title: Cholesterol metabolite cholestane-3β,5α,6β-triol suppresses epileptic seizures by negative modulation of voltage-gated sodium channels.
abstract: 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.
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, GD 510080, China.
authors.forename: Lipeng
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, GD 510080, China.
authors.forename: Youqiong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, GD 510080, China.
authors.forename: Tiandong
authors.initials: T
authors.lastname: Leng
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, GD 510080, China.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, GD 510080, China; Department of Pharmacology, Guilin Medical University, Guilin, GX 541004, China.
authors.forename: Yuehan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, GD 510080, China.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, GD 510080, China.
authors.forename: Pengxin
authors.initials: P
authors.lastname: Qiu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, GD 510006, China.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, GD 510080, China.
authors.forename: Bingzheng
authors.initials: B
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, GD 510080, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, GD 510080, China.
authors.forename: Wenli
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, GD 510080, China.
authors.forename: Xinwen
authors.initials: X
authors.lastname: Su
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, GD 510080, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yin
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, GD 510080, China.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, GD 510006, China. Electronic address: Isshhy@mail.sysu.edu.cn.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, GD 510080, China. Electronic address: ygm@mail.sysu.edu.cn.
authors.forename: Guangmei
authors.initials: G
authors.lastname: Yan
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology*; D002777:Cholestanols / Q000737:chemistry / Q000494:pharmacology*; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000009:adverse effects / Q000494:pharmacology; D007608:Kainic Acid / Q000009:adverse effects / Q000494:pharmacology; D051379:Mice; D061567:Voltage-Gated Sodium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
chemical_list: D000927:Anticonvulsants; D002777:Cholestanols; D018690:Excitatory Amino Acid Agonists; D061567:Voltage-Gated Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels; C000474:cholestane-3,5,6-triol; D002784:Cholesterol; D007608:Kainic Acid
keywords: Cholestane-3β-5α-6β-triol; Epilepsy; Oxysterol; Voltage-gated sodium channels