The opioid antagonist naltrexone decreases seizure-like activity in genetic and chemically induced epilepsy models

Abstract

Objective: A significant number of epileptic patients fail to respond to available anticonvulsive medications. To find new anticonvulsive medications, we evaluated FDA-approved drugs not known to be anticonvulsants. Using zebrafish larvae as an initial model system, we found that the opioid antagonist naltrexone exhibited an anticonvulsant effect. We validated this effect in three other epilepsy models and present naltrexone as a promising anticonvulsive candidate. Methods: Candidate anticonvulsant drugs, determined by our prior transcriptomics analysis of hippocampal tissue, were evaluated in a larval zebrafish model of human Dravet syndrome (scn1Lab mutants), in wild-type zebrafish larvae treated with the pro-convulsant drug pentylenetetrazole (PTZ), in wild-type C57bl/6J acute brain slices exposed to PTZ, and in wild-type mice treated with PTZ in vivo. Abnormal locomotion was determined behaviorally in zebrafish and mice and by field potential in neocortex layer IV/V and CA1 stratum pyramidale in the hippocampus. Results: The opioid antagonist naltrexone decreased abnormal locomotion in the larval zebrafish model of human Dravet syndrome (scn1Lab mutants) and wild-type larvae treated with the pro-convulsant drug PTZ. Naltrexone also decreased seizure-like events in acute brain slices of wild-type mice, and the duration and number of seizures in adult mice injected with PTZ. Significance: Our data reveal that naltrexone has anticonvulsive properties and is a candidate drug for seizure treatment.