Anti-inflammatory activity of the antiallergic drug 7-[4-(4-benzhydrylpiperazinyl-1)butyl]-3-methylxanthine succinate (theoritin)

封面

如何引用文章

全文:

详细

BACKGROUND: Many antagonists of histamine (H1) receptor, in addition to antihistamine action, suppress allergic inflammation by inhibiting the formation and secretion of proinflammatory cytokines. The new antiallergic drug benzhydrylpiperazinyl butylmethylxanthine succinate (theoritin), which has an antihistamine activity comparable to the known second generation H1-antihistamines, surpasses them in the ability to suppress the allergic inflammatory reaction, which allows this drug to have additional anti-inflammatory properties associated with the inhibition of the formation of proinflammatory cytokines.

AIM: This study aimed to determine the effect of theoritin on the induced release of proinflammatory cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α in cell culture in comparison with the action of the inverse agonist of H1 receptor cetirizine and a known inflammation inhibitor glucocorticosteroid dexamethasone.

MATERIALS AND METHODS: U937 cells differentiated toward macrophage-like cells were used. Cytotoxicity of the substances used was assessed in the methyltetrazolium test at different incubation times (up to 24 h). Cells were stimulated with lipopolysaccharide (LPS). The tested compounds (theoritin and cetirizine) were evaluated at concentrations from 0.001 to 100 μM and dexamethasone at 10 μM was tested when added to cells 1 h before (prophylactic effect) or 1 h after (therapeutic effect) the addition of LPS. The presence of IL-6, IL-8, and TNFα in the supernatants was determined by enzyme immunoassay.

RESULTS: For cetirizine and theoritin, no cytotoxic action was found in the tested concentrations and time points. Dexamethasone inhibited the formation of IL-6 and TNFα to the initial level and IL-8 to 50%–60%. Theoritin led to a significant concentration-dependent decrease in the LPS-induced production of IL-6, IL-8, and TNFα, and at a concentration of 100 μM, the effect of theoritin was comparable with that of dexamethasone at a concentration of 10 μM. The “prophylactic” test scheme for theoritin was more effective in suppressing LPS-induced production of proinflammatory cytokines than the “curative” one. The described effect of theoritin on LPS-induced production of proinflammatory cytokines exceeded that of the reference drug cetirizine.

CONCLUSION: In addition to its antihistaminic action, theoritin, a new antiallergic agent, inhibits LPS-induced production of proinflammatory cytokines, which may be of clinical importance in suppressing allergic inflammation.

作者简介

Igor Gushchin

National Research Center — Institute of Immunology Federal Medical-Biological Agency of Russia

编辑信件的主要联系方式.
Email: igushchin@yandex.ru
ORCID iD: 0000-0002-4465-6509
SPIN 代码: 1905-4758

MD, PhD, professor, corresponding member of Russian Academy of Sciences, head of the Departament of Clinical Immunology and Allergology

俄罗斯联邦, 24, Kashirskoe shosse, Moscow, 115522

Kirill Kryshen

Scientific and Production Association “Home of Pharmacy”

Email: info@doclinika.ru
ORCID iD: 0000-0003-1451-7716
SPIN 代码: 5650-2840

Cand. Sci. (Biol.)

俄罗斯联邦, Leningrad region, Kuzmolovsky village

Andrei Bondarenko

Scientific and Production Association “Home of Pharmacy”

Email: info@doclinika.ru
ORCID iD: 0000-0002-8437-1313
SPIN 代码: 3376-6819
俄罗斯联邦, Leningrad region, Kuzmolovsky village

