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Modeling and simulation of organophosphate-induced neurotoxicity: Prediction and validation by experimental studies
Renaud Greget1, Selma Dadak2, Laure Barbier3
1Rhenovia Pharma SAS, Mulhouse, France.
Abstract:
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.
Insights
Organophosphorus compounds can cause seizures and brain lesions. A new in silico simulator predicts that combining atropine sulfate and memantine can protect against these neurotoxic effects.
Area of Science:
- Neuroscience
- Pharmacology
- Computational Biology
Background:
- Organophosphorus (OP) compounds, including pesticides and chemical warfare agents, are potent cholinesterase inhibitors causing significant health issues like seizures and brain lesions.
- Developing effective antidotes for OP toxicity is challenging, necessitating innovative approaches like in silico modeling to identify therapeutic targets.
Purpose of the Study:
- To develop and validate a novel in silico simulator for predicting organophosphorus-induced neurotoxicity.
- To assess the neuroprotective potential of muscarinic and N-methyl-D-aspartate (NMDA) receptor antagonists against OP compounds.
Main Methods:
- Development of an in silico simulator to model the effects of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors.
- Simulation of CA1 hippocampal neuron firing in response to paraoxon (POX) exposure, validated against in vitro patch-clamp data.
- Experimental validation using in vivo electroencephalography (EEG) in mice exposed to POX, testing atropine sulfate and memantine combinations.
Main Results:
- The simulator accurately reproduced neuronal firing patterns observed in experimental models of paraoxon intoxication.
- In silico predictions indicated that atropine sulfate could prevent POX-induced neurotoxicity.
- A synergistic neuroprotective effect was predicted and experimentally confirmed for the combination of atropine sulfate and memantine.
Conclusions:
- The developed in silico simulator is a powerful tool for predicting the neurotoxicity of irreversible cholinesterase inhibitors.
- The combination of muscarinic and NMDA receptor antagonists shows significant promise as a therapeutic strategy against organophosphorus compound-induced central nervous system effects.
- This computational approach can accelerate the discovery of novel antidotes and treatment strategies for OP poisoning.
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