Delay in the thalamo-cortical loop in anterior horn cell disease : V. Natarajan, J. Paul and Z.A. Sayeed (Government General Hospital, Madras, India)

Abstract

Several preclinical and some clinical studies have revealed that the mammalian target of rapamycin (mTOR) signaling pathway appears fundamental in both genetic and acquired epilepsy syndromes. As an example, excessive activation of mTOR signaling as a consequence of loss-of-function mutations of genes encoding for tuberous sclerosis complex (TSC) 1 and 2 are linked both to development of cortical malformations and epilepsy. Other so-called “mTORopathy”-related epilepsies also include focal cortical dysplasia (CD), hemimegalencephaly, and ganglioglioma, characterized by disorganized cortical lamination, cytomegaly, and intractable epilepsy. mTOR inhibitors (e.g., rapamycin) have consistent protective effects in various models of epileptogenesis, reducing the development of spontaneous seizures in both genetic (e.g., TSC models and WAG/Rij rats) and acquired postinsult (e.g., kainate or pilocarpine post-status epilepticus) animal epilepsy models. Furthermore, clinical studies in patients with TSC and CD have now confirmed the effectiveness of mTOR inhibitors also in epileptic patients. Therefore, mTOR represents a very promising target for various forms of intractable epilepsies; however, future studies are needed in order to better define which syndromes will take advantage of this therapeutic opportunity also considering possible not-yet-identified side effects of these drugs. Finally, a very important task will be that of developing new mTOR inhibitors with a higher selectivity for the central nervous system.