, or 10.0mg/kg). Results showed discounting was steeper (indicating increased risk aversion) for rats on an ascending schedule relative to rats on the descending schedule. Furthermore, the effects of MK-801, ketamine, and ifenprodil on discounting were dependent on the schedule used. Specifically, the highest dose of each drug decreased risk taking in rats in the descending schedule, but only MK-801 (0.03mg/kg) increased risk taking in rats on an ascending schedule. These results show that probability presentation order modulates the effects of NMDA receptor ligands on risky decision making. Copyright © 2016 Elsevier Inc. All rights reserved.

Selective neuronal degeneration in the retrosplenial cortex impairs the recall of contextual fear memory.

Science.gov (United States)

Sigwald, Eric L; Genoud, Manuel E; Giachero, Marcelo; de Olmos, Soledad; Molina, Víctor A; Lorenzo, Alfredo

2016-05-01

The retrosplenial cortex (RSC) is one of the largest cortical areas in rodents, and is subdivided in two main regions, A29 and A30, according to their cytoarchitectural organization and connectivities. However, very little is known about the functional activity of each RSC subdivision during the execution of complex cognitive tasks. Here, we used a well-established fear learning protocol that induced long-lasting contextual fear memory and showed that during evocation of the fear memory, the expression of early growth response gene 1 was up-regulated in A30, and in other brain areas implicated in fear and spatial memory, however, was down-regulated in A29, including layers IV and V. To search for the participation of A29 on fear memory, we triggered selective degeneration of neurons within cortical layers IV and V of A29 by using a non-invasive protocol that takes advantage of the vulnerability that these neurons have MK801-toxicity and the modulation of this neurodegeneration by testosterone. Application of 5 mg/kg MK801 in intact males induced negligible neuronal degeneration of A29 neurons and had no impact on fear memory retrieval. However, in orchiectomized rats, 5 mg/kg MK801 induced overt degeneration of layers IV-V neurons of A29, significantly impairing fear memory recall. Degeneration of A29 neurons did not affect exploratory or anxiety-related behavior nor altered unconditioned freezing. Importantly, protecting A29 neurons from MK801-toxicity by testosterone preserved fear memory recall in orchiectomized rats. Thus, neurons within cortical layers IV-V of A29 are critically required for efficient retrieval of contextual fear memory.

In vitro incorporation of radiolabeled cholesteryl esters into high and low density lipoproteins

International Nuclear Information System (INIS)

Terpstra, A.H.; Nicolosi, R.J.; Herbert, P.N.

1989-01-01

We have developed and validated a method for in vitro incorporation of radiolabeled cholesteryl esters into low density (LDL) and high density lipoproteins (HDL). Radiolabeled cholesteryl esters dissolved in absolute ethanol were mixed with LDL or HDL in the presence of lipoprotein-deficient serum (LPDS) as a source of core lipid transfer activity. The efficiency of incorporation was dependent on: (a) the core lipid transfer activity and quantity of LPDS, (b) the mass of added radiolabeled cholesteryl esters, (c) the length of incubation, and (d) the amount of acceptor lipoprotein cholesterol. The tracer incorporation was documented by repeat density gradient ultracentrifugation, agarose gel electrophoresis, and precipitation with heparin-MnCl2. The radiolabeling conditions did not affect the following properties of the lipoproteins: (1) chemical composition, (2) electrophoretic mobility on agarose gels, (3) hydrated density, (4) distribution of apoproteins on SDS gels, (5) plasma clearance rates, and (6) immunoprecipitability of HDL apoproteins A-I and A-II. Rat HDL containing radiolabeled cholesteryl esters incorporated in vitro had plasma disappearance rates identical to HDL radiolabeled in vivo

Synthesis and biological evaluation of cyclic analogs of L-carnitine as potential agents in the treatment of myocardial ischemia

International Nuclear Information System (INIS)

Woster, P.M.

1987-01-01

The purpose of this research was to synthesize a number of cyclic, rigid analogs of L-carnitine, having a variety of predetermined positional and stereochemical orientations, to be used as probes into the spatial and conformational requirements of the enzyme known as carnitine/acylcarnitine translocase. The ability of these analogs to serve as substrates for this enzyme was to be determined by assessing the degree to which they initiate efflux of 14 C-L-carnitine from isolated heart mitochondria. Toward this end, synthesis of several such analogs was attempted, resulting in the isolation and characterization of 9 cyclic analogs of carnitine, 5 of which are previously unreported. Bioevaluation of these synthetic carnitine analogs was conducted in a previously described assay system. Rat heart mitochondria were isolated by differential centrifugation and prepared for the study by incubation with 14 C-L-carnitine. Efflux of radiolabeled carnitine was then monitored in the presence of the compound being evaluated. This represents the first instance in which non-naturally occurring analogs of L-carnitine have been shown to undergo transport via this mitochondrial translocase, suggesting the possibility that cyclic carnitine analogs may find utility as agents in the treatment of myocardial ischemia

New surface radiolabeling schemes of super paramagnetic iron oxide nanoparticles (SPIONs) for biodistribution studies.

Science.gov (United States)

Nallathamby, Prakash D; Mortensen, Ninell P; Palko, Heather A; Malfatti, Mike; Smith, Catherine; Sonnett, James; Doktycz, Mitchel J; Gu, Baohua; Roeder, Ryan K; Wang, Wei; Retterer, Scott T

2015-04-21

Nanomaterial based drug delivery systems allow for the independent tuning of the surface chemical and physical properties that affect their biodistribution in vivo and the therapeutic payloads that they are intended to deliver. Additionally, the added therapeutic and diagnostic value of their inherent material properties often provides extra functionality. Iron based nanomaterials with their magnetic properties and easily tailorable surface chemistry are of particular interest as model systems. In this study the core radius of the iron oxide nanoparticles (NPs) was 14.08 ± 3.92 nm while the hydrodynamic radius of the NPs, as determined by Dynamic Light Scattering (DLS), was between 90-110 nm. In this study, different approaches were explored to create radiolabeled NPs that are stable in solution. The NPs were functionalized with polycarboxylate or polyamine surface functional groups. Polycarboxylate functionalized NPs had a zeta potential of -35 mV and polyamine functionalized NPs had a zeta potential of +40 mV. The polycarboxylate functionalized NPs were chosen for in vivo biodistribution studies and hence were radiolabeled with (14)C, with a final activity of 0.097 nCi mg(-1) of NPs. In chronic studies, the biodistribution profile is tracked using low level radiolabeled proxies of the nanoparticles of interest. Conventionally, these radiolabeled proxies are chemically similar but not chemically identical to the non-radiolabeled NPs of interest. This study is novel as different approaches were explored to create radiolabeled NPs that are stable, possess a hydrodynamic radius of <100 nm and most importantly they exhibit an identical surface chemical functionality as their non-radiolabeled counterparts. Identical chemical functionality of the radiolabeled probes to the non-radiolabeled probes was an important consideration to generate statistically similar biodistribution data sets using multiple imaging and detection techniques. The radiolabeling approach

16 CFR 801.11 - Annual net sales and total assets.

Science.gov (United States)

2010-01-01

... 16 Commercial Practices 1 2010-01-01 2010-01-01 false Annual net sales and total assets. 801.11 Section 801.11 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS, STATEMENTS AND... person; and (2) The total assets of a person shall be as stated on the last regularly prepared balance...

21 CFR 801.150 - Medical devices; processing, labeling, or repacking.

Science.gov (United States)

2010-04-01

... originally processed or packed, shall be exempt, during the time of introduction into and movement in... otherwise accounting for the number of units in each shipment to insure that the number of units shipped is... repacking. 801.150 Section 801.150 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND...

7 CFR 801.7 - Reference methods and tolerances for near-infrared spectroscopy (NIRS) analyzers.

Science.gov (United States)

2010-01-01

... 7 Agriculture 7 2010-01-01 2010-01-01 false Reference methods and tolerances for near-infrared spectroscopy (NIRS) analyzers. 801.7 Section 801.7 Agriculture Regulations of the Department of Agriculture...), DEPARTMENT OF AGRICULTURE OFFICIAL PERFORMANCE REQUIREMENTS FOR GRAIN INSPECTION EQUIPMENT § 801.7 Reference...

Preparation of crystalline sodium norcarnitine: an easily handled precursor for the preparation of carnitine analogs and radiolabeled carnitine.

Science.gov (United States)

Colucci, W J; Turnbull, S P; Gandour, R D

1987-05-01

A procedure by which crystalline sodium norcarnitine can be prepared in large quantities and high yields has been developed. Carnitine is selectively demethylated by thiophenoxide ion in N,N-dimethylethanolamine. The reactive thiophenoxide ion is generated in situ by addition of thiophenol to this basic reaction solvent. Hence, sodium thiophenoxide, which has been used in similar applications, but is difficult to prepare, can be avoided. Accordingly, reaction of (R,S)-carnitine followed by aqueous azeotropic distillation of byproducts as well as excess starting materials and then by neutralization with sodium hydroxide gave sodium norcarnitine in 89% yield. (R)-Carnitine gave 91% yield of (R)-norcarnitine zwitterion before neutralization. A method for the facile preparation of radiolabeled (R)-carnitine is also described. Thus, methylation of sodium norcarnitine with methyl iodide in methanolic acetone produced carnitine, which precipitated, and sodium iodide, which was soluble.

One-step synthesis of an {sup 18}F-labeled boron-derived methionine analog. A substitute for {sup 11}C-methionine?

Energy Technology Data Exchange (ETDEWEB)

Liu, Zhen; Lan, Xiaoli [Huazhong University of Science and Technology, Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Wuhan (China); Huazhong University of Science and Technology, Hubei Key Laboratory of Molecular Imaging, Union Hospital, Tongji Medical College, Wuhan (China); Ehlerding, Emily B. [University of Wisconsin - Madison, Department of Medical Physics, Madison, WI (United States); Cai, Weibo [University of Wisconsin - Madison, Department of Medical Physics, Madison, WI (United States); University of Wisconsin - Madison, Department of Radiology, Madison, WI (United States); University of Wisconsin - Madison, Carbone Cancer Center, Madison, WI (United States)

2018-04-15

Amino acid-based tracers have been extensively investigated for positron emission tomography (PET) imaging of brain tumors, and {sup 11}C-methionine ({sup 11}C-MET) is one of the most extensively investigated. However, widespread clinical use of {sup 11}C-MET is challenging due to the short half-life of {sup 11}C and low radiolabeling yield. In this issue of the European Journal of Nuclear Medicine and Molecular Imaging, Yang and colleagues report an {sup 18}F-labeled boron-derived methionine analog, {sup 18}F-B-MET, as a potential substitute for {sup 11}C-MET in PET imaging of glioma. The push-button synthesis, highly efficient radiolabeling, and good imaging performance in glioma models make this tracer a promising candidate for future clinical translation. (orig.)

29 CFR 801.43 - Civil money penalties-payment and collection.

Science.gov (United States)

2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Civil money penalties-payment and collection. 801.43... OTHER LAWS APPLICATION OF THE EMPLOYEE POLYGRAPH PROTECTION ACT OF 1988 Enforcement § 801.43 Civil money... by certified check or by money order, made payable to the order of “Wage and Hour Division, Labor...

New surface radiolabeling schemes of super paramagnetic iron oxide nanoparticles (SPIONs) for biodistribution studies†

Science.gov (United States)

Nallathamby, Prakash D.; Mortensen, Ninell P.; Palko, Heather A.; Malfatti, Mike; Smith, Catherine; Sonnett, James; Doktycz, Mitchel J.; Gu, Baohua; Roeder, Ryan K.; Wang, Wei; Retterer, Scott T.

2016-01-01

Nanomaterial based drug delivery systems allow for the independent tuning of the surface chemical and physical properties that affect their biodistribution in vivo and the therapeutic payloads that they are intended to deliver. Additionally, the added therapeutic and diagnostic value of their inherent material properties often provides extra functionality. Iron based nanomaterials with their magnetic properties and easily tailorable surface chemistry are of particular interest as model systems. In this study the core radius of the iron oxide nanoparticles (NPs) was 14.08 ± 3.92 nm while the hydrodynamic radius of the NPs, as determined by Dynamic Light Scattering (DLS), was between 90–110 nm. In this study, different approaches were explored to create radiolabeled NPs that are stable in solution. The NPs were functionalized with polycarboxylate or polyamine surface functional groups. Polycarboxylate functionalized NPs had a zeta potential of –35 mV and polyamine functionalized NPs had a zeta potential of +40 mV. The polycarboxylate functionalized NPs were chosen for in vivo biodistribution studies and hence were radiolabeled with 14C, with a final activity of 0.097 nCi mg–1 of NPs. In chronic studies, the biodistribution profile is tracked using low-level radiolabeled proxies of the nanoparticles of interest. Conventionally, these radiolabeled proxies are chemically similar but not chemically identical to the non-radiolabeled NPs of interest. This study is novel as different approaches were explored to create radiolabeled NPs that are stable, possess a hydrodynamic radius of <100 nm and most importantly they exhibit an identical surface chemical functionality as their non-radiolabeled counterparts. Identical chemical functionality of the radiolabeled probes to the non-radiolabeled probes was an important consideration to generate statistically similar biodistribution data sets using multiple imaging and detection techniques. The radiolabeling approach

Capsicum annuum transcription factor WRKYa positively regulates defense response upon TMV infection and is a substrate of CaMK1 and CaMK2.

Science.gov (United States)

Huh, Sung Un; Lee, Gil-Je; Jung, Ji Hoon; Kim, Yunsik; Kim, Young Jin; Paek, Kyung-Hee

2015-01-23

Plants are constantly exposed to pathogens and environmental stresses. To minimize damage caused by these potentially harmful factors, plants respond by massive transcriptional reprogramming of various stress-related genes via major transcription factor families. One of the transcription factor families, WRKY, plays an important role in diverse stress response of plants and is often useful to generate genetically engineered crop plants. In this study, we carried out functional characterization of CaWRKYa encoding group I WRKY member, which is induced during hypersensitive response (HR) in hot pepper (Capsicum annuum) upon Tobacco mosaic virus (TMV) infection. CaWRKYa was involved in L-mediated resistance via transcriptional reprogramming of pathogenesis-related (PR) gene expression and affected HR upon TMV-P0 infection. CaWRKYa acts as a positive regulator of this defense system and could bind to the W-box of diverse PR genes promoters. Furthermore, we found Capsicum annuum mitogen-activated protein kinase 1 (CaMK1) and 2 (CaMK2) interacted with CaWRKYa and phosphorylated the SP clusters but not the MAPK docking (D)-domain of CaWRKYa. Thus, these results demonstrated that CaWRKYa was regulated by CaMK1 and CaMK2 at the posttranslational level in hot pepper.

41 CFR 109-38.801 - Obtaining SF 149, U.S. Government National Credit Card.

Science.gov (United States)

2010-07-01

.... Government National Credit Card. 109-38.801 Section 109-38.801 Public Contracts and Property Management..., U.S. Government National Credit Card § 109-38.801 Obtaining SF 149, U.S. Government National Credit Card. DOE offices electing to use national credit cards shall request the assignment of billing address...

Detection of inflammatory lesions with radiolabelled immunoglobulins

International Nuclear Information System (INIS)

Blok, D.; Rijksuniversiteit Leiden; Ogtrop, M. van; Arndt, J.W.; Camps, J.A.J.; Feitsma, R.I.J.; Pauwels, E.K.J.

1990-01-01

Previous reports on the use of radiolabelled immunoglobulins led us to undertake a pilot experiment in an animal model to investigate the potentials sodium pertechnate Tc 99m-immunoglobulin scintigraphy in the detection of infectious foci. Mice infected in one leg with staphylococcus infection in were injected with sodium pertechnote Tc 99m-immunoglobulin, albumin aggregated technetium Tc 99m or gallium citrate Ga 67. The results obtained by scintigraphy suggested a specific accumulation of radiolabelled immunoglobulin at the site of infection. Visualization of the infection and the image quality, especially the 6- and 24-h images, were clearly enhanced after the use of immunoglobulin preparations as compared with those labelled with gallium. (orig.)

The development of 99mTc-analog of Cu-DTS as an agent for imaging hypoxia

International Nuclear Information System (INIS)

Horiuchi, K.; Tsukamoto, T.; Saito, M.; Nakayama, M.; Fujibayashi, Y.; Saji, H.

2000-01-01

Works on dithiosemicarbazone (DTS) derivatives radiolabeled with divalent Cu (Cu-62, Cu-64) indicate its potentiality as an ischemic tissue detecting agent. Development of analogous derivatives labeled with the more accessible technetium-99m (Tc) is most desirable. Various synthesized DTS derivatives are radiolabeled with a novel approach, using a macromolecular Sn(II)-complex under an anaerobic condition at pH 3.4-4.5 and stabilization by ascorbate solution at pH 6.7-7.0. Characterization of Tc-DTS derivatives done by various analytical methods (TLC, HPLC, EP, PC) and by in vivo studies in normal mice and in rats myocardial LAD (left anterior descent coronary artery) occlusion model. Among tested DTS, only Tc-ATSE, Tc-ATSM and Tc-ATSM 2 showed distinctive characteristics, with the latter presenting high myocardium uptake in regions of ischemia in LAD rat myocardium model. Potentiality of the Cu-DTS mimetic agent, Tc-ATSM 2 as an ischemia-damaged myocardium agent is discussed

Current status and future developments in radiolabelled immunoassays

International Nuclear Information System (INIS)

Edwards, R.

