Cholesterol metabolite cholestane-3β,5α,6β-triol suppresses epileptic seizures by negative modulation of voltage-gated sodium channels
| Autor: | Youqiong Wang, Huanhuan Sun, Min Yan, Wenli Chen, Haiyan Hu, Jingxia Zhang, Tiandong Leng, Guangmei Yan, Bingzheng Lu, Yuehan Zhou, Xinwen Su, Wei Yin, Wenbo Zhu, Yijun Huang, Lipeng Tang, Pengxin Qiu |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
medicine.medical_specialty
Oxysterol Metabolite Clinical Biochemistry Voltage-Gated Sodium Channels Biochemistry Pathogenesis Mice chemistry.chemical_compound Epilepsy Endocrinology Internal medicine Excitatory Amino Acid Agonists medicine Animals Molecular Biology Voltage-Gated Sodium Channel Blockers Pharmacology Kainic Acid Dose-Response Relationship Drug Cholesterol Sodium channel Organic Chemistry medicine.disease Disease Models Animal chemistry Cholestane 3β 5α 6β triol Anticonvulsants Triol Cholestanols |
| Zdroj: | Steroids. 98:166-172 |
| ISSN: | 0039-128X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect