The Controversial Role of Adenosine A2A Receptor Antagonists as Neuro-protective Agents

Title: The Controversial Role of Adenosine A2A Receptor Antagonists as Neuro-protective Agents

Volume: 4 Issue: 1

Author(s): Patrizia Popoli, David Blum, Annita Pintor, Maria Teresa Tebano, Claudio Frank, Marco Gianfriddo, Maria Rosaria Domenici, Serge N. Schiffmann and Felicita Pedata

Affiliation:

Keywords: adenosine a2a receptor antagonists, neuroprotective effects, glutamate release, nmda receptor stimulation, dose-dependency, inflammatory mechanisms

Abstract: Adenosine is an endogenous modulator that regulates many Central Nervous System functions, and whose effects are mediated by four G-protein coupled receptors (A1 , A2A , A2B , A3 ). Adenosine A2A 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 A2A 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 A2A 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 A2A 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, A2A receptor antagonists seem unable to prevent the toxic effects elicited by direct stimulation of post-synaptic NMDA receptors. It is concluded that, although A2A 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.

Cite this article as:

Popoli Patrizia, Blum David, Pintor Annita, Tebano Teresa Maria, Frank Claudio, Gianfriddo Marco, Domenici Rosaria Maria, Schiffmann N. Serge and Pedata Felicita, The Controversial Role of Adenosine A2A Receptor Antagonists as Neuro-protective Agents, Current Medicinal Chemistry - Central Nervous System Agents 2004; 4 (1) . https://dx.doi.org/10.2174/1568015043477577