Therapeutic role of mammalian target of rapamycin (mTOR) inhibition in preventing epileptogenesis

Traditionally, medical therapy for epilepsy has aimed to suppress seizure activity, but has been unable to alter the progression of the underlying disease. Recent advances in our understanding of mechanisms of epileptogenesis open the door for the development of new therapies which prevent the pathogenic changes in the brain that predispose to spontaneous seizures. In particular, the mammalian target of rapamycin (mTOR) signaling pathway has recently garnered interest as an important regulator of cellular changes involved in epileptogenesis, and mTOR inhibitors have generated excitement as potential antiepileptogenic agents. mTOR hyperactivation occurs in tuberous sclerosis complex (TSC), a common genetic cause of epilepsy, as a result of genetic mutations in upstream regulatory molecules. mTOR inhibition prevents epilepsy and brain pathology in animal models of TSC. mTOR dysregulation has also been demonstrated in a variety of other genetic and acquired epilepsies, including brain tumors, focal cortical dysplasias, and animal models of brain injury due to status epilepticus or trauma. Indeed, mTOR inhibitors appear to possess antiepileptogenic properties in animal models of acquired epilepsy as well. Thus, mTOR dysregulation may represent a final common pathway in epilepsies of various causes. Therefore, mTOR inhibition is an exciting potential antiepileptogenic strategy with broad applications for epilepsy and could be involved in a number of treatment modalities, including the ketogenic diet. Further research is necessary to determine the clinical utility of rapamycin and other mTOR inhibitors for antiepileptogenesis, and to devise new therapeutic targets by further elucidating the signaling molecules involved in epileptogenesis. (C) 2011 Elsevier Ireland Ltd. All rights reserved.