Inhibition of A2AR has resulted in a complete shift of LTD to LTP, supporting a major role of A2ARs in cognitive deficits.103 Inhibition of A2AR has also been promising in reduction of excitotoxicity in neurons104,105 and in movement diminished motor symptoms in PD.54,55,106-111 Additionally, in vitro studies of A2AR antagonists have shown to prevent Aβ-induced neurotoxicity and synaptotoxicity,99,100 while A2A receptor agonists increased Aβ production.100 However, study of APP/PS1 mice treated with A2A receptor antagonist istradefylline, an anti-Parkinson drug, showed an increase in Aβ42 accumulation in cortical, but not in the hippocampal neurons.112 The underlying relationship between amyloid deposition, AD progression, and adenosine remains unclear and require more clarification.97,113,114 Nevertheless, there is an indication that activation A2A receptor can result in microglia activation and antagonists of A2A receptor can reverse this process.115 Some studies have suggested that A2A receptor inhibition might also contribute to control of astrogliosis as well,116 and selective elimination of A2A receptors from astrocytes has resulted in memory improvement in animal models of AD.113 Therefore, in addition to microglia, astrocytes might also be a responsible culprit, associating A2A receptor with neuroinflammatory and neurodegenerative diseases.
