title: Time-Dependent Protection of CB2 Receptor Agonist in Stroke.
abstract: Recent studies have indicated that type 2 cannabinoid receptor (CB2R) agonists reduce neurodegeneration after brain injury through anti-inflammatory activity. The purpose of this study was to examine the time-dependent interaction of CB2R and inflammation in stroke brain. Adult male rats were subjected to right middle cerebral artery occlusion (MCAo). CB2R mRNA expression was significantly elevated >20 fold on day 2, peaked >40-fold on day 5, and normalized on day 10 post-stroke. Inflammatory markers IBA1 and TLR4 were significantly upregulated 15 fold until day 5 after MCAo. Because of the delayed upregulation of CB2R and IBA1, we next treated animals daily with CB2R agonist AM1241 or anti-inflammatory PPAR-γ agonist pioglitazone from 2 to 5 days after MCAo. Delayed treatment with pioglitazone significantly reduced abnormal neurological scores and body asymmetry as well as brain infarction in stroke animals. No behavioral improvement or reduction in brain infarction was found in animals receiving AM1241. Pioglitazone, but not AM1241, significantly reduced IBA1 expression in the stroke cortex, suggesting that delayed treatment with AM1241 failed to alter ischemia-mediated IBA-1 upregulation. In contrast, pretreatment with AM1241 significantly reduced brain infarction and neurological deficits. In conclusion, our data support a time-dependent neuroprotection of CB2 agonist in an animal model of stroke. Delayed post- treatment with PPAR-γ agonist induced behavioral recovery and microglial suppression; early treatment with CB2R agonist suppressed neurodegeneration in stroke animals.
authors.affiliation: Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Yu
authors.affiliation: Neural Protective and Regeneration Section, National Institute on Drug Abuse, NIH, Baltimore, Maryland, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Reiner
authors.affiliation: Neural Protective and Regeneration Section, National Institute on Drug Abuse, NIH, Baltimore, Maryland, United States of America.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.affiliation: Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Kou-Jen
authors.initials: KJ
authors.lastname: Wu
authors.affiliation: Neural Protective and Regeneration Section, National Institute on Drug Abuse, NIH, Baltimore, Maryland, United States of America.
authors.forename: Qing-Rong
authors.initials: QR
authors.lastname: Liu
authors.affiliation: Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan; Neural Protective and Regeneration Section, National Institute on Drug Abuse, NIH, Baltimore, Maryland, United States of America.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002545:Brain Ischemia / Q000150:complications / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D002186:Cannabinoids / Q000494:pharmacology / Q000627:therapeutic use; D002540:Cerebral Cortex / Q000473:pathology; D018698:Glutamic Acid; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000066829:Neuroprotection / Q000187:drug effects; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: C439263:AM 1241; C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D008840:Microfilament Proteins; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D045162:Thiazolidinediones; D051197:Toll-Like Receptor 4; D018698:Glutamic Acid; D000077205:Pioglitazone