Protection against kainate-induced excitotoxicity by adenosine A2A receptor agonists and antagonists

The neuroprotective role of adenosine receptor agonists in various models of ischaemia and neuronal excitotoxicity has been attributed to adenosine A(1) receptor activation. In this study we examine the role of the A(2A), receptor in the kainate model of excitotoxicity. Kainate (10 mg/kg) was administered systemically 10 min after the intraperitoneal injection of adenosine analogues. The A(2A) agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS21680) protected the hippocampus at concentrations of 0.1 and 0.01 mg/kg, but not at 2 mu g/kg. The addition of the centrally acting adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine partially reduced protection only in the CA3a region, suggesting that only a small proportion of the protection was attributable to the A(1) receptor. A less potent A(2A) agonist, N-6-[2-(3,5-dimethyoxyphenyl)-2-(2-methylphenyl)-ethyl]adenosine (1 mg/kg), provided only partial protection against kainate. 4-(2-[7-Amino-2-[2-furyl][1,2,4]triazolo a][1,3,5]triazin-5-yl-amino]ethyl)phenol, a selective A(2A), antagonist, also showed protection against kainate-induced neuronal death, when administered alone or in combination with CGS21680. These results show that adenosine A(2A) receptor activation is protective against excitotoxicity. The protection is largely independent of A(1) receptor activation or blockade. (C) 1998 IBRO. Published by Elsevier Science Ltd.