2025年7月11日,北京大学药学院天然药物及仿生药物全国重点实验室孙崎教授和黄卓教授团队合作在Journal of Medicinal Chemistry上在线发表新型2-(2-噻吩基)噻唑并[4,5-d]嘧啶-7(6H)-酮类GABA_(A)R正向变构调节剂通过靶向β+/α-亚基界...2025年7月11日,北京大学药学院天然药物及仿生药物全国重点实验室孙崎教授和黄卓教授团队合作在Journal of Medicinal Chemistry上在线发表新型2-(2-噻吩基)噻唑并[4,5-d]嘧啶-7(6H)-酮类GABA_(A)R正向变构调节剂通过靶向β+/α-亚基界面治疗小鼠癫痫持续状态的原创性研究工作。该研究针对临床治疗癫痫持续状态(Status Epilepticus,SE)面临的苯二氮草类药物耐药性难题,开发了具有全新化学骨架的靶向疗法。展开更多
Extrasynaptic GABAA receptors （GABAARs）-mediated tonic inhibition is reported to involve in the patho- genesis of epilepsy. In this study, we used cyclo- thiazide （CTZ）-induced in vitro brain slice seizure model t...Extrasynaptic GABAA receptors （GABAARs）-mediated tonic inhibition is reported to involve in the patho- genesis of epilepsy. In this study, we used cyclo- thiazide （CTZ）-induced in vitro brain slice seizure model to explore the effect of selective activation of extrasynaptic GABAARS by 4,5,6,7-tetra- hydroisoxazolo[5,4-c] pyridine-3-ol （THIP） on the CTZ-induced epileptiform activity in hippocampal neurons. Perfusion with CTZ dose-dependently induced multiple epileptiform peaks of evoked population spikes （PSs）in CA1 pyramidal neurons, and treatment with THIP （5 μmol/L） significantly reduced the multiple PS peaks induced by CTZ stimulation. Western blot showed that the 6-subunit of the GABAAR, an extrasynaptic specific GABAAR subunit, was also significantly down-regulated in the cell membrane 2 h after CTZ treatment. Our results suggest that the CTZ-induced epileptiform activity in hippocampal CA1 neurons is suppressed by the activation of extrasynaptic GABAARs, and further support the hypothesis that tonic inhibition mediated by extrasynaptic GABAARs plays a prominent role in seizure generation.展开更多
目的:本研究通过比较不同药物干预下对GABAARα1、NMDAR1表达的影响,探讨柴贝止痫汤抑制颞叶癫痫发作的分子病理机制。方法:腹腔注射氯化锂-匹罗卡品制成颞叶癫痫模型,通过免疫组织化学方法和显微图像分析技术检测大鼠颞叶、海马的γ-...目的:本研究通过比较不同药物干预下对GABAARα1、NMDAR1表达的影响,探讨柴贝止痫汤抑制颞叶癫痫发作的分子病理机制。方法:腹腔注射氯化锂-匹罗卡品制成颞叶癫痫模型,通过免疫组织化学方法和显微图像分析技术检测大鼠颞叶、海马的γ-氨基丁酸受体(GABAARα1)和谷氨酸受体(NMDAR1)的表达。结果:GABA A Rα1的表达,与空白模型组比较,柴贝止痫汤组、柴贝止痫汤联合卡马西平组癫痫大鼠海马CA1、CA3区及颞叶皮层的GABA A Rα1亚单位表达均明显增强,有高度显著性差异(P<0.01),但柴贝止痫汤组与柴贝止痫汤联合卡马西平组之间无显著性差异(P>0.05)。与正常组比较,空白模型组和卡马西平组癫痫大鼠海马CA1、CA3区及颞叶皮层的GABA A Rα1表达均明显减少,有高度显著性差异(P<0.01)。NMDAR1的表达,与正常组比较,柴贝止痫汤组、柴贝止痫汤联合卡马西平组、卡马西平组、空白模型组海马CA1、CA3区及颞叶皮层的NMDAR1表达均明显增高,有显著性差异(P<0.05),但柴贝止痫汤组、柴贝止痫汤联合卡马西平组、卡马西平组、空白模型组各组之间无显著性差异(P>0.05)。结论:柴贝止痫汤可以提高GABA A Rα1的表达,而对NMDAR1无明显影响。对GABA A Rα1表达的调节是柴贝止痫汤控制癫痫的可能机理之一。展开更多
