Single article

DOI: 10.47026/2413-4864-2024-2-50-63

Danilova I.M., Pavlova S.I., Khobrakova V.B.

Immunomodulatory Properties of Glycyrrhizinic Acid in a Model of Cyclophosphamide-Induced Toxicity and Immunosuppression

Keywords: glycyrrhizinic acid, immunosuppression, toxicity, cyclophosphamide, pharmacology, oncology, cytostatics, antitumor drugs

Triterpenoid glycyrrhizic acid, which is part of licorice root extract, has a wide range of biological effects. It was previously revealed that due to glycyrrhizic acid the extract increases the survival rate of animals against the background of cyclophosphamide-induced toxicosis. Since cytostatics cause a wide range of side effects, including pronounced suppression of the immune system, further investigation of glycyrrhizic acid's effect on immunity is of interest. The purpose of the study was to evaluate the effect of glycyrrhizic acid on the immune response in vitro and in experimental animals against the background of cyclophosphamide administration. Materials and methods. The study was carried out in vitro on mice splenocyte culture, as well as on models of cyclophosphamide-induced toxicity and immunosuppression using cyclophosphamide at the dose of 450 mg/kg and 250 mg/kg. The survival rate of animals, the morphological presentation of splenocytes, the content of acid phosphatase, the state of cellular and humoral immunity and phagocytic activity were evaluated. Research results. Glycyrrhizic acid did not inhibit proliferation of mitogen-activated lymphocytes. Administration of glycyrrhizic acid was found to improve the morphological presentation of the spleen by virtue of increasing the size of lymphoid follicles and reducing foci of necrosis against the background of cyclophosphamide-induced toxicosis and to reduce the amount of acid phosphatase. Against the background of cyclophosphamide-induced immunosuppression, administration of glycyrrhizic acid increases the index of delayed hypersensitivity reaction, increases the number of antibody-forming cells compared with the control, improves the phagocytic activity. Conclusions. Glycyrrhizic acid improves the indices of the immune response both in vitro and in modeling cyclophosphamide-induced immunosuppression in laboratory animals. Glycyrrhizic acid improves the morphological presentation of the spleen, as well as enhances cellular, humoral immunity, the phagocytic response against the background of cyclophosphamide administration.

