Pathogenesis of neuromuscular synaptic dysfunction and transmission failure in organophosphate toxicity

About the project

Drugs that affect the breakdown of acetylcholine – the neurotransmitter that mediates communication between motor neurones and muscle – are used to treat some forms of neuromuscular disease (like myasthenia gravis). But at high doses these ‘anticholinesterase’ compounds can also have severe, toxic effects on normal neuromuscular function. One such class of anticholinesterases are the organophosphates, used widely in south Asia as agricultural insecticides. Intense exposure to some of them sometimes leads to a paralysing illness called Intermediate Myasthenic Syndrome, whose signs and symptoms resemble some forms of MND. We do yet know the cause of this illness but we have made progress both in understanding the condition and identifying potential treatments. We will shortly be submitting for publication the results of six years investigation on this project. Our data show there are multiple toxic effects of the organophosphates on both nerve endings and muscle fibres; but that these can be prevented with drugs that mitigate the flow of calcium ions into cells.

Funder(s)

Medical Research Council

Publication(s)

Eddleston M, Street JM, Self I, Thompson A, King T, Williams N, Naredo G, Dissanayake K, Yu LM, Worek F, John H, Smith S, Thiermann H, Harris JB, Eddie Clutton R
A role for solvents in the toxicity of agricultural organophosphorus pesticides
Toxicology. 2012 Apr 11;294(2-3):94-103

Primary location

Edinburgh

Principal Investigator

Other people involved

Professor Michael Eddleston (Co-I)

Professor R Eddie Clutton (Co-I)

Dr Kosala Dissanayake (postdoc)

Mr Robert Chou (research assistant)


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