title: Reduced infarct size and accumulation of microglia in rats treated with WIN 55,212-2 after neonatal stroke.
abstract: Cannabinoids have emerged as brain protective agents under neurodegenerative conditions. Many neuroprotective actions of cannabinoids depend on the activation of specific receptors, cannabinoid receptor type 1 (CB1R) and type 2 (CB2R). The aim of the present study was to determine whether the CB2R and CB1R agonist WIN 55,212-2 (WIN) protects neonatal brain against focal cerebral ischemia-reperfusion and whether anti-inflammatory mechanisms play a role in protection. Seven-day-old rats were subjected to 90-min middle cerebral artery occlusion (MCAO), and injured rats were identified by diffusion-weighted MRI during the occlusion. After reperfusion, rats were subcutaneously administered 1 mg/kg of WIN or vehicle twice daily until sacrifice. MCAO led to increased mRNA expression of CB2R (but not CB1R), chemokine receptors (CCR2 and CX3CR1), and cytokines (IL-1β and TNFα), as well as increased protein expression of chemokines MCP-1 and MIP-1α and microglial activation 24 h after MCAO. WIN administration significantly reduced microglial activation at this point and attenuated infarct volume and microglial accumulation and proliferation in the injured cortex 72 h after MCAO. Cumulatively, our results show that the cannabinoid agonist WIN protects against neonatal focal stroke in part due to inhibitory effects on microglia.
authors.affiliation: Department of Neurology, Neonatal Brain Disorders Center, University of California San Francisco, 521 Parnassus Avenue, Room C-215, San Francisco, CA 94143-0663, USA.
authors.forename: D
authors.initials: D
authors.lastname: Fernández-López
authors.forename: J
authors.initials: J
authors.lastname: Faustino
authors.forename: N
authors.initials: N
authors.lastname: Derugin
authors.forename: M
authors.initials: M
authors.lastname: Wendland
authors.forename: I
authors.initials: I
authors.lastname: Lizasoain
authors.forename: M A
authors.initials: MA
authors.lastname: Moro
authors.forename: Z S
authors.initials: ZS
authors.lastname: Vexler
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D048588:Benzoxazines / Q000494:pharmacology*; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D017628:Microglia / Q000187:drug effects / Q000473:pathology*; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D048588:Benzoxazines; D063385:Cannabinoid Receptor Modulators; D009025:Morpholines; D009281:Naphthalenes; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone