Fishing for antidotes

Oct 23, 2012
By LCGC Editors

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.

A group of investigators in the USA1 have developed a novel assay using the model organism zebrafish (Danio rerio) for the screening of existing drug libraries to identify compounds effective in the treatment of OP poisoning.The investigators found that OP administration to zebrafish larvae induced similar symptoms to those seen in humans, followed by death. The investigators used the prototypical OP azinphos-methyl to screen 1200 known drugs in a 96-well plate format and demonstrated that 16 of the drugs screened have a protective effect on the zebrafish using a LC–MS–MS based metabolite profiling approach.

Acetylcholine is an essential neurotransmitter, acting as a chemical signal for the transmission of information across synapses in the brain, undergoing formation and breakdown cyclically. OPs act to block the breakdown of acetylcholine by blocking the action of the enzyme, acetylcholine esterase. This blocking action results in an unnatural accumulation of acetylcholine within the synapse, therefore inducing continuous firing of signals resulting in behavioural and psychological symptoms. The currently used antidote for OP poisoning is a combination of atropine and pralidoxime (2-PAM); however, there are unacceptable risks of increased blood pressure associated with treatment and so identifying new drugs is a priority.

The lead investigator of the study Dr Randall Peterson told The Column, “Humans are confronted by all sorts of toxic chemicals through both accidental and intentional exposures (such as chemotherapy). Our findings suggest that zebrafish could be used to systematically screen for antidotes that are protective against organophosphate exposure 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.