title: The molecular mechanism and effect of cannabinoid-2 receptor agonist on the blood-spinal cord barrier permeability induced by ischemia-reperfusion injury.
abstract: Previous studies have shown that modulation of the receptor-mediated endocannabinoid system during ischemia injury can induce potent neuroprotective effects. However, little is known about whether cannabinoid-2 (CB2) receptor agonist would produce a protective effect on blood-spinal cord barrier (BSCB) during ischemia. Using an in vivo transient spinal cord ischemia model in rats, JWH-015 (1mg/kg, i.p.), a CB2 receptor selective agonist, or vehicles were injected 20 min before ischemia. The effects of JWH-015 on BSCB permeability, the major structural protein for the formation of caveolae, caveolin-1 (cav-1), tight junction (TJ) protein Occludin and zona occludens protein-1 (ZO-1) were examined at day 1, day 3 and day 7 of reperfusion after transient spinal cord ischemia in rats. Here we demonstrated that JWH-015 significantly down-regulated the expression of cav-1, up-regulated the expression of TJ proteins, and then decreased the permeability of BSCB compared with control group. In addition, using an in vitro BBB model, oxygen glucose deprivation (OGD) was applied to simulate spinal cord ischemia in vitro in Human brain microvascular endothelial cells (HBMECs). JWH-015 greatly increased the transepithelial electrical resistance (TEER) and changed the distribution of ZO-1 and Occludin. Moreover, JWH-015 induced the expression of p-PKB and p-FoxO1 protein and decreased the expression of cav-1, which were greatly reversed by ROS inhibitor or PI3K inhibitor. Taken together, all of these results suggested that JWH-015 might regulate the BSCB permeability and this effect could be related to paracellular and transcellular pathway. And pharmacological CB2R ligands offer a new strategy for BSCB protection during ischemic injury.
authors.affiliation: Department of Sports Medicine and Joint Surgery, The First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning Province, PR China.
authors.forename: Ming-Chao
authors.initials: MC
authors.lastname: Yang
authors.affiliation: Department of Sports Medicine and Joint Surgery, The First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning Province, PR China.
authors.forename: Hang-Zhou
authors.initials: HZ
authors.lastname: Zhang
authors.affiliation: Department of Sports Medicine and Joint Surgery, The First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning Province, PR China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Sports Medicine and Joint Surgery, The First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning Province, PR China.
authors.forename: Fu-Li
authors.initials: FL
authors.lastname: You
authors.affiliation: Department of Sports Medicine and Joint Surgery, The First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning Province, PR China. Electronic address: wyfdoctor_2015@163.com.
authors.forename: Yan-Feng
authors.initials: YF
authors.lastname: Wang
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002199:Capillary Permeability / Q000187:drug effects; D004195:Disease Models, Animal; D017097:Electric Impedance; D005070:Evans Blue / Q000493:pharmacokinetics; D005947:Glucose / Q000172:deficiency; D006735:Horseradish Peroxidase / Q000493:pharmacokinetics; D000860:Hypoxia / Q000473:pathology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D062793:Occludin / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D015427:Reperfusion Injury / Q000473:pathology*; D013116:Spinal Cord; D019108:Tight Junctions / Q000187:drug effects*; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D007211:Indoles; D062793:Occludin; D043885:Receptor, Cannabinoid, CB2; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; D005070:Evans Blue; D006735:Horseradish Peroxidase; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose; C402944:JHW 015
keywords: Blood–spinal cord barrier; Cannabinoid-2 receptor; Caveolin-1; Spinal cord ischemia reperfusion injury; Tight junction