Dataset Information

Pronounced antiseizure activity of the subtype-selective GABA_A positive allosteric modulator darigabat in a mouse model of drug-resistant focal epilepsy.

ABSTRACT:

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.

SUBMITTER: Gurrell R

PROVIDER: S-EPMC9532903 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Publications

Pronounced antiseizure activity of the subtype-selective GABA<sub>A</sub> positive allosteric modulator darigabat in a mouse model of drug-resistant focal epilepsy.

Gurrell Rachel R Iredale Philip P Evrard Alexis A Duveau Venceslas V Ruggiero Céline C Roucard Corinne C

CNS neuroscience & therapeutics 20220814 11

<h4>Aim</h4>Darigabat is an α2/3/5 subunit-selective positive allosteric modulator of GABA<sub>A</sub> 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.<h4>Methods</h4>The MTLE model is generated by single unilateral intrahippocampal injecti ...[more]

PMID: 35965432

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Dataset Information

Pronounced antiseizure activity of the subtype-selective GABA_A positive allosteric modulator darigabat in a mouse model of drug-resistant focal epilepsy.

Aim

Methods

Results

Conclusions

Publications

Pronounced antiseizure activity of the subtype-selective GABA<sub>A</sub> positive allosteric modulator darigabat in a mouse model of drug-resistant focal epilepsy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Pronounced antiseizure activity of the subtype-selective GABAA positive allosteric modulator darigabat in a mouse model of drug-resistant focal epilepsy.

Aim

Methods

Results

Conclusions

Publications

Pronounced antiseizure activity of the subtype-selective GABA<sub>A</sub> positive allosteric modulator darigabat in a mouse model of drug-resistant focal epilepsy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Pronounced antiseizure activity of the subtype-selective GABA_A positive allosteric modulator darigabat in a mouse model of drug-resistant focal epilepsy.