1998-01-01

Radioisotopes are used extensively in medical practice and their use in RIA or IRMA usually represent a small proportion of the total. Radiolabelled immunoassays based on 125 I constitute a simple didactic, cost effective and robust technology which is still regarded as the reference method in many clinical applications. The IAEA has implemented many successful programmes using the ''bulk reagent'' approach, involving 68 countries in all the different regions. The main achievements have been in technology transfer with self sufficiency in production for some countries; training of large numbers of staff; quality control and quality assurance schemes; devolution of screening programmes for neonatal congenital hypothryoidism. Alternatives to the use of radioisotopic tracers are constrained by many factors and are often only available in restricted commercial packages. They are often not suitable for technology transfer programmes and often lack any didactic component in addition to a relative high cost. The production of radiolabels using 125 I is both simple and adaptable. In addition expertise in their preparation and purification is widespread even in developing countries. Together with the ease of producing antibodies, the facts have made 125 I-radiolabelled immunoassays ideal for investigative procedures for many research activities (30,31) particularly in the medical context where radioisotopes are commonly used. In conclusion, even a superficial examination of public health statistics for various countries throughout the continents indicates a need for a simple, inexpensive and robust analytical tool. In this light, there is a predicted continuing role for radiolabelled immunoassays. (author)

29 CFR 801.65 - Appearances; representation of the Department of Labor.

Science.gov (United States)

2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Appearances; representation of the Department of Labor. 801.65 Section 801.65 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR OTHER LAWS APPLICATION OF THE EMPLOYEE POLYGRAPH PROTECTION ACT OF 1988 Administrative...

13 CFR 121.801 - May patent fees be reduced if a concern is small?

Science.gov (United States)

2010-01-01

... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false May patent fees be reduced if a concern is small? 121.801 Section 121.801 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION... for Paying Reduced Patent Fees § 121.801 May patent fees be reduced if a concern is small? These...

Daily intake and serum concentration of menaquinone-4 (MK-4) in haemodialysis patients with chronic kidney disease.

Science.gov (United States)

Wyskida, Katarzyna; Żak-Gołąb, Agnieszka; Łabuzek, Krzysztof; Suchy, Dariusz; Ficek, Rafał; Pośpiech, Kornel; Olszanecka-Glinianowicz, Magdalena; Okopień, Bogusław; Więcek, Andrzej; Chudek, Jerzy

2015-12-01

Decreased concentration of menaquinone-4 (MK-4) seems to be an important risk factor of vascular calcification in haemodialysis (HD) patients. Optimal dietary intake, as well as serum MK-4 reference range, in HD has not been determined, yet. The aim of the present study was to assess daily vitamin K1 and MK-4 intakes and their relation to serum MK-4 concentration in HD patients. Daily vitamin K1 and MK-4, micro- and macronutrients and energy intakes were assessed using 3-day food diary completed by patients and serum MK-4 concentration was measured by HPLC [limit of quantification (LOQ): 0.055 ng/mL] in 85 HD patients (51 males) and 22 apparently healthy subjects. Daily MK-4 intake was significantly lower (by 29%) among HD, while K1 consumption was similar in both groups. Daily MK-4 intake was associated with fat and protein consumption in HD (r=0.43, pintakes were weaker in HD (r=0.38 and r=0.30 respectively) than in the control group (r=0.47 and r=0.45, respectively). In multiple regression analysis the variability of serum MK-4 concentrations in HD patients was explained by its daily intake. Decreased serum MK-4 concentration in HD patients is caused by lower dietary MK-4 intake, mainly due to diminished meat consumption, and in addition, probably reduced K1 conversion. Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

SU-F-I-67: Neurometabolic Effect Induced by Repeated Exposure to Dizocilpine On Prefrontal Cortex of Schizophrenic Animal Model Using In Vivo Proton Magnetic Resonance Spectroscopy at 9.4 T

Energy Technology Data Exchange (ETDEWEB)

Yoo, C-H; Lim, S-I [Department of Biomedical Engineering, and Research Institute of Biomedical Engineering, The Catholic University of Korea College of Medicine, Seoul (Korea, Republic of); Asan Institute for Life Sciences, Asan Medical Center, Seoul (Korea, Republic of); Song, K-H; Choe, B-Y [Department of Biomedical Engineering, and Research Institute of Biomedical Engineering, The Catholic University of Korea College of Medicine, Seoul (Korea, Republic of); Woo, D-C [Asan Institute for Life Sciences, Asan Medical Center, Seoul (Korea, Republic of)

2016-06-15

Purpose: Repeated exposure of dizocilpine (MK-801) can provide a pathophysiological model for progressive development of schizophrenia. In vivo proton magnetic resonance spectroscopy ({sup 1}H MRS) was widely used for non-invasive measurement of neurometabolites, and assessment of disease-induced neurometabolic alterations. The purpose of this study was to investigate neurometabolic alteration in prefrontal cortex (PFC) with respect to progression (from first-episode to chronic stage) of schizophrenia by using in vivo {sup 1}H MRS. Methods: We used high-field {sup 1}H MRS to investigate the neurometabolic alteration in the PFC region of the rats (N = 13) by comparing before and after 6 day of MK-801 (0.5 mg/kg) treatment. A point-resolved spectroscopy (PRESS) sequence was used to obtain spectra in a 22.5 µL of volume of interest carefully located in PFC region with parameters like follow; repetition time, 5000ms; echo time (TE), 13.4 ms; averages = 256. Another experiment group (N = 11) were conducted behavior test by recording the behavior for 20 min. Results: All the rats showed hyperlocomotion, stereotyped behaviors before initiation of MRS. Significantly increased level (N = 7, p < 0.05) of N-acetylasrparate (NAA), glutamate (Glu), taurine and decreased level (N = 6, p < 0.05) of NAA, Glu and phosphocreatine were observed between baseline and day 6. Both metabolic alterations are consistent with results of first-episode and chronic schizophrenia respectively. Conclusion: From our findings, the repeated MK-801 model could be a pathophysiological model which can provide an insight into the transition from first-episode to chronic stage. This is first time to investigate effects of repeated MK-801 using high-field in vivo 1H MRS. We expect our findings can contribute to combining previous diverging results into one pathophysiological interpretation, which can postulate the origin of diverging results to the progression of schizophrenia.

Phosphodiesterase 2A Inhibitor TAK-915 Ameliorates Cognitive Impairments and Social Withdrawal in N-Methyl-d-Aspartate Receptor Antagonist-Induced Rat Models of Schizophrenia.

Science.gov (United States)

Nakashima, Masato; Imada, Haruka; Shiraishi, Eri; Ito, Yuki; Suzuki, Noriko; Miyamoto, Maki; Taniguchi, Takahiko; Iwashita, Hiroki

2018-04-01

The pathophysiology of schizophrenia has been associated with glutamatergic dysfunction. Modulation of the glutamatergic signaling pathway, including N -methyl-d-aspartate (NMDA) receptors, can provide a new therapeutic target for schizophrenia. Phosphodiesterase 2A (PDE2A) is highly expressed in the forebrain, and is a dual substrate enzyme that hydrolyzes both cAMP and cGMP, which play pivotal roles as intracellular second messengers downstream of NMDA receptors. Here we characterize the in vivo pharmacological profile of a selective and brain-penetrant PDE2A inhibitor, ( N -{(1 S )-1-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-methoxyethyl}-7-methoxy-2-oxo-2,3-dihydropyrido[2,3- b ]pyrazine-4(1 H )-carboxamide) (TAK-915) as a novel treatment of schizophrenia. Oral administration of TAK-915 at 3 and 10 mg/kg significantly increased cGMP levels in the frontal cortex, hippocampus, and striatum of rats. TAK-915 at 10 mg/kg significantly upregulated the phosphorylation of α -amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor subunit GluR1 in the rat hippocampus. TAK-915 at 3 and 10 mg/kg significantly attenuated episodic memory deficits induced by the NMDA receptor antagonist (+)-MK-801 hydrogen maleate (MK-801) in the rat passive avoidance test. TAK-915 at 10 mg/kg significantly attenuated working memory deficits induced by MK-801 in the rat radial arm maze test. Additionally, TAK-915 at 10 mg/kg prevented subchronic phencyclidine-induced social withdrawal in social interaction in rats. In contrast, TAK-915 did not produce antipsychotic-like activity; TAK-915 had little effect on MK-801- or methamphetamine-induced hyperlocomotion in rats. These results suggest that TAK-915 has a potential to ameliorate cognitive impairments and social withdrawal in schizophrenia. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Creatine affords protection against glutamate-induced nitrosative and oxidative stress.

Science.gov (United States)

Cunha, Mauricio P; Lieberknecht, Vicente; Ramos-Hryb, Ana Belén; Olescowicz, Gislaine; Ludka, Fabiana K; Tasca, Carla I; Gabilan, Nelson H; Rodrigues, Ana Lúcia S

2016-05-01

Creatine has been reported to exert beneficial effects in several neurodegenerative diseases in which glutamatergic excitotoxicity and oxidative stress play an etiological role. The purpose of this study was to investigate the protective effects of creatine, as compared to the N-Methyl-d-Aspartate (NMDA) receptor antagonist dizocilpine (MK-801), against glutamate or hydrogen peroxide (H2O2)-induced injury in human neuroblastoma SH-SY5Y cells. Exposure of cells to glutamate (60-80 mM) or H2O2 (200-300 μM) for 24 h decreased cellular viability and increased dichlorofluorescein (DCF) fluorescence (indicative of increased reactive oxygen species, ROS) and nitric oxide (NO) production (assessed by mono-nitrogen oxides, NOx, levels). Creatine (1-10 mM) or MK-801 (0.1-10 μM) reduced glutamate- and H2O2-induced toxicity. The protective effect of creatine against glutamate-induced toxicity involves its antioxidant effect, since creatine, similar to MK-801, prevented the increase on DCF fluorescence induced by glutamate or H2O2. Furthermore, creatine or MK-801 blocked glutamate- and H2O2-induced increases in NOx levels. In another set of experiments, the repeated, but not acute, administration of creatine (300 mg/kg, po) in mice prevented the decreases on cellular viability and mitochondrial membrane potential (assessed by tetramethylrhodamine ethyl ester, TMRE, probe) of hippocampal slices incubated with glutamate (10 mM). Creatine concentration-dependent decreased the amount of nitrite formed in the reaction of oxygen with NO produced from sodium nitroprusside solution, suggesting that its protective effect against glutamate or H2O2-induced toxicity might be due to its scavenger activity. Overall, the results suggest that creatine may be useful as adjuvant therapy for neurodegenerative disease treatments. Copyright © 2016 Elsevier Ltd. All rights reserved.

SU-F-I-67: Neurometabolic Effect Induced by Repeated Exposure to Dizocilpine On Prefrontal Cortex of Schizophrenic Animal Model Using In Vivo Proton Magnetic Resonance Spectroscopy at 9.4 T

International Nuclear Information System (INIS)

Yoo, C-H; Lim, S-I; Song, K-H; Choe, B-Y; Woo, D-C

2016-01-01

Purpose: Repeated exposure of dizocilpine (MK-801) can provide a pathophysiological model for progressive development of schizophrenia. In vivo proton magnetic resonance spectroscopy ("1H MRS) was widely used for non-invasive measurement of neurometabolites, and assessment of disease-induced neurometabolic alterations. The purpose of this study was to investigate neurometabolic alteration in prefrontal cortex (PFC) with respect to progression (from first-episode to chronic stage) of schizophrenia by using in vivo "1H MRS. Methods: We used high-field "1H MRS to investigate the neurometabolic alteration in the PFC region of the rats (N = 13) by comparing before and after 6 day of MK-801 (0.5 mg/kg) treatment. A point-resolved spectroscopy (PRESS) sequence was used to obtain spectra in a 22.5 µL of volume of interest carefully located in PFC region with parameters like follow; repetition time, 5000ms; echo time (TE), 13.4 ms; averages = 256. Another experiment group (N = 11) were conducted behavior test by recording the behavior for 20 min. Results: All the rats showed hyperlocomotion, stereotyped behaviors before initiation of MRS. Significantly increased level (N = 7, p < 0.05) of N-acetylasrparate (NAA), glutamate (Glu), taurine and decreased level (N = 6, p < 0.05) of NAA, Glu and phosphocreatine were observed between baseline and day 6. Both metabolic alterations are consistent with results of first-episode and chronic schizophrenia respectively. Conclusion: From our findings, the repeated MK-801 model could be a pathophysiological model which can provide an insight into the transition from first-episode to chronic stage. This is first time to investigate effects of repeated MK-801 using high-field in vivo 1H MRS. We expect our findings can contribute to combining previous diverging results into one pathophysiological interpretation, which can postulate the origin of diverging results to the progression of schizophrenia.

Opioid/NMDA receptors blockade reverses the depressant-like behavior of foot shock stress in the mouse forced swimming test.

Science.gov (United States)

Haj-Mirzaian, Arya; Ostadhadi, Sattar; Kordjazy, Nastaran; Dehpour, Ahmad Reza; Ejtemaei Mehr, Shahram

2014-07-15

Opioid and glutamatergic receptors have a key role in depression following stress. In this study, we assessed opioid and glutamatergic receptors interaction with the depressant-like behavior of acute foot-shock stress in the mouse forced swimming test. Stress was induced by intermittent foot shock stimulation during 30min and swim periods were afterwards conducted by placing mice in separated glass cylinders filled with water for 6min. The immobility time during the last 4min of the test was considered. Acute foot-shock stress significantly increased the immobility time of mice compared to non-stressed control group (P≤0.01). Administration of non-selective opioid receptors antagonist, naltrexone (1 and 2mg/kg, i.p.), and the selective non-competitive NMDA receptor antagonist, MK-801 (0.05mg/kg, i.p.), and the selective serotonin reuptake inhibitor, fluoxetine (5mg/kg), significantly reduced the immobility time in stressed animals (P≤0.01). Lower doses of MK-801 (0.01mg/kg), naltrexone (0.3mg/kg), NMDA (75mg/kg) and morphine(5mg/kg) had no effect on foot-shock stressed mice. Combined treatment of sub-effective doses of naltrexone and MK-801 significantly showed an antidepressant-like effect (P≤0.001). On the other hand, co-administration of non-effective doses of NMDA and morphine with effective doses of naltrexone and MK-801 reversed the anti-immobility effect of these drugs. Taken together, we have for the first time demonstrated the possible role of opioid/NMDA receptors signaling in the depressant-like effect of foot-shock stress, and proposed the use of drugs that act like standard anti-depressants in stress-induced depression. Copyright © 2014. Published by Elsevier B.V.

Altered neuronal excitability underlies impaired hippocampal function in an animal model of psychosis

Directory of Open Access Journals (Sweden)

Thomas eGrüter

2015-05-01

Full Text Available Psychosis is accompanied by severe attentional deficits, and impairments in associational-memory processing and sensory information processing that are ascribed to dysfunctions in prefrontal and hippocampal function. Disruptions of glutamatergic signalling may underlie these alterations: Antagonism of the N-methyl-D-aspartate receptor (NMDAR results in similar molecular, cellular, cognitive and behavioural changes in rodents and/or humans as those that occur in psychosis, raising the question as to whether changes in glutamatergic transmission may be intrinsic to the pathophysiology of the disease. In an animal model of psychosis that comprises treatment with the irreversible NMDAR-antagonist, MK801, we explored the cellular mechanisms that may underlie hippocampal dysfunction in psychosis. MK801-treatment resulted in a profound loss of hippocampal LTP that was evident 4 weeks after treatment. Whereas neuronal expression of the immediate early gene, Arc, was enhanced in the hippocampus by spatial learning in controls, MK801-treated animals failed to show activity-dependent increases in Arc expression. By contrast, a significant increase in basal Arc expression in the absence of learning was evident compared to controls. Paired-pulse facilitation was increased at the 40 ms interval indicating that NMDAR and/or fast GABAergic-mediated neurotransmission was disrupted. In line with this, MK801-treatment resulted in a significant decrease in GABA(A, and increase in GABA(B-receptor-expression in PFC, along with a significant increase of GABA(B- and NMDAR-GluN2B expression in the dentate gyrus. NMDAR-GluN1 or GluN2A subunit expression was unchanged. These data suggest that in psychosis, deficits in hippocampus-dependent memory may be caused by a loss of hippocampal LTP that arises through enhanced hippocampal neuronal excitability, altered GluN2B and GABA receptor expression and an uncoupling of the hippocampus-prefrontal cortex circuitry.

The prototypical ranitidine analog JWS-USC-75-IX improves information processing and cognitive function in animal models.

