Protection against kainate-induced excitotoxicity by adenosine A 2A receptor agonists and antagonists

Abstract

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 μg/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{2,3-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.