Long-term activation of adenosine A(2a) receptors blocks glutamate excitotoxicity in cultures of avian retinal neurons

Previous work showed the presence of adenosine receptors as well as adenosi ne uptake and release mechanisms in developing chick retinal neurons in cul ture. In the present work we show that exogenous glutamate or kainate promo tes extensive cell death in these cultures which is blocked when the cultur es are previously incubated with adenosine. Addition of glutamate or kainat e to purified cultures of retinal neurons and photoreceptors induced massiv e death of cultured cells which was inhibited in both cases by preincubatio n with MK801, an NMDA antagonist, or DNQX, an AMPA/kainate antagonist. Cell death was also greatly attenuated by preincubation with adenosine plus EHN A, an adenosine deaminase inhibitor, NBI, an adenosine uptake blocker, the permeable cAMP analogs 8-Br cAMP and Sp cAMP and the A(2a) agonists CGS 216 80 and DPMA, but not with the A(1) receptor agonist CHA. Kinetic studies pe rformed determining the intracellular LDH activity showed that maximal deat h was observed after 8 h and in concentrations of glutamate as low as 50 mu M. We also observed a time-dependent protective effect of adenosine beginni ng after 1 h of preincubation and reaching a maximal effect after 24 h, ind icating its association with changes in cellular metabolism induced by long -term exposure of cells to the nucleoside. The results show that adenosine inhibits glutamate toxicity in retinal neurons through a long-term activati on of A(2a) receptors and elevation of intracellular cyclic AMP levels. (C) 2001 Elsevier Science B.V. All rights reserved.