ABSTRACT
Radiation damage of healthy tissues represents one of the complications of radiotherapy effectiveness. This study is focused on the screening of potentially effective drugs routinely used in medical practice and involved in the mechanism of radiation injury, namely for radiation-induced production of free radicals in the body. Experiments in rats revealed significant reduction of oxidative stress (malondialdehyde) and inflammatory marker (tumor necrosis factor α) in 10 Gy irradiated groups after administration of atorvastatin and a slight decrease after tadalafil administration, which indicates that one of the possible mechanisms for mitigation of radiation-induced cardiac damage could be the modulation of nitric oxide (NO) in endothelium and phosphodiesterase 5. In addition, miRNAs were analyzed as potential markers and therapeutically effective molecules. Expression of miRNA-21 and miRNA-15b showed the most significant changes after irradiation. Atorvastatin and tadalafil normalized changes of miRNA (miRNA-1, miRNA-15b, miRNA-21) expression levels in irradiated hearts. This screening study concludes that administration of specific drugs could mitigate the negative impact of radiation on the heart, but more detailed experiments oriented to other aspects of drug effectiveness and their exact mechanisms are still needed.
Subject(s)
Atorvastatin/administration & dosage , Cardiomyopathies/drug therapy , Heart/drug effects , Radiation Injuries, Experimental/drug therapy , Tadalafil/administration & dosage , Animals , Cardiomyopathies/blood , Cardiomyopathies/diagnosis , Cardiomyopathies/etiology , Free Radicals/blood , Free Radicals/metabolism , Gamma Rays/adverse effects , Heart/radiation effects , Male , Malondialdehyde/blood , Myocardium/metabolism , Myocardium/pathology , Oxidative Stress/drug effects , Oxidative Stress/radiation effects , Radiation Injuries, Experimental/blood , Radiation Injuries, Experimental/diagnosis , Radiation Injuries, Experimental/etiology , Rats , Treatment Outcome , Tumor Necrosis Factor-alpha/bloodABSTRACT
Na,K-ATPase represents the key enzyme that maintains the homeostasis of sodium and potassium ions in the cells. It was documented that in directly irradiated organs the activity of this enzyme is decreased. The aim of present study was to clarify the remote effect of irradiation in mediastinal area on the activity of the Na,K-ATPase in kidneys in rats. Ionizing radiation in single dose 25 Gy resulted in consequent decrease of the body weight gain as well as the size of kidneys in Wistar rats. In addition, radiation induced alterations in the oxidative status of blood plasma. Irradiation also decreased the activity of renal Na,K-ATPase. Measurements of enzyme kinetics that were dependent on the concentration of energy substrate ATP or cofactor Na+ indicated that the lowered enzyme activity is probably a consequence of decreased number of active molecules of the enzyme, as suggested by lowered Vmax values. Immunoblot analysis confirmed the lowered expression of the catalytic alpha subunit together with decreased content of the glycosylated form of beta subunit in the renal tissue of irradiated rats. The ability of the enzyme to bind the substrate ATP, as well as Na+ was not affected, as shown by unaltered values of Km and KNa . Irradiation of the body in the mediastinal area despite protection of kidneys by lead plates during application of X-ray was followed by significant decline of activity of the renal Na,K-ATPase, what may result in deteriorated homeostasis in the organism.
