Roles of BCL-2 and caspase 3 in the adenosine A3 receptor-induced apoptosis

Selective A(3) adenosine receptor agonists have been shown to induce apoptosis in a variety of cell types. In this study we examined the effects of adenosine receptor agonists selective for A(1), A(2)A, or A(3) receptors on the induction of apoptosis in primary cultures of rat astrocytes and in C6 glial cells. Treatment of the cells with the A(3) receptor agonist CI-IB-MECA (10 muM) induced apoptosis in both cell types. The effects of CI-IB-MECA were partially antagonized by the A(3) receptor-selective antagonist MRS 1191. In contrast, the A(1) and A(2A) receptor agonists, CPA and CGS 21680, respectively, did not have significant effects on apoptosis in these cells. CI-IB-MECA reduced the expression of endogenous Bcl-2, whereas it did not affect the expression of Bax. Overexpression of Bcl-2 in C6 cells abrogated the induction of apoptosis induced by the A(3) agonist. CI-IB-MECA also induced an increase in caspase 3 activity and caspase inhibitors decreased the apoptosis induced by the A(3) agonist. These findings suggest that intense activation of the A(3) receptor is pro-apoptotic in glial cells via bcl2 and caspase-3 dependent pathways.