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Prevention of JNK phosphorylation as a mechanism for rosiglitazone in neuroprotection after transient cerebral ischemia: activation of dual specificity phosphatase.
Okami, Nobuya; Narasimhan, Purnima; Yoshioka, Hideyuki; Sakata, Hiroyuki; Kim, Gab Seok; Jung, Joo Eun; Maier, Carolina M; Chan, Pak H.
Afiliación
  • Okami N; Department of Neurosurgery, Department of Neurology and Neurological Sciences, and Program in Neurosciences, Stanford University School of Medicine, Stanford, CA, USA.
J Cereb Blood Flow Metab ; 33(1): 106-14, 2013 Jan.
Article en En | MEDLINE | ID: mdl-23032483
Rosiglitazone, a synthetic peroxisome proliferator-activated receptor-γ (PPARγ) agonist, prevents cell death after cerebral ischemia in animal models, but the underlying mechanism has not been clarified. In this study, we examined how rosiglitazone protects neurons against ischemia. Mice treated with rosiglitazone were subjected to 60 minutes of focal ischemia followed by reperfusion. Rosiglitazone reduced infarct volume after ischemia and reperfusion. We show that this neuroprotective effect was reversed with a PPARγ antagonist. Western blot analysis showed a significant increase in expression of phosphorylated stress-activated protein kinases (c-Jun N-terminal kinase (JNK) and p38) in ischemic brain tissue. Rosiglitazone blocked this increase. Furthermore, we observed that rosiglitazone increased expression of the dual-specificity phosphatase 8 (DUSP8) protein and messenger RNA in ischemic brain tissue. Dual-specificity phosphatase 8 is a mitogen-activated protein kinase phosphatase that can dephosphorylate JNK and p38. Another key finding of the present study was that knockdown of DUSP8 in primary cultured cortical neurons that were subjected to oxygen-glucose deprivation diminished rosiglitazone's effect on downregulation of JNK phosphorylation. Thus, rosiglitazone's neuroprotective effect after ischemia is mediated by blocking JNK phosphorylation induced by ischemia via DUSP8 upregulation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ataque Isquémico Transitorio / Fármacos Neuroprotectores / Tiazolidinedionas / Proteínas Quinasas JNK Activadas por Mitógenos / Fosfatasas de Especificidad Dual / Neuronas Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Cereb Blood Flow Metab Año: 2013 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ataque Isquémico Transitorio / Fármacos Neuroprotectores / Tiazolidinedionas / Proteínas Quinasas JNK Activadas por Mitógenos / Fosfatasas de Especificidad Dual / Neuronas Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Cereb Blood Flow Metab Año: 2013 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos