Rapamycin attenuates the development of posttraumatic epilepsy in a mouse model of traumatic brain injury.
Rapamycin attenuates the development of posttraumatic epilepsy in a mouse model of traumatic brain injury.
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雷帕霉素可减轻创伤性脑损伤小鼠模型中创伤后癫痫的发展
DOI：
10.1371/journal.pone.0064078
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wong M
中科院分区：
文献类型：
--
作者：
Guo D;Zeng L;Brody DL;Wong M
创伤性癫痫是创伤性脑损伤后致残的主要原因，也是难治性癫痫的常见原因。先前试图通过在脑外伤后立即给予治疗来预防创伤后癫痫的发展，但均以失败告终。最近，哺乳动物靶标雷帕霉素复合体1(MTORC1)通路被认为与癫痫的发生机制有关，mTORC1抑制剂雷帕霉素被认为在预防某些类型的癫痫中具有抗癫痫作用。在这项研究中，我们在一种脑外伤动物模型上验证了雷帕霉素具有抗癫痫作用的假设，以防止创伤性癫痫的发展。在小鼠控制的皮质撞击模型中，首先使用连续视频-脑电监测对脑外伤后16周的创伤后癫痫进行了详细的表征。受控性皮质撞击损伤导致mTORC1通路立即过度激活，持续至少一周，而雷帕霉素治疗可逆转这一过程。雷帕霉素减少神经元变性和苔藓纤维发芽，但对苔藓纤维发芽的影响在雷帕霉素停药后是可逆的，与抑制癫痫发生没有直接关系。大多数创伤后癫痫发作发生在伤后10周以上，在整个16周监测期间，伤后1个月雷帕霉素治疗可降低癫痫发作频率和发生创伤后癫痫的发生率。提示雷帕霉素可能是预防颅脑损伤患者创伤性癫痫的一种合理治疗方法。
Posttraumatic epilepsy is a major source of disability following traumatic brain injury (TBI) and a common cause of medically-intractable epilepsy. Previous attempts to prevent the development of posttraumatic epilepsy with treatments administered immediately following TBI have failed. Recently, the mammalian target of rapamycin complex 1 (mTORC1) pathway has been implicated in mechanisms of epileptogenesis and the mTORC1 inhibitor, rapamycin, has been proposed to have antiepileptogenic effects in preventing some types of epilepsy. In this study, we have tested the hypothesis that rapamycin has antiepileptogenic actions in preventing the development of posttraumatic epilepsy in an animal model of TBI. A detailed characterization of posttraumatic epilepsy in the mouse controlled cortical impact model was first performed using continuous video-EEG monitoring for 16 weeks following TBI. Controlled cortical impact injury caused immediate hyperactivation of the mTORC1 pathway lasting at least one week, which was reversed by rapamycin treatment. Rapamycin decreased neuronal degeneration and mossy fiber sprouting, although the effect on mossy fiber sprouting was reversible after stopping rapamycin and did not directly correlate with inhibition of epileptogenesis. Most posttraumatic seizures occurred greater than 10 weeks after TBI, and rapamycin treatment for one month after TBI decreased the seizure frequency and rate of developing posttraumatic epilepsy during the entire 16 week monitoring session. These results suggest that rapamycin may represent a rational treatment for preventing posttraumatic epilepsy in patients with TBI.
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影响因子：
158.5
作者：
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通讯作者：
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