Menthol exerts TRPM8-independent antiepileptic effects in prefrontal cortex pyramidal neurons

Menthol is a natural compound that evokes cold sensations by activating TRPM8 channels in peripheral sensory receptors. Little is known about the effects of this compound on brain neurons. It has been shown previously that menthol exerts antiepileptic effects in hippocampal neurons by enhancing GABA receptors. The aim of this patch clamp study was to assess the effects of menthol on sodium currents, action potentials and epileptiform events in cortical neurons. Menthol inhibited fast voltage-gated sodium channels and neuronal excitability defined as the number of action potentials per depolarization step. The influence of menthol on epileptic events was also assessed in this study. Interictal epileptiform events lasting <2 s were recorded in zero magnesium high potassium proepileptic extracellular solution. The frequency of these epileptiform events was inhibited by menthol (200 mu M). Ictal epileptic events lasting >100 s were recorded in zero magnesium proepileptic extracellular solution containing 4 AP. The frequency of these ictal events was potently decreased by menthol. TRPM8 channels were not involved in the inhibitory effect of menthol on ictal events because epileptic discharges persisted in the presence of the TRPM8 inhibitor AMTB. Moreover, ictal events were inhibited by therapeutic concentrations of the antiepileptic drug carbamazepine. Menthol and carbamazepine inhibited ictal events to a similar extent. This study showed that menthol exerts antiepileptic effects in cortical neurons.