Finding a better drug for epilepsy: The mTOR pathway as an antiepileptogenic target

摘要: The mammalian target of rapamycin (mTOR) signaling pathway regulates cell growth, differentiation, proliferation, and metabolism. Loss-of-function mutations in upstream regulators mTOR have been highly associated with dysplasias, epilepsy, neurodevelopmental disorders. These include tuberous sclerosis, which is due to TSC1 or TSC2 genes; phosphatase tensin homolog (PTEN) as Cowden syndrome, polyhydramnios, megalencephaly, symptomatic epilepsy syndrome (PMSE) the STE20-related kinase adaptor alpha (STRADalpha); neurofibromatosis type 1 attributed neurofibromin mutations. Inhibition may prevent improve underlying pathology mouse models disrupted signaling, PTEN TSC However timing duration its administration appear critical defining seizure pathology-related outcomes. Rapamycin application human cortical slices from patients dysplasias reduces 4-aminopyridine-induced oscillations. In multiple-hit model infantile spasms, pulse high-dose can reduce overactivation pathway, suppresses has disease-modifying effects by partially improving cognitive deficits. post-status epilepticus temporal lobe ameliorate development epilepsy-related expression spontaneous seizures, but depend on administration, possibly used. observed recurrence seizures after discontinuation suggests need for continuous maintain benefit. However, use protocols be useful certain age-specific syndromes, like whereas repetitive-pulse suffice sustain a long-term benefit genetic disorders pathway. summary, dysregulation implicated several acquired forms epileptogenesis. inhibitors reverse some these epileptogenic processes, although their upon dose well