References

  1. Murav’ev I.A., Ponomarev V.D. Sovremennoe sostoyanie issledovanii glitsirrizinovoi i glitsirretovoi kislot i ikh proizvodnykh [Current state of researches on glycyrrhizic and glycyrrhetic acids and their derivatives]. In: Voprosy izucheniya i ispol’zovaniya solodki v SSSR: sbornik nauchnykh trudov [Issues of studying and using licorice in the USSR: Collected paper]. Moscow, Nauka Publ., 1966, pp. 118–
  2. Pavlova S.I., Andreeva N.A., Khobrakova V.B. Tsitotoksichnost’ izolikviritigenina po otnosheniyu k kletkam opukholevogo i neopukholevogo proiskhozhdeniya [Isoliquiritigenin cytotoxicity against to tumor and non-tumor cells]. Voprosy obespecheniya kachestva lekarstvennykh sredstv, 2019, no. 1(23), 53–62.
  3. Pavlova S.I. Immunosupressivnye i protivoopukholevye farmakodinamicheskie effekty flavonoidov kornei solodki: dis. … d-ra med. nauk. [Immunosuppressive and antitumor pharmacodynamic effects of licorice root flavonoids. Doct. Diss.]. Moscow, 2012, 236 p.
  4. Pavlova S.I. Ispol’zovanie ekstrakta kornya solodki dlya povysheniya effektivnosti terapii zlokachestvennykh novoobrazovanii (eksperimental’noe issledovanie: … cand. med. nauk. [Improvement the effectiveness of cancer therapy by use of licorice root extract (experimental study). Cand. Diss.]. Staraya Kupavna, 2005, 106 p.
  5. Rukovodstvo po provedeniyu doklinicheskikh issledovanii lekarstvennykh sredstv. Chast’ pervaya [Guidelines for conducting preclinical studies of drugs. Part one]. Moscow, Grif i K Publ., 2012, 944 p.
  6. Pavlova S.I., Gladkov I.V., Kyagova A.A. et al. Flavonoidy kornya solodki podavlyayut indutsirovannuyu in vitro i in vivo proliferatsiyu limfotsitov [Licorice root flavonoids inhibit in vitro and in vivo induced proliferation of lymphocyte]. Rossiiskii immunologicheskii zhurnal, 2007, no. 3-4(10), pp. 279–282.
  7. Shefer T.V., Ivnitskii Yu.Yu., Reinyuk V.L. Vliyanie soka podorozhnika na proyavleniya i iskhod ostroi intoksikatsii tsiklofosfanom u krys [The influence of the plantain juice on the manifestations and outcome of acute cyclophosphamide intoxication in rats]. Profilaktika, diagnostika, lechenie, 2015, vol. 3(55), pp. 61–63.
  8. Ahlmann M., Hempel G. The effect of cyclophosphamide on the immune system: implications for clinical cancer therapy. Cancer Chemother Pharmacol, 2016, vol. 78(4), pp. 661–671. DOI: 1007/s00280-016-3152-1.
  9. Armanini D., Scali M., Zennaro M.C. et al. The pathogenesis of pseudohyperaldosteronism from carbenoxolone. Endocrinol. Invest., 1989, vol. 12(5), pp. 337–341. DOI: 10.1007/BF03350002.
  10. Burstone S. New histochemical techniques for the demonstration of tissue oxidase (cytochrome oxidase). J Histochem Cytochem, 1959, vol. 7(2), pp. 112–122. DOI: 10.1177/7.2.112.
  11. Cunningham A.J. A method of increased sensitivity for detecting single antibody-forming cells. Nature, 1965, vol. 207(5001), pp. 1106– DOI: 10.1038/2071106a0.
  12. Emadi A., Jones R.J., BrodskyA. Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol, 2009, vol. 6(11), pp. 638–647. DOI: 10.1038/nrclinonc.2009.
  13. Horigome H., Homma M., Hiranoet al. Glycyrrhetinic acid induced apoptosis in murine splenocytes. Biol Pharm Bull, 2001, vol. 24(1), pp. 54–58. DOI: 10.1248/bpb.24.54.
  14. Jian-yuan Li, Hong-yan Cao,Ping Liu et al. Glycyrrhizic acid in the treatment of liver diseases: literature review. BioMed Research International, 2014, ID DOI: 10.1155/2014/872139.
  15. Jiawei Z., Tao M., Yuanyuan W. et al. A Review of the Antiviral Activities of Glycyrrhizic Acid, Glycyrrhetinic Acid and Glycyrrhetinic Acid Monoglucuronide. Pharmaceuticals (Basel), 2023, vol. 16(5), 641. DOI: 10.3390/ph16050641.
  16. Juin S.K., Ghosh S., Majumdar S. Glycyrrhizic acid facilitates anti-tumor immunity by attenuating Tregs and MDSCs: An immunotherapeutic approach. Int Immunopharmacol, 2020, vol. 88, ID DOI: 10.1016/j.intimp.2020.106932.
  17. Kim D.H., Hong S.W., Kim B.T. et al. Biotransformation of glycyrrhizin by human intestinal bacteria and its relation to biological activities. Arch Pharm Res, 2000, vol. 23(2), pp. 172–177. DOI: 1007/BF02975509.
  18. Klein I., Isensee J., WiesenH.J. et al. Glycyrrhizic Acid Prevents Paclitaxel-Induced Neuropathy via Inhibition of OATP-Mediated Neuronal Uptake. Cells, 2023, vol. 12(9), 1249. DOI: 10.3390/cells12091249.
  19. Lee Jia Ming, Adeline Chia Yoke Yin. Therapeutic effects of glycyrrhizic acid. Nat Prod Commun, 2013, vol. 8(3), pp. 415–418.
  20. Mohammed E.A.H., Peng Y., Wang Z. et al. Synthesis, Antiviral, and Antibacterial Activity of the Glycyrrhizic Acid and Glycyrrhetinic Acid Derivatives. Russ J Bioorg Chem, 2022, vol. 48(5), pp. 906–918. DOI: 1134/S1068162022050132.
  21. Morgan A.M., Ibrahim M.A.,Hussien M. Glycyrrhizic acid modulates the atrazine-induced apoptosis in rabbit spleen. Environ Sci Pollut Res Int, 2019, vol. 26(34), pp. 34924–34930. DOI: 10.1007/s11356-019-06604-x.
  22. Seidu A.R. Exploring the Pivotal Immunomodulatory and Anti-Inflammatory Potentials of Glycyrrhizic and Glycyrrhetinic Acids. Mediators of Inflammation, 2021, ID DOI: 10.1155/2021/6699560.
  23. Selyutina O.Yu., Polyakov E. Glycyrrhizic acid as a multifunctional drug carrier – From physicochemical properties to biomedical applications: A modern insight on the ancient drug. Int J Pharm, 2019, vol. 559, pp. 271–279. DOI: 10.1016/j.ijpharm.2019.01.047.
  24. Seokwon Shin, Hyeong Won Kim,Mi-Kyeong Ko et al. Inactivated vaccine with glycyrrhizic acid adjuvant elicits potent innate and adaptive immune responses against foot-and-mouth disease. Front Microbiol, 2023, vol. 14, ID DOI: 10.3389/fmicb.2023.1289065.
  25. Si-Qi He, Meng Gao,Yun-Feng Fu et al. Glycyrrhizic acid inhibits leukemia cell growth and migration via blocking AKT/mTOR/STAT3 signaling. Int J Clin Exp Pathol, 2015, vol. 8(5), pp. 5175–5181.
  26. Takeda S., Ono H., Wakui Y. et al. Determination of glycyrrhetic acid in human serum by high-performance liquid chromatography with ultraviolet detection. Chromatogr, 1990, vol. 530(2), pp. 447–451. DOI: 10.1016/s0378-4347(00)82348-8.
  27. Yang He, Erlong Wang, Kaiyu Wang et al. Morphology of the Spleen in Oreochromis niloticus: Splenic Subregions and the Blood-Spleen Barrier. Animals (Basel), 2021, vol. 11(10), 2934. DOI: 3390/ani11102934.
  28. Zhen-Hua Zhu, Xing Li, Lin-Feng He et al. Glycyrrhizic acid, as an inhibitor of HMGB1, alleviates bleomycin-induced pulmonary toxicity in mice through the MAPK and Smad3 pathways. Immunopharmacol Immunotoxicol, 2021, vol. 43(4), pp. 461-470. DOI: 1080/08923973.2021.1939371.

