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- Title
Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex.
- Authors
Zeng, Ling-Hui; Xu, Lin; Gutmann, David H.; Wong, Michael
- Abstract
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 ( Tsc1GFAPCKO 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 Tsc1GFAPCKO mice. Methods Tsc1GFAPCKO 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 Tsc1GFAPCKO 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 Tsc1GFAPCKO mice. Late treatment with rapamycin suppressed seizures and prolonged survival in Tsc1GFAPCKO 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 Tsc1GFAPCKO mice. Interpretation Rapamycin has strong efficacy for preventing seizures and prolonging survival in Tsc1GFAPCKO mice. Ann Neurol 2008
- Publication
Annals of Neurology, 2008, Vol 63, Issue 4, p444
- ISSN
0364-5134
- Publication type
Article
- DOI
10.1002/ana.21331