Science.gov (United States)

Terry, Alvin V; Buccafusco, Jerry J; Herman, Elizabeth J; Callahan, Patrick M; Beck, Wayne D; Warner, Samantha; Vandenhuerk, Leah; Bouchard, Kristy; Schwarz, Gary M; Gao, Jie; Chapman, James M

2011-03-01

This study was designed to evaluate further a prototypical ranitidine analog, JWS-USC-75-IX, [(3-[[[2-[[(5-dimethylaminomethyl)-2-furanyl]methyl]thio]ethyl]amino]-4-nitropyridazine, JWS], for neuropharmacologic properties that would theoretically be useful for treating cognitive and noncognitive behavioral symptoms of neuropsychiatric disorders. JWS was previously found to inhibit acetylcholinesterase (AChE) activity, serve as a potent ligand at muscarinic M₂ acetylcholine receptors, and elicit positive effects on spatial learning, passive avoidance, and working memory in rodents. In the current study, JWS was evaluated for binding activity at more than 60 neurotransmitter receptors, transporters, and ion channels, as well as for inhibitory activity at AChE and butyrylcholinesterase (BChE). The results indicate that JWS inhibits AChE and BChE at low (micromolar) concentrations and that it is a functional antagonist at M₂ receptors (K(B) = 320 nM). JWS was subsequently evaluated orally across additional behavioral assays in rodents (dose range, 0.03-10.0 mg/kg) as well as nonhuman primates (dose range, 0.05-2.0 mg/kg). In rats, JWS improved prepulse inhibition (PPI) of the acoustic startle response in nonimpaired rats and attenuated PPI deficits in three pharmacologic impairment models. JWS also attenuated scopolamine and (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801)-related impairments in a spontaneous novel object recognition task and a five-choice serial reaction time task, respectively. In monkeys, JWS elicited dose-dependent improvements of a delayed match-to-sample task as well as an attention-related version of the task where randomly presented (task-relevant) distractors were presented. Thus, JWS (potentially via effects at several drug targets) improves information processing, attention, and memory in animal models and could potentially treat the cognitive and behavioral symptoms of some neuropsychiatric illnesses.

Analysis of fluorescently labeled substance P analogs: binding, imaging and receptor activation

Directory of Open Access Journals (Sweden)

Simmons Mark A

2001-06-01

Full Text Available Abstract Background Substance P (SP is a peptide neurotransmitter found in central and peripheral nerves. SP is involved in the control of smooth muscle, inflammation and nociception. The amino acid sequence of SP is Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2. Five different forms of fluorescently labeled SP have recently been synthesized, in which Alexa 488, BODIPY Fl, fluorescein, Oregon Green 488 or tetramethylrhodamine has been covalently linked to SP at Lys3. Here, these novel analogs are characterized as to their ligand binding, receptor activation and fluorescence labeling properties. Results Competition binding studies, using radiolabeled [125I] SP, revealed that all of the labeled forms of SP, except for Alexa 488-SP, effectively competed with radiolabeled SP for binding at the rat SP receptor. With the exception of Alexa 488-SP, all of the SP analogs produced Ca++ elevations and fluorescence labeling of the SP receptor expressed in Chinese hamster ovary cells. In SP-responsive neurons, BODIPY Fl-SP and Oregon Green 488-SP were as effective as unlabeled SP in producing a reduction of the M-type K+ current. Fluorescein-SP produced variable results, while tetramethylrhodamine-SP was less potent and Alexa 488-SP was less effective on intact neurons. Conclusions The above results show that fluorescent labeling of SP altered the biological activity and the binding properties of the parent peptide. Oregon Green 488 and BODIPY FL-SP are the most useful fluorophores for labeling SP without affecting its biological activity. Given these results, these probes can now be utilized in further investigations of the mechanisms of SPR function, including receptor localization, internalization and recycling.

29 CFR 801.67 - Decision and Order of Administrative Law Judge.

Science.gov (United States)

2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Decision and Order of Administrative Law Judge. 801.67 Section 801.67 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR OTHER LAWS APPLICATION OF THE EMPLOYEE POLYGRAPH PROTECTION ACT OF 1988 Administrative Proceedings...

The processing and fate of antibodies and their radiolabels bound to the surface of tumor cells in vitro: A comparison of nine radiolabels

International Nuclear Information System (INIS)

Shih, L.B.; Thorpe, S.R.; Griffiths, G.L.; Diril, H.; Ong, G.L.; Hansen, H.J.; Goldenberg, D.M.; Mattes, M.J.

1994-01-01

Processing radiolabeled degradation products is the key factor affecting retention of antibodies within the cell. In this study, the authors have analyzed the processing of antibodies labeled in nine different ways. Antibodies were labeled with three different radioisotopes and seven different forms of 125 I. Eight of the radiolabels (except 188 Re) were conjugated to the same antibody, MA103, and tested on the renal carcinoma cell line SK-RC-18 and/or the ovarian carcinoma cell line SK-OV-6. Rhenium conjugation utilized the antibody RS7, the target cell line ME180 and three of the other radiolabels were also tested with this antibody-target cell combination for comparison. Iodine conjugated to antibodies by conventional methods was rapidly released from the cell after antibody catabolism. In contrast, iodinated moieties, such as dilactitol-tyramine and inulin-tyramine were retained within cells four to five times longer. The use of radiolabels that are trapped within cells after antibody catabolism can potentially increase the dose of radiation delivered to the tumor, from the same amount of radioactivity deposited by a factor of four or five. The prolonged retention of 111 In relative to 125 I is not due to deiodination of iodine conjugates, but rather to intracellular retention of catabolic products containing 111 In, perhaps within lysosomes. 45 refs., 4 figs., 1 tab

Novel strategies for microdose studies using non-radiolabeled compounds.

Science.gov (United States)

Maeda, Kazuya; Sugiyama, Yuichi

2011-06-19

Microdose studies using non-radiolabeled compounds enable assessment of the clinical pharmacokinetics of drug candidates in humans without the need to synthesize radiolabeled compounds. We have demonstrated that the quantification limits of many drugs measured by LC-MS/MS are low enough to allow estimation of their pharmacokinetic parameters following administration of a microdose. Our previous microdose studies with LC-MS/MS demonstrated the linear pharmacokinetics of fexofenadine between microdoses and therapeutic doses. We also obtained time profiles of plasma concentrations of nicardipine and its multiple metabolites following administration of a microdose. A significant advantage of using non-radiolabeled compounds is the ability to perform cassette microdose studies. By administering multiple drug candidates to the same subject, we can select compounds with appropriate pharmacokinetic properties simultaneously. We can also clarify major factors dominating the pharmacokinetics of drug candidates by cocktail microdosing of the test compounds and probe substrates with or without specific inhibitors for enzymes/transporters. Copyright © 2011 Elsevier B.V. All rights reserved.

Assessment of radioactive residues arising from radiolabel instability in a multiple dose tissue distribution study in rats

International Nuclear Information System (INIS)

Slatter, J.G.; Sams, J.P.; Easter, J.A.

2003-01-01

Our study objectives were to quantitatively determine the effect of radiolabel instability on terminal phase radioactive tissue residues in a multiple dose tissue distribution study, to quantitatively compare tissue residue artifacts (non drug-related radioactivity) from two chemically-distinct radiolabel locations, and to conduct a definitive multiple dose tissue distribution study using the better of the two radiolabeled compounds. We compared the excretion and tissue distribution in rats of [ 14 C]linezolid, radiolabeled in two different locations, after 7 consecutive once daily [ 14 C] oral doses. The radiolabels were in the acetamide (two carbon) and oxazolidinone (isolated carbon) functional groups. Terminal phase tissue residue and excretion data were compared to data from rats dosed orally with [ 14 C]sodium acetate. Drug-related radioactivity was excreted rapidly over 24 h. After a single dose, the acetamide and oxazolidinone radiolabel sites both gave 3% of dose as exhaled 14 CO 2 . After 7 daily [ 14 C] oral doses, terminal phase radioactive tissue residues were higher from the acetamide radiolabel, relative to the oxazolidinone radiolabel, and were primarily not drug-related. In the definitive tissue distribution study, low concentrations of drug-related radioactivity in skin and thyroid were observed. We conclude that although small amounts of radiolabel instability do not significantly affect single dose tissue radioactivity C max and area under the curve (AUC), artifacts arising from radiolabel instability can prolong the apparent terminal phase half life and complicate study data interpretation. When possible, it is always preferable to use a completely stable radiolabel site. (author)

Assessment of radioactive residues arising from radiolabel instability in a multiple dose tissue distribution study in rats

Energy Technology Data Exchange (ETDEWEB)

Slatter, J.G. [Pharmacia Corp., Peapack, NJ (United States); Sams, J.P.; Easter, J.A. [Pharmacia Corp., Kalamazoo, MI (United States)] [and others

2003-05-01

Our study objectives were to quantitatively determine the effect of radiolabel instability on terminal phase radioactive tissue residues in a multiple dose tissue distribution study, to quantitatively compare tissue residue artifacts (non drug-related radioactivity) from two chemically-distinct radiolabel locations, and to conduct a definitive multiple dose tissue distribution study using the better of the two radiolabeled compounds. We compared the excretion and tissue distribution in rats of [{sup 14}C]linezolid, radiolabeled in two different locations, after 7 consecutive once daily [{sup 14}C] oral doses. The radiolabels were in the acetamide (two carbon) and oxazolidinone (isolated carbon) functional groups. Terminal phase tissue residue and excretion data were compared to data from rats dosed orally with [{sup 14}C]sodium acetate. Drug-related radioactivity was excreted rapidly over 24 h. After a single dose, the acetamide and oxazolidinone radiolabel sites both gave 3% of dose as exhaled {sup 14}CO{sub 2}. After 7 daily [{sup 14}C] oral doses, terminal phase radioactive tissue residues were higher from the acetamide radiolabel, relative to the oxazolidinone radiolabel, and were primarily not drug-related. In the definitive tissue distribution study, low concentrations of drug-related radioactivity in skin and thyroid were observed. We conclude that although small amounts of radiolabel instability do not significantly affect single dose tissue radioactivity C{sub max} and area under the curve (AUC), artifacts arising from radiolabel instability can prolong the apparent terminal phase half life and complicate study data interpretation. When possible, it is always preferable to use a completely stable radiolabel site. (author)

Partition of radiolabeled amino acids in detached wheat heads in culture

International Nuclear Information System (INIS)

Inwood, W.; Bernardin, J.

1990-01-01

The concentration of a particular amino acid supplied to a detached wheat head affected the ultimate distribution of that amino acid among the tissues of the head. Detached wheat heads (Triticum aestivum L. cv Cheyenne) were supplied with a pulse of [ 3 H]leucine in the culture medium and were chased with medium that contained glutamine as the sole nitrogen source. When the amount of radiolabel was held constant, an increasing concentration of unlabeled leucine in the pulse medium led to an increased partition of the radiolabel into the grain tissues of the head. When the concentration of unlabeled leucine was increased from zero to radiolabeled leucine was partitioned to endosperm tissue and twice as much to seedcoat tissues. An effect of amino acid concentration on radiolabel partition was also found for methionine and proline, but the effect was not as dramatic. These results suggest the existence of an amino acid transport system between the transpiration stream of the wheat head and the grain that exhibits cooperative kinetics or amino acid activation

Pharmacokinetics and biodistribution of radiolabeled avidin, streptavidin and biotin

International Nuclear Information System (INIS)

Rosebrough, S.F.

1993-01-01

The extraordinarily high affinity of avidin and streptavidin for biotin may be exploited in a two-step approach for delivering radiolabeled biotin derivatives suitable for imaging and therapy to target-bound streptavidin or avidin conjugated monoclonal antibodies (MAbs). The in vivo pharmacokinetics and biodistribution of radiolabeled avidin, streptavidin (SA) and DTPA-biocytinamide (DTPA-biotin) were studied in the rabbit and dog. SA circulated in the blood similar to other 60 kDa proteins, avidin cleared immediately and DTPA-biotin exhibited plasma clearance by glomerular filtration. (author)

Advances in infectious foci imaging using 99mTc radiolabelled antibiotics

International Nuclear Information System (INIS)

Seyedeh Fatemeh Mirshojaei

2015-01-01

Conventional methods of infection diagnosis, relying on experimental tests and culture of organisms from infected foci have continued to developing new technologies and automation. Nuclear medicine is a reliable diagnostic technique capable to detect infectious foci in human disease. A wide range of radiolabeled agents have been evaluated for demonstrating their ability to distinguish microbial infectious lesions. New researches continue to be made on the use of radiolabeled antibiotics which as well as being highly specific in the diagnosis of infection would be useful in monitoring of disease treatment. Here, the new approaches of infection scintigraphic imaging by radiolabeled antibiotics are thoroughly discussed in order to assess and compare their diagnostic value as targeting imaging radiopharmaceuticals. (author)

Agmatine protects against cell damage induced by NMDA and glutamate in cultured hippocampal neurons

Science.gov (United States)

Wang, Wei-Ping; Iyo, Abiye H.; Miguel-Hidalgo, Javier; Regunathan, Soundar; Zhu, Meng-Yang

2010-01-01

Agmatine is a polyamine and has been considered as a novel neurotransmitter or neuromodulator in the central nervous system. In the present study, the neuroprotective effect of agmatine against cell damage caused by N-methyl-d-aspartate (NMDA) and glutamate was investigated in cultured rat hippocampal neurons. Lactate dehydrogenase (LDH) activity assay, β-tubulin III immunocytochemical staining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end-labeling (TUNEL) assay were conducted to detect cell damage. Exposure of 12-day neuronal cultures of rat hippocampus to NMDA or glutamate for 1 h caused a concentration-dependent neurotoxicity, as indicated by the significant increase in released LDH activities. Addition of 100 µM agmatine into media ablated the neurotoxicity induced by NMDA or glutamate, an effect also produced by the specific NMDA receptor antagonist dizocilpine hydrogen maleate (MK801). Arcaine, an analog of agmatine with similar structure as agmatine, fully prevented the NMDA- or glutamate-induced neuronal damage. Spermine and putrescine, the endogenous polyamine and metabolic products of agmatine without the guanidine moiety of agmatine, failed to show this effect, indicating a structural relevance for this neuroprotection. Immunocytochemical staining and TUNEL assay confirmed the findings in the LDH measurement. That is, agmatine and MK801 markedly attenuated NMDA-induced neuronal death and significantly reduced TUNEL-positive cell numbers induced by exposure of cultured hippocampal neurons to NMDA. Taken together, these results demonstrate that agmatine can protect cultured hippocampal neurons from NMDA- or glutamate-induced excitotoxicity, through a possible blockade of the NMDA receptor channels or a potential anti-apoptotic property. PMID:16546145

Role of the NMDA receptor and iron on free radical production and brain damage following transient middle cerebral artery occlusion.

Science.gov (United States)

Im, Doo Soon; Jeon, Jeong Wook; Lee, Jin Soo; Won, Seok Joon; Cho, Sung Ig; Lee, Yong Beom; Gwag, Byoung Joo

2012-05-21

Excess activation of ionotropic glutamate receptors and iron is believed to contribute to free radical production and neuronal death following hypoxic ischemia. We examined the possibility that both NMDA receptor activation and iron overload determine spatial and temporal patterns of free radical production after transient middle cerebral artery occlusion (tMCAO) in male Sprague-Dawley rats. Mitochondrial free radical (MFR) levels were maximally increased in neurons in the core at 1 h and 24 h after tMCAO. Early MFR production was blocked by administration of MK-801, an NMDA receptor antagonist, but not deferoxamine, an iron chelator. Neither MK-801 nor deferoxamine attenuated late MFR production in the core. Increased MFRs were observed in penumbral neurons within 6 h and gradually increased over 24 h after tMCAO. Slowly-evolving MFRs in the core and penumbra were accompanied by iron overload. Deferoxamine blocked iron overload but reduced MFR production only in the penumbra. Combined MK-801/deferoxamine reduced late MFR production in both core and penumbra in an additive manner. Combination therapy significantly ameliorated infarction compared with monotherapy. These findings suggest that the NMDA receptor activation and iron overload mediate late MFR production and infarction after tMCAO. Copyright © 2012 Elsevier B.V. All rights reserved.

Effects of acetylpuerarin on hippocampal neurons and intracellular free calcium subjected to oxygen-glucose deprivation/reperfusion in primary culture.

Science.gov (United States)

Liu, Rui; Wei, Xin-bing; Zhang, Xiu-Mei

2007-05-25

This study was undertaken to find out the effects of acetylpuerarin on hippocampal neurons and intracellular free calcium in primary culture subjected to oxygen-glucose deprivation/reperfusion. According to different reperfusion time (1 h, 6 h, 12 h, 24 h), three concentrations (1.6 micromol l(-1), 0.4 micromol l(-1), 0.1 micromol l(-1)) of acetylpuerarin, and MK-801 (10 micromol l(-1)), a positive control drug, neurons were randomly divided into 21 groups. Each group was observed by inverted phase contrast microscope; neuron viability was measured by the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT); intracellular Ca(2+) was observed by Fura-2/AM ester through fluorospectrophotometer. The injured neurons were protected and degeneration and necrosis were alleviated in treatment groups of acetylpuerarin and MK-801. Acetylpuerarin increased the neuron viability at high, middle and low concentrations. Fluorescence detection results showed that the calcium concentration in the group treated with acetylpuerarin and MK-801 was lowered in each reperfusion time. Our results demonstrated that acetylpuerarin could protect the hippocampal neurons from ischemia-reperfusion injury in rats by alleviating the morphological damage, increasing neuron viability and decreasing calcium concentration in neuron.

Synthesis of 14C-radiolabelled Tilmicosin

International Nuclear Information System (INIS)

Crouse, G.D.; Terando, N.H.

1989-01-01

Tilmicosin was radiolabelled with carbon-14 on the 3,5-dimethylpiperidinyl sidechain as a requirement for animal metabolism studies. A new radiosynthesis of 3,5-dimethyl-piperidine was developed for this purpose. Incorporation into the desmycosin nucleus was accomplished by a reductive amination reaction. (author)

Radiolabeling of biological vectors by poly-aza-macrocyclic complexes

International Nuclear Information System (INIS)

Moreau, M.

