AMPK activates FOXO3a and promotes neuronal apoptosis in the developing rat brain during the early phase after hypoxia-ischemia

作者：Li, Deyuan; Luo, Lili; Xu, Min; Wu, Jinlin; Chen, Lina; Li, Jinhui; Liu, Zhongqiang; Lu, Guoyan; Wang, Yang; Qiao, Lina^*

来源：Brain Research Bulletin, 2017, 132: 1-9.

DOI：10.1016/j.brainresbull.2017.05.001

• AMPK
• FOXO3a
• Hypoxia-ischemia
• Neonatal rat
• Neuronal apoptosis

AMP-activated protein kinase (AMPK) is a key metabolic and stress sensor/effector. Few investigations have been performed to study the role of AMPK in developing rat brain with hypoxia-ischemia (HI). Forkhead transcriptional factor (FOX03a) has been revealed to be a critical effector of AMPK-mediated celluar apoptosis. However, it is not clear whether AMPK/FOX03a pathway is involved in neuronal apoptosis in the developing rat brain after HI. In this study, we generated hypoxia-ischemia brain damage (HIBD) model using postnatal day 7 rats. We found that activation of AMPK was accompanied by the decrease of p-mTOR, p-Akt and p-FOX03a, which induced FOXO3a translocation into the nucleus and up-regulated the expression of Bim and cleaved caspase 3 (CC3). Furthermore, we discovered that AMPK inhibition by Compound C, a selective inhibitor for AMPK activity, significantly increased the phosphorylation levels of mTOR, p-Akt and p-FOX03a, attenuated the nuclear translocation of FOX03a, and inhibited Bim and CC3 expression after HI. Moreover, AMPK inhibition reduced cellular apoptosis, attenuated brain infarct volume and promoted neurological recovery in the developing rat brain after HI. Our findings suggest that AMPK participates in the regulation of FOXO3amediated neuronal apoptosis in the developing rat brain after HI. Agents targeting AMPK may offer promise for rescuing neurons from HI-induced damage.

• 出版日期2017-6
• 单位四川大学