Adenosine A2A receptor activation reduces proinflammatory events and decreases cell death following intracerebral hemorrhage

The ubiquitous neuromodulator adenosine inhibits the production of several proinflammatory cytokines through activation of specific cell-surface adenosine receptors. We demonstrated recently that antisense oligonucleotides to tumor necrosis factor-alpha (TNF-alpha) are neuroprotective in a rat model of intracerebral hemorrhage. Therefore, we hypothesized that activation of adenosine receptors would provide protection against intracerebral hemorrhage-induced TNF-alpha production and inflammatory events. In vitro experiments showed that adenosine A(1), A(2A), and A(3) receptor subtypes were present on U937 cells, and activation of these subtypes inhibited TNF-alpha production with a rank order of A(2A) > > A(1) > A(3). Prolonged treatment of U937 cells with the A(2A) receptor agonist 2-p-(carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680) desensitized adenosine A(2A), A(1), and A(3) receptors. CGS 21680 administration directly into the striatum immediately prior to the induction of intracerebral hemorrhage inhibited TNF-alpha mRNA and, 24 hours following induction, reduced parenchymal neutrophil infiltration (p < 0.001) and TUNEL-positive cells (p < 0.002) within and bordering the hematoma. These results suggest that pharmacological strategies targeting A(2A) receptors may provide effective inhibition of acute neurotoxic proinflammatory events that occur following intracerebral hemorrhage.