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-3β,5α,6β-triol (triol), a major metabolic oxysterol of cholesterol, is an effective state-dependent negative sodium channels modulator. Triol reduced Na(+) current density in a concentration-dependent manner. 10 μM triol 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 triol may represent a novel and promising candidate for epilepsy intervention.
['Tang|Lipeng|L|', 'Wang|Youqiong|Y|', 'Leng|Tiandong|T|', 'Sun|Huanhuan|H|', 'Zhou|Yuehan|Y|', 'Zhu|Wenbo|W|', 'Qiu|Pengxin|P|', 'Zhang|Jingxia|J|', 'Lu|Bingzheng|B|', 'Yan|Min|M|', 'Chen|Wenli|W|', 'Su|Xinwen|X|', 'Yin|Wei|W|', 'Huang|Yijun|Y|', 'Hu|Haiyan|H|', 'Yan|Guangmei|G|']
D000818:Animals D000927:Anticonvulsants D002777:Cholestanols D002784:Cholesterol D004195:Disease Models, Animal D004305:Dose-Response Relationship, Drug D004827:Epilepsy D018690:Excitatory Amino Acid Agonists D007608:Kainic Acid D051379:Mice D061567:Voltage-Gated Sodium Channel Blockers D061566:Voltage-Gated Sodium Channels
Voltage-gated sodium channels Epilepsy Oxysterol Cholestane-3β-5α-6β-triol