Department of Neurosurgery, Xianyang Hospital, Yan'an University, Xianyang, 712000, People's Republic of China.
Department of Gerontology, BaoJi Central Hospital, BaoJi, 721008, People's Republic of China.
J Mol Neurosci. 2018 May;65(1):43-53. doi: 10.1007/s12031-018-1067-5. Epub 2018 Apr 26.
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.
导致血脑屏障（BBB）破坏的机制，涉及中风后水肿和出血转化，是重要但难以捉摸的。我们研究了 microRNA-21（miR-21）在脑缺血再灌注（I/R）损伤后 BBB 破坏中的介导机制。在大脑中动脉闭塞和随后的再灌注后，制备了患有脑 I/R 损伤的大鼠。在 I/R 建模之前，用 miR-382 模拟物、miR-382 抑制剂或 SB203580（MAPK 信号通路抑制剂）处理，研究了 miR-382 的潜在调节机制。与假手术大鼠相比，I/R 大鼠的 Longa 评分升高，缺血半球体积增大，脑梗死体积增大，脑组织 EB 含量增加，p38、iNOS 和 MMP-9 水平升高。通过模拟物的 miR-21 异位表达和 SB203580 的 MAPK 信号抑制降低了 Longa 评分、缺血半球体积、脑梗死体积、脑组织 EB 含量，降低了 p38、MAP2K3、iNOS 和 MMP-9 的水平。荧光素酶活性测定显示 miR-21 结合到其 3'UTR 中的 MAP2K3。miR-21 抑制剂介导的下调似乎呈现出相反的趋势。我们还发现，SB203580 的 MAPK 信号抑制可以挽救用 miR-382 抑制剂治疗的大鼠。该研究强调了 MiR-21 在脑 I/R 损伤期间的神经保护作用，以及通过靶向抑制 MAP2K3 阻断 MAPK 信号通路对 BBB 破坏的预防作用，为治疗脑缺血开辟了新的治疗途径。
