Programmed cell death in rat microglia is controlled by extracellular adenosine

The induction of programmed cell death by adenosine was investigated in cultured rat microglial cells using the enzyme-linked immunosorbent assay (ELISA) for determining DNA fragmentation. Twelve hours exposure to micromolar levels of the unselective adenosine receptor agonist 2-chloro-adenosine led to the appearance of DNA fragments in the cytosolic fraction preceding damage of the plasma membrane. This effect was still seen in the presence of an adenosine uptake blocker. Conventional A(1), A(2) or A(3) agonists and antagonists were rather ineffective, suggesting mediation via an atypical adenosine receptor subtype. Microglial DNA fragmentation was inhibited by H-7 and staurosporine but not by dibutyryl-cyclic AMP, pointing to a protein kinase C linked mechanism. Such an induction of programmed cell death by an elevation of the extracellular adenosine concentration may provide an endogenous control mechanism to limit the function of activated microglial cells.