Protection of early cellular damage in 1 Gy-irradiated mice by the elevation of extracellular adenosine

Abstract

In whole-body 1 Gy-irradiated mice a modification of early cellular damage by means of preirradiation dipyridamole and adenosine monophosphate (AMP) treatment was investigated. Both drugs were given either alone or in combination, AMP being administered i.p. at doses of 5, 10 and 15mg, dipyridamole s.c. at the dose of 2mg, 20min before AMP. The thymidine level in plasma and the amount of free polynucleotides in the thymus and spleen, both estimated at the interval of 4h after irradiation, were used as indices of early cellular damage in vivo. The elevated level of thymidine observed in the plasma of irradiated controls decreased significantly after the administration of AMP (5 mg) alone to 71%, after the combination of dipyridamole and AMP a still deeper significant fall to 60% was observed. Such a protective effect was observed when injecting AMP 15min before irradiaton. Using the interval of 65min between AMP administration and irradiation, no protection was detected. The higher doses of AMP (10, 15mg) enhanced the protective effect manifested in plasma thymidine level only moderately. The amount of free polynucleotides, elevated in the thymus and spleen of irradiated mice, was significantly decreased in the thymus of mice pretreated with the combination of dipyridamole and AMP. The results suggest that the treatment used decreases the radiation damage of the sensitive thymocyte population. It is proposed that the joint use of AMP, an adenosine prodrug, and dipyridamole, a drug inhibiting adenosine uptake by cells, leads to an elevation in extracellular adenosine which activates cell surface adenosine receptors. Both the systemic (vasodilation-hypotension- hypoxia) and cellular (elevation of cyclic AMP in sensitive cells) consequences of adenosine receptor activation may be responsible for the observed radioprotective effects.