Fishing for antidotes
Organophosphates (OPs) are commonly found in commercial pesticides and are highly toxic to humans if inhaled or ingested, resulting in both behavioural and psychological symptoms. OPs chemically modify the essential protein acetylcholine esterase, which is principally responsible for the breakdown of the essential neurotransmitter acetylcholine.
Organophosphates (OPs) are commonly found in commercial pesticides and arehighly toxic to humans if inhaled or ingested, resulting in both behavioural andpsychological symptoms. OPs chemically modify the essential protein acetylcholineesterase, which is principally responsible for the breakdown of the essentialneurotransmitter acetylcholine.
A group of investigators in the USA1 have developed a novel assay using themodel organism zebrafish (Danio rerio) for the screening of existing drug librariesto identify compounds effective in the treatment of OP poisoning.The investigatorsfound that OP administration to zebrafish larvae induced similar symptoms tothose seen in humans, followed by death. The investigators used the prototypicalOP azinphos-methyl to screen 1200 known drugs in a 96-well plate format anddemonstrated that 16 of the drugs screened have a protective effect on the zebrafishusing a LC–MS–MS based metabolite profiling approach.
Acetylcholine is an essential neurotransmitter, acting as a chemical signal for thetransmission of information across synapses in the brain, undergoing formation andbreakdown cyclically. OPs act to block the breakdown of acetylcholine by blockingthe action of the enzyme, acetylcholine esterase. This blocking action results in anunnatural accumulation of acetylcholine within the synapse, therefore inducingcontinuous firing of signals resulting in behavioural and psychological symptoms.The currently used antidote for OP poisoning is a combination of atropine andpralidoxime (2-PAM); however, there are unacceptable risks of increased bloodpressure associated with treatment and so identifying new drugs is a priority.
The lead investigator of the study Dr Randall Peterson told The Column, “Humansare confronted by all sorts of toxic chemicals through both accidental and intentionalexposures (such as chemotherapy). Our findings suggest that zebrafish could be usedto systematically screen for antidotes that are protective against organophosphateexposure or virtually any other toxic chemical.”
1. S. Jin et al, Journal of Biomolecular Screening, DOI:10.1177/1087057112458153.
This story originally appeared in The Column. Click here to view that issue.
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