Some aspects of the therapeutic effect of dental gel with IL-1β antagonist in experimental chronic generalized periodontitis

Authors

DOI:

https://doi.org/10.14739/mmt.2025.2.322333

Keywords:

chronic generalized periodontitis, oromucosal gel, heat shock proteins, IL-1β receptor antagonist

Abstract

The aim of the current study was to evaluate the therapeutic efficacy of 1 % IL-1β antagonist dental gel by its effect on biomarkers of inflammation and cytoprotection under conditions of modelling chronic generalized periodontitis in rats.

Materials and methods. Chronic generalized periodontitis (CGP) was reproduced in Wistar rats weighing 180–210 g by 8-week administration of the prooxidant Delagil (chloroquine phosphate, 30 mg/kg) and addition of EDTA (2 %) to drinking water using a calcium-deficient peroxide diet with reduced chewing function. The studied pharmacological medications were administered after the development of CGP in rats for 30 days: 1 % oromucosal gel with IL-1β receptor antagonist (RAIL-1β, 1 mg/kg) locally using a dispenser; and the antioxidant Mexidol (250 mg/kg) intragastrically for 30 days. The condition of periodontal tissues and the effect of the studied medications on the levels of inflammatory markers IL-1β, tumour necrosis factor alpha (TNF-α), matrix metalloproteinase-2 (MMP-2) and markers of endogenous neuroprotection hypoxia-induced factor 1-alpha (HIF-1α) and heat shock proteins (HSP70) were evaluated using enzyme-linked immunosorbent assay (ELISA).

Results. Modelling of CGP in rats by 8-week administration of the prooxidant Delagil and addition of EDTA to drinking water resulted in typical manifestations of the disease: bleeding, hyperaemia, and swelling of the gums; tooth mobility; formation of gingival pockets up to 8 mm against the background of increased levels of inflammation markers (TNF-α, IL-1β), and molecular markers (HIF-1α and HSP70) in the blood indicated a homeostatic response of the periodontium to inflammation and subsequent hypoxia by an increase in the synthesis of HIF-1α and HSP70. Course application of 1 % oromucosal gel with IL-1β receptor antagonist (1 μg/kg) to rats with CGP in a therapeutic regimen led to an improvement in the clinical picture of the disease: significant reduction in the size of the gingival pocket to 2.2 mm, and a significant reduction of bleeding and swelling against the background of lowering the levels of inflammatory markers in the blood: TNF-α – by 82 % (p < 0.05), metalloproteinase-2 – by 65 % (p < 0.05), and IL-1β – by 71.4 % (p < 0.05) compared to the group of untreated animals. Application of 1 % oromucosal gel with IL-1β receptor antagonist resulted in an increase in HIF-1α levels by 42 % (p < 0.05) in comparison to control indicators, and an increase in HSP70 levels by 62.8 % compared to the control group, and in 2.4 times (p < 0.05) compared to the intact group that indicated a significant impact of IL-1β receptor antagonist on the HSP70-dependent mechanisms of endogenous cytoprotection. Oromucosal gel with 1 % IL-1β receptor antagonist (1 μg/kg) was significantly superior to the reference drug Mexidol (250 mg/kg) in terms of its action on the studied parameters under conditions of CGP.

Conclusions. The obtained results substantiate the further in-depth pharmacological study of the new oromucosal gel with IL-1β receptor antagonist (1 μg/kg) for the purpose of clinical use in the treatment of generalized periodontitis. We have found that the use of IL-1β receptor antagonist in experimental CGP is more effective than Mexidol.

Author Biographies

O. O. Dmytriieva, Zaporizhzhia State Medical and Pharmaceutical University

MD, Postgraduate Student of the Department of Surgical and Propaedeutic Dentistry

 

I. F. Bielenichev, Zaporizhzhia State Medical and Pharmaceutical University

PhD, DSc, Professor, Head of the Department of Pharmacology and Medical Formulation with Course of Normal Physiology

I. B. Samura, Zaporizhzhia State Medical and Pharmaceutical University

MD, PhD, Associate Professor of the Department of Pharmacology and Medical Formulation with Course of Normal Physiology

 

