急性缺血性中风后再灌注会发生生物能量下降。然而,限制能量代谢的分子机制及其对卒中后认知和情绪并发症的影响尚不清楚.在本研究中,我们证明p53转录反应负责神经元三磷酸腺苷(ATP)缺乏和进行性神经精神障碍,涉及线粒体电压依赖性阴离子通道(VDAC)的下调。神经元p53转录激活microRNA-183(miR-183)簇的启动子,从而上调miR-183-5p(miR-183)的生物发生,miR-96-5p(miR-96),和miR-182-5p。miR-183和miR-96都直接靶向和转录后抑制VDAC。p53的神经元消融保护免受ATP缺乏和神经功能缺损,而卒中后拯救miR-183/VDAC信号逆转了这些益处.有趣的是,发现细胞周期蛋白依赖性激酶9(CDK9)在皮质神经元中富集,并上调缺血后神经元中p53诱导的miR-183簇的转录。CDK9抑制剂oroxylinA后处理主要通过抑制miR-183簇/VDAC轴促进神经元ATP产生,进一步改善了长期感觉运动能力和空间记忆,减轻中风后小鼠的抑郁样行为。我们的发现揭示了一种内在的CDK9/p53/VDAC通路,该通路驱动神经元生物能量下降,并成为卒中后认知障碍和抑郁的基础。从而突出了oroxylinA治疗更好结局的潜力.
Bioenergy decline occurs with reperfusion following acute ischemic stroke. However, the molecular mechanisms that limit energy metabolism and their impact on post-stroke cognitive and emotional complications are still unclear. In the present study, we demonstrate that the p53 transcriptional response is responsible for neuronal adenosine triphosphate (ATP) deficiency and progressively neuropsychiatric disturbances, involving the downregulation of mitochondrial voltage-dependent anion channels (VDACs). Neuronal p53 transactivated the promoter of microRNA-183 (miR-183) cluster, thereby upregulating biogenesis of miR-183-5p (miR-183), miR-96-5p (miR-96), and miR-182-5p. Both miR-183 and miR-96 directly targeted and post-transcriptionally suppressed VDACs. Neuronal ablation of p53 protected against ATP deficiency and neurological deficits, whereas post-stroke rescue of miR-183/VDAC signaling reversed these benefits. Interestingly, cyclin-dependent kinase 9 (CDK9) was found to be enriched in cortical neurons and upregulated the p53-induced transcription of the miR-183 cluster in neurons after ischemia. Post-treatment with the CDK9 inhibitor oroxylin A promoted neuronal ATP production mainly through suppressing the miR-183 cluster/VDAC axis, further improved long-term sensorimotor abilities and spatial memory, and alleviated depressive-like behaviors in mice following stroke. Our findings reveal an intrinsic CDK9/p53/VDAC pathway that drives neuronal bioenergy decline and underlies post-stroke cognitive impairment and depression, thus highlighting the therapeutic potential of oroxylin A for better outcomes.