Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, PR China.
Weihai Marine Organism & Medical Technology Research Institute, Harbin Institute of Technology, Weihai 264209, PR China.
Bioorg Med Chem. 2021 Dec 15;52:116522. doi: 10.1016/j.bmc.2021.116522. Epub 2021 Nov 20.
Stroke is a major public health problem with an imperative need for a more effective and tolerated therapy. Neuroprotective therapy may be an effective therapeutic intervention for stroke. The morbidity and mortality of stroke-induced secondary brain injury is mainly caused by neuronal apoptosis, which can be executed in a caspase-dependent or apoptosis inducing factor (AIF)-dependent manner. As apoptosis is an energy-dependent process with a relative time delay, abnormal energy metabolism could be a significant and fundamental pathophysiological basis of stroke. To our knowledge, convincible evidences that AMPK inhibition exerts neuroprotection in cerebral ischemia injury via anti-apoptosis remain to be investigated. Accordingly, the aims of this study were to investigate the protective effects of AMPK inhibitor BML-275 on cerebral ischemic/reperfusion (I/R) injury and to elucidate the underlying mechanisms. Cerebral ischemia was induced by transient middle cerebral artery occlusion (tMCAO) in male C57BL/6 mice. The therapeutic effects of BML-275 were evaluated by infarct sizes, neurological scores and the proportion of apoptotic neurons after 24 h of reperfusion. The cell apoptosis markers cyt c and AIF were also evaluated. The results showed that intraperitoneally administration of BML-275 alleviate the cerebral infarction, neurological deficit and neuronal apoptosis induced by MCAO. BML-275 simultaneously induces anti-apoptosis and decreases the expression of cyt c and AIF. This study supports the hypothesis that anti-apoptosis is one of potential neuroprotective strategies for the treatment of stroke.
中风是一个主要的公共卫生问题，迫切需要更有效和耐受的治疗方法。神经保护治疗可能是中风的一种有效治疗干预措施。中风引起的继发性脑损伤的发病率和死亡率主要是由神经元凋亡引起的，凋亡可以通过半胱天冬酶依赖性或凋亡诱导因子（AIF）依赖性方式执行。由于凋亡是一个依赖能量的过程，具有相对的时间延迟，因此异常的能量代谢可能是中风的一个重要和基本的病理生理基础。据我们所知，令人信服的证据表明，AMPK 抑制剂通过抗细胞凋亡在脑缺血损伤中发挥神经保护作用，这仍然需要进一步研究。因此，本研究的目的是研究 AMPK 抑制剂 BML-275 对脑缺血/再灌注（I/R）损伤的保护作用，并阐明其潜在机制。雄性 C57BL/6 小鼠通过短暂性大脑中动脉闭塞（tMCAO）诱导脑缺血。通过再灌注 24 小时后的梗死面积、神经评分和凋亡神经元比例来评估 BML-275 的治疗效果。还评估了细胞凋亡标志物细胞色素 c 和 AIF。结果表明，腹腔内给予 BML-275 可减轻 MCAO 引起的脑梗死、神经功能缺损和神经元凋亡。BML-275 同时诱导抗细胞凋亡并降低细胞色素 c 和 AIF 的表达。这项研究支持了抗细胞凋亡是中风治疗的潜在神经保护策略之一的假说。
