Developing Antiepileptogenic Drugs for Acquired Epilepsy: Targeting the Mammalian Target of Rapamycin (mTOR) Pathway.

Abstract

While current medications for epilepsy are primarily symptomatic treatments that suppress seizures, one of the main goals of future drug development in epilepsy is the identification of antiepileptogenic or disease-modifying therapies that can completely prevent epilepsy or slow its progression. A rational antiepileptogenic strategy is to target primary cell signaling pathways that initially trigger the downstream mechanisms causing epileptogenesis. Recent work implicates the mammalian target of rapamycin (mTOR) pathway as mediating epileptogenesis in a genetic epilepsy, Tuberous Sclerosis Complex (TSC), and suggests that mTOR inhibitors, such as rapamycin, may have antiepileptogenic properties for epilepsy in TSC. As mTOR regulates multiple cellular functions that may contribute to epileptogenesis in general, including ion channel expression, synaptic plasticity, and programmed cell death, mTOR inhibitors might also represent an effective antiepileptogenic therapy for other, more common types of epilepsy, such as acquired epilepsies due to brain injuries. Here, we describe evidence from a recently-published study that mTOR mediates epileptogenesis in a popular animal model of acquired limbic epilepsy due to brain injury following kainate-induced status epilepticus, and that rapamycin has antiepileptogenic effects in this model. Furthermore, putative pathways and mechanisms upstream and downstream from mTOR involved in epileptogenesis in the kainite model are considered, identifying possible additional therapeutic targets. Finally, the potential translational applications of this and other animal model data for developing antiepileptogenic therapies for people with acquired epilepsy due to brain injury are discussed.