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

Michael Mayne, Julie Fotheringham, Hui Jin Yan, Christopher Power, Marc R. Del Bigio, James Peeling, Jonathan D. Geiger

Research output: Contribution to journalArticlepeer-review

138 Scopus citations


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-α (TNF-α) 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-α production and inflammatory events. In vitro experiments showed that adenosine A1, A2A, and A3 receptor subtypes were present on U937 cells, and activation of these subtypes inhibited TNF-α production with a rank order of A2A > > A1 > A3. Prolonged treatment of U937 cells with the A2A receptor agonist 2-p-(carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680) desensitized adenosine A2A, A1, and A3 receptors. CGS 21680 administration directly into the striatum immediately prior to the induction of intracerebral hemorrhage inhibited TNF-α 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 A2A receptors may provide effective inhibition of acute neurotoxic proinflammatory events that occur following intracerebral hemorrhage.

Original languageEnglish (US)
Pages (from-to)727-735
Number of pages9
JournalAnnals of Neurology
Issue number6
StatePublished - 2001
Externally publishedYes

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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