Anti-cytokine effects of chalcon analogues in experimental "cytokine storm" in rats

Abstract

The aim of the study was to evaluate the anti-cytokine effects of chalcon analogues in an experimental “cytokine storm”.

Materials and methods. The “cytokine storm” was modeled in rats by intraperitoneal injection of lipopolysaccharide at a dose of 10 mg / kg. The test compounds and the reference drug dexamethasone were administered intraperitoneal 60 minutes after lipopolysaccharide injection at doses of 20 mg / kg and 3 mg / kg, respectively. After 24 hours, changes of the cytokines concentration in blood serum (IL-1â, IL-6, IL-10, and TNF-á), body temperature, and the severity of pulmonary edema were evaluated.

Results. In the study, it was found that the administration of all the test-compounds reduced symptoms of hypercytokinemia, reflected in the decrease in the concentration of proinflammatory cytokines IL-1â, IL-6, and TNF-á with high content of IL-10 in serum. At the same time, the body temperature and pulmonary edema in rats against the background of the injection of the test chalcon analogues relative to animals that did not receive pharmacological support also decreased. Against the background of the administration of dexamethasone to animals, the concentration of IL-6, IL-1â and TNF-á decreased by 25.0% (p < 0.05); 44.1% (p < 0.05) and 33.3% (p < 0.05), as well as an increase in the content of IL-10 by 60.0% (p < 0.05), with a decrease in pulmonary edema and body temperature. It should be noted that there were no statistically significant differences between the groups of animals that were received the studied chalcon analogues and the reference drug.

Conclusion. The study showed the relevance of further study of representatives of a number of chalcon derivatives as non-hormonal means of correcting the “cytokine storm” with a high therapeutic potential.

Keywords

inflammation / “cytokine storm” / chalcons, cytokines

References

[1] Soy M, Keser G, Atagündüz P, et al. Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol. 2020;39(7):2085–2094. DOI: 10.1007/s10067-020-05190-5

[2] Soy M., Keser G., Atagündüz P. et al. Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment // Clin. Rheumatol. 2020. Vol. 39, No. 7. P. 2085–2094. DOI: 10.1007/s10067-020-05190-5

[3] Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25:625–638. DOI: 10.1016/j.bbmt.2018.12.758

[4] Lee D.W., Santomasso B.D., Locke F.L. et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells // Biol. Blood Marrow. Transplant. 2019. No. 25. P. 625–638. DOI: 10.1016/j.bbmt.2018.12.758

[5] Sinha P, Matthay MA, Calfee CS. Is a “cytokine storm” relevant to COVID-19? JAMA Intern Med. 2020;180(9):1152–1154. DOI: 10.1001/jamainternmed.2020.3313

[6] Sinha P., Matthay M.A., Calfee C.S. Is a “cytokine storm” relevant to COVID-19? // JAMA Intern. Med. 2020. Vol. 180, No. 9. P. 1152–1154. DOI: 10.1001/jamainternmed.2020.3313

[7] Kang S, Tanaka T, Narazaki M, Kishimoto T. Targeting interleukin-6 signaling in clinic. Immunity. 2019;50(4):1007–1023. DOI: 10.1016/j.immuni.2019.03.026

[8] Kang S., Tanaka T., Narazaki M., Kishimoto T. Targeting interleukin-6 signaling in clinic // Immunity. 2019. Vol. 50, No. 4. P. 1007–1023. DOI: 10.1016/j.immuni.2019.03.026

[9] Henderson LA, Canna SW, Schulert GS, et al. On the alert for cytokine storm: immunopathology in COVID-19. Arthritis Rheumatol. 2020;72(7):1059–1063. DOI: 10.1002/art.41285

[10] Henderson L.A., Canna S.W., Schulert G.S. et al. On the alert for cytokine storm: immunopathology in COVID-19 // Arthritis Rheumatol. 2020. Vol. 72, No. 7. P. 1059–1063. DOI: 10.1002/art.41285

[11] Daikonya A, Katsuki S, Kitanaka S. Antiallergic agents from natural sources 9. Inhibition of nitric oxide production by novel chalcone derivatives from Mallotus philippinensis (Euphorbiaceae). Chem Pharm Bull (Tokyo). 2004;52(11):1326–1329. DOI: 10.1248/cpb.52.1326

[12] Daikonya A., Katsuki S., Kitanaka S. Antiallergic agents from natural sources 9. Inhibition of nitric oxide production by novel chalcone derivatives from Mallotus philippinensis (Euphorbiaceae) // Chem. Pharm. Bull. (Tokyo). 2004. Vol. 52, No. 11. P. 1326–1329. DOI: 10.1248/cpb.52.1326

[13] Zhang H, Sha J, Feng X, et al. Dexmedetomidine ameliorates LPS induced acute lung injury via GSK-3β/STAT3-NF-κB signaling pathway in rats. Int Immunopharmacol. 2019;74:105717. DOI: 10.1016/j.intimp.2019.105717

[14] Zhang H., Sha J., Feng X. et al. Dexmedetomidine ameliorates LPS induced acute lung injury via GSK-3β/STAT3-NF-κB signaling pathway in rats // Int. Immunopharmacol. 2019, No. 74. P. 105717. DOI: 10.1016/j.intimp.2019.105717

