title: Cannabidiol prevents a post-ischemic injury progressively induced by cerebral ischemia via a high-mobility group box1-inhibiting mechanism.
abstract: We examined the cerebroprotective mechanism of cannabidiol, the non-psychoactive component of marijuana, against infarction in a 4-h mouse middle cerebral artery (MCA) occlusion model. Cannabidiol was intraperitoneally administrated immediately before and 3h after cerebral ischemia. Infarct size and myeloperoxidase (MPO) activity, a marker of neutrophil, monocyte/macropharge, were measured at 24h after cerebral ischemia. Activated microglia and astrocytes were evaluated by immunostaining. Moreover, high-mobility group box1 (HMGB1) was also evaluated at 1 and 3 days after MCA occlusion. In addition, neurological score and motor coordination on the rota-rod test were assessed at 1 and 3 days after cerebral ischemia. Cannabidiol significantly prevented infarction and MPO activity at 20h after reperfusion. These effects of cannabidiol were not inhibited by either SR141716 or AM630. Cannabidiol inhibited the MPO-positive cells expressing HMGB1 and also decreased the expression level of HMGB1 in plasma. In addition, cannabidiol decreased the number of Iba1- and GFAP-positive cells at 3 days after cerebral ischemia. Moreover, cannabidiol improved neurological score and motor coordination on the rota-rod test. Our results suggest that cannabidiol inhibits monocyte/macropharge expressing HMGB1 followed by preventing glial activation and neurological impairment induced by cerebral ischemia. Cannabidiol will open new therapeutic possibilities for post-ischemic injury via HMGB1-inhibiting mechanism.
authors.affiliation: Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Hayakawa
authors.forename: Kenichi
authors.initials: K
authors.lastname: Mishima
authors.forename: Keiichi
authors.initials: K
authors.lastname: Irie
authors.forename: Mai
authors.initials: M
authors.lastname: Hazekawa
authors.forename: Shohei
authors.initials: S
authors.lastname: Mishima
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujioka
authors.forename: Kensuke
authors.initials: K
authors.lastname: Orito
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Egashira
authors.forename: Shutaro
authors.initials: S
authors.lastname: Katsurabayashi
authors.forename: Kotaro
authors.initials: K
authors.lastname: Takasaki
authors.forename: Katsunori
authors.initials: K
authors.lastname: Iwasaki
authors.forename: Michihiro
authors.initials: M
authors.lastname: Fujiwara
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D001930:Brain Injuries / Q000209:etiology / Q000517:prevention & control*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002185:Cannabidiol / Q000627:therapeutic use*; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism*; D020287:In Situ Nick-End Labeling / Q000379:methods; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D008297:Male; D051379:Mice; D008840:Microfilament Proteins; D009043:Motor Activity / Q000502:physiology; D009460:Neurologic Examination; D009195:Peroxidase / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D015424:Reperfusion; D013778:Tetrazolium Salts; D013997:Time Factors
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D024243:HMGB1 Protein; D008840:Microfilament Proteins; D013778:Tetrazolium Salts; D002185:Cannabidiol; C009591:triphenyltetrazolium; D009195:Peroxidase; D010751:Phosphopyruvate Hydratase