Journal
NEUROTOXICOLOGY
Volume 54, Issue -, Pages 140-152Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.neuro.2016.04.013
Keywords
Acetylcholine; Acetyl- and/or butyryl-cholinesterase; gamma-Aminobutyric acid; N-Methyl-D-aspartate; Organophosphorus; Paraoxon
Categories
Funding
- IRBA (Institut de recherche biornedicale des armees)
- IGF (Institut de Genomique Fonctionnelle)
- CNRS, Montpellier
- France
- Rhenovia Pharma
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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.
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