A3 adenosine receptor agonist reduces brain ischemic injury and inhibits inflammatory cell migration in rats

In Young Choi, Jae Chul Lee, Chung Ju, Sunyoung Hwang, Geum Sil Cho, Hyuk Woo Lee, Won Jun Choi, Lak Shin Jeong, Won-Ki Kim

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)2042-2052
Number of pages11
JournalAmerican Journal of Pathology
Volume179
Issue number4
DOIs
Publication statusPublished - 2011 Oct 1

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Adenosine A3 Receptor Agonists
Brain Injuries
Cell Movement
Adenosine A3 Receptors
Middle Cerebral Artery Infarction
Microglia
Reperfusion
Adenosine A3 Receptor Antagonists
Wounds and Injuries
Cell Migration Inhibition
rho GTP-Binding Proteins
Corpus Callosum
Therapeutics
Interleukin-1
Chemokines
Lipopolysaccharides
Monocytes
Oxidative Stress
Down-Regulation
Stroke

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

A3 adenosine receptor agonist reduces brain ischemic injury and inhibits inflammatory cell migration in rats. / Choi, In Young; Lee, Jae Chul; Ju, Chung; Hwang, Sunyoung; Cho, Geum Sil; Lee, Hyuk Woo; Choi, Won Jun; Jeong, Lak Shin; Kim, Won-Ki.

In: American Journal of Pathology, Vol. 179, No. 4, 01.10.2011, p. 2042-2052.

Research output: Contribution to journalArticle

Choi, In Young ; Lee, Jae Chul ; Ju, Chung ; Hwang, Sunyoung ; Cho, Geum Sil ; Lee, Hyuk Woo ; Choi, Won Jun ; Jeong, Lak Shin ; Kim, Won-Ki. / A3 adenosine receptor agonist reduces brain ischemic injury and inhibits inflammatory cell migration in rats. In: American Journal of Pathology. 2011 ; Vol. 179, No. 4. pp. 2042-2052.
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