Department of Neurosurgery, Affiliated Hospital of Weifang Medical University, China.
Department of Ultrasonography, Affiliated Hospital of Weifang Medical University, China.
FEBS Open Bio. 2019 May;9(5):859-869. doi: 10.1002/2211-5463.12614. Epub 2019 Apr 11.
Stroke is a leading cause of death and disability, but treatment options remain limited. Recent studies have suggested that cerebral ischemia-induced neurogenesis plays a vital role in post-stroke repair. Overactivation of AMP-activated protein kinase (AMPK), a master sensor of energy balance, has been reported to exacerbate neuron apoptosis, but the role of chronic AMPK stimulus in post-stroke recovery remains unclear. MicroRNAs have emerged as regulators of neurogenesis and have been reported to be involved in neurological function. In this study, we verified that miR-27b directly targets AMPK and inhibits AMPK expression. In cultured neural stem cells, miR-27b inhibitor improved proliferation and differentiation via the AMPK signaling pathway, but did not have an obvious effect on cell viability under oxygen and glucose deprivation conditions. In a mouse middle cerebral artery occlusion model, administration of miR-27b inhibitor significantly enhanced behavioral function recovery and spatial memory. Up-regulation of neurogenesis was observed both in the subventricular zone and in the hippocampal dentate gyrus. Collectively, our data suggest that miR-27b inhibition promotes recovery after ischemic stroke by regulating AMPK activity. These findings may facilitate the development of novel therapeutic strategies for stroke.
中风是导致死亡和残疾的主要原因，但治疗选择仍然有限。最近的研究表明，脑缺血诱导的神经发生在中风后修复中起着至关重要的作用。AMP 激活蛋白激酶 (AMPK) 的过度激活，作为能量平衡的主要传感器，已被报道会加剧神经元凋亡，但慢性 AMPK 刺激在中风后恢复中的作用尚不清楚。microRNAs 已成为神经发生的调节因子，并被报道参与神经功能。在本研究中，我们验证了 miR-27b 可直接靶向 AMPK 并抑制 AMPK 的表达。在培养的神经干细胞中，miR-27b 抑制剂通过 AMPK 信号通路改善增殖和分化，但在缺氧和葡萄糖剥夺条件下对细胞活力没有明显影响。在小鼠大脑中动脉闭塞模型中，给予 miR-27b 抑制剂可显著增强行为功能恢复和空间记忆。在侧脑室和海马齿状回中均观察到神经发生的上调。总的来说，我们的数据表明，miR-27b 的抑制通过调节 AMPK 活性促进缺血性中风后的恢复。这些发现可能为中风的治疗策略的发展提供新的思路。
