Potential new therapeutic modality revealed through agent-based modeling of the neuromuscular junction and acetylcholinesterase inhibitionReportar como inadecuado




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Theoretical Biology and Medical Modelling

, 11:42

Cell biology

Abstract

BackgroundOne of the leading causes of death and illness within the agriculture industry is through unintentionally ingesting or inhaling organophosphate pesticides. OP intoxication directly inhibits acetylcholinesterase, resulting in an excitatory signaling cascade leading to fasciculation, loss of control of bodily fluids, and seizures.

MethodsOur model was developed using a discrete, rules-based modeling approach in NetLogo. This model includes acetylcholinesterase, the nicotinic acetylcholine receptor responsible for signal transduction, a single release of acetylcholine, organophosphate inhibitors, and a theoretical novel medical countermeasure. We have parameterized the system considering the molecular reaction rate constants in an agent-based approach, as opposed to apparent macroscopic rates used in differential equation models.

ResultsOur model demonstrates how the cholinergic crisis can be mitigated by therapeutic intervention with an acetylcholinesterase activator. Our model predicts signal rise rates and half-lives consistent with in vitro and in vivo data in the absence and presence of inhibitors. It also predicts the efficacy of theoretical countermeasures acting through three mechanisms: increasing catalytic turnover of acetylcholine, increasing acetylcholine binding affinity to the enzyme, and decreasing binding rates of inhibitors.

ConclusionWe present a model of the neuromuscular junction confirming observed acetylcholine signaling data and suggesting that developing a countermeasure capable of reducing inhibitor binding, and not activator concentration, is the most important parameter for reducing organophosphate OP intoxication.

KeywordsNeuromuscular junction Acetylcholinesterase Organophosphate intoxication Medical countermeasure Allosteric enzyme regulation Agent-based model Electronic supplementary materialThe online version of this article doi:10.1186-1742-4682-11-42 contains supplementary material, which is available to authorized users.

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Autor: Richard R Chapleau - Peter J Robinson - John J Schlager - Jeffery M Gearhart

Fuente: https://link.springer.com/







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