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哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,m TOR)在皮质发育不良(Cortical dysplasia,CD)及癫痫动物模型中超活化。在神经元特异性Pten基因敲除(Neuronsubsetspecific Pten knockout,NS-Pten KO)小鼠模型中,尽管在早期癫痫发生过程中抑制m TOR信号通路能够减少癫痫样活动,但m TOR抑制剂在癫痫建立后的作用尚不清楚。文章通过建立伴有严重慢性癫痫的NS-Pten KO成年小鼠模型,探究m TOR抑制剂对其癫痫样活动和其他神经病理的作用。NSPten KO小鼠癫痫样活动、m TOR信号通路的异常调节和相关神经病理随年龄增长的变化通过视频脑电(video-electroencephalography,VEEG),蛋白免疫印迹和免疫组化检测。NS-Pten KO小鼠出生后9周开始接受m TOR抑制剂雷帕霉素治疗(10 mg/kg i.p,5d/周)并采用VEEG监测癫痫样活动。通过蛋白免疫印迹和免疫组化检测雷帕霉素的作用。试验发现,随着年龄增长,NS-Pten KO小鼠的癫痫样活动恶化,同时伴有m TOR复合物1和2(m TOR complex 1 and 2,m TORC1 and m TORC2)调节异常和进展性的星形胶质细胞和小胶质细胞增生。雷帕霉素治疗抑制癫痫样活动,改善基线脑电活动并提高严重癫痫NS-Pten KO小鼠的预后。在分子水平,雷帕霉素治疗降低m TORC1和m TORC2水平并减少星形胶质细胞和小胶质细胞增生。研究表明在NS-Pten KO小鼠中,雷帕霉素成功治疗癫痫有较宽的时间窗。抑制m TOR可能是CD伴慢性癫痫及m TOR信号通路基因调节异常的潜在治疗手段。
Mammalian mammalian target of rapamycin (mTOR) is hyperactivated in cortical dysplasia (CD) and epileptic animal models. In the neuron-specific Pten knockout (NS-Pten knockout, NS-Pten knockout, mouse model of NSO-Pten knockout), although inhibition of the mTOR signaling pathway during early epilepsy can reduce epileptiform activity, mTOR inhibitors are established in epilepsy After the role is not clear. This article explored the role of mTOR inhibitors in their epileptiform activity and other neuropathies by establishing an NS-Pten KO adult mouse model with severe chronic epilepsy. Epileptiform activity, abnormal regulation of mTOR signaling pathways, and changes in neuropathology associated with age in NSPten KO mice were examined by video-electroencephalography (VEEG), Western blot, and immunohistochemistry. NS-Pten KO mice received mTOR inhibitor rapamycin (10 mg / kg i.p., 5d / week) 9 weeks after birth and monitored epileptiform activity using VEEG. The effect of rapamycin was detected by Western blotting and immunohistochemistry. It was found that the epileptiform activity of NS-Pten KO mice deteriorated with age, accompanied by aberrant and progressive modulation of mTOR complex 1 and 2 (mTORC1 and mTORC2) Astrocytes and microglia proliferate. Rapamycin treatment inhibits epileptiform activity, improves baseline EEG activity, and improves prognosis in severe epileptic NS-Pten KO mice. At the molecular level, rapamycin treatment reduces both mTORC1 and mTORC2 levels and reduces astrocyte and microglial cell proliferation. Studies have shown that in NS-Pten KO mice, rapamycin has a wider time window for the successful treatment of epilepsy. Suppression of mTOR may be a potential therapeutic approach for the abnormal gene regulation of CD with chronic epilepsy and mTOR signaling pathway.