Therapeutic role of targeting mTOR signaling and neuroinflammation in epilepsy

Abstract Existing therapies for epilepsy are primarily symptomatic and target mechanisms of neuronal transmission in order to restore the excitatory/inhibitory imbalance in the brain after seizures. However, approximately one third of individuals with epilepsy have medically refractory epilepsy and do not respond to available treatments. There is a critical need for the development of therapeutics that extend beyond manipulation of excitatory neurotransmission and target pathological changes underlying the cause of the disease. Epilepsy is a multifaceted condition, and it could be that effective treatment involves the targeting of several mechanisms. There is evidence for both dysregulated PI3K/Akt/mTOR (mTOR) signaling and heightened neuroinflammatory processes following seizures in the brain. Signaling via mTOR has been implicated in several epileptogenic processes, including synaptic plasticity mechanisms and changes in ion channel expression following seizures. Inflammatory signaling, such as increased synthesis of cytokines and other immune molecules, has also shown to play a significant role in the development of chronic epilepsy. mTOR pathway activation and immune signaling are known to interact in normal physiological states, as well as influence one another following seizures. Simultaneous inhibition of both processes could be a promising therapeutic avenue to prevent the development of chronic epilepsy by targeting two key pathological mechanisms implicated in epileptogenesis.