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 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.
Mayne
M
M
Department of Pharmacology, University of Manitoba, Winnipeg, Canada. mmayne@cc.umanitoba.ca
Fotheringham
J
J
Yan
H J
HJ
Power
C
C
Del Bigio
M R
MR
Peeling
J
J
Geiger
J D
JD
D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D007276:Injections, Intraventricular; D008297:Male; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D010627:Phenethylamines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D010835:Phytohemagglutinins / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D020298:U937 Cells
D010627:Phenethylamines; D010835:Phytohemagglutinins; D058906:Purinergic P1 Receptor Agonists; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; D014409:Tumor Necrosis Factor-alpha; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000262:Adenylyl Cyclases; D000241:Adenosine; D013755:Tetradecanoylphorbol Acetate