Abstract Details

Mesial temporal lobe epilepsy (MTLE) is the most common form of drug-refractory epilepsy. Most of the morphological and electrophysiological features of human MTLE can be reproduced in mouse by unilateral intrahippocampal injection of kainate (MTLE mouse model). The MTLE model displays differential sensitivity to antiepileptic drugs and has a utility in the identification of new treatments for drug-resistant forms of focal epilepsy.

Darigabat is an α2/3/5 subunit-selective positive allosteric modulator of the GABA_A receptor that has previously demonstrated broad spectrum activity in several preclinical models of epilepsy as well as in a clinical photosensitive epilepsy model. Here, we evaluated if selective enhancement of the inhibitory effect of GABA via this mechanism would suppress the aberrant overexcitation that underlies epileptic activity in a model of treatment-resistant focal seizures.

The MTLE mouse model is generated by unilateral intrahippocampal injection of a single low dose (1 nmole) of kainic acid in adult mice, and subsequent epileptic activity is recorded following implantation of a bipolar electrode under general anaesthesia. After a period of epileptogenesis (~4 weeks), spontaneous and recurrent hippocampal paroxysmal discharges (HPD; focal seizures) can be recorded using intracerebral electroencephalography. The number and cumulated duration of HPDs were recorded following administration of vehicle (PO), darigabat (0.3-10 mg/kg, PO), and the positive control diazepam (2 mg/kg, IP).