Understanding neuromuscular transmission failure in organophosphorus pesticide toxicity
About the project
Intermediate syndrome in organophosphorus toxicity is debilitating condition whereby people experience delayed muscle paralysis including of the respiratory muscle. Failure of neuromuscular junction (NMJ) transmission appears to cause the muscle paralysis.
Our goal is to understand the mechanisms of NMJ transmission failure in organophosphorus toxicity, not only to help treat those affected, but also as a platform to investigate other diseases related to NMJ transmission failure. Utilising electrophysiological techniques (e.g. tension measurements, intracellular recordings and patch clamp recordings) along with morphological approaches (calcium imaging, immunocytochemistry) we have been able to differentiate some of the key components of NMJ transmission failure.
Our major findings include: (i) omethoate, a pesticide anti-AChE metabolite, shows prolongs endplate depolarization and induces NMJ hypercontraction with impaired transmission; and (ii) cyclohexanol, an agricultural pesticide solvent metabolite, causes depression and prolongation of endplate potentials, thus myasthenic muscle contractions. Cyclohexanol can also bind to the nicotinic acetylcholine receptor and impair its gating mechanisms. Hypothermia and magnesium infusion seem to mitigate NMJ transmission failure, demonstrating their potential value as a treatment in humans.
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Publication(s)
Primary location
Principal Investigator
Other people involved
Richard Ribchester (Co-PI)
Michael Eddleston (Co-PI)
Tom Gillingwater (Collaborator)
Tom Wishart (Collaborator)