V. I. Salnykov, Zaporizhzhia State Medical and Pharmaceutical University

MD, Assistant of the Department of Surgical and Propaedeutic Dentistry

References

  1. Martínez-García M, Hernández-Lemus E. Periodontal inflammation and systemic diseases: an overview. Front Physiol. 2021;12:709438. doi: https://doi.org/10.3389/fphys.2021.709438
  2. Li Y, Xiang Y, Ren H, Zhang C, Hu Z, Leng W, et al. Association between periodontitis and dental caries: a systematic review and meta-analysis. Clin Oral Investig. 2024;28(6):306. doi: https://doi.org/10.1007/s00784-024-05687-2
  3. Huang D, Wang YY, Li BH, Wu L, Xie WZ, Zhou X, et al. Association between periodontal disease and systemic diseases: a cross-sectional analysis of current evidence. Military Med Res. 2024;11(1):74. doi: https://doi.org/10.1186/s40779-024-00583-y
  4. Janakiram C, Dye BA. A public health approach for prevention of periodontal disease. Periodontol 2000. 2020;84(1):202-14. doi: https://doi.org/10.1111/prd.12337
  5. Bhuyan R, Bhuyan SK, Mohanty JN, Das S, Juliana N, Juliana IF. Periodontitis and its inflammatory changes linked to various systemic diseases: a review of its underlying mechanisms. Biomedicines. 2022;10(10):2659. doi: https://doi.org/10.3390/biomedicines10102659
  6. López-Valverde N, López-Valverde A, Montero J, Rodríguez C, Macedo de Sousa B, Aragoneses JM. Antioxidant, anti-inflammatory and antimicrobial activity of natural products in periodontal disease: a comprehensive review. Front Bioeng Biotechnol. 2023;11:1226907. doi: https://doi.org/10.3389/fbioe.2023.1226907
  7. Gonçalves S, Fernandes L, Caramelo A, Martins M, Rodrigues T., Matos RS. Soothing the itch: the role of medicinal plants in alleviating pruritus in palliative care. Plants. 2024;13(24):3515. doi: https://doi.org/10.3390/plants13243515
  8. Emerald M. Medicinal plants: Therapeutic potential, safety, and toxicity. In: Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays. Cham: Springer International Publishing; 2024. p. 1327-97. doi: https://doi.org/10.1007/978-3-031-35529-5_90
  9. Pázmándi K, Szöllősi AG, Fekete T. The "root" causes behind the anti-inflammatory actions of ginger compounds in immune cells. Front Immunol. 2024;15:1400956. doi: https://doi.org/10.3389/fimmu.2024.1400956
  10. Siddiqui R, Badran Z, Boghossian A, Alharbi AM, Alfahemi H, Khan NA. The increasing importance of the oral microbiome in periodontal health and disease. Future Sci OA. 2023;9(8):FSO856. doi: https://doi.org/10.2144/fsoa-2023-0062
  11. Sabaoui Z, Lakhdar L. Essential Oils in Periodontics. What is the Interest? Integr J Med Sci. 2021;8:1-3. doi: https://doi.org/10.15342/ijms.2021.499
  12. Menéndez SG, Manucha W. Nanopharmacology as a new approach to treat neuroinflammatory disorders. Transl Neurosci. 2023;14(1):20220328. doi: https://doi.org/10.1515/tnsci-2022-0328
  13. Nasiri K, Masoumi SM, Amini S, Goudarzi M, Tafreshi SM, Bagheri A, et al. Recent advances in metal nanoparticles to treat periodontitis. J Nanobiotechnology. 2023;21(1):283. doi: https://doi.org/10.1186/s12951-023-02042-7
  14. Bapat R, Chaubal TV, Dharmadhikari S, Abdulla AM, Bapat P, Alexander A, et al. Recent advances of gold nanoparticles as biomaterial in dentistry. Int J Pharm. 2020;586:119596. doi: https://doi.org/10.1016/j.ijpharm.2020.119596
  15. Brierly G, Celentano A, Breik O, Moslemivayeghan E, Patini R, McCullough M, et al. Tumour necrosis factor alpha (TNF-α) and oral squamous cell carcinoma. Cancers (Basel). 2023;15(6):1841. doi: https://doi.org/10.3390/cancers15061841
