Abstract
The treatment of stroke is limited by a short therapeutic window and a lack of effective clinical drugs. Methylene blue (MB) has been used in laboratories and clinics since the 1890s. Few studies have reported the neuroprotective role of MB in cerebral ischemia-reperfusion injury. However, whether and how MB protects against acute cerebral ischemia (ACI) injury was unclear. In this study, we investigated the effect of MB on this injury and revealed that MB protected against ACI injury by augmenting mitophagy. Using a rat middle cerebral artery occlusion (MCAO) model, we demonstrated that MB improved neurological function and reduced the infarct volume and necrosis after ACI injury. These improvements depended on the effect of MB on mitochondrial structure and function. ACI caused the disorder and disintegration of mitochondrial structure, while MB ameliorated the destruction of mitochondria. In addition, mitophagy was inhibited at 24 h after stroke and MB augmented mitophagy. In an oxygen-glucose deprivation (OGD) model in vitro, we further revealed that the elevation of mitochondrial membrane potential (MMP) by MB under OGD conditions mediated the augmented mitophagy. In contrast, exacerbating the decline of MMP during OGD abolished the MB-induced activation of mitophagy. Taken together, MB promotes mitophagy by maintaining the MMP at a relatively high level, which contributes to a decrease in necrosis and an improvement in neurological function, thereby protecting against ACI injury.
Highlights
Stroke is a primary cause of disability and death worldwide
As mitophagy is directly induced by the loss of mitochondrial membrane potential (MMP) [27,31,32,33], we further explored whether the effect of Methylene blue (MB) on mitophagy was mediated by the regulation of MMP
We found that ischemia caused massive cerebral infarction in the vehicle control (VC) group; all three doses of MB reduced the infarct volume and, among these doses, the medium dose of MB displayed the most significant effect, an approximate 50% reduction in the infarct volume (Figures 1A–B)
Summary
Stroke is a primary cause of disability and death worldwide. The treatment of stroke is constrained by a therapeutic window consisting of a few hours, and effective drugs for the treatment of stroke are extremely scarce. A few studies have shown that MB reduces cerebral ischemia-reperfusion injury [11,12,13]. Fewer than 5% of patients with ischemic stroke can obtain thrombolytic treatment in the therapeutic window [14]. More than 95% of patients suffer permanent cerebral ischemia due to not receiving reperfusion in time. The importance and necessity of ACI treatment lies in early intervention, without considering reperfusion or not, to reduce the mortality and disability. The research and development of neuroprotective drugs for the treatment of acute ischemic stroke is clinically significant. We demonstrate for the first time that MB attenuates ACI injury and that its protective effect is related to the induction of mitophagy
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