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

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Abstract

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.

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About the authors

Igor S. Gushchin

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

Author for correspondence.
Email: igushchin@yandex.ru
ORCID iD: 0000-0002-4465-6509
SPIN-code: 1905-4758

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

Russian Federation, 24, Kashirskoe shosse, Moscow, 115522

Kirill L. Kryshen

Scientific and Production Association “Home of Pharmacy”

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

Cand. Sci. (Biol.)

Russian Federation, Leningrad region, Kuzmolovsky village

Andrei B. Bondarenko

Scientific and Production Association “Home of Pharmacy”

Email: info@doclinika.ru
ORCID iD: 0000-0002-8437-1313
SPIN-code: 3376-6819
Russian Federation, Leningrad region, Kuzmolovsky village

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Supplementary files

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1. Fig. 1. Results of evaluating the cytotoxic effect of cetirizine on U937 cells differentiated into macrophages. Y-axis: cell viability (optical density as a percentage of control). X-axis: cetirizine concentration in μM. Hereinafter, the mean value (M) + standard deviation (SD) are given. # Differences are statistically significant in comparison with the control (0 μM), nonparametric Kruskall-Wallis test, multiple comparisons using Dunn’s test, p <0.05, n=6.

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2. Fig. 2. Results of evaluating the cytotoxic effect of theoritin on U937 cells differentiated into macrophages. Y-axis: cell viability (optical density as a percentage of control). X-axis: theoritin concentration in μM. # Differences are statistically significant in comparison with the control (0 μM), nonparametric Kruskall–Wallis test, multiple comparisons using Dunn’s test, p <0.05, n=6.

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3. Fig. 3. Influence of the studied compounds on the level of LPS-induced production of IL-6: а ― test compounds were added 1 hour before treatment with LPS cells; b ― test compounds were added 1 hour after treatment with LPS cells (LPS 10 μg/ml; dexamethasone 10 μM). Y-axis: concentration of IL-6 (pg/ml) in the supernatant. X-axis: concentration of test compounds (theoritin and cetirizine) added to the cells in μM. Here and in Fig. 4, 5: ЛПС ― lipopolysaccharide; ТРТ ― theoritin; ЦТР ― cetirizine; ДКМ ― dexamethasone. * Differences are statistically significant in comparison with the background level (negative control), Student’s t-test; ** differences are statistically significant in comparison with LPS, Student’s t-test (for dexamethasone); # differences are statistically significant in comparison with LPS, ANOVA post-hoc Dunnett’s test, p <0.05, n=8.

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4. Fig. 4. Influence of the studied compounds on the level of LPS-induced production of IL-8: а ― test compounds were added 1 hour before treatment with LPS cells; b ― test compounds were added 1 hour after treatment with LPS cells (LPS 10 μg/ml; dexamethasone 10 μM). Y-axis: concentration of IL-8 (pg/ml) in the supernatant. X-axis: concentration of test compounds (theoritin and cetirizine) added to the cells in μM.

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5. Fig. 5. Influence of the studied compounds on the level of LPS-induced TNFα production: а ― test compounds were added 1 hour before treatment with LPS cells; b ― test compounds were added 1 hour after treatment with LPS cells (LPS 10 μg/ml; dexamethasone 10 μM). Y-axis: TNFα concentration (pg/ml) in the supernatant. X-axis: concentration of test compounds (theoritin and cetirizine) added to the cells in μM.

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