  16. Afzal S, Abdul Manap AS, Attiq A, Albokhadaim I, Kandeel M, Alhojaily SM. From imbalance to impairment: the central role of reactive oxygen species in oxidative stress-induced disorders and therapeutic exploration. Front Pharmacol. 2023;14:1269581. doi: https://doi.org/10.3389/fphar.2023.1269581
  17. Papathanasiou E, Conti P, Carinci F, Lauritano D, Theoharides TC. IL-1 superfamily members and periodontal diseases. J Dent Res. 2020;99(13):1425-34. doi: https://doi.org/10.1177/0022034520945209
  18. Pyrillou K, Burzynski LC, Clarke MC. Alternative pathways of IL-1 activation, and its role in health and disease. Front. Immunol. 2020;11:613170. doi: https://doi.org/10.3389/fimmu.2020.613170
  19. Herrero-Cervera A., Soehnlein O, Kenne E. Neutrophils in chronic inflammatory diseases. Cell Mol Immunol. 2022;19(2):177-91. doi: https://doi.org/10.1038/s41423-021-00832-3
  20. Behm C, Nemec M, Blufstein A, Schubert M, Rausch-Fan X, Andrukhov O, et al. Interleukin-1β induced matrix metalloproteinase expression in human periodontal ligament-derived mesenchymal stromal cells under in vitro simulated static orthodontic forces. Int J Mol Sci. 2021;22(3):1027. doi: https://doi.org/10.3390/ijms22031027
  21. Cheng R, Wu Z, Li M, Shao M, Hu T. Interleukin-1β is a potential therapeutic target for periodontitis: a narrative review. Int J Oral Sci. 2020;12(1):2. doi: https://doi.org/10.1038/s41368-019-0068-8
  22. Geng J, Wang F, Huang Z, Chen X, Wang Y. Perspectives on anti-IL-1 inhibitors as potential therapeutic interventions for severe COVID-19. Cytokine. 2021;143:155544. doi: https://doi.org/10.1016/j.cyto.2021.155544
  23. Dmytriieva OO, Belenichev IF, Burlaka BS. Optimisation of the composition of safe dental gel with IL-1β antagonist for the treatment of inflammatory periodontal diseases Zaporozhye medical journal. 2024;26(2):134-43. doi: https://doi.org/10.14739/2310-1210.2024.2.292521
  24. Dmytriieva OO, Bielenichev I.F, Samura IB, Salnykov VI, Robota DV. The effect of dental gel with IL-1β antagonist on indicators of nitrosative stress and antioxidant system in rats with experimental chronic generalized periodontitis. Modern medical technology. 2024;16(3):214-9. doi: https://doi.org/10.14739/mmt.2024.3.303351
  25. Kiani AK, Pheby D, Henehan G, Brown R, Sieving P, Sykora P, et al. Ethical considerations regarding animal experimentation. J Prev Med Hyg. 2022 Oct 17;63(2 Suppl 3):E255-66. doi: https://doi.org/10.15167/2421-4248/jpmh2022.63.2S3.2768
  26. American Veterinary Medical Association. AVMA guidelines for the euthanasia of animals: 2020 edition. Version 2020.0.1. Available from: https://www.avma.org/sites/default/files/2020-02/Guidelines-on-Euthanasia-2020.pdf
  27. Parkhomenko D, Belenichev IF, Kuchkovskyi OM, Ryzhenko V. Characteristics of HIF-1Α and HSP70 MRNA expression, level, and interleukins in experimental chronic generalized periodontitis. MicroRNA. 2024;13(2):132-9. doi: https://doi.org/10.2174/0122115366264794240327073739
  28. McPherson RA, Pincus MR. Henry’s clinical diagnosis and management by laboratory methods. 24th ed. Philadelphia, PA: Elsevier - Health Sciences Division; 2021.
  29. Belenichev I, Salnykov V, Samura I. The effect of selenase on inflammatory and cytoprotective markers in experimental chronic generalized periodontitis. Biomed Pharmacol J. 2024;17(3):1911-9. doi: https://doi.org/10.13005/bpj/2993
