Neuroprotection induced by stimulating A(1) or blocking A(2A) adenosine receptors: An apparent paradox

Adenosine is involved as an endogenous modulator of nerve and glial cell fu nctions in pathological processes occurring in conditions of hypoxia/hypogl ycemia and also in neurodegenerative diseases. Thus, adenosine levels rise rapidly in the brain areas affected by ischemic insult; it reduces excitato ry amino acid release and Ca2+ influx. This results in neuroprotective acti ons. There is evidence that both A(1) and A(2A) adenosine receptors, in an opposite manner, are involved in this process. Stimulation of A(1) receptor s in isolated neurons or brain slices and in animal models of stroke produc es neuroprotection. The same net effect is achieved in models of either glo bal or focal ischemia with blockade of A(2A) adenosine receptors by a varie ty of nonselective and selective adenosine receptor antagonists. This appar ent paradox can be explained by considering that stimulation of either A(1) or A(2A) receptors exerts opposing effects on excitotoxic neuronal glutama te release and a differential regulation of the potentially neurotoxic micr oglial cell functions. These adenosine effects seem to be determined by the cellular activation state and achieved by influencing the size and timing of intracellular Ca2+ and cAMP signals, balancing the pathologically altere d cross-talk of these second messengers. Whether a reinforcement of the ade nosine-controlled second messenger generation, an enhancement of A(1) recep tor stimulation or a blockade of A(2A) receptors, or a combined approach be tter supports neuroprotection presumably depends on the nature of the patho logical process and on the timepoint at which the pharmacological intervent ion is started. Drug Dev. Res. 45:387-393, 1998. (C) 1998 Wiley-Liss, Inc.