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

• Published in: Neurotoxicology (Park Forest South) Vol. 54; pp. 140 - 152
• Main Authors: Greget, Renaud, Dadak, Selma, Barbier, Laure, Lauga, Fabien, Linossier-Pierre, Sandra, Pernot, Fabien, Legendre, Arnaud, Ambert, Nicolas, Bouteiller, Jean-Marie, Dorandeu, Frédéric, Bischoff, Serge, Baudry, Michel, Fagni, Laurent, Moussaoui, Saliha
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2016; Elsevier
• Subjects: Acetyl- and/or butyryl-cholinesterase; Acetylcholine; Acetylcholinesterase - metabolism; Animals; Brain Waves - drug effects; Cholinesterase Reactivators - pharmacology; Computer Simulation; Disease Models, Animal; Enzyme Inhibitors - therapeutic use; Excitatory Amino Acid Antagonists - pharmacology; Excitatory Postsynaptic Potentials - drug effects; Hippocampus - drug effects; Hippocampus - metabolism; Life Sciences; Male; Memantine - pharmacology; Membrane Potentials - drug effects; Mice; Models, Neurological; N-Methyl-d-aspartate; Neurons - drug effects; Neurotoxicity Syndromes - drug therapy; Neurotoxicity Syndromes - etiology; Neurotoxicity Syndromes - pathology; Neurotoxicity Syndromes - physiopathology; Organophosphates - toxicity; Organophosphorus; Oximes - pharmacology; Paraoxon; Paraoxon - toxicity; Pyridinium Compounds - pharmacology; γ-Aminobutyric acid; Organophosphorus; γ-Aminobutyric acid; Acetylcholine; Acetyl- and/or butyryl-cholinesterase; N-Methyl-d-aspartate; Paraoxon; gamma-Aminobutyric acid
• ISSN: 0161-813X; 1872-9711
• DOI: 10.1016/j.neuro.2016.04.013

•A novel in silico model of Organophosphorus (OP)-induced neuronal toxicity is set up.•This model enables predicting effect of drugs on OP-induced neuronal hyperexcitability.•The predicted effects of atropine, memantine, their combination are validated in vivo.•The use of the in silico modeling early in the antidote screening process is proposed. 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 CA1 hippocampal neurons triggered by exposure to paraoxon (POX), as found in patch-clamp recordings in in vitro mouse hippocampal slices. In the case of POX 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 POX 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.