  30. Belenichev IF, Aliyeva OG, Popazova OO, Bukhtiyarova NV. Involvement of heat shock proteins HSP70 in the mechanisms of endogenous neuroprotection: the prospect of using HSP70 modulators. Front Cell Neurosci. 2023;17:1131683. doi: https://doi.org/10.3389/fncel.2023.1131683
  31. Belenichev I, Popazova O, Bukhtiyarova N, Savchenko D, Oksenych V, Kamyshnyi O. Modulating nitric oxide: implications for cytotoxicity and cytoprotection. Antioxidants (Basel). 2024;13(5):504. doi: https://doi.org/10.3390/antiox13050504
  32. Leira Y, Iglesias-Rey R, Gómez-Lado N, Aguiar P, Sobrino T, D'Aiuto F, et al. Periodontitis and vascular inflammatory biomarkers: an experimental in vivo study in rats. Odontology. 2020;108(2):202-12. doi: https://doi.org/10.1007/s10266-019-00461-3
  33. Lee J, Lee JB, Song HY, Son MJ, Li L, Rhyu IC, et al. Diagnostic Models for Screening of periodontitis with inflammatory mediators and microbial profiles in saliva. Diagnostics (Basel). 2020;10(10):820. doi: https://doi.org/10.3390/diagnostics10100820
  34. Alayash Z, Baumeister S-E, Holtfreter B, Kocher T, Baurecht H, Ehmke B, et al. Inhibition of tumor necrosis factor receptor 1 and the risk of periodontitis. Front. Immunol. 2023;14:1094175. doi: https://doi.org/10.3389/fimmu.2023.1094175
  35. Brodzikowska A, Górski B, Bogusławska-Kapała A. Association between IL-1 gene polymorphisms and stage III grade B periodontitis in Polish population. Int J Environ Res Public Health. 2022;19(22):14687. doi: https://doi.org/10.3390/ijerph192214687
  36. Wang RP, Huang J, Chan KW, Leung WK, Goto T, Ho YS, et al. IL-1β and TNF-α play an important role in modulating the risk of periodontitis and Alzheimer's disease. J Neuroinflammation. 2023;20(1):71. doi: https://doi.org/10.1186/s12974-023-02747-4
  37. Radzki D, Negri A, Kusiak A, Obuchowski M. Matrix metalloproteinases in the periodontium – vital in tissue turnover and unfortunate in periodontitis. Int J Mol Sci. 2024;25(5):2763. doi: https://doi.org/10.3390/ijms25052763
  38. Jansson L, Lundmark A, Modin C, Abadji D, Yucel-Lindberg T. Intra-individual cytokine profile in peri-implantitis and periodontitis: A cross-sectional study. Clin Oral Implants Res. 2021;32(5):559-68. doi: https://doi.org/10.1111/clr.13725
  39. Jansson L, Lundmark A, Modin C, Gustafsson A, Yucel-Lindberg T. Levels of matrix metalloproteinase-1 (MMP-1), MMP-2, MMP-3, osteopontin, pentraxin-3, and thymic stromal lymphopoietin in crevicular fluid samples from peri-implantitis, periodontitis, and healthy sites. J Periodontal Res. 2024;00:1-11. doi: https://doi.org/10.1111/jre.13338
  40. Bernal-Sánchez KK, Lara-Carrillo E, Velázquez-Enriquez U, Casanova-Rosado JF, Casanova-Rosado AJ, Morales-Valenzuela AA, et al. Clinical and socio-demographic factors associated with dental extractions in a clinical sample. Braz Dent J. 2023;34(6):121-9. doi: https://doi.org/10.1590/0103-6440202305355
  41. Furuse N, Takai H, Ogata Y. Effects of initial periodontal therapy on heat shock protein 70 levels in gingival crevicular fluid from periodontitis patients. J Clin Med. 2020;9(10):3072. doi: https://doi.org/10.3390/jcm9103072
  42. Li M, Huang S, Zhang Y, Song Z, Fu H, Lin Z, et al. Regulation of the unfolded protein response transducer IRE1α by SERPINH1 aggravates periodontitis with diabetes mellitus via prolonged ER stress. Cell Signal. 2022;91:110241. doi: https://doi.org/10.1016/j.cellsig.2022.110241
