[On the mechanism of radioprotective effect of NO-synthase inhibitors].

We studied the influence on hemodynamics and radioprotective activity of two inhibitors of NO-synthase (NOS)--isothiourea derivatives with different NOS isoform selectivity: T1023--a selective inhibitor of endothelial and inducible NOS; and NTT2--a highly selective inhibitor of neuronal NOS. Both compounds at a dose of 1/7 LD50/15 caused a vasopressive effect and baroreflex response in normal Wistar rats. However, the nature of hemodynamic changes was qualitatively different. T1023 caused a prolonged elevation of vascular tone and reflex shift resulted in a significant and lasting reduction in the systemic blood flow (35-45%), which created conditions for the development of circulatory hypoxia. The use of NTT2 caused a reflex change in hemodynamics accompanied by vasodilation; and systemic blood flow was maintained at the initial level. T1023 effectively protected mice subjected to 10 Gy γ-irradiation and their bone marrow stem cells irradiated with 6 Gy, not yielding to the radioprotective effect of cystamine. NTT2 at these doses did not show any radioprotective effect. The obtained results support the leading mechanism of the radioprotective effect of NOS inhibitors is the induction of hypoxia. With this mechanism of action a significant radioprotective activity can be expected for the inhibitors which effectively suppress primarily endothelial NOS.

[Radioprotective properties of isothiourea derivatives with NO-inhibitory mechanism of action].

The study of the radioprotective activity of S-[2-alkyl (aryl) sulfonyl]-S-ethyl derivatives of (vinyl)-isothiourea in (he model of the survival of mice exposed to gamma-radiation at a dose of 10 Gy has shown that the incorporation of additional sulfur-containing groups does not increase the radioprotective properties of compounds. In contrast to aminoalkil thiols, the effectiveness of the radiation protection action of the isothiourea (ITU) derivatives studied clearly correlates with the NO-inhibitory activity. This fact allowed us to assume that the radioprotective effect of S-substituted ITU caused inhibition of the endogenous synthesis of NO, which promotes the development of circulatory hypoxia, and that a further search for the radioprotective agents in this class of chemicals should be considered as the search for effective inhibitors of NO-synthase (NOS). The theoretical analysis of the conformity of molecular structures to the composition and topology of the active center of NOS-inhibitors allowed us to prognosticate a number of new ITU derivatives with the potential NOS-inhibiting ability. As a result of further theoretical and experimental studies, four S,N-disubstituted ITU derivatives - active non-selective NOS-inhibitors, were first identified and synthesized. These compounds exhibited a pronounced and prolonged vasopressive effects at doses of 0.01-0.05 LD50/15 in the models of severe hemorrhagic and endotoxic shock, and provided 65-100% 30-day survival at doses of 0.2-0.3 LD50/15 in the mice irradiated by gamma-rays at a dose of 10 Gy (LD98/30).The findings suggest the pronounced radioprotective effect of NOS-inhibitors among the ITU-derivatives.

Evaluation of psychoemotional status of rats after brain injury and systemic transplantation of mesenchymal stem cells.

We studied the effects of systemic transplantation of mesenchymal stem cells obtained after culturing of autologous bone marrow on psychophysiological status of Wistar rats after diffuse brain trauma. Two months after systemic injection of mesenchymal stem cells we observed a decrease in manifestations of emotional behavioral reactions (anxiety and excitability) and shortening of the time of realization of drinking behavior in a T-maze. A significant positive effect of systemic transfusion of mesenchymal stem cells on avoidance conditioning in a shuttle box was observed 3 months after brain injury.

[Toxicity and side effects of antibiotics in radiation sickness and during the use of aminothiol group radioprotective agents]. / Toksichnost' i pobochnoe deistvie antibiotikov pri luchevoi bolezni i v usloviiakh primeneniia radioprotektorov aminotiol'noi gruppy.

It was shown in experiments on mice, rats and rabbits that resistance of animals in the state of acute radiation sickness to severe intoxication by aminoglycoside antibiotics, such as streptomycin, dihydrostreptomycin and monomycin did not significantly change. The exception was kanamycin the toxicity of which during the period of the acute state of radiation sickness increased by 30 per cent. The use of cystamine and merkamine before irradiation or their administration to non-irradiated animals resulted in lowering of the antibiotic tolerance by 1.5--2 times. The above aftereffects of the radioprotectors was observed within 3--12 days after their use and was most pronounced for the combination of cystamine and streptomycin. The acute toxicity of tetracyclines did not significantly differ at various stages of radiation disease and at the background of cystamine use. No significant cumulation of the toxicity of aminoglycoside antibiotics and tetracyclines or signs of adaptation in the healthy and irradiated animals was observed on prolong treatment with therapeutic doses. Cystamine had no effect on the tolerance of the antibiotics on their prolonged use.