Hematopoietic effects of spleen lymphocytes treated with an original anticonvulsant during long-term alcohol consumption

Excessive alcohol consumption has a negative effect on hematopoiesis, which manifests with significant suppression of both blood cell production, and structural changes in hematopoietic precursors, i.e., by suppression of their maturation, up to pancytopenia. One may distinguish between the direct effect of alcohol (toxicity to bone marrow, hematopoietic precursors and mature blood cells), and the indirect action caused by deficiency of trophic factors. Alcohol addicts often develop anemia, due to premature destruction of erythroid cells. Thrombocytopenia, also being an important feature of hematological disorders in alcoholism, results in spontaneous bleeding and petechiae. Chronic alcohol consumption also has a suppressive effect on production and functioning of white blood cells, resulting in poor resistance to bacterial infections. We have previously identified the immunomodulatory properties of an innovative anticonvulsant, meta-chlorobenzhydrylurea (m-CBHU). Its positive effect was determined upon intragastric administration in long-term alcoholized mice, In a recent study, splenic lymphocytes, being in vitro exposed to the mentioned anticonvulsant, have shown a positive psychoneuromodulatory effect during chronic ethanol intoxication. These effects seem to proceed via relatively independent mechanisms. In this study, the effects of intravenous transfusion of m-CBHU-treated spleen lymphocytes on bone marrow hematopoiesis and peripheral blood cells were tested in murine model of chronic alcoholism. In the bone marrow of syngeneic recipients (long-term alcoholized mice), a decreased colony-forming activity of hematopoietic precursors was observed: the population of erythroid precursors was significantly reduced. Decreased counts of granulocyte-macrophage precursors were also detected at a trend level. The only exception was the population of early progenitors, where the number of colonies did not change. In peripheral blood, a decreased number of lymphocytes, platelets, erythrocytes and leukocytes was observed associated with increase in the population of segmented neutrophils, suggesting peripheral inflammation. Lymphocytes pre-cultured with meta-chlorobenzhydryl urea, after intravenous administration to syngeneic long-term alcoholized recipients, had a corrective effect on a number of hematopoietic parameters, which manifested with restoration of the colony-forming activity of bone marrow hematopoietic precursors to the levels comparable to those in intact age-matched mice, along with decrease of segmented neutrophils and restoration of RBC and lymphocyte counts as wells as a tendency for increase in platelet counts in peripheral blood. The data obtained may suggest the efficiency of meta-chlorobenzhydrylurea-modulated lymphocytes in correction of distinct changes in hematopoiesis associated with long-term ethanol intoxication.

1. Ballard H.S. The hematological complications of alcoholism. Alcohol Health. Res. World, 1997, Vol. 21, pp. 42-52.

2. Goodson C.M., Clark B.J., Douglas I.S. Predictors of severe alcohol withdrawal syndrome: a systematic review and meta-analysis. Alcohol Clin. Exp. Res., 2014, Vol. 38, no. 10, pp. 2664-2677.

3. Latvala J., Parkkila S., Niemelä O. Excess alcohol consumption is common in patients with cytopenia: studies in blood and bone marrow cells. Alcohol Clin. Exp. Res., 2004, Vol. 28, pp. 619-624.

4. Manappallil R.G. Acute onset pancytopenia following alcohol heavy drinking. Asian J. Bio-Med. Res., 2016, Vol. 2, no. 2, pp. 2454-6275.

5. Markova E.V. Immune cells and regulation of behavioral reactions in health and disease. Krasnoyarsk: Scientific and Innovation Center, 2021. 184 p. (In Russ.)

6. Markova E., Knyazheva M., Savkin I., Shushpanova T. Effect of original anticonvulsant meta-chlorobenzhydryl-urea on behavioral and immune parameters in mice with active and passive behavior types in experimental alcoholism. Eur. Psychiatry, 2017, Vol. 41, no. S1, pp. S742-S743.

7. Markova E.V., Savkin I.V., Anikeeva O.S., Shushpanova T.V. Immunomodulatory effect of original anticonvulsant meta-chloro-benzhydryl-urea in mice with experimental alcoholism. Eur. Psychiatry, 2019. Vol. 56, no. S1, pp. S662-S663.

8. Markova E.V., Savkin I.V., Knyazheva M.A., Shushpanova T.V. Anticonvulsant with immunomodulating properties in alcoholism therapy: experimental study. Siberian Herald of Psychiatry and Addiction Psychiatry, 2020, no. 1, pp. 14-22. (In Russ.)

9. Markova E.V., Savkin I.V., Serenko E.V., Knyazheva M.A., Shevchenko Yu.A. The central effects of peripherally administered immune cells modulated by an original anticonvulsant in experimental alcoholism. Neurochem. J., 2023, Vol. 17, no. 4, pp. 534-542.

10. Markova E.V., Savkin I.V., Shushpanova T.V., Knyazheva M.A., Anikeeva O.S. Immunomodulator. Patent RU 2691143 C1, June 11, 2019.

11. Pasala S., Barr T., Messaoudi I. Impact of Alcohol Abuse on the Adaptive Immune System. Alcohol Res., 2015, Vol. 37, no. 2, pp. 185-197.

12. Savage D., Lindenbaum J. Anemia in alcoholics. Medicine, 1986, Vol. 65, no. 5, pp. 322-338.

13. Shi X., DeLucia A.L., Bao J., Zhang P. . Alcohol Abuse and Disorder of Granulopoiesis. Pharmacol. Ther., 2019, Vol. 198, pp. 206-219.

14. Silczuk А., Habrat В. Alcohol-induced thrombocytopenia: Current review. Alcohol, 2020, Vol. 86, pp. 9-16.

15. Smith C., Gasparetto M., Jordan C., Pollyea D.A., Vasiliou V. The effects of alcohol and aldehyde dehydrogenases on disorders of hematopoiesis. Adv. Exp. Med. Biol., 2015, Vol. 815, pp. 349-359.