mTOR inhibitors in epilepsy management: from bench to bedside
Substantial and growing body of evidence now supports the role of mTOR pathway activation in epilepsy both in preclinical and clinical settings. In humans, mTOR activation has been showed to play an important role in seizures and epileptogenesis in numerous acquired and genetic epilepsies. Moreover, several studies indicate that mTOR signaling pathway is implicated in multidrug resistance resulting from P-gp expression in chronic epilepsy. Thus, the use of mTOR inhibitors is widely considered as an emerging potential therapy in many epilepsies. Tuberous sclerosis complex (TSC) is a genetic disorder characterized the development of hamartomas in various organs and tissues. The molecular hallmark of the disease is the overactivation of mTOR pathway resulting from inactivating mutations in either TSC1 or TSC2 genes. Epilepsy is present in 80–90% of TSC patients and usually appears in the first year of life. In the majority of affected patients, epilepsy is associated with developmental delay. Preclinical studies showed that mTOR inhibition with sirolimus might alleviate or prevent seizures in animal models of TSC. In recent years, many case reports showed beneficial effect of mTOR inhibitors in TSC patients with drug-resistant epilepsy. EXIST-3 trial was the first clinical study to show efficacy of everolimus in drug-resistant epilepsy associated with TSC. There are few other trials of mTOR inhibitors in epilepsy associated with TSC, focal cortical dysplasias, and Sturge-Weber ongoing. Given the data from basic research and the results of first clinical studies, mTOR inhibitors should be considered as promising therapeutic option in drug-resistant epilepsies.