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Published on: June 12, 2018
Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex
Ling-Hui Zeng1, Lin Xu, David H Gutmann
1Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
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 Tsc1(GFAP)CKO 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.
Insights
Rapamycin effectively prevents and treats epilepsy in Tsc1(GFAP)CKO mice by inhibiting the mTOR pathway. This treatment also reduces brain abnormalities and prolongs survival in these mice.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Tuberous sclerosis complex (TSC) is a common genetic cause of epilepsy.
- TSC gene inactivation hyperactivates the mammalian target of rapamycin (mTOR) pathway.
- Tsc1(GFAP)CKO mice models exhibit glial proliferation, epilepsy, and premature death.
Purpose of the Study:
- To investigate the efficacy of rapamycin in preventing and treating epilepsy in Tsc1(GFAP)CKO mice.
- To assess rapamycin's impact on cellular and molecular brain abnormalities associated with TSC.
- To evaluate rapamycin's effect on survival rates in the Tsc1(GFAP)CKO mouse model.
Main Methods:
- Tsc1(GFAP)CKO mice and controls received early or late rapamycin/vehicle treatment.
- Seizures were monitored via video-electroencephalogram (EEG).
- Brain histology and Western blotting assessed astrogliosis, neuronal organization, and molecular markers.
Main Results:
- Early rapamycin treatment prevented epilepsy and premature death.
- Late rapamycin treatment suppressed seizures and extended survival in affected mice.
- Rapamycin normalized mTOR pathway activation, reduced astrogliosis, improved neuronal organization, and increased brain size.
Conclusions:
- Rapamycin demonstrates significant efficacy in preventing and treating epilepsy in the Tsc1(GFAP)CKO mouse model.
- Rapamycin normalizes key molecular and cellular pathologies in this TSC model.
- These findings support rapamycin as a potential therapeutic agent for TSC-associated epilepsy.
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