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

Abstract

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.

Fig. 1

Schematic diagram of the mTOR signaling pathway. The rapamycin-sensitive mTOR complex (mTORC1) acts on numerous downstream effectors to inhibit macroautophagy and to promote protein translation, transcription, microtubule growth, and cell cycle progression. mTORC1 activity is largely regulated by extracellular nutrients and growth factors and intracellular energy and amino acid stores. Many of these upstream signaling pathways converge on the hamartin/tuberin complex, which are the gene products of TSC1 and TSC2. Tuberin contains a GTP-ase activating protein (GAP) domain that, when complexed with hamartin, inactivates Rheb and thus inhibits mTOR. Insulin and other growth factors activate PI3K/Akt signaling, which relieves the hamartin/tuberin inhibition of mTOR activity, thereby promoting protein synthesis, cell growth, and proliferation. Amino acid-induced activation of mTOR occurs downstream of hamartin/tuberin, and also promotes mTOR-mediated anabolic processes. Conversely, energy or oxygen deprivation activates the hamartin/tuberin complex by stimulating AMPK or REDD1/2 signaling, respectively, to turn off mTOR activity and energy-consuming cellular processes when resources are scarce. 4E-BP1, elongation factor 4E binding protein 1; AMPK, AMP-activated protein kinase; eIF4E, elongation initiation factor 4E; PDK1, phosphoinositide-dependent kinase-1; PI3K, class I phosphoinositide-3 kinase; PTEN, phosphatase and tensin homolog on chromosome 10; RHEB, Ras homolog enriched in brain; S6K, ribosomal S6 kinase; VSP34, class III phosphoinositide-3 kinase vacuolar protein sorting 34.

Fig. 2

Mechanisms of mTOR dysregulation in epilepsy and mTOR inhibition in antiepileptogenesis. (A) Malformations of cortical development. In tuberous sclerosis complex, mutation in either the TSC1 or TSC2 gene results in overactivation of mTOR via loss of function of the hamartin/tuberin complex, leading to dysregulation of mTOR’s downstream functions that contribute to tumor predisposition and epileptogenesis. PTEN mutations result in loss of inhibition of PI3K/Akt signaling, which may explain why mouse models with neuronal Pten mutations exhibit mTOR hyperactivation and seizures. FCDIIb have increased pS6 expression consistent with mTOR hyperactivation, as well as increased expression of PDK1 which is suggestive of increased PI3K/Akt signaling as a possible mechanism for mTOR dysregulation and epileptogenesis. Solid arrows denote expected direction of change with TSC; dotted arrows show expected direction of change with PTEN mutation. (B) Putative mechanism of mTOR hyperactivation in models of acquired epilepsy after status epilepticus or traumatic brain injury. Excessive glutamate release during status epilepticus or after trauma may result in NMDA receptor-mediated activation of PI3K/Akt signaling, which would be expected to relieve the hamartin/tuberin inhibition of mTOR, causing a cascade of cellular events that likely contribute to epileptogenesis. (C) Proposed mechanisms of antiepileptogenic effect of mTOR inhibition. Rapamycin directly inhibits mTORC1, thereby preventing the downstream effects implicated in epileptogenesis caused by mTOR dysregulation of any etiology. Curcumin has also been shown to inhibit mTOR, which may explain its apparent antiepileptogenic effects. The ketogenic diet decreases insulin levels, and thus would be expected to inhibit mTOR activity indirectly by decreasing PI3K/Akt signaling.