Role of NMDA receptor-dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries.
Nat Med
; 15(12): 1399-406, 2009 Dec.
Article
en En
| MEDLINE
| ID: mdl-19966780
Excitotoxic neuronal damage caused by overactivation of N-methyl-D-aspartate glutamate receptors (NMDARs) is thought to be a principal cause of neuronal loss after stroke and brain trauma. Here we report that activation of sterol regulatory element binding protein-1 (SREBP-1) transcription factor in affected neurons is an essential step in NMDAR-mediated excitotoxic neuronal death in both in vitro and in vivo models of stroke. The NMDAR-mediated activation of SREBP-1 is a result of increased insulin-induced gene-1 (Insig-1) degradation, which can be inhibited with an Insig-1-derived interference peptide (Indip) that we have developed. Using a focal ischemia model of stroke, we show that systemic administration of Indip not only prevents SREBP-1 activation but also substantially reduces neuronal damage and improves behavioral outcome. Our study suggests that agents that reduce SREBP-1 activation such as Indip may represent a new class of neuroprotective therapeutics against stroke.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Corteza Cerebral
/
Isquemia Encefálica
/
Receptores de N-Metil-D-Aspartato
/
Proteína 1 de Unión a los Elementos Reguladores de Esteroles
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Nat Med
Asunto de la revista:
BIOLOGIA MOLECULAR
/
MEDICINA
Año:
2009
Tipo del documento:
Article
País de afiliación:
Canadá
Pais de publicación:
Estados Unidos