Neuroprotection by A2A receptor antagonists

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Abstract
Activation of A2A receptors has been shown to protect neurons in the hippocampus from damage caused by excitotoxins or from cerebral insults such as ischaemia. For example, the A2A agonist 2‐p‐(2‐carboxyethyl)phenethylamino‐5′‐N‐ethylcarboxamidoadenosine hydrochloride (CGS 21680) protects the hippocampus at concentrations which are only partially blocked by the centrally acting adenosine A1 receptor antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine (CPX), suggesting that protection is mediated largely by the A2A receptor. However, selective antagonists at the A2A receptor, such as 4‐(2‐[7‐amino‐2‐{2‐furyl}{1,2,4}triazolo{2,3‐a}{1,3,5}triazin‐5‐yl‐amino]ethyl)phenol (ZM 241385), also show protection against neuronal death produced by ischaemia or excitotoxicity. In addition, A2A receptor antagonists can reduce damage produced by combinations of subthreshold doses of the endogenous excitotoxin quinolinic acid and free radicals. The TdT‐mediated dUTP‐biotin nick end labeling (TUNEL) method has revealed that, after systemic kainic acid administration, staining was apparent in the CA1 region of the hippocampus only, even though damage was present in both the CA1 and CA3a areas. In animals injected intrahippocampally, both apoptosis and damage were limited to the CA3 region. Intrahippocampal co‐injection of kainate together with ZM 241385 did not induce apoptosis even though damage was apparent. This suggests that the adenosine A2A receptor may play a role in the route by which cells die during excitotoxicity. Overall, A2A receptor antagonists appear to be promising candidates as new drugs for the prevention of neuronal damage and death in the central nervous system. Drug Dev. Res. 52:323–330, 2001.