Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex.

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 (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.

• Authors: Ling-Hui Zeng, Lin Xu, David H Gutmann, Michael Wong
• Journal: Annals of neurology (Ann Neurol) Vol. 63 Issue 4 Pg. 444-53 (Apr 2008) ISSN: 1531-8249 [Electronic] United States
• PMID: 18389497 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Tsc1 protein, mouse
• Tuberous Sclerosis Complex 1 Protein
• Tumor Suppressor Proteins
• Sirolimus

Topics

• Animals
• Disease Models, Animal
• Epilepsy (etiology, genetics, prevention & control)
• Mice
• Mice, Knockout
• Sirolimus (therapeutic use)
• Tuberous Sclerosis (complications, drug therapy, genetics)
• Tuberous Sclerosis Complex 1 Protein
• Tumor Suppressor Proteins (deficiency, genetics, physiology)