2012-01-01

This work conducted at the 'Institut de Chimie Moleculaire de l'Universite de Bourgogne' carries at first on the synthesis of bifunctional chelating agents suitable for the chelation of trivalent radio-metals, including indium-111. The greater part of this work was then dedicated to the grafting of a DOTA derivative bifunctional chelating agent on different antibodies or fragments of monoclonal antibodies: trastuzumab (anti-HER2 treatment of breast cancer), cetuximab (anti EGFR, treatment of many cancers, including colorectal cancer) and abciximab (antiplatelet). Particular attention was paid to the characterization of various immuno-conjugates. The critical step of this thesis consisted in the indium-111 radiolabeling of two previously prepared immuno-conjugates: trastuzumab and cetuximab. These steps of radiolabelling allowed us to determine the immunoreactive fraction and affinity of each radiotracer. Thus, we were able to study the in vivo biodistribution of the radiotracers in tumour-bearing mice by SPECT-CT. We also developed an original method for the labeling of a Fab antibody fragment in order to monitor the biodistribution of the antiplatelet agent (abciximab). Finally, we also validated the concept of multimodal imaging through grafting and radiolabeling of a bimodal agent for optical and SPECT imaging on bacterial lipopolysaccharide. Thanks to this work, we gained an expertise in antibodies radiolabeling. The results obtained allow to consider the labeling of antibodies or other biomolecules, and the use of other radionuclides for PET imaging and radioimmunotherapy. (author)

25 CFR 170.801 - What is the BIA Road Maintenance Program?

Science.gov (United States)

2010-04-01

... 25 Indians 1 2010-04-01 2010-04-01 false What is the BIA Road Maintenance Program? 170.801 Section... ROADS PROGRAM BIA Road Maintenance § 170.801 What is the BIA Road Maintenance Program? The BIA Road... subpart contains a list of activities that are eligible for funding under the BIA road maintenance program. ...

21 CFR 801.125 - Medical devices for use in teaching, law enforcement, research, and analysis.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Medical devices for use in teaching, law enforcement, research, and analysis. 801.125 Section 801.125 Food and Drugs FOOD AND DRUG ADMINISTRATION... Directions for Use § 801.125 Medical devices for use in teaching, law enforcement, research, and analysis. A...

Chemical radiolabeling of carboxyatractyloside by [14C]acetic anhydride

International Nuclear Information System (INIS)

Block, M.R.; Pougeois, R.; Vignais, P.V.

1980-01-01

The authors report the synthesis and biological properties of a radiolabeled derivative of CAT obtained with acetylation of the primary alcohol of CAT with radiolabeled acetic anhydride. They also investigate the question of mutual exclusion of CAT and BA for binding to the mitochondrial ADP/ATP carrier in double labeling experiments based on the use of [ 3 H]BA and [ 14 C]Ac-CAT. The results are consistent with the view that the ADP/ATP carrier possesses two separate interacting binding sites for AT (or CAT) and for BA. (Auth.)

14 CFR 1214.801 - Definitions.

Science.gov (United States)

2010-01-01

... flight price as defined in the Shuttle policy. (2) The two-shift operation dedicated flight price for Spacelab missions is the sum of: (i) The Shuttle dedicated flight price as defined in the Shuttle policy... Services § 1214.801 Definitions. (a) Shuttle policy. The appropriate subpart (1214.1 or 1214.2) governing...

68Ga-THP-PSMA: A PET Imaging Agent for Prostate Cancer Offering Rapid, Room-Temperature, 1-Step Kit-Based Radiolabeling.

Science.gov (United States)

Young, Jennifer D; Abbate, Vincenzo; Imberti, Cinzia; Meszaros, Levente K; Ma, Michelle T; Terry, Samantha Y A; Hider, Robert C; Mullen, Greg E; Blower, Philip J

2017-08-01

The clinical impact and accessibility of 68 Ga tracers for the prostate-specific membrane antigen (PSMA) and other targets would be greatly enhanced by the availability of a simple, 1-step kit-based labeling process. Radiopharmacy staff are accustomed to such procedures in the daily preparation of 99m Tc radiopharmaceuticals. Currently, chelating agents used in 68 Ga radiopharmaceuticals do not meet this ideal. The aim of this study was to develop and evaluate preclinically a 68 Ga radiotracer for imaging PSMA expression that could be radiolabeled simply by addition of 68 Ga generator eluate to a cold kit. Methods: A conjugate of a tris(hydroxypyridinone) (THP) chelator with the established urea-based PSMA inhibitor was synthesized and radiolabeled with 68 Ga by adding generator eluate directly to a vial containing the cold precursors THP-PSMA and sodium bicarbonate, with no further manipulation. It was analyzed after 5 min by instant thin-layer chromatography and high-performance liquid chromatography. The product was subjected to in vitro studies to determine PSMA affinity using PSMA-expressing DU145-PSMA cells, with their nonexpressing analog DU145 as a control. In vivo PET imaging and ex vivo biodistribution studies were performed in mice bearing xenografts of the same cell lines, comparing 68 Ga-THP-PSMA with 68 Ga-HBED-CC-PSMA. Results: Radiolabeling was complete (>95%) within 5 min at room temperature, showing a single radioactive species by high-performance liquid chromatography that was stable in human serum for more than 6 h and showed specific binding to PSMA-expressing cells (concentration giving 50% inhibition of 361 ± 60 nM). In vivo PET imaging showed specific uptake in PSMA-expressing tumors, reaching 5.6 ± 1.2 percentage injected dose per cubic centimeter at 40-60 min and rapid clearance from blood to kidney and bladder. The tumor uptake, biodistribution, and pharmacokinetics were not significantly different from those of 68 Ga

An Efficient and Straightforward Method for Radiolabeling of Nanoparticles with {sup 64}Cu via Click Chemistry

Energy Technology Data Exchange (ETDEWEB)

Lee, Dong-Eun [Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of); Kim, Kwangmeyung [Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791 (Korea, Republic of); Park, Sang Hyun [Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of); Department of Radiobiotechnology and Applied Radioisotope Science, Korea University of Science and Technology, Deajeon 305-350 (Korea, Republic of)

2015-07-01

Recently, nanoparticles have received a great deal of interest in diagnosis and therapy applications. Since nanoparticles possess intrinsic features that are often required for a drug delivery system and diagnosis, they have potential to be used as platforms for integrating imaging and therapeutic functions, simultaneously. Intrinsic issues that are associated with theranostic nanoparticles, particularly in cancer treatment, include an efficient and straightforward radiolabeling method for understanding the in vivo biodistribution of nanoparticles to reach the tumor region, and monitoring therapeutic responses. Herein, we investigated a facile and highly efficient strategy to prepare radiolabeled nanoparticles with {sup 64}Cu via a strain-promoted azide, i.e., an alkyne cycloaddition strategy, which is often referred to as click chemistry. First, the azide (N3) group, which allows for the preparation of radiolabeled nanoparticles by copper-free click chemistry, was incorporated into glycol chitosan nanoparticles (CNPs). Second, the strained cyclooctyne derivative, dibenzyl cyclooctyne (DBCO) conjugated with a 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid (DOTA) chelator, was synthesized for preparing the pre-radiolabeled alkyne complex with {sup 64}Cu radionuclide. Following incubation with the {sup 64}Cu-radiolabeled DBCO complex (DBCO-PEG4-Lys-DOTA-{sup 64}Cu with high specific activity, 18.5 GBq/μ mol), the azide-functionalized CNPs were radiolabeled successfully with {sup 64}Cu, with a high radiolabeling efficiency and a high radiolabeling yield (>98%). Importantly, the radiolabeling of CNPs by copper-free click chemistry was accomplished within 30 min, with great efficiency in aqueous conditions. After {sup 64}Cu-CNPs were intravenously administered to tumor-bearing mice, the real time, in vivo biodistribution and tumor-targeting ability of {sup 64}Cu-CNPs were quantitatively evaluated by micro-PET images of tumor-bearing mice. These results

Development of biomarker specific of pancreatic beta cells (incretin radiolabelled) for image of beta functional mass in diabetic and obese: study in animal model

International Nuclear Information System (INIS)

Seo, Daniele

2017-01-01

Increased prevalence of obesity worldwide, has become a vast concern, stimulating investigations focusing prevention and therapy of this condition. The association of type 2 diabetes or insulin resistance aggravates the prognosis of obesity. Even patients successfully submitted to bariatric or metabolic surgery, may not be cured of diabetes, as improvement of circulating values of glucose and insulin not necessarily reflects recovery of pancreatic beta cell mass. There is no consensus about how to estimate beta cell mass in vivo. Available tools suffer from low sensitivity and specificity, often being as well cumbersome and expensive. Radiolabeled incretins, such as glucagon-like-peptide 1 (GLP-1) analogs, seem to be promising options for the measurement of beta cell mass in diabetes and insulinoma. The objective of this study was the development of two conjugates of GLP-1 analog, radiolabeled with 99m Technetium, as a noninvasive imaging method for the estimation of pancreatic beta cell mass, in the presence of obesity. Animal models were selected, including hyperlipidic diet-induced obesity, diet restricted obesity, and as controls, alloxan diabetes. Results indicated that both radiotracers achieved over 97% radiochemical yield. The most successful product was 99m Tc-HYNIC-βAla-Exendin-4. Low beta cell mass uptake occurred in diet-induced obesity. Diet-restricted obesity, with substantial shedding of excess body weight, was followed by remarkable decrease of fasting blood glucose, however beta cell mass uptake was only mildly improved. Future studies are recommended in obesity, type 2 diabetes, and dieting, including bariatric and metabolic operations. (author)

Radiolabeled monoclonal antibodies for imaging and therapy: Potential, problems, and prospects: Scientific highlights

International Nuclear Information System (INIS)

Srivastava, S.C.; Buraggi, G.L.

1986-01-01

This meeting focused on areas of research on radiolabeled monoclonal antibodies. Topics covered included the production, purification, and fragmentation of monoclonal antibodies and immunochemistry of hybridomas; the production and the chemistry of radionuclides; the radiohalogenation and radiometal labeling techniques; the in-vivo pharmacokinetics of radiolabeled antibodies; the considerations of immunoreactivity of radiolabeled preparations; the instrumentation and imaging techniques as applied to radioimmunodetection; the radiation dosimetry in diagnostic and therapeutic use of labeled antibodies; the radioimmunoscintigraphy and radioimmunotherapy studies; and perspectives and directions for future research. Tutorial as well as scientific lectures describing the latest research data on the above topics were presented. Three workshop panels were convened on ''Methods for Determining Immunoreactivity of Radiolabeled Monoclonal Antibodies - Problems and Pitfalls,'' Radiobiological and Dosimetric Considerations for Immunotherapy with Labeled Antibodies,'' and ''The Human Anti-Mouse Antibody Response in Patients.''

Long-circulating liposomes radiolabeled with [18F]fluorodipalmitin ([18F]FDP)

International Nuclear Information System (INIS)

Marik, Jan; Tartis, Michaelann S.; Zhang, Hua; Fung, Jennifer Y.; Kheirolomoom, Azadeh; Sutcliffe, Julie L.; Ferrara, Katherine W.

2007-01-01

Synthesis of a radiolabeled diglyceride, 3-[ 18 F]fluoro-1,2-dipalmitoylglycerol [[ 18 F]fluorodipalmitin ([ 18 F]FDP)], and its potential as a reagent for radiolabeling long-circulating liposomes were investigated. The incorporation of 18 F into the lipid molecule was accomplished by nucleophilic substitution of the p-toluenesulfonyl moiety with a decay-corrected yield of 43±10% (n=12). Radiolabeled, long-circulating polyethylene-glycol-coated liposomes were prepared using a mixture of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, cholesterol, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy(polyethyleneglycol)-2000] ammonium salt (61:30:9) and [ 18 F]FDP with a decay-corrected yield of 70±8% (n=4). PET imaging and biodistribution studies were performed with free [ 18 F]FDP and liposome-incorporated [ 18 F]FDP. Freely injected [ 18 F]FDP had the highest uptake in the liver, spleen and lungs. Liposomal [ 18 F]FDP remained in blood circulation at near-constant levels for at least 90 min, with a peak concentration near 2.5%ID/cc. Since [ 18 F]FDP was incorporated into the phospholipid bilayer, it could potentially be used for radiolabeling a variety of lipid-based drug carriers

Lymphoma: current status of clinical and preclinical imaging with radiolabeled antibodies

Energy Technology Data Exchange (ETDEWEB)

England, Christopher G. [University of Wisconsin School of Medicine and Public Health, Department of Medical Physics, Madison, WI (United States); Rui, Lixin [University of Wisconsin School of Medicine and Public Health, Department of Medicine, Madison, WI (United States); University of Wisconsin School of Medicine and Public Health, Carbone Cancer Center, Madison, WI (United States); Cai, Weibo [University of Wisconsin School of Medicine and Public Health, Department of Medical Physics, Madison, WI (United States); University of Wisconsin School of Medicine and Public Health, Carbone Cancer Center, Madison, WI (United States); University of Wisconsin School of Medicine and Public Health, Department of Radiology, Madison, WI (United States)

2017-03-15

Lymphoma is a complex disease that arises from cells of the immune system with an intricate pathology. While lymphoma may be classified as Hodgkin or non-Hodgkin, each type of tumor is genetically and phenotypically different and highly invasive tissue biopsies are the only method to investigate these differences. Noninvasive imaging strategies, such as immunoPET, can provide a vital insight into disease staging, monitoring treatment response in patients, and dose planning in radioimmunotherapy. ImmunoPET imaging with radiolabeled antibody-based tracers may also assist physicians in optimizing treatment strategies and enhancing patient stratification. Currently, there are two common biomarkers for molecular imaging of lymphoma, CD20 and CD30, both of which have been considered for investigation in preclinical imaging studies. In this review, we examine the current status of both preclinical and clinical imaging of lymphoma using radiolabeled antibodies. Additionally, we briefly investigate the role of radiolabeled antibodies in lymphoma therapy. As radiolabeled antibodies play critical roles in both imaging and therapy of lymphoma, the development of novel antibodies and the discovery of new biomarkers may greatly affect lymphoma imaging and therapy in the future. (orig.)

Lymphoma: current status of clinical and preclinical imaging with radiolabeled antibodies

International Nuclear Information System (INIS)

England, Christopher G.; Rui, Lixin; Cai, Weibo

2017-01-01

Lymphoma is a complex disease that arises from cells of the immune system with an intricate pathology. While lymphoma may be classified as Hodgkin or non-Hodgkin, each type of tumor is genetically and phenotypically different and highly invasive tissue biopsies are the only method to investigate these differences. Noninvasive imaging strategies, such as immunoPET, can provide a vital insight into disease staging, monitoring treatment response in patients, and dose planning in radioimmunotherapy. ImmunoPET imaging with radiolabeled antibody-based tracers may also assist physicians in optimizing treatment strategies and enhancing patient stratification. Currently, there are two common biomarkers for molecular imaging of lymphoma, CD20 and CD30, both of which have been considered for investigation in preclinical imaging studies. In this review, we examine the current status of both preclinical and clinical imaging of lymphoma using radiolabeled antibodies. Additionally, we briefly investigate the role of radiolabeled antibodies in lymphoma therapy. As radiolabeled antibodies play critical roles in both imaging and therapy of lymphoma, the development of novel antibodies and the discovery of new biomarkers may greatly affect lymphoma imaging and therapy in the future. (orig.)

40 CFR 1042.801 - General provisions.

Science.gov (United States)

2010-07-01

... government (or one of its political subdivisions) for the purpose of reducing emissions. The exemption does not apply where the sponsoring government specifies that inclusion in the retrofit program is not... 1042.801 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR POLLUTION CONTROLS...

Viscosity of saturated helium-3-helium-4 mixture below 200 mK

NARCIS (Netherlands)

Zeegers, J.C.H.; Waele, de A.T.A.M.; Gijsman, H.M.

1991-01-01

The shear viscosity of saturated3He-4He mixture has been measured at temperatures between 7 mK and 200 mK using a vibrating-wire viscometer and a calibrated pressure cell. The reliability of the vibrating-wire technique was tested by measuring the viscosity of pure4He. The results are internally

Irradiation performance of experimental fast reactor 'JOYO' MK-1 driver fuel assemblies

International Nuclear Information System (INIS)

Itaki, Toshiyuki; Kono, Keiichi; Tachi, Hirokatsu; Yamanouchi, Sadamu; Yuhara, Shunichi; Shibahara, Itaru

1985-01-01

The experimental fast reactor ''JOYO'' completed it's breeder core (MK-I) operation in January 1982. The MK-I driver fuel assemblies were removed from the core sequencially in order of burnup increase and have been under postirradiation examination (PIE). The PIE has almost been completed for 30 assemblies including the highest burnup assemblies of 48,000 MWD/MTM. It has been confirmed that all fuel assemblies have exhibited satisfactory performance without detrimental assembly deformation or without any indications of fuel pin breach. The irradiation conditions of the MK-I core were somewhat more moderate than those conditions envisioned for prototypic reactor. However the results of the examination revealed the typical irradiation behavior of LMFBR fuels, although such characteristics were benign as compared with those anticipated in high burnup fuels. Systematic performance data have been accumulated through the fuel fabrication, irradiation and postirradiation examination processes. Based on these data, the MK-I fuel designing and fabrication techniques were totally confirmed. This technical experience and the associated insight into irradiation behavior have established a milestone to the next step of fast reactor fuel development. (author)

29 CFR 801.72 - Responsibility of the Office of Administrative Law Judges.

Science.gov (United States)

2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Responsibility of the Office of Administrative Law Judges. 801.72 Section 801.72 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR OTHER LAWS APPLICATION OF THE EMPLOYEE POLYGRAPH PROTECTION ACT OF 1988 Administrative...

