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Involvement of the JNK/FOXO3a/Bim Pathway in Neuronal Apoptosis after Hypoxic-Ischemic Brain Damage in Neonatal Rats.

  • Author(s): Li, Deyuan
  • Li, Xihong
  • Wu, Jinlin
  • Li, Jinhui
  • Zhang, Li
  • Xiong, Tao
  • Tang, Jun
  • Qu, Yi
  • Mu, Dezhi
  • et al.
Abstract

c-Jun N-terminal kinase (JNK) plays a key role in the regulation of neuronal apoptosis. Previous studies have revealed that forkhead transcription factor (FOXO3a) is a critical effector of JNK-mediated tumor suppression. However, it is not clear whether the JNK/FOXO3a pathway is involved in neuronal apoptosis in the developing rat brain after hypoxia-ischemia (HI). In this study, we generated an HI model using postnatal day 7 rats. Fluorescence immunolabeling and Western blot assays were used to detect the distribution and expression of total and phosphorylated JNK and FOXO3a and the pro-apoptotic proteins Bim and CC3. We found that JNK phosphorylation was accompanied by FOXO3a dephosphorylation, which induced FOXO3a translocation into the nucleus, resulting in the upregulation of levels of Bim and CC3 proteins. Furthermore, we found that JNK inhibition by AS601245, a specific JNK inhibitor, significantly increased FOXO3a phosphorylation, which attenuated FOXO3a translocation into the nucleus after HI. Moreover, JNK inhibition downregulated levels of Bim and CC3 proteins, attenuated neuronal apoptosis and reduced brain infarct volume in the developing rat brain. Our findings suggest that the JNK/FOXO3a/Bim pathway is involved in neuronal apoptosis in the developing rat brain after HI. Agents targeting JNK may offer promise for rescuing neurons from HI-induced damage.

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