Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex
Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex
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DOI：
10.1002/ana.21331
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发表时间：
2008-04-01
影响因子：
11.2
通讯作者：
Wong, Michael
中科院分区：
文献类型：
--
作者：
Zeng, Ling-Hui;Xu, Lin;Wong, Michael
目的：脑硬化综合征（TSC）是癫痫最常见的遗传病因之一。TSC基因失活导致雷帕霉素信号通路的哺乳动物靶标的超活化，提出了有趣的可能性，即雷帕霉素抑制剂的哺乳动物靶标可能有效地预防或治疗TSC患者的癫痫。主要在神经胶质中Tsc 1基因有条件失活的小鼠（Tsc 1（GFAP）CKO小鼠）发生神经胶质增生、进行性癫痫和过早死亡。在这里，我们测试了雷帕霉素是否可以预防或逆转癫痫，以及其他细胞和分子的脑异常Tsc 1（GFAP）CKO mice.Methods：Tsc 1（GFAP）CKO小鼠和同窝对照组动物与雷帕霉素或车辆开始在出生后第14天（早期治疗）或6周龄（晚期治疗），相应的时间之前和之后的TscIGFAPCKO小鼠神经系统异常的发作。通过连续视频脑电图监测小鼠的癫痫发作和长期存活。组织学检查脑星形胶质细胞增生和神经元组织。磷酸-S6和其他分子标记物的表达与epileptogenesis.Results：早期治疗与雷帕霉素预防癫痫的发展和过早死亡的车辆治疗的Tsc 1（GFAP）CKO小鼠观察。雷帕霉素晚期治疗抑制了已经发生癫痫的Tsc 1（GFAP）CKO小鼠的癫痫发作并延长了其生存期。相应地，雷帕霉素抑制异常激活的哺乳动物靶细胞的雷帕霉素通路，星形胶质细胞增生，神经元解体，并增加脑大小在Tsc 1（GFAP）CKO mice.Interpretation：雷帕霉素有很强的疗效，防止癫痫发作和延长生存Tsc 1（GFAP）CKO小鼠。
Objective: Tuberous sclerosis complex (TSC) represents one of the most common genetic causes of epilepsy. TSC gene inactivation leads to hyperactivation of the mammalian target of rapamycin signaling pathway, raising the intriguing possibility that mammalian target of rapamycin inhibitors might be effective in preventing or treating epilepsy in patients with TSC. Mice with conditional inactivation of the Tsc1 gene primarily in glia (Tsc1(GFAP) CKO mice) develop glial proliferation, progressive epilepsy, and premature death. Here, we tested whether rapamycin could prevent or reverse epilepsy, as well as other cellular and molecular brain abnormalities in Tsc1(GFAP)CKO mice.Methods: Tsc1(GFAP)CKO mice and littermate control animals were treated with rapamycin or vehicle starting at postnatal day 14 (early treatment) or 6 weeks of age (late treatment), corresponding to times before and after onset of neurological abnormalities in TsclGFAPCKO mice. Mice were monitored for seizures by serial video-electroencephalogram and for long-term survival. Brains were examined histologically for astrogliosis and neuronal organization. Expression of phospho-S6 and other molecular markers correlating with epileptogenesis was measured by Western blotting.Results: Early treatment with rapamycin prevented the development of epilepsy and premature death observed in vehicle-treated Tsc1(GFAP)CKO mice. Late treatment with rapamycin suppressed seizures and prolonged survival in Tsc1(GFAP)CKO mice that had already developed epilepsy. Correspondingly, rapamycin inhibited the abnormal activation of the mammalian target of rapamycin pathway, astrogliosis, and neuronal disorganization, and increased brain size in Tsc1(GFAP)CKO mice.Interpretation: Rapamycin has strong efficacy for preventing seizures and prolonging survival in Tsc1(GFAP)CKO mice.