Mr Nissim Dahan, MK, Minister of Health, Israel, at the ATLAS exhibition

CERN Multimedia

Laurent Guiraud

2001-01-01

Photo 01: L. to r.:Dr Jim Allaby, Dr Peter Jenni, Prof. Bracha Regev, Chief Scientist, Ministry of Health, Mr Nissim Dahan, MK, Minister of Health, Dr Boaz Lev, Director General, Ministry of Health, Dr Hans F. Hoffmann and Dr Georges Mikenberg. Photo 02: Mr Nissim Dahan, MK, Minister of Health, Israel, signing the Guest Book.

Electrochemical separation of 90-yttrium in the electrochemical 90Sr/90Y generator and its use for radiolabelling of DOTA-conjugated somatostatin analog [DOTA0, Tyr3] octreotate

Directory of Open Access Journals (Sweden)

Petrović Đorđe Ž.

2012-01-01

Full Text Available Radiopharmaceuticals based on 90Y are widely used in the treatment of malignant deseases. In order to meet the requirements for their future application, a 90Sr/90Y generator was developed and 90Y eluted from this locally produced generator was used for the radiolabelling of the DOTA-conjugated somatostatin analog [DOTA0,Tyr3] octreotate and the preparation of [90Y-DOTA0,Tyr3] octreotate (90Y-DOTATATE for peptide receptore radionuclide therapy. 90Sr/90Y generator was based on the electrochemical separation of 90Y from 90Sr in a two-cycle electrolysis procedure. Three electrode cells were used to perform both electrolyses. In both cycles, working electrodes were kept on constant potential. The pH of the solution was adjusted to 2.7 of the value before the electrolyses. The radionuclidic purity of the 90Y solution was analysed by ITLC and extraction paper chromatography. The labelling of peptide (100 mg DOTATATE with 90YCl3 was performed at 95°C for 30 minutes. Radiochemical purity was determined by HPLC and chromatographic separation, using a solid SepPak C-18 column. Results obtained confirmed the efficiency of our electrochemical separation technique and quality control methods for 90Y. The achieved efficiency of the 90Sr/90Y generator above 96% of the theoretical value represents a good basis for the further development of this generator. The labelling of the DOTATATE with 90Y exhibited a high efficiency, too: there was less than 1% of 90Y3+in the 90Y-DOTATATE.

Radiolabelling of autologous leucocytes: technique and clinical application

International Nuclear Information System (INIS)

Strobl-Jaeger, E.; Kolbe, H.; Ludwig, H.; Sinzinger, H.

1988-01-01

Gamma-camera imaging after injection of radiolabelled autologous leucocytes can be very helpful in the diagnosis, localization and further clinical treatment of inflammatory diseases. We present a technique allowing sterile separation of white blood cells and labelling with 99m Tc-phytate or -oxine and with 111 In-oxine, -oxine sulphate or -tropolone. The method is non-invasive and the radiation dose amounts to less than 80 mrad using 100 μCi 111 Indium. The use of radiolabelled granulocytes is of particular diagnostic value in patients with septicaemia of unknown origin. Whole body scanning allows not only visualization of enhanced splenic uptake in septicaemia, but also localization of an inflammatory process. Preferential indications for a diagnostic approach using radiolabelled granulocytes are inflammatory abdominal processes which cannot easily be documented by means of other non-invasive techniques, such as inflammatory bowel disease (Crohn's diseases and ulcerative colitis), arthritic processes and abscesses of the liver and spleen, as well as subphrenic and retroperitoneal abscesses. Untreated osteomyelitis can be located with the help of labelled granulocytes, but in patients treated with antibiotics a false negative result is obtained in approximately 50 % of cases for as yet unknown reasons, even in the presence of a still active osteomyelitic process. (Authors)

MK-2206, an AKT Inhibitor, Promotes Caspase-Independent Cell Death and Inhibits Leiomyoma Growth

Science.gov (United States)

Sefton, Elizabeth C.; Qiang, Wenan; Serna, Vanida; Kurita, Takeshi; Wei, Jian-Jun; Chakravarti, Debabrata

2013-01-01

Uterine leiomyomas (ULs), benign tumors of the myometrium, are the number one indication for hysterectomies in the United States due to a lack of an effective alternative therapy. ULs show activation of the pro-survival AKT pathway compared with normal myometrium; however, substantial data directly linking AKT to UL cell survival are lacking. We hypothesized that AKT promotes UL cell survival and that it is a viable target for inhibiting UL growth. We used the investigational AKT inhibitor MK-2206, currently in phase II trials, on cultured primary human UL and myometrial cells, immortalized leiomyoma cells, and in leiomyoma grafts grown under the kidney capsule in mice. MK-2206 inhibited AKT and PRAS40 phosphorylation but did not regulate serum- and glucocorticoid-induced kinase and ERK1/2, demonstrating its specificity for AKT. MK-2206 reduced UL cell viability and decreased UL tumor volumes. UL cells exhibited disruption of mitochondrial structures and underwent cell death that was independent of caspases. Additionally, mammalian target of rapamycin and p70S6K phosphorylation were reduced, indicating that mammalian target of rapamycin complex 1 signaling was compromised by AKT inhibition in UL cells. MK-2206 also induced autophagy in UL cells. Pretreatment of primary UL cells with 3-methyladenine enhanced MK-2206-mediated UL cell death, whereas knockdown of ATG5 and/or ATG7 did not significantly influence UL cell viability in the presence of MK-2206. Our data provide molecular evidence for the involvement of AKT in UL cell survival and suggest that AKT inhibition by MK-2206 may be a viable option to consider for the treatment of ULs. PMID:24002033

18 CFR 801.9 - Watershed management.

Science.gov (United States)

2010-04-01

... 18 Conservation of Power and Water Resources 2 2010-04-01 2010-04-01 false Watershed management... GENERAL POLICIES § 801.9 Watershed management. (a) The character, extent, and quality of water resources... management including soil and water conservation measures, land restoration and rehabilitation, erosion...

Radiolabelled blood elements techniques and clinical applications

International Nuclear Information System (INIS)

Thakur, M.L.

1992-01-01

Over the past few years, in nuclear medicine, the diagnostic applications of radiolabelled blood elements in general, and of radiolabelled white blood cells in particular, have become increasingly popular. This is primarily due to the introduction of lipid soluble 111 In-oxine as an agent, which not only is an excellent and a reliable tracer for blood cells but also enables the investigators to study the in vivo cell kinetics and map the localization of labelled cells by external gamma scintigraphy. The tracer has the modest half life of 67 hours and decays with the emission of two gamma photons (173 and 247 keV) in high abundance. This technique has provided a powerful tool to study the in vivo cell kinetics in health and localize abnormal lesions in diseases which invoke intense focal cellular concentration

Radiolabelled blood elements techniques and clinical applications

Energy Technology Data Exchange (ETDEWEB)

Thakur, M L

1993-12-31

Over the past few years, in nuclear medicine, the diagnostic applications of radiolabelled blood elements in general, and of radiolabelled white blood cells in particular, have become increasingly popular. This is primarily due to the introduction of lipid soluble {sup 111}In-oxine as an agent, which not only is an excellent and a reliable tracer for blood cells but also enables the investigators to study the in vivo cell kinetics and map the localization of labelled cells by external gamma scintigraphy. The tracer has the modest half life of 67 hours and decays with the emission of two gamma photons (173 and 247 keV) in high abundance. This technique has provided a powerful tool to study the in vivo cell kinetics in health and localize abnormal lesions in diseases which invoke intense focal cellular concentration 5 figs, 2 tabs

Pharmacodynamics of Imipenem in Combination with beta-Lactamase Inhibitor MK7655 in a Murine Thigh Model

NARCIS (Netherlands)

Mavridou, E.; Melchers, M.J.B.; Mil, A.C. van; Mangin, E.; Motyl, M.R.; Mouton, J.W.

2015-01-01

MK7655 is a newly developed beta-lactamase inhibitor of class A and class C carbapenemases. Pharmacokinetics (PK) of imipenem-cilastatin (IMP/C) and MK7655 were determined for intraperitoneal doses of 4 mg/kg to 128 mg/kg of body weight. MIC and pharmacodynamics (PD) studies of MK7655 were performed

High-dose dextromethorphan produces myelinoid bodies in the hippocampus of rats

Directory of Open Access Journals (Sweden)

Hai-Quyen Tran

2016-10-01

Full Text Available Dextromethorphan (DM administered at supra-antitussive doses produce psychotoxic and neurotoxic effects in humans. We administered DM (80 mg/kg to rats intraperitoneally to determine the ultrastructural change induced by DM, because intraperitoneal route is sensitive for the behavioral responses. Treatment with DM resulted in mitochondrial dysfunction and formation of myelinoid bodies in the hippocampus. MK-801 [(+-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] attenuated DM-induced cytosolic oxidative burdens. However, neither MK-801 nor naloxone affected DM-induced mitochondrial dysfunction and formation of myelinoid bodies, indicating that the neurotoxic mechanism needs to be further elucidated. Therefore, the spectrum of toxicological effects associated with DM need to be reassessed.

21 CFR 801.1 - Medical devices; name and place of business of manufacturer, packer or distributor.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Medical devices; name and place of business of manufacturer, packer or distributor. 801.1 Section 801.1 Food and Drugs FOOD AND DRUG ADMINISTRATION... § 801.1 Medical devices; name and place of business of manufacturer, packer or distributor. (a) The...

The effects of the CXCR2 antagonist, MK-7123, on bone marrow functions in healthy subjects

DEFF Research Database (Denmark)

Hastrup, Nina; Khalilieh, Sauzanne; Dale, David C.

2015-01-01

; or bone marrow fat to cell balance as assessed by MRI. MK-7123 was generally well tolerated with neutropenia being the most common adverse event; however, there were no clinical symptoms associated with decreased ANCs. These findings indicate that the CXCR2 antagonist MK-7123 causes rapidly reversible...... of either MK-7123 (30 mg, po, daily for 28 days) or placebo on peripheral blood counts and bone marrow myeloid cell populations. MK-7123 caused a reversible decrease (approximately 50%) in the ANC as demonstrated on days 1 and 28, the first and last days of the treatment period. Bone marrow aspirate smears...

Qualification campaign of the 50 mK hybrid sorption-ADR cooler for SPICA/SAFARI

Science.gov (United States)

Duval, J.-M.; Duband, L.; Attard, A.

2015-12-01

SAFARI (SpicA FAR-infrared Instrument) is an infrared instrument planned to be part of the SPICA (SPace Infrared telescope for Cosmology and Astrophysics) Satellite. It will offer high spectral resolution in the 30 - 210 μm frequency range. SAFARI will benefit from the cold telescope of SPICA and to obtain the required detectors sensitivity, a temperature of 50 mK is required. This temperature is reached thanks to the use of a hybrid sorption - ADR (Adiabatic Demagnetization Refrigerator) cooler presented here. This cooler provides respectively 14 μW and 0.4 μW of cooling power at 300 mK and 50 mK. The cooler is planned to advantageously use two thermal interfaces of the instrument at 1.8 and 4.9 K. One of the challenges discussed in this paper is the low power available at each intercept. A dedicated laboratory electronic is being designed based on previous development with a particular focus on the 50 mK readout. Temperature regulation at 50 mK is also discussed. This cooler has been designed following flight constraints and will reach a high TRL, including mechanical and environmental tests at the end of the on-going qualification campaign.

Activity of MK-7655 combined with imipenem against Enterobacteriaceae and Pseudomonas aeruginosa.

Science.gov (United States)

Livermore, David M; Warner, Marina; Mushtaq, Shazad

2013-10-01

MK-7655 is a novel inhibitor of class A and C β-lactamases. We investigated its potential to protect imipenem. Chequerboard MICs were determined by CLSI agar dilution: (i) for Enterobacteriaceae with carbapenemases; (ii) for Enterobacteriaceae with carbapenem resistance contingent on combinations of impermeability together with an extended-spectrum β-lactamase or AmpC enzyme; and (iii) for Pseudomonas aeruginosa and other non-fermenters. At a concentration of 4 mg/L, MK-7655 reduced imipenem MICs for Enterobacteriaceae with KPC carbapenemases from 16-64 mg/L to 0.12-1 mg/L. Synergy also was seen for Enterobacteriaceae with impermeability-mediated carbapenem resistance, with weaker synergy seen for isolates with the OXA-48 enzyme. On the other hand, MK-7655 failed to potentiate imipenem against Enterobacteriaceae with metallo-carbapenemases. In the case of P. aeruginosa, where endogenous AmpC confers slight protection versus imipenem, 4 mg/L MK-7655 reduced the MIC of imipenem for all isolates, except those with metallo-carbapenemases: the MICs of imipenem fell from 1-2 mg/L to 0.25-0.5 mg/L for imipenem-susceptible P. aeruginosa and from 16-64 mg/L to 1-4 mg/L for OprD-deficient strains. No potentiation was seen for chryseobacteria or for Stenotrophomonas maltophilia. MK-7655 potentiated imipenem against Enterobacteriaceae with KPC carbapenemases or combinations of β-lactamase and impermeability, but not those with metallo-carbapenemases. It augmented the activity of imipenem against P. aeruginosa in general and OprD mutants in particular.

Fluoxetine reverses the behavioral despair induced by neurogenic stress in mice: role of N-methyl-d-aspartate and opioid receptors.

Science.gov (United States)

Haj-Mirzaian, Arya; Kordjazy, Nastaran; Ostadhadi, Sattar; Amiri, Shayan; Haj-Mirzaian, Arvin; Dehpour, AhmadReza

2016-06-01

Opioid and N-methyl-d-aspartate (NMDA) receptors mediate different effects of fluoxetine. We investigated whether opioid and NMDA receptors are involved in the protective effect of fluoxetine against the behavioral despair induced by acute physical stress in male mice. We used the forced swimming test (FST), tail suspension test (TST), and open-field test (OFT) for behavioral evaluation. We used fluoxetine, naltrexone (opioid receptor antagonist), MK-801 (NMDA receptor antagonist), morphine (opioid receptor agonist), and NMDA (NMDA receptor agonist). Acute foot-shock stress (FSS) significantly induced behavioral despair (depressive-like) and anxiety-like behaviors in tests. Fluoxetine (5 mg/kg) reversed the depressant-like effect of FSS, but it did not alter the locomotion and anxiety-like behavior in animals. Acute administration of subeffective doses of naltrexone (0.3 mg/kg) or MK-801 (0.01 mg/kg) potentiated the antidepressant-like effect of fluoxetine, while subeffective doses of morphine (1 mg/kg) and NMDA (75 mg/kg) abolished this effect of fluoxetine. Also, co-administration of subeffective doses of naltrexone (0.05 mg/kg) and MK-801 (0.003 mg/kg) with fluoxetine (1 mg/kg) induced a significant decrease in the immobility time in FST and TST. Our results showed that opioid and NMDA receptors (alone or in combination) are involved in the antidepressant-like effect of fluoxetine against physical stress.

The effects of inferior olive lesion on strychnine seizure

International Nuclear Information System (INIS)

Anderson, M.C.; Chung, E.Y.; Van Woert, M.H.

1990-01-01

Bilateral inferior olive lesions, produced by systemic administration of the neurotoxin 3-acetylpyridine (3AP) produce a proconvulsant state specific for strychnine-induced seizures and myoclonus. We have proposed that these phenomena are mediated through increased excitation of cerebellar Purkinje cells, through activation of glutamate receptors, in response to climbing fiber deafferentation. An increase in quisqualic acid (QA)-displaceable [ 3 H]AMPA [(RS)-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid] binding in cerebella from inferior olive-lesioned rats was observed, but no difference in [ 3 H]AMPA binding displaced by glutamate, kainic acid (KA) or glutamate diethylester (GDEE) was seen. The excitatory amino acid antagonists GDEE and MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10 imine] were tested as anticonvulsants for strychnine-induced seizures in 3AP inferior olive-lesioned and control rats. Neither drug effected seizures in control rats, however, both GDEE and MK-801 produced a leftward shift in the strychnine-seizure dose-response curve in 3AP inferior olive-lesioned rats. GDEE also inhibited strychnine-induced myoclonus in the lesioned group, while MK-801 had no effect on myoclonus. The decreased threshold for strychnine-induced seizures and myoclonus in the 3AP-inferior olive-lesioned rats may be due to an increase in glutamate receptors as suggested by the [ 3 H]AMPA binding data

Sexually dimorphic development and binding characteristics of NMDA receptors in the brain of the platyfish

Science.gov (United States)

Flynn, K. M.; Schreibman, M. P.; Yablonsky-Alter, E.; Banerjee, S. P.

