Abstract
We hypothesize that enhancing mitochondrial base excision repair (BER) capability in brain will reduce reperfusion-associated ischemic brain injury. Post-stroke reperfusion was modeled in mice via transient filament occlusion of the middle cerebral artery (60 min) (transient MCAO). Administration of a TAT-modified form of a DNA glycosylase (EndoIII) following reperfusion of the brain reduced resultant brain infarct volume. Protection was dose-dependent, BER enzyme specific, and regionally specific (more effective via the jugular vein). EndoIII is compatible with tissue plasminogen activator (tPA). The time window of a single dose of EndoIII effect is 3 h following reperfusion onset. These data suggest a novel approach to enhance protection of reperfused brain in the setting of revascularization procedures (thrombectomy or thrombolytic therapy) following stroke.
Highlights
Drug treatments for acute stroke, based on parenchymal neuroprotection, have had remarkably few successes [1, 2]
With the effectiveness of thrombolysis and endovascular thrombectomy, vascular reperfusion is the therapeutic focus of acute stroke treatment
One approach to therapy directed against reperfusion injury is to focus on DNA glycosylases as sentinel molecules affected by reperfusion injury induced by pathological reactive oxidative species
Summary
Drug treatments for acute stroke, based on parenchymal neuroprotection, have had remarkably few successes [1, 2]. With the effectiveness of thrombolysis (tPA) and endovascular thrombectomy, vascular reperfusion is the therapeutic focus of acute stroke treatment To optimize such reperfusion therapy, attention has turned to investigating methods to reduce the reperfusion-induced second wave of oxidative stress in the brain as an adjunct to reperfusion therapy [3, 4]. Such an approach must, at least, be compatible with tPA. As a therapy to reduce oxidative stress to neurons which occurs following reperfusion, enhancing BER activity may be a viable therapeutic approach. Neuroprotection was observed in the absence and presence of tPA; this approach has utility as an adjunct therapy for stroke
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