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The use of animals as sentinels for exposure to toxins is not new but has come a long way since the first canary was brought into a coal mine. A recent twist took the sentinel from airborne to aquatic, establishing three key results: first, zebrafish are a viable model for cyanide exposure in humans. Second, zebrafish provide an excellent medium for high-throughput chemical screening. And third, riboflavin can mitigate the harmful effects of cyanide toxicity in zebrafish. The research was done by Anjali Nath and Randall Peterson (Harvard Medical School, Charlestown, MA, and Broad Institute, Cambridge, MA) with colleagues at the University of California (Irvine and San Diego) and the US Army Medical Research Institute of Chemical Defense (Aberdeen, MD). Future work will test whether riboflavin also acts as a cyanide antidote in mammalian models. In a press release, Peterson said, “Hopefully, the cyanide biomarkers and antidotes we discover with the help of zebrafish can one day improve our ability to diagnose and treat humans affected by cyanide poisoning.”

In the first part of their study, the scientists exposed zebrafish to cyanide and monitored their responses. Cyanide produced toxic effects in zebrafish that were similar to those reported in rabbits and humans, including bradycardia, neuronal necrosis, metabolic dysfunction and death. The similarities of cyanide-induced toxicity in these species validated the use of zebrafish as a model of human cyanide exposure. “We are encouraged to see that many of the effects of cyanide on zebrafish mirror the effects on humans,” Peterson confirmed. Cyanide exposure also resulted in elevated inosine concentrations in all three species, suggesting that inosine level could be a valid biomarker for cyanide exposure, potentially useful in both diagnosis and antidote development.

Next, the researchers developed a high-throughput, in vivo, whole-organism assay to systematically test whether thousands of compounds could protect zebrafish against cyanide toxicity (FASEB J. 27, 1928–1938; 2013). They screened 3,120 candidate drugs and identified four that rescued zebrafish from otherwise lethal doses of cyanide: cisplatin, carboplatin, methotrexate and riboflavin. The first three compounds are chemotherapeutic agents, whereas riboflavin is a vitamin. Riboflavin was the most effective antidote of the four and did not appear to have negative side effects in fish or humans, unlike the other three compounds.

In further tests, riboflavin mitigated the effects of cyanide on neurobehavioral and metabolic function in the fish. “Riboflavin normalizes many of the cyanide-induced neurological and metabolic perturbations in zebrafish,” the article states.