1999-01-01

This study investigated age- and gender-specific variations in properties of the glutamate N-methyl-d-aspartate receptor (NMDAR) in a freshwater teleost, the platyfish (Xiphophorus maculatus). Prior localization of the immunoreactive (ir)-R1 subunit of the NMDAR protein (R1) in cells of the nucleus olfactoretinalis (NOR), a primary gonadotropin-releasing hormone (GnRH)-containing brain nucleus in the platyfish, suggests that NMDAR, as in mammals, is involved in modulation of the platyfish brain-pituitary-gonad (BPG) axis. The current study shows that the number of cells in the NOR displaying ir-R1 is significantly increased in pubescent and mature female platyfish when compared to immature and senescent animals. In males, there is no significant change in ir-R1 expression in the NOR at any time in their lifespan. The affinity of the noncompetitive antagonist ((3)H)MK-801 for the NMDAR is significantly increased in pubescent females while maximum binding of ((3)H)MK-801 to the receptor reaches a significant maximum in mature females. In males, both MK-801 affinity and maximum binding remain unchanged throughout development. This is the first report of gender differences in the association of NMDA receptors with neuroendocrine brain areas during development. It is also the first report to suggest NMDA receptor involvement in the development of the BPG axis in a nonmammalian vertebrate. Copyright 1999 Academic Press.

Radiolabeling Of Albumin Particles With Yttrium-90

International Nuclear Information System (INIS)

Nguyen Thi Thu; Nguyen Thi Khanh Giang; Bui Van Cuong, Vo Thi Cam Hoa

2011-01-01

This paper presents the process of the radiolabeling of microaggregated albumin particles with radionuclide Yttrium-90 using the directed method. The albumin microsphere kit was prepared in sodium phosphate buffer. The original solution includes 2 mg albumin particle and 0.5 mg stannous chloride dihydrate. The albumin particles size was ranged from 5 ?m to 30 ?m. The mixture was washed three times with phosphate buffer saline, pH 7.2 by centrifugation and suspended in 0.5 M sodium acetate buffer, pH 6. Yttrium - 90 in 1.0 M acetic acid was collected from 90 Sr/ 90 Y generator. The labeling of the particles with Y-90 (185 MBq) was performed at pH 5.5 in acetate buffer with agitating for 60 min at room temperature. The labeled albumin suspensions were centrifuged at 3000 rpm for 15 min. Labeling yields was calculated using centrifugation, filtration and compared with paper chromatography, which is developed in the Tris Acetic EDTA. In this system, the unbound of Y-90 migrates to an R f of 0.9-1.0 and the radiolabeled albumin particles remains at the point of origin (R f = 0). The size of 90 Y-albumin particles was compared with the albumin particles in the original solution to be sure that they did not change during the labeling treatment. The radiolabeling yields were more than 80%. The labeled compound was dialysis in phosphate buffer. The radiochemical purity was 98%. The 90 Y- albumin is an ideal radiopharmaceutical for potential use in malignant cancer treatment as brachytherapy. (author)

2 CFR 801.930 - Debarring official (Department of Veterans Affairs supplement to government-wide definition at 2...

Science.gov (United States)

2010-01-01

... 2 Grants and Agreements 1 2010-01-01 2010-01-01 false Debarring official (Department of Veterans Affairs supplement to government-wide definition at 2 CFR 180.930). 801.930 Section 801.930 Grants and... DEBARMENT AND SUSPENSION Definitions § 801.930 Debarring official (Department of Veterans Affairs supplement...

2 CFR 801.1010 - Suspending official (Department of Veterans Affairs supplement to government-wide definition at 2...

Science.gov (United States)

2010-01-01

... 2 Grants and Agreements 1 2010-01-01 2010-01-01 false Suspending official (Department of Veterans Affairs supplement to government-wide definition at 2 CFR 180.1010). 801.1010 Section 801.1010 Grants and... DEBARMENT AND SUSPENSION Definitions § 801.1010 Suspending official (Department of Veterans Affairs...

Pharmacodynamics of Imipenem in Combination with β-Lactamase Inhibitor MK7655 in a Murine Thigh Model

Science.gov (United States)

Mavridou, Eleftheria; Melchers, Ria J. B.; van Mil, Anita C. H. A. M.; Mangin, E.; Motyl, Mary R.

2014-01-01

MK7655 is a newly developed beta-lactamase inhibitor of class A and class C carbapenemases. Pharmacokinetics (PK) of imipenem-cilastatin (IMP/C) and MK7655 were determined for intraperitoneal doses of 4 mg/kg to 128 mg/kg of body weight. MIC and pharmacodynamics (PD) studies of MK7655 were performed against several beta-lactamase producing Pseudomonas aeruginosa and Klebsiella pneumoniae strains to determine its effect in vitro and in vivo. Neutropenic mice were infected in each thigh 2 h before treatment with an inoculum of approximately 5 × 106 CFU. They were treated with IMP/C alone (every 2 hours [q2h], various doses) or in combination with MK7655 in either a dose fractionation study or q2h for 24 h and sacrificed for CFU determinations. IMP/MK7655 decreased MICs regarding IMP MIC. The PK profiles of IMP/C and MK7655 were linear over the dosing range studied and comparable with volumes of distribution (V) of 0.434 and 0.544 liter/kg and half-lives (t1/2) of 0.24 and 0.25 h, respectively. Protein binding of MK7655 was 20%. A sigmoidal maximum effect (Emax) model was fit to the PK/PD index responses. The effect of the inhibitor was not related to the maximum concentration of drug in serum (Cmax)/MIC, and model fits for T>MIC and area under the concentration-time curve (AUC)/MIC were comparable (R2 of 0.7 and 0.75), but there appeared to be no significant relationship of effect with dose frequency. Escalating doses of MK7655 and IMP/C showed that the AUC of MK7655 required for a static effect was dependent on the dose of IMP/C and the MIC of the strain, with a mean area under the concentration-time curve for the free, unbound fraction of the drug (fAUC) of 26.0 mg · h/liter. MK7655 shows significant activity in vivo and results in efficacy of IMP/C in otherwise resistant strains. The exposure-response relationships found can serve as a basis for establishing dosing regimens in humans. PMID:25403667

Synthesis of sup 14 C-radiolabelled Tilmicosin

Energy Technology Data Exchange (ETDEWEB)

Crouse, G D; Terando, N H [Lilly (Eli) and Co., Indianapolis, IN (USA). Lilly Research Labs.

1989-04-01

Tilmicosin was radiolabelled with carbon-14 on the 3,5-dimethylpiperidinyl sidechain as a requirement for animal metabolism studies. A new radiosynthesis of 3,5-dimethyl-piperidine was developed for this purpose. Incorporation into the desmycosin nucleus was accomplished by a reductive amination reaction. (author).

48 CFR 801.403 - Individual deviations.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Individual deviations. 801... Individual deviations. (a) Authority to authorize individual deviations from the FAR and VAAR is delegated to... nature of the deviation. (d) The DSPE may authorize individual deviations from the FAR and VAAR when an...

Thermometry using 1/8 W carbon resistors in a temperature region around 10 mK

International Nuclear Information System (INIS)

Kobayasi, S.; Shinohara, M.; Ono, K.

1976-01-01

The resistance-temperature characteristics of 1/8 W carbon resistors of grade ERC-18SG, manufactured by Matsushita, with the nominal values of 48, 82, 100, 220 and 330 Ω have been measured in the region 4.2 K to 25 mK and their application as thermometers in this region is confirmed. For the 82 Ω resistor, measurements were taken at temperatures below 10mK. The temperature dependence of the resistance was found to be linear on the log-log plot over a wide range below 50 mK. The sensitivity remains finite even at 6 mK, but below 10 mK rapid measurements were prevented by a considerable increase in the thermal relaxation time. Measurement of the characteristics of several 100 Ω resistors from two different sets showed that resistors from the same set separate into two groups with different characteristics. This become appreciable at temperatures below 4.2 K, so it is difficult to predict the behaviour of Matsushite resistors below 4.2 K from the characteristics at higher temperatures. (author)

Synthesis, radiolabeling and biodistribution of a new opioid glucuronide derivative. Ethyl-morphine glucuronide (em-glu)

International Nuclear Information System (INIS)

Enginar, H.

2012-01-01

In current study, ethyl-morphine (em) was synthesized from the morphine and glucuronidated via enzymatic mechanism. The conjugated glucuronide ethyl-morphine (em-glu) was radiolabeled with 131 I using iodogen method. The quality control studies of radiolabeled compound ( 131 I-em-glu) were done with Thin Layer Radio Chromatography to confirm the radiolabeling efficiency. Biodistribution studies of 131 I labeled em-glu were run on healthy male Albino Wistar rats. The distribution figures demonstrated that 131 I-em-glu was eliminated through the small intestine, large intestine and accumulated in urinary bladder both receptor blocked and unblocked biodistribution studies. A greater uptake of the radiolabeled substance was observed in the m.pons, hypothalamus and mid brain than in the other branches of the rats' brains. (author)

De-coupling of blood flow and metabolism in the rat brain induced by glutamate

International Nuclear Information System (INIS)

Hirose, Shinichiro; Momosaki, Sotaro; Sasaki, Kazunari; Hosoi, Rie; Abe, Kohji; Inoue, Osamu; Gee, A.

2009-01-01

Glutamate plays an essential role in neuronal cell death in many neurological disorders. In this study, we examined both glucose metabolism and cerebral blood flow in the same rat following infusion of glutamate or ibotenic acid using the dual-tracer technique. The effects of MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, and 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-kainate receptor antagonist, on the changes in the glucose metabolism and cerebral blood flow induced by glutamate were also examined. The rats were microinjected with glutamate (1 μmol/μl, 2 μl) or ibotenic acid (10 μg/μl, 1 μl) into the right striatum, and dual-tracer autoradiograms of [ 18 F]fluorodeoxyglucose (FDG) and [ 14 C]iofetamine (IMP) were obtained. MK-801 and NBQX were injected intravenously about 45 and 30 min, respectively, after the infusion of glutamate. De-coupling of blood flow and metabolism was noted in the glutamate-infused hemisphere (as assessed by no alteration of [ 18 F]FDG uptake and significant decrease of [ 14 C]IMP uptake). Pretreatments with MK-801, NBQX, or combined use of MK-801 and NBQX did not affect the de-coupling of the blood flow and metabolism induced by glutamate. A histochemical study revealed that about 20% neuronal cell death had occurred in the striatum at 105 min after the infusion of glutamate. In addition, a significant increase of the [ 18 F]FDG uptake and decrease of [ 14 C]IMP uptake were also seen in the rat brain infused with ibotenic acid. These results indicate that glutamate and ibotenic acid caused a significant de-coupling of blood flow and glucose metabolism in the intact rat brain during the early phase of neurodegeneration. It is necessary to evaluate the relation between metabotropic glutamate receptors and de-coupling of blood flow and metabolism. (author)

Qualification campaign of the 50 mK hybrid sorption-ADR cooler for SPICA/SAFARI

International Nuclear Information System (INIS)

Duval, J-M; Duband, L; Attard, A

2015-01-01

SAFARI (SpicA FAR-infrared Instrument) is an infrared instrument planned to be part of the SPICA (SPace Infrared telescope for Cosmology and Astrophysics) Satellite. It will offer high spectral resolution in the 30 - 210 μm frequency range. SAFARI will benefit from the cold telescope of SPICA and to obtain the required detectors sensitivity, a temperature of 50 mK is required. This temperature is reached thanks to the use of a hybrid sorption - ADR (Adiabatic Demagnetization Refrigerator) cooler presented here. This cooler provides respectively 14 μW and 0.4 μW of cooling power at 300 mK and 50 mK. The cooler is planned to advantageously use two thermal interfaces of the instrument at 1.8 and 4.9 K. One of the challenges discussed in this paper is the low power available at each intercept. A dedicated laboratory electronic is being designed based on previous development with a particular focus on the 50 mK readout. Temperature regulation at 50 mK is also discussed. This cooler has been designed following flight constraints and will reach a high TRL, including mechanical and environmental tests at the end of the on-going qualification campaign. (paper)

Hsp27 regulates Akt activation and polymorphonuclear leukocyte apoptosis by scaffolding MK2 to Akt signal complex.

Science.gov (United States)

Wu, Rui; Kausar, Hina; Johnson, Paul; Montoya-Durango, Diego E; Merchant, Michael; Rane, Madhavi J

2007-07-27

We have shown previously that Akt exists in a signal complex with p38 MAPK, MAPK-activated protein kinase-2 (MK2), and heat shock protein 27 (Hsp27) and MK2 phosphorylates Akt on Ser-473. Additionally, dissociation of Hsp27 from Akt, prior to Akt activation, induced polymorphonuclear leukocyte (PMN) apoptosis. However, the role of Hsp27 in regulating Akt activation was not examined. This study tested the hypothesis that Hsp27 regulates Akt activation and promotes cell survival by scaffolding MK2 to the Akt signal complex. Here we show that loss of Akt/Hsp27 interaction by anti-Hsp27 antibody treatment resulted in loss of Akt/MK2 interaction, loss of Akt-Ser-473 phosphorylation, and induced PMN apoptosis. Transfection of myristoylated Akt (AktCA) in HK-11 cells induced Akt-Ser-473 phosphorylation, activation, and Hsp27-Ser-82 phosphorylation. Cotransfection of AktCA with Hsp27 short interfering RNA, but not scrambled short interfering RNA, silenced Hsp27 expression, without altering Akt expression in HK-11 cells. Silencing Hsp27 expression inhibited Akt/MK2 interaction, inhibited Akt phosphorylation and Akt activation, and induced HK-11 cell death. Deletion mutagenesis studies identified acidic linker region (amino acids 117-128) on Akt as an Hsp27 binding region. Deletion of amino acids 117-128 on Akt resulted in loss of its interaction with Hsp27 and MK2 but not with Hsp90 as demonstrated by immunoprecipitation and glutathione S-transferase pulldown studies. Co-transfection studies demonstrated that constitutively active MK2 (MK2EE) phosphorylated Aktwt (wild type) on Ser-473 but failed to phosphorylate Akt(Delta117-128) mutant in transfixed cells. These studies collectively define a novel role of Hsp27 in regulating Akt activation and cellular apoptosis by mediating interaction between Akt and its upstream activator MK2.

Radiolabeled platelets

International Nuclear Information System (INIS)

Datz, F.L.; Taylor, A.T.

1986-01-01

Initial interest in developing techniques to radiolabel platelets was spurred by the lack of an accurate method for measuring platelet life span in both normals and in thrombocytopenic patients. Early investigators could obtain only rough estimates of platelet life spans by monitoring the platelet counts of thrombocytopenic patients undergoing platelet transfusions. Labels were also sought that would allow imaging of platelets in vivo in order to better understand the pathophysiology of atherosclerosis, thrombophlebitis, and clotting disorders, and to improve the clinical diagnosis of these diseases. Two types of platelet labels were investigated: cohort (pulse) labels and random labels. Cohort labels are taken up by megakaryocytes in the bone marrow and incorporated in the DNA and other components of the forming platelet. In theory, only freshly released platelets of a uniform age are labeled. Random labels, on the other hand, tag platelets in the peripheral blood, labeling platelets of all ages

Comparison of endogenous and radiolabeled bile acid excretion in patients with idiopathic chronic diarrhea

International Nuclear Information System (INIS)

Schiller, L.R.; Bilhartz, L.E.; Santa Ana, C.A.

1990-01-01

Fecal recovery of radioactivity after ingestion of a bolus of radiolabeled bile acid is abnormally high in most patients with idiopathic chronic diarrhea. To evaluate the significance of this malabsorption, concurrent fecal excretion of both exogenous radiolabeled bile acid and endogenous (unlabeled) bile acid were measured in patients with idiopathic chronic diarrhea. Subjects received a 2.5-microCi oral dose of taurocholic acid labeled with 14C in the 24th position of the steroid moiety. Endogenous bile acid excretion was measured by a hydroxysteroid dehydrogenase assay on a concurrent 72-h stool collection. Both radiolabeled and endogenous bile acid excretion were abnormally high in most patients with chronic diarrhea compared with normal subjects, even when equivoluminous diarrhea was induced in normal subjects by ingestion of osmotically active solutions. The correlation between radiolabeled and endogenous bile acid excretion was good. However, neither radiolabeled nor endogenous bile acid excretion was as abnormal as is typically seen in patients with ileal resection, and none of these diarrhea patients responded to treatment with cholestyramine with stool weights less than 200 g. These results suggest (a) that this radiolabeled bile acid excretion test accurately reflects excess endogenous bile acid excretion; (b) that excess endogenous bile acid excretion is not caused by diarrhea per se; (c) that spontaneously occurring idiopathic chronic diarrhea is often associated with increased endogenous bile acid excretion; and (d) that bile acid malabsorption is not likely to be the primary cause of diarrhea in most of these patients

High-dose dextromethorphan produces myelinoid bodies in the hippocampus of rats.

Science.gov (United States)

Tran, Hai-Quyen; Chung, Yoon Hee; Shin, Eun-Joo; Kim, Won Ki; Lee, Jae-Chul; Jeong, Ji Hoon; Wie, Myung Bok; Jang, Choon-Gon; Yamada, Kiyofumi; Nabeshima, Toshitaka; Kim, Hyoung-Chun

2016-10-01

Dextromethorphan (DM) administered at supra-antitussive doses produce psychotoxic and neurotoxic effects in humans. We administered DM (80 mg/kg) to rats intraperitoneally to determine the ultrastructural change induced by DM, because intraperitoneal route is sensitive for the behavioral responses. Treatment with DM resulted in mitochondrial dysfunction and formation of myelinoid bodies in the hippocampus. MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] attenuated DM-induced cytosolic oxidative burdens. However, neither MK-801 nor naloxone affected DM-induced mitochondrial dysfunction and formation of myelinoid bodies, indicating that the neurotoxic mechanism needs to be further elucidated. Therefore, the spectrum of toxicological effects associated with DM need to be reassessed. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Apparatus intended for measuring heat capacity and heat transfer down to mK range

International Nuclear Information System (INIS)

Hebral, B.; Frossati, G.; Godfrin, H.; Schumacher, G.; Thoulouze, D.

