Curr. Med. Chem. – Central Nervous System Agents, 2004, 4, 000-000 1 1568-0150/04 $45.00+.00 © 2004 Bentham Science Publishers Ltd. The Controversial Role of Adenosine A 2A Receptor Antagonists as Neuroprotective Agents Patrizia Popoli a* , David Blum b , Annita Pintor a , Maria Teresa Tebano a , Claudio Frank a , Marco Gianfriddo c , Maria Rosaria Domenici a , Serge N. Schiffmann b and Felicita Pedata c a Department of Pharmacology, Istituto Superiore di Sanità, Rome (Italy), b Laboratory of Neurophysiology, Université Libre de Bruxelles, 1070, Brussels, (Belgium), c Department of Preclinical and Clinical Pharmacology, University of Florence (Italy) Abstract: Adenosine is an endogenous modulator that regulates many Central Nervous System functions, and whose effects are mediated by four G-protein coupled receptors (A 1 , A 2A , A 2B , A 3 ). Adenosine A 2A receptors have been recently regarded as promising targets for the development of neuroprotective strategies. In particular, since an abnormal glutamate outflow is thought to play a crucial role in triggering the cellular events leading to excitotoxic neuronal death, and since A 2A receptors positively modulate glutamate outflow, it has been supposed that their blockade could represent a suitable approach to the treatment of neurodegenerative diseases. In agreement with this hypothesis, both the genetic inactivation and the pharmacological blockade of A 2A receptors proved effective in several models of brain injury. In some studies, the neuroprotective effects of A 2A receptor antagonists correlated well with their ability to prevent injury- or toxin- stimulated glutamate outflow. The “beneficial” effects of A 2A receptor antagonists at the pre-synaptic sites (namely their ability to attenuate glutamate release), however, seem to occur only at very low doses and at certain time points after the insult is given. Moreover, A 2A receptor antagonists seem unable to prevent the toxic effects elicited by direct stimulation of post-synaptic NMDA receptors. It is concluded that, although A 2A antagonists show clear neuroprotective effects in models of brain injury, their actual therapeutic potential needs to be confirmed in a wider range of doses, at different stages of brain injury as well as in models of neurodegenerative diseases, in which pre- and post-synaptic effects play different relative roles. Keywords: Adenosine A 2A receptor antagonists; Neuroprotective effects; Glutamate release; NMDA receptor stimulation; Dose-dependency; Inflammatory mechanisms. 1. THE NEUROMODULATORY ROLE OF ADENOSINE IN THE CENTRAL NERVOUS SYSTEM (CNS) Adenosine is an endogenous modulator which is present virtually in all tissues and which plays a pivotal role in intercellular communication. In the CNS, adenosine may act as a neurotransmitter, a neuromodulator or “a retaliatory metabolite” [1]. The main pathways of adenosine production, release and metabolism in the brain have been recently reviewed by Latini and Pedata [2]. The main source of adenosine is represented by ATP whose intracellular degradation proceeds via adenylate kinase to ADP and AMP, and then formation of adenosine via cytosolic 5'-nucleotidase. Although the mechanism most commonly implicated in adenosine release is through bi- directional nucleoside transporters which transfer adenosine following its concentration gradient, evidence of a neuronal Ca 2+ -dependent release of adenosine does not exclude the existence of an excitation-coupled release mechanism. In the last years ATP was accepted as a neurotransmitter or modulator in the CNS [3]. Since adenosine may also derive *Address correspondence to this author at the Department of Pharmacology Istituto Superiore di Sanità Viale Regina Elena, 299 00161 Rome Italy; Tel: +39-06-49902482; Fax: +39-06-49387104; E-mail: patrizia.popoli@iss.it from released ATP, which is dephosphorilated to AMP which on its turn is converted to adenosine by extracellular 5'-nucleotidases [4], the contribution of extracellularly released nucleotide to extracellular adenosine remains a matter of debate. Under conditions of hypoxia/ischemia in which breakdown of ATP occurs and there is a mismatch between ATP degradation and resynthesis, adenosine intracellular concentration greatly increases, and it is likely that under these conditions extracellular adenosine mainly derives per se from cells. In in vivo and in vitro studies, it was evaluated that adenosine is present extracellularly at concentrations which can stimulate its higher affinity A 1 and A 2A receptors. Under conditions of hypoxia/ischemia, adenosine rises to concentrations which can stimulate also its lower affinity A 3 and A 2B receptors. Under these last conditions, adenosine is considered as an homeostatic cell signal, which tends to maintain the resting state by counteracting uncontrolled activation of neuronal and glial cells [5], and as a promoter of trophic effects in both neurons and glia (reviewed in [6]). In heart and brain, adenosine may favor tissue adaptation to ischemic insults (reviewed in [7]). Although adenosine effects are generally regarded as beneficial, a great complexity arises from the different distribution and the different functions of its receptors [8].