Vigabatrin inhibits seizures and mTOR pathway activation in a mouse model of tuberous sclerosis complex.

Zhang, Bo; McDaniel, Sharon S; Rensing, Nicholas R; Wong, Michael

Zhang, Bo; McDaniel, Sharon S; Rensing, Nicholas R; Wong, Michael.

Afiliación

Zhang B; Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, United States of America.

PLoS One ; 8(2): e57445, 2013.

Article en En | MEDLINE | ID: mdl-23437388

RESUMEN

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.

Asunto(s)

Anticonvulsivantes/farmacología; Astrocitos/efectos de los fármacos; Encéfalo/efectos de los fármacos; Convulsiones/tratamiento farmacológico; Serina-Treonina Quinasas TOR/genética; Esclerosis Tuberosa/tratamiento farmacológico; Vigabatrin/farmacología; Animales; Astrocitos/metabolismo; Astrocitos/patología; Encéfalo/metabolismo; Proliferación Celular/efectos de los fármacos; Células Cultivadas; Modelos Animales de Enfermedad; Regulación de la Expresión Génica/efectos de los fármacos; Humanos; Ratones; Ratones Noqueados; Convulsiones/genética; Convulsiones/metabolismo; Convulsiones/patología; Transducción de Señal/efectos de los fármacos; Serina-Treonina Quinasas TOR/antagonistas & inhibidores; Serina-Treonina Quinasas TOR/metabolismo; Esclerosis Tuberosa/genética; Esclerosis Tuberosa/metabolismo; Esclerosis Tuberosa/patología; Proteína 1 del Complejo de la Esclerosis Tuberosa; Proteínas Supresoras de Tumor/deficiencia; Proteínas Supresoras de Tumor/genética; Ácido gamma-Aminobutírico/biosíntesis

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Convulsiones / Esclerosis Tuberosa / Encéfalo / Astrocitos / Vigabatrin / Serina-Treonina Quinasas TOR / Anticonvulsivantes Límite: Animals / Humans Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2013 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

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