Modeling of acute radiation bone marrow syndrome in the experiment on mice

Relevance. Radiation injuries with the variety of clinical forms occupy an important place in a military therapeutic pathology. Acute radiation sickness (ARS) is the result of the biological effects of the ionizing radiation on a body. Currently, there are ongoing studies in the area of radiobiology and radiological pharmacology, with the main purpose to assess safety, pharmacodynamics and mechanisms of the new radioprotective drugs. However, for successful study of their pharmacological activity in the model of ARS (mice) it is necessary to clarify mechanisms of acute radiation injury and also identify optimal radiation doses for studying specific parameters.
Intention. Development of a model of acute radiation bone marrow syndrome in the experiment on mice irradiated in the dose range of 3–9 Gy.
Methods. The experiments were carried out in animal model (350 male mice). Life expectancy, the dynamics of body weight, the basic hematological parameters and functional states (Tail Flick, Grip Strength System, Retention on a Horizontal Grid, Rotarod and Light-dark test), 30-day survival were studied post-exposure (3-9 Gy).
Results and Discussion. The obtained results indicate that the body weight dynamics, survival, life expectancy, severity of leukocytopenia and thrombocytopenia, and also changes in the total functional status of the animals in acute radiation injury (3–9 Gy) are dose-dependent. Besides, the obtained data substantiate a differentiated approach to the choice of irradiation doses and terms of registration of parameters when studying potentially promising radioprotective drugs.
Conclusion. For research of effective application of physiologically active substances in the experimental model of acute radiation injury in mice it is advisable to use the following radiation doses: 5 Gy – to evaluate hemostimulating activity of therapeutic agents with registration of indicators on days 3–28 after exposure, 6.5 Gy – to assess survival and life expectancy over 30 days; 8 Gy – to study functional state of animals (4 days in the Light-Dark Test, 4, 7 and 10 days in Retention on a Horizontal Grid).

1. Butomo N.V., Grebenyuk A.N., Legeza V.I. Osnovy meditsinskoi radiobiologii [Fundamentals of medical radiobiology]. Ed. I.B. Ushakov. Sankt-Peterburg. 384 p. (In Russ.)

2. Genes V.S. Tablitsy dostovernykh razlichii mezhdu gruppami nablyudenii po kachestvennym pokazatelyam: posobie po statisticheskoi obrabotke rezul’tatov nablyudenii i opytov v meditsine i biologii [Tables of significant differences between groups by quality indicators: guidelines for statistical processing of results of observations and experiments in the medicine and biology]. Moskva. 1964. 80 p. (In Russ.)

3. Grebenyuk A.N., Boyarintsev V.V., Sidorov D.A. Zadachi meditsinskoi sluzhby v oblasti obespecheniya toksiko-radiologicheskoi bezopasnosti voennosluzhashchikh [Purposes of medical service in area of assurance of toxical-radiologic defense of service men]. Voenno-meditsinskii zhurnal [Military medical journal]. 2009. Vol. 330, N 4. Pp. 12–16. (In Russ.)

4. Grebenyuk A.N., Legeza V.I. Perspektivy ispol’zovaniya radioprotektorov dlya povysheniya effektivnosti meditsinskoi protivoradiatsionnoi zashchity Vooruzhennykh sil [Prospects of the use of radioprotectors for improvement of anti-radiation medicine in the Armed Forces]. Voenno-meditsinskii zhurnal [Military medical journal]. 2013. Vol. 334, N 7. Pp. 46–50. (In Russ.)

5. Grebenyuk A.N., Legeza V.I., Tarumov R.A. Radiomitigatory: perspektivy ispol’zovaniya v sisteme meditsinskoi protivoradiatsionnoi zashchity [Radiomitigators: prospects for use in medical radiation protection]. Voenno-meditsinskii zhurnal [Military medical journal]. 2014. Vol. 335, N 6. Pp. 39–43. (In Russ.)

6. Grebenyuk A.N., Strelova O.Yu., Legeza V.I., Stepanova E.N. Osnovy radiobiologii i radiatsionnoi meditsiny [Fundamentals of radiobiology and radiation medicine: tutorial]. Sankt-Peterburg. 2012. 225 p. (In Russ.)

7. Direktiva 2010/63/EU Evropeiskogo parlamenta i soveta evropeiskogo soyuza po okhrane zhivotnykh, ispol’zuemykh v nauchnykh tselyakh [Directive 2010/63/EU of the European Parliament and the Council of the European Union for the protection of animals used for scientific purposes]. Sankt-Peterburg. 2012. 48 p. (In Russ.)

