A cannabinoid receptor 2 agonist reduces blood–brain barrier damage via induction of MKP-1 after intracerebral hemorrhage in rats

• Published in: Brain research Vol. 1697; pp. 113 - 123
• Main Authors: Li, Lin, Yun, Debo, Zhang, Yuan, Tao, Yihao, Tan, Qiang, Qiao, Fei, Luo, Bo, Liu, Yi, Fan, Runjin, Xian, Jishu, Yu, Anyong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15-10-2018
• Subjects: Blood–brain barrier; Cannabinoid receptor type 2; Intracerebral hemorrhage; MKP-1; Neuroinflammation; Neuroinflammation; Cannabinoid receptor type 2; MKP-1; Intracerebral hemorrhage; Blood–brain barrier
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2018.06.006

•A CB2R agonist (JWH133) enhancing the expression of MKP-1 following ICH.•MKP-1/MAPKs Signaling Pathway regulated the inflammatory response after ICH.•JWH133 provided a potentially translatable therapeutic strategy for ICH.
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.
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.
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 1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) 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.
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.