[15] Xiao J, Lin F, Pan L, et al. Dexamethasone on alleviating lung ischemia/reperfusion injury in rats by regulating PI3K/AKT pathway. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2020;32(2):188–193. (In Chinese). DOI: 10.3760/cma.j.cn121430-20190723-00035

[16] Xiao J., Lin F., Pan L. et al. Dexamethasone on alleviating lung ischemia/reperfusion injury in rats by regulating PI3K/AKT pathway // Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2020. Vol. 32, No. 2. P. 188–193. (In Chinese). DOI: 10.3760/cma.j.cn121430-20190723-00035

[17] Pozdnyakov DI, Voronkov AV, Rukovitsyna VM. Chromon-3-aldehyde derivatives restore mitochondrial function in rat cerebral ischemia. Iran J Basic Med Sci. 2020;23(9):1172–1183. DOI: 10.22038/ijbms.2020.46369.10710

[18] Pozdnyakov D.I., Voronkov A.V., Rukovitsyna V.M. Chromon-3-aldehyde derivatives restore mitochondrial function in rat cerebral ischemia // Iran. J. Basic Med. Sci. 2020. Vol. 23, No. 9. P. 1172–1183. DOI: 10.22038/ijbms.2020.46369.10710

[19] Niu F, Xu X, Zhang R, et al. Ursodeoxycholic acid stimulates alveolar fluid clearance in LPS-induced pulmonary edema via ALX/cAMP/PI3K pathway. J Cell Physiol. 2019;234(11):20057–20065. DOI: 10.1002/jcp.28602

[20] Niu F., Xu X., Zhang R. et al. Ursodeoxycholic acid stimulates alveolar fluid clearance in LPS-induced pulmonary edema via ALX/cAMP/PI3K pathway // J. Cell. Physiol. 2019. Vol. 234, No. 11. P. 20057–20065. DOI: 10.1002/jcp.28602

[21] Kim JS, Lee JY, Yang JW, et al. Immunopathogenesis and treatment of cytokine storm in COVID-19. Theranostics. 2021;11(1):316–329. DOI: 10.7150/thno.49713

[22] Kim J.S., Lee J.Y., Yang J.W. et al. Immunopathogenesis and treatment of cytokine storm in COVID-19 // Theranostics. 2021. Vol. 11, No. 1. P. 316–329. DOI: 10.7150/thno.49713

[23] Lansbury LE, Rodrigo C, Leonardi-Bee J, et al. Corticosteroids as adjunctive therapy in the treatment of influenza: an updated Cochrane systematic review and meta-analysis. Crit Care Med. 2020;48(2):e98–e106. DOI: 10.1097/CCM.0000000000004093

[24] Lansbury L.E., Rodrigo C., Leonardi-Bee J. et al. Corticosteroids as adjunctive therapy in the treatment of influenza: an updated Cochrane systematic review and meta-analysis // Crit. Care Med. 2020. Vol. 48, No. 2. P. e98–e106. DOI: 10.1097/CCM.0000000000004093

[25] Wu H, Wang Y, Zhang Y, et al. Breaking the vicious loop between inflammation, oxidative stress and coagulation, a novel anti-thrombus insight of nattokinase by inhibiting LPS-induced inflammation and oxidative stress. Redox Biol. 2020;32:101500. DOI: 10.1016/j.redox.2020.101500

[26] Wu H., Wang Y., Zhang Y. et al. Breaking the vicious loop between inflammation, oxidative stress and coagulation, a novel anti-thrombus insight of nattokinase by inhibiting LPS-induced inflammation and oxidative stress // Redox Biol. 2020. No. 32. P. 101500. DOI: 10.1016/j.redox.2020.101500

[27] Baldwin AS. Regulation of cell death and autophagy by IKK and NF-kappaB: critical mechanisms in immune function and cancer. Immunol Rev. 2012;246:327–345. DOI: 10.1111/j.1600-065X.2012.01095.x

[28] Baldwin A.S. Regulation of cell death and autophagy by IKK and NF-kappaB: critical mechanisms in immune function and cancer // Immunol. Rev. 2012. No. 246. P. 327–345. DOI: 10.1111/j.1600-065X.2012.01095.x

[29] Zhuang C, Zhang W, Sheng C, et al. Chalcone: a privileged structure in medicinal chemistry. Chem Rev. 2017;117(12):7762–7810. DOI: 10.1021/acs.chemrev.7b00020

[30] Zhuang C., Zhang W., Sheng C. et al. Chalcone: a privileged structure in medicinal chemistry // Chem. Rev. 2017. Vol. 117, No. 12. P. 7762–7810. DOI: 10.1021/acs.chemrev.7b00020

[31] Zhang Y, Xu T, Wu B, et al. Targeting myeloid differentiation protein 2 by the new chalcone L2H21 protects LPS-induced acute lung injury. J Cell Mol Med. 2017;21(4):746–757. DOI: 10.1111/jcmm.13017

[32] Zhang Y., Xu T., Wu B. et al. Targeting myeloid differentiation protein 2 by the new chalcone L2H21 protects LPS-induced acute lung injury // J. Cell Mol. Med. 2017. Vol. 21, No. 4. P. 746–757. DOI: 10.1111/jcmm.13017

RIGHTS & PERMISSIONS

Chernikov M.V., Pozdnyakov D.I., Rukovitsina V.M., Oganesyan E.T.