microRNA-21 Confers Neuroprotection Against Cerebral Ischemia-Reperfusion Injury and Alleviates Blood-Brain Barrier Disruption in Rats via the MAPK Signaling Pathway.

The mechanism contributing to blood-brain barrier (BBB) disruption, involved in poststroke edema and hemorrhagic transformation, is important but elusive. We investigated microRNA-21 (miR-21)-mediated mechanism in the disruption of BBB following cerebral ischemia-reperfusion (I/R) injury. Rats with cerebral I/R injury were prepared after middle cerebral artery occlusion and subsequent reperfusion. The underlying regulatory mechanisms of miR-382 were investigated with treatment of miR-382 mimics, miR-382 inhibitors, or SB203580 (an inhibitor of the MAPK signaling pathway) prior to I/R modeling. Compared with sham-operated rats, rats following I/R showed increased Longa's scores, ischemic hemisphere volume, cerebral infarct volume, EB content in brain tissues, enhanced levels of p38, iNOS, and MMP-9. The ectopic expression of miR-21 by mimics and MAPK signaling inhibition by SB203580 reduced Longa's scores, ischemic hemisphere volume, cerebral infarct volume, EB content in brain tissues, decreased levels of p38, MAP2K3, iNOS, and MMP-9. The luciferase activity determination showed miR-21 bound to MAP2K3 in its 3'UTR. miR-21 downregulation mediated by inhibitors appeared to yield an opposed trend. We also found that MAPK signaling inhibition by SB203580 could rescue rats with treatment of miR-382 inhibitors. The study highlights the neuroprotective role of MiR-21 during cerebral I/R injury and its preventive effect against BBB disruption by blocking the MAPK signaling pathway via targeted inhibition of MAP2K3, potentially opening a novel therapeutic avenue for the treatment of cerebral ischemia.