Role of mTOR inhibitors in epilepsy treatment.
In spite of the fact, that subsequent new antiepileptic drugs (AEDs) are being introduced into clinical practice, the percentage of drug-resistant epilepsy cases remains stable. Although a substantial progress has been made in safety profile of antiepileptic drugs, currently available substances have not been unambiguously proven to display disease-modifying effect in epilepsy and their mechanisms of action influence mainly on the end-stage phase of epileptogenesis, namely seizures. Prevention of epileptogenesis requires new generation of drugs modulating molecular pathways engaged in epileptogenesis processes. The mammalian target of rapamycin (mTOR) pathway is involved in highly epileptogenic conditions, such as tuberous sclerosis complex (TSC) and represents a reasonable target for antiepileptogenic interventions. In animal models of TSC mTOR inhibitors turned out to prevent the development of epilepsy and reduce underlying brain abnormalities. Accumulating evidence from animal studies suggest the role of mTOR pathway in acquired forms of epilepsy. Preliminary clinical studies with patients affected by TSC demonstrated seizure reduction and potential disease-modifying effect of mTOR inhibitors. Further studies will determine the place for mTOR inhibitors in the treatment of patients with TSC as well as its potential antiepileptogenic effect in other types of genetic and acquired epilepsies. This review presents current knowledge of mTOR pathway physiology and pathology in the brain, as well as potential clinical use of its inhibitors.
"Living with Parkinson disease" Foundation, Warszawa, Poland. Electronic address: sadowski.ks@gmail.com.
Krzysztof
K
Sadowski
Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warszawa, Poland.
Katarzyna
K
Kotulska-Jóźwiak
Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warszawa, Poland.
Sergiusz
S
Jóźwiak
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome
D000927:Anticonvulsants; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
Epilepsy; Epileptogenesis; Rapamycin; Tuberous sclerosis; mTOR inhibitors