Different roles of adenosine A1, A2A and A3 receptors in controlling kainate-induced toxicity in cortical cultured neurons

Adenosine is a neuromodulator that can control brain damage through activation of A1, A2A and A3 receptors, which are located in both neurons and other brain cells. We took advantage of cultured neurons to investigate the role of neuronal adenosine receptors in the control of neurotoxicity caused by kainate and cyclothiazide. Both A1, A2A and A3 receptors were immunocytochemically identified in cortical neurons. Activation of A1 receptors with 100 nM CPA did not modify the extent of neuronal death whereas the A1 receptor antagonist, DPCPX (50 nM), attenuated neurotoxicity by 28 ± 5%, and effect similar to that resulting from the removal of endogenous adenosine with 2 U/ml of adenosine deaminase (27 ± 3% attenuation of neurotoxicity). In the presence of adenosine deaminase, DPCPX had no further effect and CPA now exacerbated neurotoxicity by 42 ± 4%. Activation of A2A receptor with 30 nM CGS21680 attenuated neurotoxicity by 40 ± 8%, an effect prevented by the A2A receptor antagonists, SCH58261 (50 nM) or ZM241385 (50 nM), which by themselves were devoid of effect. Finally, neither A3 receptor activation with Cl-IB-MECA (100-500 nM) nor blockade with MRS1191 (5 μM) modified neurotoxicity. These results show that A1 receptor activation enhances and A2A receptor activation attenuates neurotoxicity in cultured cortical neurons, indicating that these two neuronal adenosine receptors directly control neurodegeneration. Interestingly, the control by adenosine of neurotoxicity in cultured neurons is similar to that observed in vivo in newborn animals and is the opposite of what is observed in adult brain preparations where A1 receptor activation and A2A receptor blockade are neuroprotective.