Open AccessPronounced antiseizure activity of the subtype‐selective GABA A positive allosteric modulator darigabat in a mouse model of drug‐resistant focal epilepsy
Author(s) -
Gurrell Rachel,
Iredale Philip,
Evrard Alexis,
Duveau Venceslas,
Ruggiero Céline,
Roucard Corinne
Publication year - 2022
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.13927
Subject(s) - epilepsy , epileptogenesis , pharmacology , medicine , allosteric regulation , diazepam , anesthesia , hippocampal formation , kainic acid , hippocampus , drug resistant epilepsy , allosteric modulator , gabaa receptor , receptor , glutamate receptor , psychiatry
Aim Darigabat is an α2/3/5 subunit‐selective positive allosteric modulator of GABA A receptors that has demonstrated broad‐spectrum activity in several preclinical models of epilepsy as well as in a clinical photoepilepsy trial. The objective here was to assess the acute antiseizure effect of darigabat in the mesial temporal lobe epilepsy (MTLE) mouse model of drug‐resistant focal seizures. Methods The MTLE model is generated by single unilateral intrahippocampal injection of low dose (1 nmole) kainic acid in adult mice, and subsequent epileptiform activity is recorded following implantation of a bipolar electrode under general anesthesia. After a period of epileptogenesis (~4 weeks), spontaneous and recurrent hippocampal paroxysmal discharges (HPD; focal seizures) are recorded using intracerebral electroencephalography. The number and cumulated duration of HPDs were recorded following administration of vehicle (PO), darigabat (0.3–10 mg kg −1 , PO), and positive control diazepam (2 mg kg −1 , IP). RESULTS Darigabat dose‐dependently reduced the expression of HPDs, demonstrating comparable efficacy profile to diazepam at doses of 3 and 10 mg kg −1 . CONCLUSIONS Darigabat exhibited a robust efficacy profile in the MTLE model, a preclinical model of drug‐resistant focal epilepsy. A Phase II proof‐of‐concept placebo‐controlled, adjunctive‐therapy trial (NCT04244175) is ongoing to evaluate efficacy and safety of darigabat in patients with drug‐resistant focal seizures.