Adenosine A2A receptor antagonism and neuroprotection: mechanisms, lights, and shadows.
Adenosine A2A receptor antagonists are regarded as potential neuroprotective drugs, although the mechanisms underlying their effects remain to be elucidated. In this review, quinolinic acid (QA)-induced striatal toxicity was used as a tool to investigate the mechanisms of the neuroprotective effects of A2A receptor antagonists. After having examined the effects of selective A2A receptor antagonists toward different mechanisms of QA toxicity, we conclude that (1) the effect elicited by A2A receptor blockade on QA-induced glutamate outflow may be one of the mechanisms of the neuroprotective activity of A2A receptor antagonists; (2) A2A receptor antagonists have a potentially worsening influence on QA-dependent NMDA receptor activation; and (3) the ability of A2A receptor antagonists to prevent QA-induced lipid peroxidation does not correlate with the neuroprotective effects. These results suggest that A2A receptor antagonists may have either potentially beneficial or detrimental influence in models of neurodegeneration that are mainly due to increased glutamate levels or enhanced sensitivity of NMDA receptors, respectively.
Popoli
Patrizia
P
Department of Drug Research and Evaluation, Istituto Superiore di Sanità, Roma, Italy.
Minghetti
Luisa
L
Tebano
Maria Teresa
MT
Pintor
Annita
A
Domenici
Maria Rosaria
MR
Massotti
Marino
M
D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D017378:Quinolinic Acid / Q000633:toxicity; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists; D013268:Stimulation, Chemical
D058917:Adenosine A2 Receptor Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D017378:Quinolinic Acid