Cholesterol metabolite cholestane-3β,5α,6β-triol suppresses epileptic seizures by negative modulation of voltage-gated sodium channels

Imbalance of excitation and inhibition in neurons is implicated in the pathogenesis of epilepsy. Voltage-gated sodium channels, which play a vital role in regulating neuronal excitability, are one of the major targets for developing anti-epileptic drugs. Here we provide evidence that cholestane-3 beta,5 alpha,6 beta-triol (triol), a major metabolic oxysterol of cholesterol, is an effective state-dependent negative sodium channels modulator. Trial reduced Na+ current density in a concentration-dependent manner. 10 mu M trial shifted steady-state/fast/slow inactivation curves of sodium channels toward the hyperpolarizing direction. Additionally, triol reduced voltage-gated sodium currents in a voltage- and frequency-dependent manner. In a kainic acid-induced seizures mouse model, triol (25 mg/kg) significantly increased the latency of seizure onset and attenuated seizure severity. Our findings provide novel insights for understanding the modulatory role of a small-molecular oxysterol on voltage-gated sodium channels and suggest trial may represent a novel and promising candidate for epilepsy intervention. (C) 2015 Elsevier Inc. All rights reserved.