Adenosine A(3) receptors and viability of astrocytes

We investigated the role of the A(3) adenosine receptor in cells of the ast roglial lineage (both rat primary astrocytes and human astrocytoma ADF cell s) by means of the selective A(3) agonists N-6-(3-iodobenzyl)-adenosine-5'- N-methyluronamide (IB-MECA) and CI-IB-MECA, and by utilizing the selective AS receptor antagonist MRS1191. Exposure of ADF cells to mu M concentration s of either agonist resulted in reduction of cell number, likely due to cel l death. In both rat astrocytes and human astrocytoma cells, at concentrati ons 2-3 orders of magnitude lower (which were not associated with cytotoxic ity), these same agonists induced a marked reorganization of the cytoskelet on, with appearance of stress fibers and numerous cell protrusions. Functio nally, these morphological changes were associated with cell protection, as demonstrated by a significant reduction of spontaneous apoptosis in A(3) a gonist-treated cells. To confirm a role for the A(3) receptor in this effec t, MRS1191 completely counteracted CI-IB-MECA-induced reduction of spontane ous apoptosis. In ADF cells, Ay agonists also induced changes in the intrac ellular distribution of the anti-apoptotic protein Bcl-X-L which became loc alized in cell protrusions. Also, this effect was specifically antagonized by MRS1191. These dual actions of A(3) agonists in vitro may have important in vivo implications. For example, a robust and acute activation of the A( 3) receptor following massive adenosine release during ischemia may contrib ute to brain cell death; conversely, a subthreshold activation of this rece ptor prior to ischemia may trigger protective mechanisms (i.e., induction o f stress fibers and of a Bcl-X-L-dependent reorganization of cytoskeleton) making the brain more resistant to subsequent insults ("ischemic tolerance" ). Drug Dev. Res. 45:379-386, 1998. (C) 1998 Wiley-Liss, Inc.