Astrocytic P2Y₁ 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 50 -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-a, 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)-jB 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-jB pathway.

Cooperation between NMDA-Type Glutamate and P2 Receptors for Neuroprotection during Stroke: Combining Astrocyte and Neuronal Protection

“…P2Y 1 receptor block was highly protective in high-density cultures. P2Y 1 receptor block delays anoxic depolarization in hippocampal slices [52], but the current data are consistent with reports that P2Y 1 block is effective against ischemic injury in vivo [53][54][55]. P2Y 1 receptor activation stimulates glutamate release from cultured hippocampal and spinal cord astrocytes but not neurons, while P2Y 1 receptor antagonists reduce ATP induced glutamate release from astrocytes [56][57][58].…”

Purinergic Signaling and Blood Vessels in Health and Disease

“…Thus platelet aggregation inhibitors, such as clopidogrel, an antagonist of ADP-sensitive P2Y 12 receptors, have been used to prevent and treat coronary artery disease (Zeidner et al, 2008). It has been suggested that ADPmediated migration of host smooth muscle-like cells and CD45 + leukocytes, via P2Y 12 receptors, may play a role in the development of transplant arteriosclerosis, partly by monocyte chemoattractant protein-1 (Harada et al, 2011). Prasugrel, a P2Y 12 receptor antagonist, has been used for the treatment of acute coronary syndrome (Jauregui et al, 2009).…”

Supportive or detrimental roles of P2Y receptors in brain pathology?—The two faces of P2Y receptors in stroke and neurodegeneration detected in neural cell and in animal model studies

“…The influence of P2Y 1 receptor agonists and antagonists on the outcome of transient MCAO in mice was investigated [90]. Here, the carotid artery of mice was reversibly occluded by insertion of a nylon monofilament for 30 or 60 min.…”

“…Taken together, this study suggests that P2Y 1 receptor activation by MRS2365 initiates the NFκB pathway enhancing the inflammatory response and increasing the infarct size after stroke. Blocking the P2Y 1 receptor by MRS2179 attenuates the inflammatory response and decreases the infarct size [90].…”