  43. Takai H, Furuse N, Ogata Y. Anti-heat shock protein 70 levels in gingival crevicular fluid of Japanese patients with chronic periodontitis. J Oral Sci. 2020;62(3):281-4. doi: https://doi.org/10.2334/josnusd.19-0159
  44. Kzar WA, Abbas RF. Association of Polymorphism with Periodontitis and Salivary Levels of Hypoxia-Inducible Factor-1α. Eur J Dent. 2025;19(1):133-43. doi: https://doi.org/10.1055/s-0044-1785530
  45. Taylor CT, Scholz CC. The effect of HIF on metabolism and immunity. Nat Rev Nephrol. 2022;18(9):573-87. doi: https://doi.org/10.1038/s41581-022-00587-8
  46. Shan C, Xia Y, Wu Z, Zhao J. HIF-1α and periodontitis: Novel insights linking host-environment interplay to periodontal phenotypes. Prog Biophys Mol Biol. 2023;184:50-78. doi: https://doi.org/10.1016/j.pbiomolbio.2023
  47. Yan K, Wu C, Ye Y, Li L, Wang X, He W, et al. A20 inhibits osteoclastogenesis via TRAF6-dependent autophagy in human periodontal ligament cells under hypoxia. Cell Prolif. 2020;53(3):e12778. doi: https://doi.org/10.1111/cpr.12778
  48. Lin XJ, Yuan Q, Zhou J, Dong YL, Sunchuri D, Guo ZL. Cellular senescence: A new perspective on the suppression of periodontitis (Review). Mol Med Rep. 2024;30(6):238. doi: https://doi.org/10.3892/mmr.2024.13362
  49. Bishop EL, Gudgeon N and Dimeloe S. Control of T Cell Metabolism by Cytokines and Hormones. Front. Immunol. 2021;12:653605. doi: https://doi.org/10.3389/fimmu.2021.653605
  50. Chaparro A, Lozano M, Gaedechens D, López C, Albers D, Hernández M, et al. Exploring the expression of pro-inflammatory and hypoxia-related microRNA-20a, microRNA-30e, and microRNA-93 in periodontitis and gingival mesenchymal stem cells under hypoxia. Int J Mol Sci. 2022;23(18):10310. doi: https://doi.org/10.3390/ijms231810310
  51. Kazmi S, Salehi-Pourmehr H, Sadigh-Eteghad S, Farhoudi M. The efficacy and safety of interleukin-1 receptor antagonist in stroke patients: A systematic review. J Clin Neurosci. 2024;120:120-8. doi: https://doi.org/10.1016/j.jocn.2024.01.009
  52. Хu J, Zheng Y, Zhao Y, Zhang Y, Li H, Zhang A, et al. Succinate/IL-1β signaling axis promotes the inflammatory progression of endothelial and exacerbates atherosclerosis. Front Immunol. 2022;13:817572. doi: https://doi.org/10.3389/fimmu.2022.817572
  53. Lacher SE, Skon-Hegg C, Ruis BL, Krznarich J, Slattery M. An antioxidant response element regulates the HIF1α axis in breast cancer cells. Free Radic Biol Med. 2023;204:243-251. doi: https://doi.org/10.1016/j.freeradbiomed.2023.05.003

Downloads

Additional Files

Published

2025-06-25

How to Cite

Dmytriieva, O. O., Bielenichev, I. F., Samura, I. B., & Salnykov, V. I. (2025). Some aspects of the therapeutic effect of dental gel with IL-1β antagonist in experimental chronic generalized periodontitis. Modern Medical Technology, 17(2), 124–131. https://doi.org/10.14739/mmt.2025.2.322333

Issue

Vol. 17 No. 2 (2025)

Section

Original research

License

Copyright (c) 2025 O. O. Dmytriieva, I. F. Bielenichev, I. B. Samura, V. I. Salnykov

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

The work is provided under the terms of the Public Offer and of Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). This license allows an unlimited number of persons to reproduce and share the Licensed Material in all media and formats. Any use of the Licensed Material shall contain an identification of its Creator(s) and must be for non-commercial purposes only.