A cannabinoid receptor 2 agonist reduces blood-brain barrier damage via induction of MKP-1 after intracerebral hemorrhage in rats
A cannabinoid receptor 2 agonist reduces blood-brain barrier damage via induction of MKP-1 after intracerebral hemorrhage in rats
复制标题
大麻素受体 2 激动剂通过诱导大鼠脑出血后的 MKP-1 减少血脑屏障损伤
DOI：
10.1016/j.brainres.2018.06.006
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发表时间：
2018-10-15
期刊：
影响因子：
2.9
通讯作者：
Yu, Anyong
中科院分区：
文献类型：
--
作者：
Li, Lin;Yun, Debo;Yu, Anyong
背景和目的：血脑屏障（blood-brain barrier，BBB）的破坏和脑水肿的发生是脑出血（intracerebral hemorrhage，ICH）后最致命的继发性损伤。方法：192只成年雄性SD大鼠随机分为假手术组（Sham）、ICH +溶媒组（Vehicle）、ICH + JWH 1.0 mg/kg组、ICH + JWH 1.5 mg/kg组和ICH + JWH 2.0 mg/kg组，每组10只。ICH + SR + JWH。免疫印迹和免疫荧光染色后24 h处死动物，检测JWH 133对脑含水量、神经行为功能缺损和血脑屏障（BBB）通透性的影响，同时采用酶联免疫吸附试验（ELISA）检测血肿周围炎性细胞因子的浓度。JWH 133（1.5mg/kg）给药改善了脑水肿、神经缺陷和血脑屏障损伤以及小胶质细胞活化。促炎介质白细胞介素1 β（IL-1 β）、白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）和基质金属肽酶-2/9（MMP 2/9）的表达减弱，但单核细胞趋化蛋白-1（MCP-1）未减弱。此外，封闭小带-1（ZO-1）和紧密连接蛋白-5表达的降低被JWH 133部分恢复。此外，JWH 133上调MKP-1的表达水平，这导致MAPKs信号通路活化的抑制，尤其是ERK和P38。结论：CB 2 R激动剂可减轻脑出血大鼠的神经炎症反应，保护血脑屏障通透性。进一步的分子机制可能是通过增强MKP-1的表达，进而抑制MAPK信号转导途径。(C)2018由Elsevier B. V.出版
Background and purpose: The blood-brain barrier (BBB) disruption and the following development of brain edema, is the most life-threatening secondary injury after intracerebral hemorrhage (ICH). This study is to investigate a potential role and mechanism of JWH133, a selected cannabinoid receptor type2 (CB2R) agonist, on protecting blood-brain barrier integrity after ICH.Methods: 192 adult male Sprague-Dawley (SD) rats were randomly divided into Sham; ICH + Vehicle; ICH + JWH 1.0 mg/kg, ICH + JWH 1.5 mg/kg and ICH + JWH 2.0 mg/kg; ICH + SR + JWH respectively. Animals were euthanized at 24 h following western blots and immunofluorescence staining, we also examined the effect of JWH133 on the brain water contents, neurobehavioral deficits and blood brain barrier (BBB) permeability, meanwhile reassessed the inflammatory cytokines concentrations around the hematoma by enzyme-linked immunosorbent assay (ELISA) in each group.Results: JWH133 (1.5 mg/kg) administration ameliorated brain edema, neurological deficits and blood-brain barrier damage, as well as microglia activation. The expression of pro-inflammatory mediators interleukin 1 beta (IL-1 beta interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and matrix metallopeptidase-2/9 (MMP2/9) were attenuated, but not monocyte chemoattractant protein-1 (MCP-1). Additionally, decreases in zonula occludens-1 (ZO-1) and claudin-5 expression were partially recovered by JWH133. Furthermore, JWH133 upregulated the expression level of MKP-1, which leads to the inhibition of MAPKs signaling pathway activation, especially for ERK and P38. However, these effects were reversed by pretreatment with a selective CB2R antagonist, SR144528.Conclusions: CB2R agonist alleviated neuroinflammation and protected blood-brain barrier permeability in a rat ICH model. Further molecular mechanisms revealed which is probably mediated by enhancing the expression of MKP-1, then inhibited MAPKs signal transduction. (C) 2018 Published by Elsevier B.V.