文摘2025年7月11日,北京大学药学院天然药物及仿生药物全国重点实验室孙崎教授和黄卓教授团队合作在Journal of Medicinal Chemistry上在线发表新型2-(2-噻吩基)噻唑并[4,5-d]嘧啶-7(6H)-酮类GABA_(A)R正向变构调节剂通过靶向β+/α-亚基界面治疗小鼠癫痫持续状态的原创性研究工作。该研究针对临床治疗癫痫持续状态(Status Epilepticus,SE)面临的苯二氮草类药物耐药性难题,开发了具有全新化学骨架的靶向疗法。
基金supported by grants from the National Natural Science Foundation of China(31129003,81100815,81171224, 81401082,and 81301108)the Science and Technology Commission of Shanghai Municipality,China(13DJ1400302, 13ZR1406500,and 11ZR1401700)
文摘Extrasynaptic GABAA receptors （GABAARs）-mediated tonic inhibition is reported to involve in the patho- genesis of epilepsy. In this study, we used cyclo- thiazide （CTZ）-induced in vitro brain slice seizure model to explore the effect of selective activation of extrasynaptic GABAARS by 4,5,6,7-tetra- hydroisoxazolo[5,4-c] pyridine-3-ol （THIP） on the CTZ-induced epileptiform activity in hippocampal neurons. Perfusion with CTZ dose-dependently induced multiple epileptiform peaks of evoked population spikes （PSs）in CA1 pyramidal neurons, and treatment with THIP （5 μmol/L） significantly reduced the multiple PS peaks induced by CTZ stimulation. Western blot showed that the 6-subunit of the GABAAR, an extrasynaptic specific GABAAR subunit, was also significantly down-regulated in the cell membrane 2 h after CTZ treatment. Our results suggest that the CTZ-induced epileptiform activity in hippocampal CA1 neurons is suppressed by the activation of extrasynaptic GABAARs, and further support the hypothesis that tonic inhibition mediated by extrasynaptic GABAARs plays a prominent role in seizure generation.
文摘目的:本研究通过比较不同药物干预下对GABAARα1、NMDAR1表达的影响,探讨柴贝止痫汤抑制颞叶癫痫发作的分子病理机制。方法:腹腔注射氯化锂-匹罗卡品制成颞叶癫痫模型,通过免疫组织化学方法和显微图像分析技术检测大鼠颞叶、海马的γ-氨基丁酸受体(GABAARα1)和谷氨酸受体(NMDAR1)的表达。结果:GABA A Rα1的表达,与空白模型组比较,柴贝止痫汤组、柴贝止痫汤联合卡马西平组癫痫大鼠海马CA1、CA3区及颞叶皮层的GABA A Rα1亚单位表达均明显增强,有高度显著性差异(P<0.01),但柴贝止痫汤组与柴贝止痫汤联合卡马西平组之间无显著性差异(P>0.05)。与正常组比较,空白模型组和卡马西平组癫痫大鼠海马CA1、CA3区及颞叶皮层的GABA A Rα1表达均明显减少,有高度显著性差异(P<0.01)。NMDAR1的表达,与正常组比较,柴贝止痫汤组、柴贝止痫汤联合卡马西平组、卡马西平组、空白模型组海马CA1、CA3区及颞叶皮层的NMDAR1表达均明显增高,有显著性差异(P<0.05),但柴贝止痫汤组、柴贝止痫汤联合卡马西平组、卡马西平组、空白模型组各组之间无显著性差异(P>0.05)。结论:柴贝止痫汤可以提高GABA A Rα1的表达,而对NMDAR1无明显影响。对GABA A Rα1表达的调节是柴贝止痫汤控制癫痫的可能机理之一。
