Pronounced antiepileptic activity of the subtype-selective GABAA -positive allosteric modulator PF-06372865 in the GAERS absence epilepsy model.

Abstract

Antiepileptic drugs that modulate GABA have the potential to aggravate or improve the symptoms of absence epilepsy. PF-06372865 is a positive allosteric modulator (PAM) of α2/3/5 subunit-containing GABAA receptors with minimal activity at α1-containing receptors, which are believed to mediate many of the adverse events associated with benzodiazepines. The aim of this study was to assess the antiepileptic effect of PF-06372865 in a preclinical model of absence seizures. Genetic absence epilepsy rats from Strasbourg (GAERS) was implanted with four cortical electrodes over the frontoparietal cortex, and the number and cumulated duration of spike-and-wave discharges (SWDs) were recorded for 10-90minutes following administration of vehicle, PF-06372865, and positive controls diazepam and valproate. PF-06372865 (0.3, 1, 2, 10mgkg-1 ) dose-dependently reduced the expression of SWDs, including full suppression at the highest doses by 30minutes after administration. PF-06372865 demonstrated robust efficacy in suppressing SWDs in the GAERS model of absence epilepsy. To our knowledge, this is the first demonstration of antiepileptic activity of an α2/3/5-subtype-selective GABAA PAM in a model of absence epilepsy. Further study of the antiepileptic properties of PF-06372865 is warranted in patients with absence seizures.