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Adenosine A 2A receptor activation reduces proinflammatory events and decreases cell death following intracerebral hemorrhage
Author(s) -
Mayne Michael,
Fotheringham Julie,
Yan HuiJin,
Power Christopher,
Del Bigio Marc R.,
Peeling James,
Geiger Jonathan D.
Publication year - 2001
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.1010
Subject(s) - cgs 21680 , proinflammatory cytokine , adenosine a2a receptor , adenosine , agonist , adenosine receptor , receptor , tumor necrosis factor alpha , neuroprotection , pharmacology , medicine , endocrinology , inflammation
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 A 1 , A 2A , and A 3 receptor subtypes were present on U937 cells, and activation of these subtypes inhibited TNF‐α 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‐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 A 2A receptors may provide effective inhibition of acute neurotoxic proinflammatory events that occur following intracerebral hemorrhage.