title: Vigabatrin inhibits seizures and mTOR pathway activation in a mouse model of tuberous sclerosis complex.
abstract: Epilepsy is a common neurological disorder and cause of significant morbidity and mortality. Although antiseizure medication is the first-line treatment for epilepsy, currently available medications are ineffective in a significant percentage of patients and have not clearly been demonstrated to have disease-specific effects for epilepsy. While seizures are usually intractable to medication in tuberous sclerosis complex (TSC), a common genetic cause of epilepsy, vigabatrin appears to have unique efficacy for epilepsy in TSC. While vigabatrin increases gamma-aminobutyric acid (GABA) levels, the precise mechanism of action of vigabatrin in TSC is not known. In this study, we investigated the effects of vigabatrin on epilepsy in a knock-out mouse model of TSC and tested the novel hypothesis that vigabatrin inhibits the mammalian target of rapamycin (mTOR) pathway, a key signaling pathway that is dysregulated in TSC. We found that vigabatrin caused a modest increase in brain GABA levels and inhibited seizures in the mouse model of TSC. Furthermore, vigabatrin partially inhibited mTOR pathway activity and glial proliferation in the knock-out mice in vivo, as well as reduced mTOR pathway activation in cultured astrocytes from both knock-out and control mice. This study identifies a potential novel mechanism of action of an antiseizure medication involving the mTOR pathway, which may account for the unique efficacy of this drug for a genetic epilepsy.
authors: Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors: Bo
authors: B
authors: Zhang
authors: Sharon S
authors: SS
authors: McDaniel
authors: Nicholas R
authors: NR
authors: Rensing
authors: Michael
authors: M
authors: Wong
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D012640:Seizures / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics; D020888:Vigabatrin / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis
chemical_list: D000927:Anticonvulsants; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D005680:gamma-Aminobutyric Acid; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020888:Vigabatrin