CHANGES IN THE CHEMICAL COMPOSITION OF BLOOD AND BRAIN OF RATS UNDER THE CONDITIONS OF MODELING OF THE MYELOABLATION REGIMEN OF CYCLOPHOSPHAMIDE ADMINISTRATION

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Abstract

When modeling myeloablation cytostatic chemotherapy with cyclophosphamide in rats fulminant hyperammonemia was observed accompanied by an increase in the content of ammonia and glutamine, a decrease in the content of pyruvic and lactic acids in brain tissue. A positive correlation between the indicators of azotemia and the content of ammonia and glutamine in brain tissue was established. In loading test with ammonium acetate changes in the chemical composition of blood and brain tissue were more pronounced. The data obtained indicate the intensification of the intake of gastrointestinal ammonia into the brain from the blood, which leads to the depletion of the tissue pool of pyruvate with the introduction of cyclophosphane in doses used for myeloablation. Such changes create the conditions for disruption of energy supply of neurological functions during myeloablative cytotoxic chemotherapy using cyclophosphamide.

About the authors

Yu. Yu. Ivnitsky

Institute of Toxicology, Federal Medical Biological Agency

Author for correspondence.
Email: neugierig@mail.ru

Ivnitsky Jury Jurievich

195043, Saint Petersburg

Russian Federation

T. V. Schafer

State Scientific Research Test Institute of the Military Medicine, Ministry of Defense of the Russian Federation

Email: schafer@yandex.ru

Schafer Timur Vasilievich

192019, Saint Petersburg

Russian Federation

A. A. Tyaptin

State Scientific Research Test Institute of the Military Medicine, Ministry of Defense of the Russian Federation