1978-01-01

A cryogenic apparatus to perform heat capacity and heat transfer measurements in the range 1.5 mK-50 mK is described. Measurements are performed in an adiabatic demagnetization cell attached to a dilution refrigerator. Heat capacity measurements were effected on CMN-helium systems; the CMN specific heat was deduced above 1.6 mK when using liquid 3 He or a mixture 1.1% 3 He - 98.9% 4 He. A specific heat anomaly was observed with 4 He below 10 mK. It does not seen possible to interprete it by simple thermal equilibrium considerations. The superfluid 3 He heat capacity was also deduced from the results obtained with liquid 3 He under pressure. In heat transfer measurements at the interface CMN-mixture 3 He- 4 He, the temperature dependence of the thermal boundary resistance is in rather good agreement with other powder results. The measured resistances are larger than those predicted by the classical phonon process [fr

Quantitative autoradiographic mapping of focal herpes simplex virus encephalitis using a radiolabeled antiviral drug

International Nuclear Information System (INIS)

Price, R.

1984-01-01

A method of mapping herpes simplex viral infection comprising administering a radiolabeled antiviral active 5-substituted 1-(2'-deoxy-2'-substituted-D-arabinofuranosyl) pyrimidine nucleoside to the infected subject, and scanning the area in which the infection is to be mapped for the radiolabel

48 CFR 801.602-73 - Review requirements for scarce medical specialist contracts and contracts for health-care resources.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Review requirements for scarce medical specialist contracts and contracts for health-care resources. 801.602-73 Section 801.602... Responsibilities 801.602-73 Review requirements for scarce medical specialist contracts and contracts for health...

Metabolic comparison of radiolabeled aniline- and phenol-phthaleins with 131I

International Nuclear Information System (INIS)

Avcibasi, Ugur; Avcibasi, Nesibe; Unak, Turan; Unak, Perihan; Mueftueler, Fazilet Zuemruet; Yildirim, Yeliz; Dincalp, Haluk; Guemueser, Fikriye Guel; Dursun, Ebru Rueksen

2008-01-01

The metabolic comparison of aniline- and phenol-phthaleins radiolabeled with 131 I ( 131 I-APH and 131 I-PPH, respectively) has been investigated in this study. To compare the metabolic behavior of these phthaleins and their glucuronide conjugates radiolabeled with 131 I, scintigraphic and biodistributional techniques were applied using male Albino rabbits. The results obtained have shown that these compounds were successfully radioiodinated with a radioiodination yield of about 100%. Maximum uptakes of 131 I-APH and 131 I-PPH, which were metabolized as N- and O-glucuronides, were observed within 2 h in the bladder and in the small intestine, respectively. In the case of verification of considerably up taking of these compounds also by tumors developed in the small intestine and in the bladder tissues, these results can be expected to be encouraging to test these compounds, which will be radiolabeled with other radioiodines such as 125 I, 123 I and 124 I as imaging and therapeutic agents in nuclear medical applications

Metabolic comparison of radiolabeled aniline- and phenol-phthaleins with (131)I.

Science.gov (United States)

Avcibaşi, Uğur; Avcibaşi, Nesibe; Unak, Turan; Unak, Perihan; Müftüler, Fazilet Zümrüt; Yildirim, Yeliz; Dinçalp, Haluk; Gümüşer, Fikriye Gül; Dursun, Ebru Rükşen

2008-05-01

The metabolic comparison of aniline- and phenol-phthaleins radiolabeled with (131)I ((131)I-APH and (131)I-PPH, respectively) has been investigated in this study. To compare the metabolic behavior of these phthaleins and their glucuronide conjugates radiolabeled with (131)I, scintigraphic and biodistributional techniques were applied using male Albino rabbits. The results obtained have shown that these compounds were successfully radioiodinated with a radioiodination yield of about 100%. Maximum uptakes of (131)I-APH and (131)I-PPH, which were metabolized as N- and O-glucuronides, were observed within 2 h in the bladder and in the small intestine, respectively. In the case of verification of considerably up taking of these compounds also by tumors developed in the small intestine and in the bladder tissues, these results can be expected to be encouraging to test these compounds, which will be radiolabeled with other radioiodines such as (125)I, (123)I and (124)I as imaging and therapeutic agents in nuclear medical applications.

Radiolabeling parameters of 177Lu-DOTA-RITUXIMAB

International Nuclear Information System (INIS)

Massicano, Adriana V.F.; Alcarde, Lais F.; Oliveira, Ricardo S.; Mengatti, Jair; Araujo, Elaine B. de

2013-01-01

Cancer treatment using radioimmunotherapy (RIT) has been the focus of much research in the last two decades. In RIT, a radioisotope is coupled to a monoclonal antibody (mAb) to form a tumor-specific target agent to improve the cytocidal effect of the mAbs. RIT allows the systemic delivery of radiation to disease target by mAbs while sparing normal tissues. Rituximab® (Mabthera - Roche) is a chimeric mouse-human monoclonal antibody; it selectively binds with high affinity to the CD20 antigen, a hydrophobic transmembrane protein, which is expressed on B-lymphocytes and in more than 90% of B cell non-Hodgkin's lymphomas (NHL). The conjugation and radiolabeling process involve special conditions of pH and temperature, long processes of manipulation and mixing. All this process can damage the antibody structure and compromise its clinical application. Therefore, these parameters must be largely studied. The aim of this work was to evaluate the best radiolabeling conditions of DOTA-rituximab. Briefly, 10 mg of antibody previously purified by ultrafiltration device was conjugated with DOTA-NHS-ester (Macrocyclics) in 50 fold molar excess. The reaction was conducted for 1 hour in phosphate buffer pH 8.0 and gently mixing at room temperature, remaining for 24 hours under refrigeration. The immunoconjugated was purified by size exclusion column and ultrafiltration device. The radiolabeled parameters studied were: immunoconjugated mass, activity of 177 LuCl 3 , reaction time, temperature and pH. The radiochemical purity of the preparations was determined using analysis by thin layer chromatography (TLC-SG plates). The best studied condition presented radiochemical purity above 95% and the integrity of antibody was preserved. (author)

Elevated Lipoprotein(A Impairs Platelet Radiolabeling Yield

Directory of Open Access Journals (Sweden)

Susanne Granegger

2015-02-01

Full Text Available Objectives: Platelet radiolabeling in clinical routine usually results in labeling efficiencies (LE above 80%. A variety of risk factors and clinical conditions are known to impair platelet labeling yield, among them elevated triglycerides and low-density lipoproteins. The potential influence of lipoprotein(a (Lp(a, an atherogenic lipoprotein particle containing a kringle subunit, which is widely found in the proteins of fibrinolysis pathway, has never been studied. Normal Lp(a levels range below 30 mg/ dl. The exact prevalence of elevated Lp(a is unknown, most likely ranging below 10%. Even more rare is an isolated elevation despite an otherwise normal lipoprotein profile. Methods: We examined the role of isolated elevated Lp(a (> 50 mg/dl, ranging up to 440 mg/dl compared to patients with normal lipid profile. Platelets were radiolabeled with in-111-oxine at 37 °C for 5 minutes using ISORBE-consensus methodology. Results: The findings indicate that already at levels below 100 mg/dl Lp(a decreases LE. LE assessment after cross-incubation of hyper-Lp(a platelets with normal Lp(a plasma and vice versa reveals that platelets rather than the plasmatic environment are responsible for the deterioration of labeling yield. This behavior already has been reported for elevated low-density lipoproteins. Apparently, the quantitative influence of LDL and Lp(a/mg is comparable. Plotting the sum of LDL and Lp(a versus LE reveals a clear significant negative correlation. Conclusion: As extremely elevated Lp(a, particularly above 150 mg/dl, may significantly impair labeling results. We therefore recommend to include extremely elevated Lp(a into the list of parameters, which should be known before performing radiolabeling of human platelets.

Preparation and radiolabeling of human serum albumin (HSA)-coated magnetite nanoparticles for magnetically targeted therapy

International Nuclear Information System (INIS)

Zhang Chunfu; Cao Jinquan; Yin Duanzhi; Wang Yongxian; Feng Yanlin; Tan Jiajue

2004-01-01

In this paper, we describe the preparation of human serum albumin-coated magnetic particles of about 200 nm in diameter with narrow size distribution radiolabeled with 188 Re for the purpose of magnetically targeted therapy. The optimum radiolabeling conditions are: SnCl 2 ·2H 2 O 8 mg/ml, citric acid 20 mg/ml, vitamin C 8 mg/ml, labeling volume 500 μl and a reaction time of 3 h. The stability of the radiolabeled particles is suitable for in vivo study

Method for radiolabeling proteins with technetium-99m

International Nuclear Information System (INIS)

Crockford, D.R.; Rhodes, B.A.

1984-01-01

In accordance with this invention, a substrate to be radiolabeled with technetium-99m is admixed with a buffered stannous chloride composition having a pH between about 4.5 and about 8.5 wherein the stannous chloride is produced from a non-oxidized tin source, the buffered stannous chloride is purged of oxygen and the buffer comprises a mixture of alkali metal biphthalate and an alkali metal tartrate. Alternatively, the buffer may include alkali metal borate or gentisate. The stannous chloride solution is admixed with the buffer and the resultant mixture is neutralized with sodium hydroxide. The neutralized solution then is admixed with the substrate eventually to be radiolabeled with technetium-99m. This solution is allowed to incubate for several hours (usually over 15 hours) in the absence of oxygen and at room temperature

In vitro metabolism of radiolabeled carbohydrates by protective cecal anaerobic bacteria.

Science.gov (United States)

Hume, M E; Beier, R C; Hinton, A; Scanlan, C M; Corrier, D E; Peterson, D V; DeLoach, J R

1993-12-01

Cecal anaerobic bacteria from adult broilers were cultured in media containing .25% glucose or .25% lactose. Media also contained either [14C]-labeled lactose, glucose, galactose, or lactic acid as metabolic tracers. Cultures were analyzed at 4, 8, and 12 h for pH, radiolabeled and unlabeled volatile fatty acids, and lactic acid. The pH values of cultures containing .25% lactose were significantly (P galactose, lactose > glucose. The volatile fatty acids in which radiolabel was most concentrated were acetic acid, propionic acid, or butyric acid.

Preparation and radiolabeling of human serum albumin (HSA)-coated magnetite nanoparticles for magnetically targeted therapy

Energy Technology Data Exchange (ETDEWEB)

Zhang Chunfu E-mail: zchunfu@yahoo.com.cn; Cao Jinquan; Yin Duanzhi; Wang Yongxian; Feng Yanlin; Tan Jiajue

2004-12-01

In this paper, we describe the preparation of human serum albumin-coated magnetic particles of about 200 nm in diameter with narrow size distribution radiolabeled with {sup 188}Re for the purpose of magnetically targeted therapy. The optimum radiolabeling conditions are: SnCl{sub 2}{center_dot}2H{sub 2}O 8 mg/ml, citric acid 20 mg/ml, vitamin C 8 mg/ml, labeling volume 500 {mu}l and a reaction time of 3 h. The stability of the radiolabeled particles is suitable for in vivo study.

Quantitation of radiolabeled compounds eluting from the HPLC system

International Nuclear Information System (INIS)

Kessler, M.J.

1982-01-01

Three techniques are compared for the quantitation of various radiolabeled compounds eluting in the high performance liquid chromatography system. The first technique requires fraction-collecting the effluent from the HPLC, removing an aliquot to scintillation vials, and counting each fraction in a liquid scintillation counter. The second uses direct interface of the HPLC effluent to a flow-through radioactivity detector. The third involves quantitation of various radiolabeled compounds (proteins, steroids, and nucleotides) by splitting the effluent from the HPLC with an electronic steam splitter, thus diverting a present portion to the fraction collector for further chemical characterization and the remainder to the radioactivity flow detector for direct quantitation. A direct comparison of the chromatograms and the radioactivity counting efficiencies of these three techniques is presented

Evaluation of radiolabeling of annexin A5 with technetium-99m: influence of the labeling methods on physico-chemical and biological properties of the compounds

International Nuclear Information System (INIS)

Santos, Josefina da Silva

2009-01-01

Annexin A5 (ANXA5) is an intracellular human protein of 36 kDa with high affinity for membrane-bound phosphatidylserine that is selectively exposed on the surface of cells undergoing apoptosis. Apoptosis is important in normal physiology and innumerous pathologic states. Clinical applications for ANXA5 imaging are being developed in oncology, organ transplantation and cardiovascular diseases. Many strategies to radiolabel the protein have been described, including direct labeling, derivatization through a bifunctional chelating agent (BFC), production of mutated protein or peptide analogs. Several 99 mTc-labeling techniques have been reported using different cores, including [Tc=O] +3 , [Tc]HYNIC, [Tc≡N]+2 and [Tc(CO 3 )] +1 . In this study, we evaluated the influence of 99 mTc cores on biological behavior and physico-chemical properties of radiolabeled annexin. Radiolabeling procedure using [Tc≡N] +2 core was a two-step procedure including the reaction of 99 mTcO4 - with SDH in the presence of SnCl 2 and PDTA to obtain the intermediate 99 mTcN-SDH, and successive addition of ANXA5. The results obtained were not satisfactory, despite the high efficiency in the production of the intermediate. The [Tc=O] +3 core was produced using the ethylene dicysteine (EC) as BFC. TSTU was employed in the derivatization to produce the corresponding hydroxysuccinimide ester. Different ANXA5:EC ratios were studied and all labeling conditions resulted in high radiochemical yield but with differences in lipophilicity, stability, biological distribution and affinity for apoptotic cells. The HYNIC-ANXA5 also produced the labeled protein with high radiochemical yield. The stability of the radiolabeled ANXA5 was evaluated after storing at room temperature, at 2 - 8 degree C and in human serum at 37 degree C. The analysis of these results showed that the 99 mTc-EC-ANXA5 (ratio 10-2) was the most stable compound in all the studied conditions. Partition coefficient assay resulted in

A novel method for radiolabeling antigen-binding receptors of lymphocytes

International Nuclear Information System (INIS)

Choi, Y.S.; Lee, M.S.; Rosenspire, A.J.

1983-01-01

Antigen-binding receptor (ABR) molecules have been selectively radiolabeled and isolated from immunized chicken spleen cells. The specific radiolabeling of the receptors has been accomplished by utilizing a novel technique employing lactoperoxidase (LPO) covalently linked to antigen (Ag) for which human gammaglobulin was used. The cell surface ABRs were first bound to the Ag-LPO conjugates through specific recognition sites on the Ag portion of the conjugates. The bound LPO portions were then allowed to catalyze the radioiodination of the ABRs. After radiolabeling, cells were solubilized with detergents, ABRs still bound to Ag-LPO conjugates were directly isolated from the lysates via immunoaffinity chromatography utilizing an immunoaffinity reagent directed toward the antigen portion of the ABR-Ag-LPO complex. The radioactive materials were then analyzed via SDS-PAGE under reducing conditions. Most of the specifically-labeled and isolated materials were immunoglobulin (Ig). Both the membrane-bound form of the heavy chain as well as the secreted form were detected, along with the light chain. An additional polypeptide was also selectively labeled and isolated along with the Ig. This may be a molecule closely associated with the membrane immunoglobulin on the B-cell surface. (author)

Radiolabeling, biodistribution and tumor imaging of stealth liposomes containing methotrexate

International Nuclear Information System (INIS)

Subramanian, N; Arulsudar, N; Chuttani, K; Mishra, P; Sharma, R.K; Murthy, R.S.R

2003-01-01

To study the utility of sterically stabilized liposomes (stealth liposomes) in tumor scintigraphy by studying its biodistribution and accumulation in target tissue after radiolabeling with Technetium-99m (99mTC). Conventional and Stealth liposomes were prepared by lipid film hydration method using methotrexate as model anticancer drug. Radiolabeling of the liposomes was carried out by direct labeling using reduced 99mTc. Experimental conditions for maximum labeling yield were optimized. The stability studies were carried out to check binding strength of the radiolabeled complexes. The blood kinetic study was carried out in rabbits after giving the labeled complex by intravenous administration through ear vein. The biodistribution studies were carried out in the Ehrlich ascites tumor (EAT) bearing mice after intravenous administration through tail vein, showed prolonged circulation in blood and significant increase in the accumulation in tumor for the sterically stabilized liposomes compared to the conventional liposomes. The gamma scintigraphic image shows the distribution of the stealth liposomes in liver, spleen, kidney and tumor. The study gives precise idea about the use of stealth liposomes in tumor scintigraphy and organ distribution studies (Au)

Enhanced specificity in immunoscreening of expression cDNA clones using radiolabeled antigen overlay

International Nuclear Information System (INIS)

Chao, S.; Chao, L.; Chao, J.