8. Karkishchenko V.N., Fokin Yu.V., Kazakova L.Kh. Metodiki izucheniya fiziologicheskikh funktsii laboratornykh zhivotnykh dlya doklinicheskikh issledovanii v sportivnoi meditsine [Methods of studying physiological functions of laboratory animals for preclinical studies in sports medicine]. Biomeditsina [Biomedicine]. 2012. N 4. Pp. 15–21. (In Russ.)

9. Mazaeva Yu.V., Malysheva E.V. Korrektsiya vozdeistviya tsitostatikov na psikhofiziologicheskie funktsii laboratornykh myshei s pomoshch’yu fitoekstrakta volodushki zolotistoi (bupleurum aureum) [Correction of effects of drugs on physiological functions of mice with bupleurum aureum phytoextract]. Vestnik Tomskogo gosudarstvennogo universiteta [Bulletin of Tomsk State University]. 2015. N 4. Pp. 945–949. (In Russ.)

10. Medvedeva Yu.S., Arkhipova E.N., Alchinova I.B. Osobennosti organizmennogo otveta myshei raznykh linii na ostroe gamma-obluchenie [Features of the organism response of mice of different lines to acute gamma-irradiation]. Biomeditsina [Biomedicine]. 2013. N 2. Pp. 61–73. (In Russ.)

11. Ob utverzhdenii pravil laboratornoi praktiki [Approval of rules for laboratory practice] : prikaz Ministerstva zdravookhraneniya Rossii ot 19.06.2003 N 267 [Order of the Ministry of Health of the Russian Federation of 19.06.2003 N 267]. (In Russ.)

12. Rukovodstvo po provedeniyu doklinicheskikh issledovanii lekarstvennykh sredstv [The guidelines for preclinical studies of pharmaceuticals]. Moskva. 2012. Pt. 1. 944 p. (In Russ.)

13. Khalimov Yu.Sh., Grebenyuk A.N., M.A. Karamullin [et al.]. Sovremennye vozmozhnosti okazaniya terapevticheskoi pomoshchi pri vozniknovenii massovykh sanitarnykh poter’ radiatsionnogo profilya [Modern possibilities of providing therapeutic assistance in situations of mass sanitary losses of the radiation profile]. Voenno-meditsinskii zhurnal [Military medical journal]. 2012. Vol. 333, N 2. Pp. 24–32. (In Russ.)

14. Cantinha R.S., Amaral A., Borrely S.I. [et al]. Effects of high dose rate gamma radiation on survival and reproduction of biomphalaria glabrata. INAC. 2009. Vol. 7434. Pp. 11–18.

15. Grdina D.J., Murley J.S., Kataoka Y. Radioprotectants: current status and new directions. Radiat. Res. 2005. Vol. 163, N 6. Рp. 704–705.

16. Grebenyuk A., Zatsepin V., Aksenova N., Timoshevsky A. Effects of early therapeutic administration of interleukin-1β on survival rate and bone marrow haemopoiesis in irradiated mice. Acta Medica (Hradec Kralove). 2010. Vol. 53, N 4. Pp. 221–224.

17. Landes R.D., Lensing S.Y., Jensen M.H. [et al]. Statistical analysis of survival data from radiation countermeasure experiments. Radiat. Res. 2012. Vol.177, N 5. Pp. 546–554.

18. Seed T.M. Radiation protectants: current status and future prospects. Health Phys. 2005. Vol. 89, N 5. Pp. 531–545.

19. Singh V.K., Newman V.L., Romaine P.L. [et al]. Use of biomarkers for assessing radiation injury and efficacy of countermeasures. Expert Rev. Mol. Diagn. 2016. Vol. 16, N 1. Pp. 65–81.

20. Singh V.K., Romaine P.L., Newman V.L., Seed T.M. Medical countermeasures for unwanted CBRN exposures: part II radiological and nuclear threats with review of recent countermeasure patients. Expert Opin. Ther. Pat. 2016. Vol. 26, N 12. Pp. 1399–1408.

21. Waselenko J.K., McVittie T.J., Blakely W.F. [at al.]. Medical management of the acute radiation syndrome: recommendations of the Strategic National Stockpile Radiation Working Group. Ann. Intern. Med. 2004. Vol. 140, N 12. Pp. 1037–1051.

22. Williams J.P., Brown S.L., Georges G.E. [et al]. Animal models for medical countermeasures to radiation exposure. Radiat. Res. 2010. Vol. 173, N 4. Pp. 557–578.

23. Xiao M., Whitnall M.H. Pharmacological countermeasures for the acute radiation syndrome. Cur. Mol. Pharmacol. 2009. Vol. 2. Pp. 122–133.