AMPK inhibitor BML-275 induces neuroprotection through decreasing cyt c and AIF expression after transient brain ischemia.

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.