Email: tyaptin@mail.ru

Tyaptin Alexander Andreevich

192019, Saint Petersburg

Russian Federation

V. L. Rejniuk

Institute of Toxicology, Federal Medical Biological Agency

Email: vladton@mail.ru

Rejniuk Vladimir Leonidovich

195043, Saint Petersburg

Russian Federation

References

  1. Kharfan-Dabaja M.A., Reljie T., El-Asmar J., Nishihori T., Ayala E., Hamadani M. et al. Reduced-intencity or myeloablative allogenic hematopoetic cell transplantacion for mantle cell lymphoma: a systematic review. Future oncol. 2016; 22 (12): 2631-42.
  2. Haioun C., Lepage E., Gisselbrecht C., Salles G., Coiffier B., Brice P. et al. Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin’s lymphoma: final analysis d’Etude des lymphomes de l’Adulte study. J. Clin. Oncol. 2000; 18: 3025-30.
  3. Atilla E., Atilla P.A., Demirer T. A review of myeloablative vs reduced intensity/ non-myeloablative regimens in allogeneic hematopoietic stem cell transplantations. Balkan Med J. 2017, 34 (1): 1-9.
  4. Schafer T.V., Ivnitsky J.J., Rejniuk V.L. Cyclophosphamide-induced leakage of gastrointestinal ammonia into the common bloodstream in rats. Drug Chem. Toxicol. 2011; 34: 25-31.
  5. Clifford P., Bhardwaj B.V., Whittaker L.R. Intensive nitrogen mustard therapy with abdominal aortic occlusion in nasopharyngeal carcinoma. Brit. J. Cancer. 1965; 19: 51-71.
  6. Fraiser L.H., Kanekai S., Kehrer J.P. Cyclophosphamide toxicity. Characterizing and avoiding the problem. Drugs. 1991; 42: 781-95.
  7. Sayed-Ahmed M. Progression of cyclophosphamide-induced acute renal metabolic damage in carnitine-depleted rat model. Clin. Exp. Nephrology. 2010; 14 (5): 418-26.
  8. Ekena J., Wood E., Manchester A., Chun R., Trepanier L.A. Glutathione-S-transferasetheta genotypes and the risk of cyclophosphamide toxicity in dogs. Vet Comp Oncol. 2018; 16(4): 529-34.
  9. Dasarathy S., Mookerjee R.P., Rackayova V., Rangroo Thrane V., Vairappan B., Ott P. et al. Ammonia toxicity: from head to toe? Metab Brain Dis. 2017 Apr; 32(2): 529-38.
  10. Kosenko E.A., Kaminskiy Yu.G. Cellular mechanisms of toxicity of ammonia. Moscow.: Izd-vo LKI; 2008 (in Russian).
  11. Norenberg M.D., Rama Rao K.V., Jayakumar A.R. Ammonia neurotoxicity and the mitochondrial permeability transition. J. Bioenerg. Biomembr. 2004; 36: 303-7.
  12. Kozlov N.B. Ammonia, its metabolism and role in disease. Moscow.: Meditsina; 1971 (in Russian).
  13. Zaychik A.Sh., Churilov L.P. Fundamentals of pathochemistry. Saint-Petersburg.: Elbi-SPb; 2000 (in Russian).
  14. Unger C., Eibl H., von Heyden H.W., Krisch B., Nagel G.A. Blut-Hirn-Schranke und das Eindringen von Zytostatika. Klin. Wochenschr. 1985; 63 (12): 565-71.
  15. Orbach D., Brisse H., Doz F. Central neurological manifestations during chemotherapy in children. Arch. Pediatr. 2003; 10 (6): 533-9.
  16. Cooper A.J.L., Plum F. Biochemistry and phisiology of brain ammonia. Physiol. Rev. 1987; 67: 440-519.
  17. Ivnitsky J.J., Schafer T.V., Rejniuk V.L. Promotion of the toxic action of cyclophosphamide by digestive tract luminal ammonia in rats. ISRN Toxicology. 2011; (Article ID 450875). Available at: http://www.hindawi.com/isrn/toxicology/2011/450875
  18. Kim K., Lee W., Benevenga N.J. Feeding diets containing high levels of milk products or cellulose decrease urease activity and ammonia production in rat intestine. J. Nutr. 1998; 128: 1186-91.
  19. Khabriev R.U., ed. Manual on experimental (preclinical) study of new pharmacological substances. 2nd ed. Moscow.: Meditsina; 2005 (in Russian).
  20. Whitehead T.P., Whittaker S.R.F. A method for the determination of glutamine in cerebrospinal fluid and the results in hepatic coma. J. Clin. Pathol. 1955; 8: 81-4.
  21. R: A language and environment for statistical computing. Vienna: R Foundation for Statistical Computing. 2017. Available at: http://www.r-project.org/.
  22. Dagley S., Nicholson D.E. An introduction to metabolic pathways. Oxford, Edinburg: Blackwell Scientific Publications; 1970.
  23. Edson N.L. Ketogenesis – antiketogenesis. 1. The influence of ammonium chloride on ketone-body formation in liver. Biochem. J. 1935; 29 (9): 2082-94.
  24. Dadsetan S., Kukolj E., Bak L.K., Sorensen M., Ott P., Vilstrup H. et al. Brain alanine formation as an ammonia-scavenging pathway during hyperammonemia: effects of glutamine synthetase inhibition in rats and astrocyte-neuron co-cultures. J. Cereb. Blood Flow Metab. 2013; 33 (8): 1235-41.
  25. Dadsetan S. Inhibition of glutamine synthesis induces glutamate dehydrogenase-dependent ammonia fixation into alanine in co-cultures of astrocytes and neurons. Neurochem. Int. 2011; 59 (4): 482-8.
  26. Khurtsilava O.G., ed., Pluzhnikov N.N., ed., Nakatis Ya.A., ed. Oxidative stress and inflammation: a pathogenetic partnership. Saint-Petersburg.: Izd-vo SPBGU im. I. I. Mechnikova; 2012 (in Russian).
  27. Zelenin K.N., Alekseev V.V. A general and bioorganic chemistry. Saint-Petersburg.: Elbi-SPb; 2003 (in Russian).
  28. Lai J.S., Cooper A.J. Neurotoxicity of ammonia and fatty acids: differential inhibition of mitochondrial dehydrogenases by ammonia and fatty acyl coenzyme A derivates. Neurochem. Res. 1991; 16 (7): 795-803.
  29. Ott P., Clemmesen O., Larssen F.S. Cerebral metabolic disturbances in the brain during acute liver failure: From hyperammonemia to energy failure and proteolysis. Neurochem. Int. 2005; 47 (1-2): 13-8.
  30. Schafer T.V., Rejniuk V.L., Malakhovsky V.N., Ivnitsky J.J. The role of the digestive tract luminal ammonia pool in cyclophosphamide toxicity in rat. medline.ru. 2010; 11. Available at: http://www.medline.ru/public/art/tom11/art44.html (Accessed 5 March 2019, in Russian).

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Copyright (c) 2019 Ivnitsky Y.Y., Schafer T.V., Tyaptin A.A., Rejniuk V.L.


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