Anti-seizure effects of WS-3, a TRPM8 agonist, on focal onset seizure mouse model via reduction of extracellular glutamate levels

The development of novel anti-seizure drugs targeting novel mechanisms is crucial, especially for patients with intractable epilepsy. Previous studies using focal onset seizure rodent models have demonstrated that Icilin and WS-3, agonists of the transient receptor potential melastatin 8 (TRPM8) channel, suppress drug-induce epileptiform discharges (EDs) and seizures (ESs). In contrast, TRPM8 deficiency exacerbates EDs and ESs. This study investigated the mechanism underlying the anti-seizure effects of the TRPM8 agonist, WS-3, using a focal onset seizure mouse model. Mice were injected with WS-3 either before or after administering the seizure inducer, penicillin G potassium. EDs, ESs, and glutamate levels were subsequently evaluated. In wild-type (WT) mice, WS-3 injected after the seizure inducer reduced glutamate levels and ED power by 44% and 60%, respectively, with a positive correlation between WS-3 efficacy and these parameters. WS-3 injection before seizure induction suppressed the increase in glutamate levels and the development of ED and ES, with positive correlations observed among the three parameters. Conversely, TRPM8-knockout mice showed no anti-seizure effects from WS-3. TRPM8 deficiency led to a further increase in the glutamate levels, ED power, and ES severity after the seizure inducer injection. Additionally, TRPM8-deficient mice experienced EDs with fewer glutamate exposures and shortened latency to ED development following seizure induction. These findings suggest that TRPM8 agonists suppress the development of EDs and ESs by reduction of extracellular glutamate levels, indicating that TRPM8 channels may represent a promising treatment option for epilepsy.