Abstract
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 A1, A2A, and A3 receptor subtypes were present on U937 cells, and activation of these subtypes inhibited TNF-alpha 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-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 A2A receptors may provide effective inhibition of acute neurotoxic proinflammatory events that occur following intracerebral hemorrhage.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine / administration & dosage
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Adenosine / analogs & derivatives*
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Adenosine / pharmacology
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Adenosine / therapeutic use
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Adenylyl Cyclases / metabolism
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Animals
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Apoptosis* / drug effects
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Cerebral Hemorrhage / drug therapy
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Cerebral Hemorrhage / enzymology
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Cerebral Hemorrhage / metabolism
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Cerebral Hemorrhage / pathology*
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Chemotaxis, Leukocyte / drug effects
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Humans
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In Situ Nick-End Labeling
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Inflammation / drug therapy
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Inflammation / enzymology
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Inflammation / metabolism
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Inflammation / pathology
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Injections, Intraventricular
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Male
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Neutrophils / cytology
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Neutrophils / drug effects
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Neutrophils / immunology
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Phenethylamines / administration & dosage
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Phenethylamines / pharmacology
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Phenethylamines / therapeutic use
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Phytohemagglutinins / pharmacology
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Purinergic P1 Receptor Agonists*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Rats
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Rats, Sprague-Dawley
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Receptor, Adenosine A2A
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Receptor, Adenosine A3
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Receptors, Purinergic P1 / metabolism*
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Tetradecanoylphorbol Acetate / pharmacology
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / genetics
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U937 Cells
Substances
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Phenethylamines
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Phytohemagglutinins
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Purinergic P1 Receptor Agonists
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RNA, Messenger
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Receptor, Adenosine A2A
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Receptor, Adenosine A3
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Receptors, Purinergic P1
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Tumor Necrosis Factor-alpha
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2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
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Adenylyl Cyclases
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Adenosine
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Tetradecanoylphorbol Acetate