mTOR inhibition in epilepsy: A literature review

Abstract

Hyperactivation of the mammalian target of the rapamycin (mTOR) pathway causes epilepsies, neurodevelopmental disorders, and malformations of cortical development, collectively known as mTORopathies. These conditions arise from loss-of-function variants in negative regulators or gain-of-function variants in positive regulators of the mTOR pathway. Conventional antiseizure medications mainly target downstream effectors such as ion channels or neurotransmitter activity to suppress seizures. On the contrary, extensive pre-clinical and clinical evidence has demonstrated that mTOR inhibitors have anti-epileptogenic or disease-modifying effects, potentially preventing epilepsy or slowing disease progression rather than merely controlling seizures. In general, mTOR inhibitors bind to mTOR protein, preventing its interactions with substrates and disrupting mTOR complex assembly, thereby suppressing downstream activities. In this review, we provide a comprehensive overview of the mTOR signaling pathway, outline the spectrum of mTORopathies and its subset (GATORopathies), and highlight the clinical applications of mTOR inhibitors, particularly everolimus, along with other potential mTOR-modulating agents.