title: A3 adenosine receptor agonist reduces brain ischemic injury and inhibits inflammatory cell migration in rats.
abstract: A3 adenosine receptor (A3AR) is recognized as a novel therapeutic target for ischemic injury; however, the mechanism underlying anti-ischemic protection by the A3AR agonist remains unclear. Here, we report that 2-chloro-N(6)-(3-iodobenzyl)-5'-N-methylcarbamoyl-4'-thioadenosine (LJ529), a selective A3AR agonist, reduces inflammatory responses that may contribute to ischemic cerebral injury. Postischemic treatment with LJ529 markedly reduced cerebral ischemic injury caused by 1.5-hour middle cerebral artery occlusion, followed by 24-hour reperfusion in rats. This effect was abolished by the simultaneous administration of the A3AR antagonist MRS1523, but not the A2AAR antagonist SCH58261. LJ529 prevented the infiltration/migration of microglia and monocytes occurring after middle cerebral artery occlusion and reperfusion, and also after injection of lipopolysaccharides into the corpus callosum. The reduced migration of microglia by LJ529 could be related with direct inhibition of chemotaxis and down-regulation of spatiotemporal expression of Rho GTPases (including Rac, Cdc42, and Rho), rather than by biologically relevant inhibition of inflammatory cytokine/chemokine release (eg, IL-1β, TNF-α, and MCP-1) or by direct inhibition of excitotoxicity/oxidative stress (not affected by LJ529). The present findings indicate that postischemic activation of A3AR and the resultant reduction of inflammatory response should provide a promising therapeutic strategy for the treatment of ischemic stroke.
authors.affiliation: Department of Neuroscience, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: In-Young
authors.initials: IY
authors.lastname: Choi
authors.forename: Jae-Chul
authors.initials: JC
authors.lastname: Lee
authors.forename: Chung
authors.initials: C
authors.lastname: Ju
authors.forename: Sunyoung
authors.initials: S
authors.lastname: Hwang
authors.forename: Geum-Sil
authors.initials: GS
authors.lastname: Cho
authors.forename: Hyuk Woo
authors.initials: HW
authors.lastname: Lee
authors.forename: Won Jun
authors.initials: WJ
authors.lastname: Choi
authors.forename: Lak Shin
authors.initials: LS
authors.lastname: Jeong
authors.forename: Won-Ki
authors.initials: WK
authors.lastname: Kim
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058909:Adenosine A3 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D020520:Brain Infarction / Q000150:complications / Q000473:pathology; D001930:Brain Injuries / Q000150:complications* / Q000473:pathology / Q000517:prevention & control*; D002545:Brain Ischemia / Q000150:complications / Q000473:pathology* / Q000517:prevention & control*; D002465:Cell Movement / Q000187:drug effects*; D018932:Chemokine CCL2 / Q000378:metabolism; D005947:Glucose / Q000172:deficiency; D007249:Inflammation / Q000150:complications / Q000473:pathology*; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000187:drug effects / Q000473:pathology; D016202:N-Methylaspartate / Q000633:toxicity; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013872:Thionucleosides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: C510478:2-chloro-N(6)-(3-iodobenzyl)-5'-N-methylcarbamoyl-4'-thioadenosine; D058909:Adenosine A3 Receptor Agonists; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D013872:Thionucleosides; D014409:Tumor Necrosis Factor-alpha; D016202:N-Methylaspartate; D020741:rho GTP-Binding Proteins; D005947:Glucose; D000241:Adenosine