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

Ann Neurol. 2001 Jun;49(6):727-35. doi: 10.1002/ana.1010.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / administration & dosage
  • Adenosine / analogs & derivatives*
  • Adenosine / pharmacology
  • Adenosine / therapeutic use
  • Adenylyl Cyclases / metabolism
  • Animals
  • Apoptosis* / drug effects
  • Cerebral Hemorrhage / drug therapy
  • Cerebral Hemorrhage / enzymology
  • Cerebral Hemorrhage / metabolism
  • Cerebral Hemorrhage / pathology*
  • Chemotaxis, Leukocyte / drug effects
  • Humans
  • In Situ Nick-End Labeling
  • Inflammation / drug therapy
  • Inflammation / enzymology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Injections, Intraventricular
  • Male
  • Neutrophils / cytology
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Phenethylamines / administration & dosage
  • Phenethylamines / pharmacology
  • Phenethylamines / therapeutic use
  • Phytohemagglutinins / pharmacology
  • Purinergic P1 Receptor Agonists*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Adenosine A2A
  • Receptor, Adenosine A3
  • Receptors, Purinergic P1 / metabolism*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics
  • U937 Cells

Substances

  • Phenethylamines
  • Phytohemagglutinins
  • Purinergic P1 Receptor Agonists
  • RNA, Messenger
  • Receptor, Adenosine A2A
  • Receptor, Adenosine A3
  • Receptors, Purinergic P1
  • Tumor Necrosis Factor-alpha
  • 2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
  • Adenylyl Cyclases
  • Adenosine
  • Tetradecanoylphorbol Acetate