1989-01-01

A highly sensitive and specific method has been developed for immunoscreening clones from an expression cDNA library. The procedures utilize a radiolabeled antigen detection method described originally for the immunoblotting of plasma proteins. Screening of rat alpha 1-antitrypsin clones was used. Comparison between Western blots of alpha 1-antitrypsin using both labeled antigen and protein A detection methods showed that the former yielded lower background and greater sensitivity than the latter. Further, this technique was shown to have a lower detection limit of less than 20 ng through Western blot analysis of varying concentrations of alpha 1-antitrypsin. The procedures are based on the expression of the protein by cDNA clones containing the DNA inserts in the correct reading frame. Following the transfer of phage proteins to nitrocellulose membranes, the bivalent antibodies bind monovalently to both nitrocellulose-bound-antigen in the phage lysates and radiolabeled antigen. The radiolabeled antigen overlay method is superior to the protein A detection method in sensitivity, specificity and reproducibility. This improved method can be applied in general for screening expression cDNA libraries, provided that the specific antiserum and radiolabeled antigen are available

Plasma drug concentrations and clinical effects of a peripheral alpha-2-adrenoceptor antagonist, MK-467, in horses sedated with detomidine.

Science.gov (United States)

Vainionpää, Mari H; Raekallio, Marja R; Pakkanen, Soile A E; Ranta-Panula, Ville; Rinne, Valtteri M; Scheinin, Mika; Vainio, Outi M

2013-05-01

To investigate plasma drug concentrations and the effect of MK-467 (L-659'066) on sedation, heart rate and gut motility in horses sedated with intravenous (IV) detomidine. Experimental randomized blinded crossover study. Six healthy horses. Detomidine (10 μg kg(-1) IV) was administered alone (DET) and in combination with MK-467 (250 μg kg(-1) IV; DET + MK). The level of sedation and intestinal sounds were scored. Heart rate (HR) and central venous pressure (CVP) were measured. Blood was collected to determine plasma drug concentrations. Repeated measures anova was used for HR, CVP and intestinal sounds, and the Student's t-test for pairwise comparisons between treatments for the area under the time-sedation curve (AUCsed ) and pharmacokinetic parameters. Significance was set at p Detomidine-induced intestinal hypomotility was prevented by MK-467. AUCsed was significantly higher with DET than DET + MK, but maximal sedations scores did not differ significantly between treatments. MK-467 lowered the AUC of the plasma concentration of detomidine, and increased its volume of distribution and clearance. MK-467 prevented detomidine induced bradycardia and intestinal hypomotility. MK-467 did not affect the clinical quality of detomidine-induced sedation, but the duration of the effect was reduced, which may have been caused by the effects of MK-467 on the plasma concentration of detomidine. MK-467 may be useful clinically in the prevention of certain peripheral side effects of detomidine in horses. © 2013 The Authors. Veterinary Anaesthesia and Analgesia © 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

Radiolabeling of substance P with Lutetium-177 and biodistribution study in AR42J pancreatic tumor xenografted Nude mice

International Nuclear Information System (INIS)

Araujo, Bortoleti de; Pujatti, Priscilla Brunelli; Barrio, Ofelia; Caldeira, Jose S.; Mengatti, Jair; Suzuki, Miriam F.

2008-01-01

Pancreatic tumor (PT) is a neuroendocrine neoplasm that usually origin metastases in the respiratory and gastrointestinal tract. In recent years, new developments in targeted therapies have emerged and the presence of peptide receptors at the cell membrane of PT constitutes the basis of the clinical use of specific radiolabeled ligands. Substance P, an 11-amino acid peptide which has an important role in modulating pain transmission trough neurokinin 1 and 2 receptors (NKr), may play a role in the pathogenesis of PT, because approximately 10% of these tumors over express NKr. The aim of the present work was to produce a pure and stable SP analog (DOTA-SP) radiolabeled with Lutetium-177 ( 177 Lu), and to evaluate its in vivo target to AR42J pancreatic tumor cells in Nude mice in other to verify if SP can be used in this pancreatic tumor detection and treatment. 177 Lu (half-life 6.7 days) has both β and γ-emissions suitable for radiotherapy and imaging respectively. Substance P was successfully labeled with high yield (>99%) at optimized conditions and kept stable for more than 72 hours at 4 deg C and 24 hours in human plasma. Biodistribution studies showed that SP excretion was mainly performed by renal pathway. In addition, 177 Lu-DOTA-SP showed higher uptake by tumor than normal pancreas, indicating the presence of NK receptors in AR42J pancreatic tumor. (author)

Microassay for measurement of binding of radiolabelled ligands to cell surface molecules

International Nuclear Information System (INIS)

Woof, J.M.; Burton, D.R.

1988-01-01

An improved technique for measuring the binding of radiolabelled ligands to cell surface molecules has been developed by modification of a procedure using centrifugation through a water-immiscible oil to separate free and cell-bound ligand. It maximises the percentage of ligand bound since cell-bound and free ligand can be separated easily and reproducibly even when very small reaction volumes are used. This permits low levels of ligand radiolabelling and relatively low numbers of cells to be used

Microreactor and method for preparing a radiolabeled complex or a biomolecule conjugate

Energy Technology Data Exchange (ETDEWEB)

Reichert, David E; Kenis, Paul J. A.; Wheeler, Tobias D; Desai, Amit V; Zeng, Dexing; Onal, Birce C

2015-03-17

A microreactor for preparing a radiolabeled complex or a biomolecule conjugate comprises a microchannel for fluid flow, where the microchannel comprises a mixing portion comprising one or more passive mixing elements, and a reservoir for incubating a mixed fluid. The reservoir is in fluid communication with the microchannel and is disposed downstream of the mixing portion. A method of preparing a radiolabeled complex includes flowing a radiometal solution comprising a metallic radionuclide through a downstream mixing portion of a microchannel, where the downstream mixing portion includes one or more passive mixing elements, and flowing a ligand solution comprising a bifunctional chelator through the downstream mixing portion. The ligand solution and the radiometal solution are passively mixed while in the downstream mixing portion to initiate a chelation reaction between the metallic radionuclide and the bifunctional chelator. The chelation reaction is completed to form a radiolabeled complex.

Investigation of bacterial adherence to a non-precious alloy with radiolabeling method

International Nuclear Information System (INIS)

Sonugelen, M.; Iyiyapici Destan, U.; Oeztuerk, B.; Yurt Lambrecht, F.

2006-01-01

The objective of this study was to investigate the bacterial adherence to a non-precious alloy with radiolabeling method. S. mutans, E. coliand C. albicanswere labeled with 99m Tc by using stannous chloride and their radiolabeling yields were calculated. After the labeling procedure, metal disks (3 mm x 10 mm) were treated with microorganisms. The amount of labeled microorganisms adhered on metal surfaces was determined by activity measurements. The labeling yields for S. mutans, E. coliand C. albicanswere 69.95 ± 7.58%, 78.84 ± 0.44% and 79.71 ± 10.17%, respectively. The mean values for adherence for S. mutans, E. coliand C. albicans on metal samples were 7.02 ± 2.18%, 0.96 ± 0.49% and 8.80 ± 8.24%, respectively. The radiolabeling method could be considered as safe and precise for determining the adherence of microorganisms. (author)

16 CFR 801.4 - Secondary acquisitions.

Science.gov (United States)

2010-01-01

... fifteen days (or in the case of a cash tender offer, 10 days) after “A” files, pursuant to § 801.30. 2. If... remain the same. Since “A” would be acquiring control of B, all of B's holdings in X would be... corporation. B's voting securities are cancelled, and B's shareholders are to receive cash in return. Since S...

Blockade of NMDA receptors blocks the acquisition of cocaine conditioned approach in rats.

Science.gov (United States)

Galaj, Ewa; Seepersad, Neal; Dakmak, Zena; Ranaldi, Robert

2018-01-05

Conditioned stimuli (CSs) exert motivational effects on both adaptive and pathological reward-related behaviors, including drug taking and seeking. We developed a paradigm that allows us to investigate the neuropharmacology by which previously neutral stimuli acquire the capacity to function as CSs and elicit (intravenous) cocaine conditioned approach and used this paradigm to test the role of NMDA receptor stimulation in the acquisition of cocaine conditioned approach. Rats were injected systemically with the NMDA receptor antagonist, MK-801, before the start of 4 consecutive conditioning sessions, each of which consisted of 20 randomly presented light/tone (CS) presentations paired with cocaine infusion contingent upon nose pokes. Rats later were subjected to a CS-only test. To test the role of NMDA receptor stimulation in the already established conditioned approach, rats were injected with MK-801 prior to the CS-only test that occurred after 18 CS-cocaine conditioning sessions. Blockade of NMDA receptors significantly impaired the acquisition of cocaine-conditioned approach as indicated by the emission of significantly fewer nose pokes and significantly longer latencies to nose poke during CS presentations. When MK-801 treatment was applied after the acquisition of conditioned approach responding it had no effect on these measures. These results suggest that NMDA receptor stimulation plays an important role in the acquisition of reward-related conditioned responses driven by intravenous cocaine-associated CSs. Copyright © 2017 Elsevier B.V. All rights reserved.

Repeated Blockade of NMDA Receptors during Adolescence Impairs Reversal Learning and Disrupts GABAergic Interneurons in Rat Medial Prefrontal Cortex

Directory of Open Access Journals (Sweden)

Jitao eLi

2016-03-01

Full Text Available Adolescence is of particular significance to schizophrenia, since psychosis onset typically occurs in this critical period. Based on the N-methyl-D-aspartate (NMDA receptor hypofunction hypothesis of schizophrenia, in this study, we investigated whether and how repeated NMDA receptor blockade during adolescence would affect GABAergic interneurons in rat medial prefrontal cortex (mPFC and mPFC-mediated cognitive functions. Specifically, adolescent rats were subjected to intraperitoneal administration of MK-801 (0.1, 0.2, 0.4 mg/kg, a non-competitive NMDA receptor antagonist, for 14 days and then tested for reference memory and reversal learning in the water maze. The density of parvabumin (PV-, calbindin (CB- and calretinin (CR-positive neurons in mPFC were analyzed at either 24 hours or 7 days after drug cessation. We found that MK-801 treatment delayed reversal learning in the water maze without affecting initial acquisition. Strikingly, MK-801 treatment also significantly reduced the density of PV+ and CB+ neurons, and this effect persisted for 7 days after drug cessation at the dose of 0.2 mg/kg. We further demonstrated that the reduction in PV+ and CB+ neuron densities was ascribed to a downregulation of the expression levels of PV and CB, but not to neuronal death. These results parallel the behavioral and neuropathological changes of schizophrenia and provide evidence that adolescent NMDA receptors antagonism offers a useful tool for unraveling the etiology of the disease.

Bystander responses in three-dimensional cultures containing radiolabelled and unlabelled human cells

International Nuclear Information System (INIS)

Pinto, M.; Azzam, E. I.; Howell, R. W.

2006-01-01

Research on the radiation-induced bystander effect has been carried out mainly in 2-D tissue culture systems. This study uses a 3-D model, wherein apparently normal human diploid fibroblasts (AG1522) are grown in a carbon scaffold, to investigate the induction of a G 1 checkpoint in bystander cells present alongside radiolabelled cells. Cultures were simultaneously pulse-labelled with 3 H-deoxycytidine ( 3 HdC) to selectively irradiate a minor fraction of cells, and bromodeoxyuridine (BrdU) to identify the radiolabelled cells. After thorough washing of cultures, iododeoxyuridine (IdU) was administered to detect proliferating bystander cells. The cultures were harvested at various times thereafter, and cells were reacted with two monoclonal antibodies specific to IdU/BrdU or BrdU, respectively, stained with propidium iodide, and subjected to multi-parameter flow cytometry. Cell-cycle progression was followed in radiolabelled cells (BrdU + ) that were chronically irradiated by low energy beta particles emitted by DNA-incorporated 3 H, and in unlabelled bystander cells (BrdU - ) by a flow cytometry based cumulative labelling index assay. As expected, radiolabelled cells were delayed, in a dose-dependent manner, in G 2 and subsequently G 1 . No delay occurred in progression of bystander cells through G 1 , when the labelled cells were irradiated at dose rates up to 0.32 Gy h -1 . (authors)

48 CFR 801.602-70 - General review requirements.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false General review... AFFAIRS GENERAL DEPARTMENT OF VETERANS AFFAIRS ACQUISITION REGULATION SYSTEM Career Development, Contracting Authority, and Responsibilities 801.602-70 General review requirements. (a) Contracting officers...

26 CFR 1.801-5 - Total reserves.

Science.gov (United States)

2010-04-01

... TAXES Life Insurance Companies § 1.801-5 Total reserves. (a) Total reserves defined. For purposes of... its highest aggregate reserve by taking State A's requirement of 10 against its life insurance business and adding it to State B's requirement of 7 against its annuity business. (b) Reserves required by...

Spinal Pain and Occupational Disability: A Cohort Study of British Apache AH Mk1 Pilots

Science.gov (United States)

2013-09-01

British RW community. 33 References Apache AH Mk1. 2012. Agusta Westland. http://www.agustawestland.com/ product /apache-ah- mk1-0. Ang, B., and...muscles Physical ex and stretching Continued pt and stretching exercises Use pt session included pumpkin bobs to stretch the neck. No effects noticed

Localisation and mechanism of renal retention of radiolabelled somatostatin analogues

Energy Technology Data Exchange (ETDEWEB)

Melis, Marleen; Krenning, Eric P.; Bernard, Bert F.; Jong, Marion de [Erasmus MC, Department of Nuclear Medicine, Rotterdam (Netherlands); Barone, Raffaella [UCL, Centre of Nuclear Medicine and Laboratory of PET, Brussels (Belgium); Visser, Theo J. [Erasmus MC, Department of Internal Medicine, Rotterdam (Netherlands)

2005-10-01

Radiolabelled somatostatin analogues, such as octreotide and octreotate, are used for tumour scintigraphy and radionuclide therapy. The kidney is the most important critical organ during such therapy owing to the reabsorption and retention of radiolabelled peptides. The aim of this study was to investigate in a rat model both the localisation and the mechanism of renal uptake after intravenous injection of radiolabelled somatostatin analogues. The multi-ligand megalin/cubilin receptor complex, responsible for reabsorption of many peptides and proteins in the kidney, is an interesting candidate for renal endocytosis of these peptide analogues. For localisation studies, ex vivo autoradiography and micro-autoradiography of rat kidneys were performed 1-24 h after injection of radiolabelled somatostatin analogues and compared with the renal anti-megalin immunohistochemical staining pattern. To confirm a role of megalin in the mechanism of renal retention of [{sup 111}In-DTPA]octreotide, the effects of three inhibitory substances were explored in rats. Renal ex vivo autoradiography showed high cortical radioactivity and lower radioactivity in the outer medulla. The distribution of cortical radioactivity was inhomogeneous. Micro-autoradiography indicated that radioactivity was only retained in the proximal tubules. The anti-megalin immunohistochemical staining pattern showed a strong similarity with the renal [{sup 111}In-DTPA]octreotide ex vivo autoradiograms. Biodistribution studies showed that co-injection of positively charged d-lysine reduced renal uptake to 60% of control. Sodium maleate reduced renal [{sup 111}In-DTPA]octreotide uptake to 15% of control. Finally, cisplatin pre-treatment of rats reduced kidney uptake to 70% of control. Renal retention of [{sup 111}In-DTPA]octreotide is confined to proximal tubules in the rat kidney, in which megalin-mediated endocytosis may play an important part. (orig.)

Albumin-derived peptides efficiently reduce renal uptake of radiolabelled peptides

International Nuclear Information System (INIS)

Vegt, Erik; Eek, Annemarie; Oyen, Wim J.G.; Gotthardt, Martin; Boerman, Otto C.; Jong, Marion de

2010-01-01

In peptide-receptor radionuclide therapy (PRRT), the maximum activity dose that can safely be administered is limited by high renal uptake and retention of radiolabelled peptides. The kidney radiation dose can be reduced by coinfusion of agents that competitively inhibit the reabsorption of radiolabelled peptides, such as positively charged amino acids, Gelofusine, or trypsinised albumin. The aim of this study was to identify more specific and potent inhibitors of the kidney reabsorption of radiolabelled peptides, based on albumin. Albumin was fragmented using cyanogen bromide and six albumin-derived peptides with different numbers of electric charges were selected and synthesised. The effect of albumin fragments (FRALB-C) and selected albumin-derived peptides on the internalisation of 111 In-albumin, 111 In-minigastrin, 111 In-exendin and 111 In-octreotide by megalin-expressing cells was assessed. In rats, the effect of Gelofusine and albumin-derived peptides on the renal uptake and biodistribution of 111 In-minigastrin, 111 In-exendin and 111 In-octreotide was determined. FRALB-C significantly reduced the uptake of all radiolabelled peptides in vitro. The albumin-derived peptides showed different potencies in reducing the uptake of 111 In-albumin, 111 In-exendin and 111 In-minigastrin in vitro. The most efficient albumin-derived peptide (peptide 6), was selected for in vivo testing. In rats, 5 mg of peptide 6 very efficiently inhibited the renal uptake of 111 In-minigastrin, by 88%. Uptake of 111 In-exendin and 111 In-octreotide was reduced by 26 and 33%, respectively. The albumin-derived peptide 6 efficiently inhibited the renal reabsorption of 111 In-minigastrin, 111 In-exendin and 111 In-octreotide and is a promising candidate for kidney protection in PRRT. (orig.)

48 CFR 801.602-71 - Basic review requirements.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Basic review requirements... GENERAL DEPARTMENT OF VETERANS AFFAIRS ACQUISITION REGULATION SYSTEM Career Development, Contracting Authority, and Responsibilities 801.602-71 Basic review requirements. Contracting officers must obtain...