Astrocytic P2Y1 receptor is involved in the regulation of cytokine/chemokine transcription and cerebral damage in a rat model of cerebral ischemia

Kazuya Kuboyama, Hideki Harada, Hidetoshi Tozaki-Saitoh, Makoto Tsuda, Kazuo Ushijima, Kazuhide Inoue

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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 (P2Y1 R) has not been implicated in cerebral ischemia. In this study, we found that the astrocytic P2Y1 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 P2Y1 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. P2Y1 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)-B 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-B pathway.

Original languageEnglish
Pages (from-to)1930-1941
Number of pages12
JournalJournal of Cerebral Blood Flow and Metabolism
Volume31
Issue number9
DOIs
Publication statusPublished - Sep 1 2011

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All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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