Antiseizure potential of the triple T-type calcium channel blocker ACT-709478 (apinocaltamide) in rodent models.

Abstract

Objective: T-type Ca²⁺ channels in the brain contribute to the generation of spike-and-wave discharges (SWDs). Absence seizures are defined by the occurrence of SWDs and are associated with impairment of consciousness. ACT-709478 is a selective and highly potent blocker of the low-voltage-activated T-type Ca²⁺ channels, Ca_v3.1, Ca_v3.2, and Ca_v3.3, with no relevant activity on other targets. Our aim was to investigate the efficacy of ACT-709478 in reducing absence-like and other types of seizures in rodents.

Methods: We studied the effect of oral ACT-709478 on SWDs in two models of absence-like epilepsy, Wistar Albino Glaxo from Rijswijk (WAG/Rij) rats and Genetic Absence Epilepsy Rats from Strasbourg (GAERS), and compared it to first-line monotherapy. We also assessed the potential of ACT-709478 to reduce generalized convulsive seizures in audiogenic seizure-sensitive (AGS) mice and in the maximal electroshock threshold test (MEST) in mice, as well as in one model of focal onset seizures, the amygdala kindling rat model. We tested combinations of ACT-709478 with the broadly used first-line medication valproate in AGS mice.

Results: ACT-709478 suppressed SWDs in WAG/Rij rats and GAERS with efficacy equivalent to or superior to that of first-line monotherapy. ACT-709478 also reduced the severity of generalized convulsive seizures in the AGS mouse model and the MEST in mice, albeit at higher concentration. ACT-709478 had synergistic effects against generalized convulsive seizures, when combined with valproate, and had no effect on focal onset seizures.

Significance: Based on its efficacy profile in rodent models, ACT-709478 represents a promising drug candidate for the treatment of absence epilepsy such as childhood absence epilepsy or syndromes featuring SWDs. It could possibly also be beneficial for epileptic syndromes presenting with additional seizure types.