About authors

Danilova Irina M.
Senior Lecturer, Department of Pharmacology, Clinical Pharmacology and Biochemistry, Chuvash State University, Russia, Cheboksary (medicine345@mail.ru; ORCID: https://orcid.org/0009-0000-7836-8081)
Pavlova Svetlana I.
Doctor of Medical Sciences, Associate Professor, Head of the Department of Pharmacology, Clinical Pharmacology and Biochemistry, Chuvash State University, Russia, Cheboksary (flavonoid@yandex.ru; ORCID: https://orcid.org/0000-0001-9976-7866)
Khobrakova Valentina B.
Doctor of Biological Sciences, Associate Professor, Head of the Laboratory of Experimental Pharmacology, Institute of General and Experimental Biology, Siberian Branch of the Russian Academy of Sciences, Russia, Ulan-Ude (val0808@mail.ru; ORCID: https://orcid.org/0000-0002-4689-5706)

Article link

Danilova I.M., Pavlova S.I., Khobrakova V.B. Immunomodulatory Properties of Glycyrrhizinic Acid in a Model of Cyclophosphamide-Induced Toxicity and Immunosuppression [Electronic resource] // Acta medica Eurasica. – 2024. – №2. P. 50-63. – URL: https://acta-medica-eurasica.ru/en/single/2024/2/7/. DOI: 10.47026/2413-4864-2024-2-50-63.