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Research Article: MicroRNA-383-5p regulation of NADPH oxidase 4 alleviates hemorrhagic transformation and improves acute outcomes after endovascular recanalization in acute ischemic stroke

Date Published: 2026-06-24

Abstract:
Hemorrhagic transformation (HT) following reperfusion therapy is associated with poor outcomes in patients with acute ischemic stroke. Here, we determined the role of microRNA-383-5p (miR-383-5p) in alleviating HT-associated injury using models of middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reoxygenation (OGD/R). Two hundred and five hyperglycemic rats were used to establish a model of HT induced by mechanical recanalization after 5 hours of MCAO, followed by 3 and 6 hours of recanalization; then, miR-383-5p agomir was administered intravenously before recanalization. Analysis involved brain water content; hemorrhage severity; infarct volume; blood-brain barrier (BBB) disruption; neuronal apoptosis, reactive oxygen species (ROS) production; along with the expression levels of miR-383-5p, NADPH oxidase 4 (NOX4), interleukin 1 beta (IL-1?), and BBB-associated proteins. The expression of miR-383-5p and NOX4 was also evaluated in neurons after OGD/R, whereas neuronal injury and ROS production were assessed following intervention with miR-383-5p and small interfering RNA. In the MCAO model, intravenous administration of miR-383-5p agomir increased miR-383-5p and suppressed NOX4 upregulation in peri-infarct tissue and in brain microvascular endothelial cells, neurons, and astrocytes, as demonstrated by immunohistochemical fluorescent staining. Increased levels of miR-383-5p alleviated brain edema, infarct volume, and the severity of hemorrhage; reduced ROS overproduction, neuronal apoptosis, and IL-1? overexpression in astrocytes; and preserved BBB integrity after mechanical recanalization following ischemia, thereby improving acute neurological outcomes assessed at 3 and 6 hours after recanalization. Following OGD/R, reduced miR-383-5p and increased NOX4 expression were detected in neurons. Elevated miR-383-5p levels reduced neuronal injury, ROS overproduction, and NOX4 overexpression in OGD/R-treated neurons. NOX4 was confirmed as a direct target gene of miR-383-5p. MiR-383-5p alleviated oxidative stress injury, neuronal apoptosis, inflammation, and preserved BBB integrity by regulating NOX4. Therefore, miR-383-5p represents a potential therapeutic target to reduce HT and improve outcomes during the acute phase of recanalization after endovascular treatment for acute ischemic stroke.

Introduction:
Hemorrhagic transformation (HT) following reperfusion therapy is associated with poor outcomes in patients with acute ischemic stroke. Here, we determined the role of microRNA-383-5p (miR-383-5p) in alleviating HT-associated injury using models of middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reoxygenation (OGD/R).

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