Saikosaponin A modulates remodeling of Kv4.2-mediated A-type voltage-gated potassium currents in rat chronic temporal lobe epilepsy.
Saikosaponin A modulates remodeling of Kv4.2-mediated A-type voltage-gated potassium currents in rat chronic temporal lobe epilepsy.
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DOI：
10.2147/dddt.s166408
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Xie W
中科院分区：
文献类型：
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作者：
Hong Y;Deng N;Jin HN;Xuan ZZ;Qian YX;Wu ZY;Xie W
慢性颞叶癫痫（chronic temporal lobe epilepsy，cTLE）是最常见的难治性癫痫。近年来的研究表明，柴胡皂苷A（SaikosaponinA，SSa）能抑制4种动作电位诱发的癫痫样放电，并选择性地增加瞬时失活K+电流（IntensionalInactivatingK + currents，IA）。然而，SSa对IA的作用机制尚不清楚。在本研究中，我们全面评估了SSa的抗惊厥活性，并探讨其是否通过重塑Kv4.2介导的A型电压门控钾电流（Kv4.2-mediated IA）在Li-pilocarpine诱导的癫痫大鼠模型中发挥抗癫痫作用。所有体外自发性复发性癫痫发作（SRS）均采用连续视频监测记录。采用尼氏染色法观察SSa对癫痫持续状态大鼠海马CA 1区神经元的保护作用，免疫组化、Western blot和定量逆转录PCR检测海马CA 1区及邻近皮质Kchip 1和Kv4.2的表达。我们使用全细胞电流钳记录来评估SSa在cTLE的海马神经元培养模型中的抗惊厥活性，而全细胞电压钳记录用于评估SSa对Kv4.2介导的IA的调节作用。SSa治疗在8周的过程中显著降低了SRS的频率和持续时间，并增加了Kchip 1和Kv4.2的产生。此外，SSa减弱海马神经元模型中的自发复发性癫痫样放电（SRED），并上调Kv4.2介导的IA。SSa在我们的cTLE大鼠模型中在体内和体外均发挥了疾病修饰作用; Kv4.2介导的IA的增加可能有助于SSa的抗惊厥机制。
Chronic temporal lobe epilepsy (cTLE) is the most common intractable epilepsy. Recent studies have shown that saikosaponin A (SSa) could inhibit epileptiform discharges induced by 4 action potentials and selectively increase the transient inactivating K+ currents (IA). However, the mechanisms of SSa on IA remain unclear. In this study, we comprehensively evaluated the anticonvulsant activities of SSa and explored whether or not it plays an anti-epileptic role in a Li-pilocarpine induced epilepsy rat model via remodeling Kv4.2-mediated A-type voltage-gated potassium currents (Kv4.2-mediated IA). All in vitro spontaneous recurrent seizures (SRS) were recorded with continuous video monitoring. Nissl’s staining was used to evaluate the SSa protection of neurons and immunohistochemistry, Western blot, and quantitative reverse transcription PCR were used to quantify the expression of Kchip1 and Kv4.2 in the hippocampal CA1 field and the adjacent cortex following Li-pilocarpine induced status epilepticus. We used whole-cell current-clamp recordings to evaluate the anticonvulsant activities of SSa in a hippocampal neuronal culture model of cTLE, while whole-cell voltage-clamp recordings were used to evaluate the modulatory effects of SSa on Kv4.2-mediated IA. SSa treatment significantly reduced the frequency and duration of SRS over the course of eight weeks and increased the production of Kchip1 and Kv4.2. In addition, SSa attenuated spontaneous recurrent epileptiform discharges (SREDs) in the hippocampal neuronal model and up-regulated Kv4.2-mediated IA. SSa exerted a disease-modifying effect in our cTLE rat model both in vivo and in vitro; the increase in Kv4.2-mediated IA may contribute to the anticonvulsant mechanisms of SSa.