title: Astrocytic P2Y(1) receptor is involved in the regulation of cytokine/chemokine transcription and cerebral damage in a rat model of cerebral ischemia.
abstract: After brain ischemia, significant amounts of adenosine 5'-triphosphate are released or leaked from damaged cells, thus activating purinergic receptors in the central nervous system. A number of P2X/P2Y receptors have been implicated in ischemic conditions, but to date the P2Y(1) receptor (P2Y(1)R) has not been implicated in cerebral ischemia. In this study, we found that the astrocytic P2Y(1)R, via phosphorylated-RelA (p-RelA), has a negative effect during cerebral ischemia/reperfusion. Intracerebroventricular administration of the P2Y(1)R agonist, MRS 2365, led to an increase in cerebral infarct volume 72 hours after transient middle cerebral artery occlusion (tMCAO). Administration of the P2Y(1)R antagonist, MRS 2179, significantly decreased infarct volume and led to recovered motor coordination. The effects of MRS 2179 occurred within 24 hours of tMCAO, and also markedly reduced the expression of p-RelA and interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1/chemokine (C-C motif) ligand 2 (CCL2), and interferon-inducible protein-10/chemokine (C-X-C motif) ligand 10 (CXCL10) mRNA. P2Y(1)R and p-RelA were colocalized in glial fibrillary acidic protein-positive astrocytes, and an increase in infarct volume after MRS 2365 treatment was inhibited by the nuclear factor (NF)-κB inhibitor ammonium pyrrolidine dithiocarbamate. These results provide evidence that the P2Y(1)R expressed in cortical astrocytes may help regulate the cytokine/chemokine response after tMCAO/reperfusion through a p-RelA-mediated NF-κB pathway.
authors.affiliation: Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, University of Kyushu, Higashi-ku, Fukuoka, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kuboyama
authors.forename: Hideki
authors.initials: H
authors.lastname: Harada
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Tozaki-Saitoh
authors.forename: Makoto
authors.initials: M
authors.lastname: Tsuda
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ushijima
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Inoue
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D054022:Cerebrum / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D058472:Receptors, Purinergic P2Y1 / Q000276:immunology*; D015533:Transcriptional Activation
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D012333:RNA, Messenger; D058472:Receptors, Purinergic P2Y1