Adenosine A1 and A3 receptors protect astrocytes from hypoxic damage

Eur J Pharmacol. 2008 Oct 31;596(1-3):6-13. doi: 10.1016/j.ejphar.2008.08.002. Epub 2008 Aug 13.


Brain levels of adenosine are elevated during hypoxia. Through effects on adenosine receptors (A(1), A(2A), A(2B) and A(3)) on astrocytes, adenosine can influence functions such as glutamate uptake, reactive gliosis, swelling, as well as release of neurotrophic and neurotoxic factors having an impact on the outcome of metabolic stress. We have studied the roles of these receptors in astrocytes by evaluating their susceptibility to damage induced by oxygen deprivation or exposure to the hypoxia mimic cobalt chloride (CoCl(2)). Hypoxia caused ATP breakdown and purine release, whereas CoCl(2) (0.8 mM) mainly reduced ATP by causing cell death in human D384 astrocytoma cells. Further experiments were conducted in primary astrocytes prepared from specific adenosine receptor knock-out (KO) and wild type (WT) mice. In WT cells purine release following CoCl(2) exposure was mainly due to nucleotide release, whereas hypoxia-induced intracellular ATP breakdown followed by nucleoside efflux. N-ethylcarboxamidoadenosine (NECA), an unselective adenosine receptor agonist, protected from cell death following hypoxia. Cytotoxicity was more pronounced in A(1)R KO astrocytes and tended to be higher in WT cells in the presence of the A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Genetic deletion of A(2A) receptor resulted in less prominent effects. A(3)R KO glial cells were more affected by hypoxia than WT cells. Accordingly, the A(3) receptor agonist 2-chloro-N(6)-(3-iodobenzyl)-N-methyl-5'-carbamoyladenosine (CL-IB-MECA) reduced ATP depletion caused by hypoxic conditions. It also reduced apoptosis in human astroglioma D384 cells after oxygen deprivation. In conclusion, the data point to a cytoprotective role of adenosine mediated by both A(1) and A(3) receptors in primary mouse astrocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / metabolism
  • Adenosine A1 Receptor Agonists
  • Adenosine A3 Receptor Agonists
  • Adenosine Triphosphate / metabolism
  • Animals
  • Animals, Newborn
  • Apoptosis
  • Astrocytes / cytology
  • Astrocytes / metabolism*
  • Cell Hypoxia
  • Cell Survival
  • Cells, Cultured
  • Cobalt / pharmacology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology
  • Mice
  • Mice, Knockout
  • Purines / metabolism
  • Receptor, Adenosine A1 / genetics
  • Receptor, Adenosine A1 / physiology*
  • Receptor, Adenosine A2A / genetics
  • Receptor, Adenosine A2A / physiology
  • Receptor, Adenosine A3 / genetics
  • Receptor, Adenosine A3 / physiology*


  • Adenosine A1 Receptor Agonists
  • Adenosine A3 Receptor Agonists
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Purines
  • Receptor, Adenosine A1
  • Receptor, Adenosine A2A
  • Receptor, Adenosine A3
  • Cobalt
  • Adenosine Triphosphate
  • cobaltous chloride
  • Adenosine