title: A Cannabinoid Receptor 2 Agonist Prevents Thrombin-Induced Blood-Brain Barrier Damage via the Inhibition of Microglial Activation and Matrix Metalloproteinase Expression in Rats.
abstract: Thrombin mediates the life-threatening cerebral edema and blood-brain barrier (BBB) damage that occurs after intracerebral hemorrhage (ICH). We previously found that the selective cannabinoid receptor 2 (CB2R) agonist JWH-133 reduced brain edema and neurological deficits following germinal matrix hemorrhage (GMH). We explored whether CB2R stimulation ameliorated thrombin-induced brain edema and BBB permeability as well as the possible molecular mechanism involved. A total of 144 Sprague-Dawley (S-D) rats received a thrombin (20 U) injection in the right basal ganglia. JWH-133 (1.5 mg/kg) or SR-144528 (3.0 mg/kg) and vehicle were intraperitoneally (i.p.) injected 1 h after surgery. Brain water content measurement, Evans blue (EB) extravasation, Western blot, and immunofluorescence were used to study the effects of a CB2R agonist 24 h after surgery. The results demonstrated that JWH-133 administration significantly decreased thrombin-induced brain edema and reduced the number of Iba-1-positive microglia. JWH-133 also decreased the number of P44/P42(+)/Iba-1(+) microglia, lowered Evans blue extravasation, and inhibited the elevated matrix metallopeptidase (MMP)-9 and matrix metallopeptidase (MMP)-12 activities. However, a selective CB2R antagonist (SR-144528) reversed these effects. We demonstrated that CB2R stimulation reduced thrombin-induced brain edema and alleviated BBB damage. We also found that matrix metalloproteinase suppression may be partially involved in these processes.
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, No. 30, Gaotanyan Street, Chongqing, 400038, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, No. 30, Gaotanyan Street, Chongqing, 400038, People's Republic of China.
authors.forename: Yihao
authors.initials: Y
authors.lastname: Tao
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, No. 30, Gaotanyan Street, Chongqing, 400038, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, No. 30, Gaotanyan Street, Chongqing, 400038, People's Republic of China.
authors.forename: Qianwei
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, No. 30, Gaotanyan Street, Chongqing, 400038, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, No. 30, Gaotanyan Street, Chongqing, 400038, People's Republic of China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, No. 30, Gaotanyan Street, Chongqing, 400038, People's Republic of China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, No. 30, Gaotanyan Street, Chongqing, 400038, People's Republic of China.
authors.forename: Liming
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, Sichuan Provincial Corps Hospital, Chinese People's Armed Police Forces, Leshan, People's Republic of China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, No. 30, Gaotanyan Street, Chongqing, 400038, People's Republic of China.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, No. 30, Gaotanyan Street, Chongqing, 400038, People's Republic of China.
authors.forename: Hua
authors.initials: H
authors.lastname: Feng
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, No. 30, Gaotanyan Street, Chongqing, 400038, People's Republic of China. zhichen8888@yeah.net.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D001929:Brain Edema / Q000378:metabolism; D001930:Brain Injuries / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D002186:Cannabinoids / Q000494:pharmacology*; D004195:Disease Models, Animal; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013917:Thrombin / Q000008:administration & dosage*; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D002186:Cannabinoids; D043885:Receptor, Cannabinoid, CB2; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D013917:Thrombin; D020782:Matrix Metalloproteinases; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC
keywords: Blood–brain barrier; Cannabinoid receptor; Matrix metalloproteinase; Thrombin; p44/42 MAPK