4.4 Article

Modeling and simulation of organophosphate-induced neurotoxicity: Prediction and validation by experimental studies

期刊

NEUROTOXICOLOGY
卷 54, 期 -, 页码 140-152

出版社

ELSEVIER SCIENCE BV
DOI: 10.1016/j.neuro.2016.04.013

关键词

Acetylcholine; Acetyl- and/or butyryl-cholinesterase; gamma-Aminobutyric acid; N-Methyl-D-aspartate; Organophosphorus; Paraoxon

资金

  1. IRBA (Institut de recherche biornedicale des armees)
  2. IGF (Institut de Genomique Fonctionnelle)
  3. CNRS, Montpellier
  4. France
  5. Rhenovia Pharma

向作者/读者索取更多资源

Exposure to organophosphorus (OP) compounds, either pesticides or chemical warfare agents, represents a major health problem. As potent irreversible inhibitors of cholinesterase, OP may induce seizures, as in status epilepticus, and occasionally brain lesions. Although these compounds are extremely toxic agents, the search for novel antidotes remains extremely limited. In silico modeling constitutes a useful tool to identify pharmacological targets and to develop efficient therapeutic strategies. In the present work, we developed a new in silico simulator in order to predict the neurotoxicity of irreversible inhibitors of acetyl- and/or butyrylcholinesterase (ChE) as well as the potential neuroprotection provided by antagonists of cholinergic muscarinic and glutamate N-methyl-D-aspartate (NMDA) receptors. The simulator reproduced firing of CM hippocampal neurons triggered by exposure to paraoxon (PDX), as found in patch-clamp recordings in in vitro mouse hippocampal slices. In the case of PDX intoxication, it predicted a preventing action of the muscarinic receptor antagonist atropine sulfate, as well as a synergistic action with the non-competitive NMDA receptor antagonist memantine. These in silico predictions relative to beneficial effects of atropine sulfate combined with memantine were recapitulated experimentally in an in vivo model of PDX in adult male Swiss mice using electroencephalic (EEG) recordings. Thus, our simulator is a new powerful tool to identify protective therapeutic strategies against OP central effects, by screening various combinations of muscarinic and NMDA receptor antagonists. (C) 2016 Elsevier Inc. All rights reserved.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.4
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据