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.

Clemizole and trazodone are effective antiseizure treatments in a zebrafish model of STXBP1 disorder

“…Drug solutions (~0.5 mL) were bath applied using a polyethylene disposable transfer pipette (Fisherbrand #13–711‐7 M) to agarose‐embedded larvae at room temperature. All drugs were tested at a concentration of 1 mM as previous studies empirically indicate millimolar (mM) drug concentrations are appropriate for acute pharmacology studies in agarose‐embedded larvae 16,24–30 . Experiments were performed on at least three independent clutches of larvae for each drug.…”

Commentary on “Antiseizure activity by opioid receptor antagonism, new evidence”

“…Next, a selection of compounds was functionally tested in a behavioral assay with zebrafish larvae and was found to suppress PTZ‐induced seizures 4 . In the present follow‐up study, Morgan Sturgeon and coworkers discovered that naltrexone, a compound previously found in the C‐Map query, was able to decrease the abnormal locomotion of PTZ‐treated zebrafish larvae and homozygous scn1Lab mutant (scn1Lab −/− ) zebrafish 5 …”

“…4 In the present follow-up study, Morgan Sturgeon and coworkers discovered that naltrexone, a compound previously found in the C-Map query, was able to decrease the abnormal locomotion of PTZ-treated zebrafish larvae and homozygous scn1Lab mutant (scn1Lab −/− ) zebrafish. 5 The latter mutant fish represent a model of Dravet syndrome (DS), a severe and highly drug-resistant developmental and epileptic encephalopathy, in the majority of cases due to SCN1A gene mutations, with onset of recurrent seizures during the first year of life of patients. 6 Of note, the zebrafish DS model was previously used to identify potential treatment options for Dravet syndrome 7 and to further decipher the mechanism of action of fenfluramine, 8 a therapeutic that together with cannabidiol is now considered second-line treatment for DS patients.…”

“…12 In previous studies, naltrexone has demonstrated antiseizure but also proseizure effects at different doses using different animal models. 5 It is therefore tempting to think that the conflicting profile of the compound largely depends on the amount of different opioid receptors occupied, in combination with their relative distribution across different areas of the brain and the epileptic foci involved. In the current study, the homozygous scn1Lab mutant zebrafish larvae were exposed by immersion to 75 μM naltrexone at 7dpf (days post-fertilization), but it is presently not known how much compound entered the brain, and what the affinity is for the zebrafish's individual opioid receptors.…”

“…In previous studies, naltrexone has demonstrated antiseizure but also proseizure effects at different doses using different animal models 5 . It is therefore tempting to think that the conflicting profile of the compound largely depends on the amount of different opioid receptors occupied, in combination with their relative distribution across different areas of the brain and the epileptic foci involved.…”