参考

  1. Gushchin IS, Orlov SM, Czju NL. On the triggering mechanism of anaphylactic reactions in rat mast cells. Allergol Immunopathol (Madr). 1974;2(2):69–76.
  2. Gushchin IS, Uvnäs B. In vitro uptake of 5-hydroxytryptamine and dopamine by rat mast cells after exocytosis induced by antigen or compound 48/80. Acta Physiol Scand. 1976;98(2):168–174. doi: 10.1111/j.1748-1716.1976.tb00236.x
  3. Gushchin IS, Zebrev AI, Chitaeva VG, et al. Polyfunctional antiallergic compounds combining antihistamine activity with stabilization of mast cells and basophils. Pharmaceutical Chemistry Journal. 1987;21(11):1313–1318. (In Russ).
  4. Mashkovsky MD, Yakhontov LN, Kaminka ME, Mikhlina EE. Further developments in research on the chemistry and pharmacology of synthetic quinuclidine derivatives. Prog Drug Res. 1983;27:9–61. doi: 10.1007/978-3-0348-7115-0_1
  5. Leurs R, Church MK, Taglialatela M. H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects. Clin Exp Allergy. 2002;32(4):489–498. doi: 10.1046/j.0954-7894.2002.01314.x
  6. Cheng KC, Hsu JY, Fu LS, et al. Influence of cetirizine and loratadine on granulocyte-macrophage colony-stimulating factor and interleukin-8 release in A549 human airway epithelial cells stimulated with interleukin-1beta. J Microbiol Immunol Infect. 2006;39(3):206–211.
  7. Glushkov RG, Yuzhakov SD, Alekseev MV, et al. New group of 1- and 7-[ω-(benzhydryl) alkyl]-3-methylxantine derivatives possessing antihistaminic properties. Pharmaceutical Chemistry Journal. 2011;45(1):3–13. (In Russ).
  8. Glushkov RG, Yuzhakov SD. Experience in creating new drugs using traditional technologies. Pharmaceutical Chemistry Journal. 2011;45(9):3–7. (In Russ).
  9. Nebreda AD, Zappia CD, González AR, et al. Involvement of histamine H1 and H2 receptor inverse agonists in receptor’s crossregulation. Eur J Pharmacol. 2019;847:42–52. doi: 10.1016/j.ejphar.2019.01.026
  10. Plumb JA. Cell sensitivity assays: the MTT assay. Methods Mol Med. 2004;88:165–169. doi: 10.1385/1-59259-406-9:165
  11. Sundström C, Nilsson K. Establishment and characterization of a human histiocytic lymphoma cell line (U-937). Int J Cancer. 1976;17(5):565–577. doi: 10.1002/ijc.2910170504
  12. Garrelds IM, van Hal PT, Haakmat RC, et al. Time dependent production of cytokines and eicosanoids by human monocytic leukaemia U937 cells; effects of glucocorticosteroids. Mediators Inflamm. 1999;8(4-5):229–235. doi: 10.1080/09629359990397
  13. Haque MA, Jantan I, Harikrishnan H. Zerumbone suppresses the activation of inflammatory mediators in LPS-stimulated U937 macrophages through MyD88-dependent NF- κB/ MAPK/PI3K-Akt signaling pathways. Int Immunopharmacol. 2018;55:312–322. doi: 10.1016/j.intimp.2018.01.001
  14. Shih MY, Hsu JY, Weng YS, Fu LS. Influence of cetirizine and levocetirizine on two cytokines secretion in human airway epithelial cells. Allergy Asthma Proc. 2008;29(5):480–485. doi: 10.2500/aap.2008.29.3156
  15. Arnold R, Rihoux J, König W. Cetirizine counter-regulates interleukin-8 release from human epithelial cells (A549). Clin Exp Allergy. 1999;29(12):1681–1691. doi: 10.1046/j.1365-2222.1999.00630.x
  16. Ohtani T, Aiba S, Mizuashi M, et al. Evaluation of the efficacy of antihistamines using human monocyte-derived dendritic cells stimulated with histamine. J Am Acad Dermatol. 2003;49(2):234–242. doi: 10.1067/s0190-9622(03)01478-6
  17. Küsters S, Schuligoi R, Hüttenbrink KB, et al. Effects of antihistamines on leukotriene and cytokine release from dispersed nasal polyp cells. Arzneimittelforschung. 2002;52(2):97–102. doi: 10.1055/s-0031-1299863
  18. Lippert U, Möller A, Welker P, et al. Inhibition of cytokine secretion from human leukemic mast cells and basophils by H1- and H2-receptor antagonists. Exp Dermatol. 2000;9(2):118–124. doi: 10.1034/j.1600-0625.2000.009002118.x
  19. Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev. 2006;58(3):488–520. doi: 10.1124/pr.58.3.5
  20. Yoneda M, Sugimoto N, Katakura M, et al. Theobromine up-regulates cerebral brain-derived neurotrophic factor and facilitates motor learning in mice. J Nutr Biochem. 2017;39:110–116. doi: 10.1016/j.jnutbio.2016.10.002
  21. Kaliner M. Symposium on allergic lung disease. IV. Immunologic mechanisms for release of chemical mediators of anaphylaxis from human lung tissue. Can Med Assoc J. 1974;110(4):431.
  22. Geraets L, Moonen HJ, Wouters EF, et al. Caffeine metabolites are inhibitors of the nuclear enzyme poly(ADP-ribose)polymerase-1 at physiological concentrations. Biochem Pharmacol. 2006;72(7):902–910. doi: 10.1016/j.bcp.2006.06.023
  23. Jang YJ, Koo HJ, Sohn EH, et al. Theobromine inhibits differentiation of 3T3-L1 cells during the early stage of adipogenesis via AMPK and MAPK signaling pathways. Food Funct. 2015;6(7):2365–2374. doi: 10.1039/c5fo00397k
  24. Fuggetta MP, Zonfrillo M, Villivà C, et al. Inflammatory microenvironment and adipogenic differentiation in obesity: the inhibitory effect of theobromine in a model of human obesity in vitro. Mediators Inflamm. 2019;2019:1515621. doi: 10.1155/2019/1515621.

补充文件

附件文件
动作
1. JATS XML
下载

版权所有 © Pharmarus Print Media, 2021

##common.cookie##