Adenosine A(2A) 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 adeno sine 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 hemorrh age-induced TNF-alpha production and inflammatory events. In vitro experime nts showed that adenosine A(1), A(2A), and A(3) receptor subtypes were pres ent on U937 cells, and activation of these subtypes inhibited TNF-alpha pro duction 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 aden osine A(2A), A(1), and A(3) receptors. CGS 21680 administration directly in to the striatum immediately prior to the induction of intracerebral hemorrh age inhibited TNF-alpha mRNA and, 24 hours following induction, reduced par enchymal neutrophil infiltration (p < 0.001) and TUNEL-positive cells (p < 0.002) within and bordering the hematoma. These results suggest that pharma cological strategies targeting A(2A) receptors may provide effective inhibi tion of acute neurotoxic proinflammatory events that occur following intrac erebral hemorrhage.