The effects of diclofenac, an inhibitor of prostaglandin synthesis, were studied on the acute radiation syndrome elicited in mice by fractional irradiation. Several haematological parameters were evaluated in mice irradiated with 5x2 Gy and 3x, 4x, or 5x3 Gy (intervals between fractions 24 h) from a 60Co gamma-ray source. The animals were treated with diclofenac either before each fraction or only once before the last fraction. The survival of mice was recorded after the irradiation regimen of 5x3 Gy followed by a "top-up" dose of 3.5 Gy given 24 h after the last radiation fraction. Statistically significant enhancement of the endogenous spleen colony formation and of leukopoiesis was found in mice treated with diclofenac repeatedly, as compared with both saline-treated irradiated controls and animals administered a single diclofenac dose, if a sublethal total radiation dose had been accumulated. However, following accumulation of a lethal total radiation dose, slightly impaired survival was observed in mice given diclofenac. It follows from the results that diclofenac is a suitable drug for enhancing leukopoiesis impaired by sublethal fractionated irradiation. Nevertheless, undesirable side effects of this drug negatively influence the survival of experimental animals following a lethal accumulated radiation dose.
We have recently demonstrated that the combined administration of dipyridamole and adenosine monophospate to mice induces radioprotective effects in terms of postirradiation haemopoietic recovery in animals irradiated with a single dose. The aim of the present experiments was to investigate the radioprotective ability of the drug combination under conditions of fractionated radiation treatment. It has been shown that administration of drugs either 15 or 60 min before each of the five daily 3-Gy doses of gamma-radiation enhances haemopoietic recovery and survival of mice exposed to an additional "top-up" dose of 3.5 Gy. Furthermore, it has been ascertained that the regimen using administration of the drugs 60 min prior to irradiation is more effective than administration of the drugs 15 min prior to irradiation. Due to the evidence that administration of the drugs 15 min prior to irradiation protects the organism mainly via mechanisms of systemic hypoxia while the pretreatment 60 min before irradiation avoids the role of hypoxia and mainly induces cell proliferation effects, our results suggest a more effective protective role of mechanisms stimulating haemopoiesis under conditions of fractionated radiation. The data may provide a basis for more rational use of radioprotection in fractionated radiation regimens.
The effects of ionizing radiation on pineal melatonin and on key enzymes of its metabolism have been studied in our laboratory. After adaptation to an artificial light/dark cycle of 12:12 h, male Wistar rats were fractionally whole-body irradiated with a dose of 2.4 Gy of gamma-rays twice a week up to total doses of 4.8, 9.6 or 14.4 Gy. Irradiation and sham-irradiation were performed in the late afternoon. The rats were sacrificed at 24:00 to 01:00 h in darkness, 6 h, 3 or 5 days after the last exposure. Pineal and serum melatonin concentrations, pineal activities of serotonin N-acetyltransferase (NAT) and of monoamine oxidase (MAO) were determined. The NAT activities in the rats irradiated with 4.8 and 9.6 Gy decreased at some intervals without changes of melatonin concentration. Irradiation with a total dose of 14.4 Gy decreased NAT activity and the concentration of pineal and serum melatonin 6 h and 3 days after the last exposure. The activity of MAO, estimated only in the rats irradiated with the dose of 14.4 Gy, increased significantly 3 days after irradiation. The fractionated irradiation up to the dose of 14.4 Gy caused a transient decrease in pineal melatonin synthesis. This could be the consequence of preferential oxidative deamination of serotonin in comparison with its N-acetylation, leading to melatonin biosynthesis.