A pulse rapamycin therapy for infantile spasms and associated cognitive decline.
A pulse rapamycin therapy for infantile spasms and associated cognitive decline.
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DOI：
10.1016/j.nbd.2011.03.021
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发表时间：
2011-08
影响因子：
6.1
通讯作者：
Galanopoulou, Aristea S.
中科院分区：
文献类型：
--
作者：
Raffo, Emmanuel;Coppola, Antonietta;Ono, Tomonori;Briggs, Stephen W.;Galanopoulou, Aristea S.
关键词：
婴儿痉挛是一种癫痫发作，表现在婴儿时期的一系列癫痫脑病中，通常会导致认知障碍。他们目前的治疗方法，包括促肾上腺皮质激素(ACTH)、大剂量类固醇或Vigabatrin，并不总是有效的，可能与严重的副作用有关。MTOR途径TORC1复合体的过度激活与某些与婴儿痉挛有关的遗传性和获得性疾病的发病机制有关，如结节性硬化症。在这里，我们测试了雷帕霉素，一种TORC1抑制剂，作为一种潜在的治疗婴儿痉挛的可能性，在多次打击的ACTH难治性婴儿痉挛的大鼠模型中，这与结节性硬化症无关。出现痉挛后给予雷帕霉素或赋形剂。比较它们对痉挛、其他癫痫发作、在Barnes迷宫中的表现以及免疫荧光法检测皮质磷酸化S6核糖体蛋白(pS6：A TORC1靶标)的作用。雷帕霉素抑制痉挛呈剂量依赖关系，并改善视觉空间学习，尽管它不能减少其他新出现的癫痫发作的频率。大剂量雷帕霉素脉冲治疗可显著抑制痉挛，改善认知功能，且无明显副作用。治疗有效的雷帕霉素剂量使痉挛小鼠皮质区pS6表达正常化，pS6表达增加。这些发现支持TORC1的病理性过度激活可能与婴儿痉挛的发病机制有关，包括那些与结节性硬化症无关的痉挛。此外，大剂量、脉冲雷帕霉素治疗婴儿痉挛是一种前景看好、耐受性良好和改善疾病的新疗法，包括那些对ACTH无效的痉挛。
Infantile spasms are seizures manifesting within a spectrum of epileptic encephalopathies of infancy that often lead to cognitive impairment. Their current therapies, including adrenocorticotropic hormone (ACTH), high dose steroids, or vigabatrin, are not always effective and may be associated with serious side effects. Overactivation of the TORC1 complex of the mTOR pathway is implicated in the pathogenesis of certain genetic and acquired disorders that are linked with infantile spasms, like tuberous sclerosis. Here, we tested the therapeutic potential of rapamycin, a TORC1 inhibitor, as a potential treatment for infantile spasms in the multiple-hit rat model of ACTH-refractory symptomatic infantile spasms, which is not linked to tuberous sclerosis. Rapamycin or vehicle were given after spasms appeared. Their effects on spasms, other seizures, performance in Barnes maze, and expression of the phosphorylated S6 ribosomal protein (pS6: a TORC1 target) in the cortex, using immunofluorescence, were compared. Rapamycin suppressed spasms dose-dependently and improved visuospatial learning, although it did not reduce the frequency of other emerging seizures. High-dose pulse rapamycin effected acute and sustained suppression of spasms and improved cognitive outcome, without significant side effects. Therapeutically effective rapamycin doses normalized the pS6 expression, which was increased in perilesional cortical regions of pups with spasms. These findings support that pathological overactivation of TORC1 may be implicated in the pathogenesis of infantile spasms, including those that are not linked to tuberous sclerosis. Furthermore, a high-dose, pulse rapamycin treatment is a promising, well tolerated and disease-modifying new therapy for infantile spasms, including those refractory to ACTH.
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影响因子：
2.5
作者：
Brattstrom, C;Sawe, J;Groth, CG
通讯作者：
Groth, CG
DOI：
10.1126/science.1190287
发表时间：
2010-08-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li N;Lee B;Liu RJ;Banasr M;Dwyer JM;Iwata M;Li XY;Aghajanian G;Duman RS
通讯作者：
Duman RS
影响因子：
1.7
作者：
Eun, So Hee;Kang, Hoon Chul;Kim, Heung Dong
通讯作者：
Kim, Heung Dong
影响因子：
4.3
作者：
Ljungberg, M. Cecilia;Sunnen, C. Nicole;D'Arcangelo, Gabriella
通讯作者：
D'Arcangelo, Gabriella
影响因子：
5.6
作者：
Engel, Jerome, Jr.
通讯作者：
Engel, Jerome, Jr.