Abstract
Ischemic postconditioning provides robust neuroprotection, therefore, determining the molecular events may provide promising targets for stroke treatment. Here, we showed that the expression of functional mitochondrial voltage-dependent anion channel proteins (VDAC1, VDAC2, and VDAC3) reduced in rat vulnerable hippocampal CA1 subfield after global ischemia. Ischemic postconditioning restored VDACs to physiological levels. Stabilized VDACs contributed to the benefits of postconditioning. VDAC1 was required for maintaining neuronal Ca2+ buffering capacity. We found that microRNA-7 (miR-7) was responsible for postischemic decline of VDAC1 and VDAC3. Notably, miR-7 was more highly expressed in the peripheral blood of patients with acute ischemic stroke compared to healthy controls. Inhibition of miR-7 attenuated neuronal loss and ATP decline after global ischemia, but also diminished the infarct volume with improved neurological functions after focal ischemia. Thus, ischemic postconditioning protects against mitochondrial damage by stabilizing VDACs. MiR-7 may be a potential therapeutic target for ischemic stroke.
Highlights
Stroke is one of the leading causes of adult disability and mortality worldwide[1]
To further determine whether ischemic postconditioning confers mitochondrial protection, we measured the expression of the mitochondrial functional Voltage-dependent anion channels (VDACs) after global ischemia with or without postconditioning
The stable expression of cytochrome c oxidase subunit 4 (COX4) and unaltered mtDNA copy number precluded the possibility of mitochondrial number reduction at the early stage of reperfusion in the CA1 subfield (Fig. 1a–c), which is consistent with previous study[26,27]
Summary
Stroke is one of the leading causes of adult disability and mortality worldwide[1]. Acute ischemic stroke (AIS), caused by systemic hypoperfusion, in situ thrombosis, or embolism, is the most prevalent form of cerebrovascular disease. The only widely approved clinical treatment, causes an additional delayed damage to the ischemic brain[2,3,4]. Much attention has been focused on developing novel neuroprotective strategies for administration after brain ischemia. A single or a series of brief interference (s) in the cerebral blood supply performed after a prolonged severe brain ischemia, has been shown to protect against delayed neuronal loss after brain ischemia[5,6,7,8,9]. The molecular mechanisms underlying the endogenous neuroprotective effects remain to be defined
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