Li Deyuan, Luo Lili, Xu Min, Wu Jinlin, Chen Lina, Li Jinhui, Liu Zhongqiang, Lu Guoyan, Wang Yang, Qiao Lina
Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Birth Defects and Related Disease of Women and Children (Sichuan University), Ministry of Education, Chengdu，Sichuan 610041, China.
Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Birth Defects and Related Disease of Women and Children (Sichuan University), Ministry of Education, Chengdu，Sichuan 610041, China.
Brain Res Bull. 2017 Jun;132:1-9. doi: 10.1016/j.brainresbull.2017.05.001. Epub 2017 May 10.
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 (FOXO3a) has been revealed to be a critical effector of AMPK-mediated celluar apoptosis. However, it is not clear whether AMPK/FOXO3a 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-FOXO3a, 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, Akt and FOXO3a, attenuated the nuclear translocation of FOXO3a, 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 FOXO3a-mediated neuronal apoptosis in the developing rat brain after HI. Agents targeting AMPK may offer promise for rescuing neurons from HI-induced damage.
AMP激活的蛋白激酶（AMPK）是一种关键的代谢和应激传感器/效应器。很少有研究探讨AMPK在发育中的大鼠脑缺氧缺血（HI）中的作用。已发现叉头转录因子（FOXO3a）是AMPK介导的细胞凋亡的关键效应器。然而，尚不清楚AMPK/FOXO3a通路是否参与HI后发育中的大鼠脑神经元凋亡。在本研究中，我们使用出生后第7天的大鼠建立了缺氧缺血性脑损伤（HIBD）模型。我们发现，AMPK的激活伴随着p-mTOR、p-Akt和p-FOXO3a的减少，这诱导了FOXO3a易位至细胞核并上调了Bim和裂解的半胱天冬酶3（CC3）的表达。此外，我们发现，用AMPK活性的选择性抑制剂Compound C抑制AMPK后，显著增加了HI后mTOR、Akt和FOXO3a的磷酸化水平，减弱了FOXO3a的核易位，并抑制了Bim和CC3的表达。此外，抑制AMPK可减少细胞凋亡，减轻发育中的大鼠脑HI后的脑梗死体积并促进神经功能恢复。我们的研究结果表明，AMPK参与了HI后发育中的大鼠脑FOXO3a介导的神经元凋亡的调控。靶向AMPK的药物可能为挽救神经元免受HI诱导的损伤带来希望。
