TRPV1 antagonist AMG9810 suppresses focal epileptiform discharges and seizures by decreasing extracellular glutamate concentrations in mice

Abstract

The development of targeted anti-epilepsy drugs is crucial, as 30 % of patients with epilepsy are resistant to current therapeutics. Transient receptor potential vanilloid 1 (TRPV1) channel antagonists have been demonstrated to suppress drug-induced epileptiform discharges (EDs) and seizures (ESs). Here, we investigated the correlation between the anti-epileptiform efficacy of AMG9810 and extracellular glutamate levels. The somatosensory cortices of male C57BL/6N mice were intracortically injected with penicillin G (PG: 200 IU, 1 μL/10 min), a seizure inducer that inhibits the GABA_A receptor. The mice were intracortically injected with AMG9810 (3 μM, 1 μL/10 min) either before or after PG administration. EDs, ESs, and glutamate levels were subsequently evaluated. The results of each experiment were compared between the vehicle and AMG9810-injected groups. AMG9810 injected after PG reduced glutamate levels and ED power, and there was a positive correlation between AMG9810 efficacy and these parameters. Injecting AMG9810 before PG injection decreased the increase in glutamate levels and development of EDs and ESs, with positive correlations observed among the three parameters. These findings suggest that TRPV1 antagonists suppress the development of EDs and ESs by decreasing extracellular glutamate levels, indicating that TRPV1 channels may represent a promising treatment option for epilepsy.