CHRONIC ADMINISTRATION OF SELECTIVE ADENOSINE A(1) RECEPTOR AGONIST OR ANTAGONIST IN CEREBRAL-ISCHEMIA

The effect of chronic administration of selective adenosine A(1) recep tor agonists and antagonists on the outcome of cerebral ischemia is en tirely unknown. Therefore, we have investigated the impact of such reg imens on the hippocampal adenosine A(1) receptor density, and on the r ecovery from 10 min forebrain ischemia in gerbils. While acutely admin istered N-6-cyclopentyladenosine (CPA) given at 0.02 mg/kg resulted on ly in a significant reduction of mortality, at 1 mg/kg it improved bot h survival and neuronal preservation in the hippocampal CA1 region. Ac ute treatment with 1,3-dipropyl-8-cyclopentylxanthine (CPX) significan tly worsened the outcome and enhanced neuronal destruction. The effect s of chronic administration of these drugs (15 days followed by 1 drug -free day) were opposite. Thus, although chronic CPA at 0.02 mg/kg did not have any effect at all, at 1 mg/kg both survival and neuronal pre servation were significantly poorer than in controls, while chronic CP X resulted in a significant improvement of both measures. These result s were not accompanied by adenosine A(1) receptor up- or downregulatio n. Our study indicates that highly selective adenosine analogues may h ave therapeutic potential in treatment of cerebral ischemia/stroke and possibly other neurodegenerative disorders as well.