EXPLORING THE ANTI-INFLAMMATORY PROPERTIES OF METFORMIN IN EXPERIMENTAL HEMORRHOID MODELS
DOI:
https://doi.org/10.22159/ijap.2025v17i2.53174Keywords:
Anti-inflammatory effects, Gene expression, Hemorrhoids, Leukocyte infiltration, MetforminAbstract
Objective: This study investigated the anti-inflammatory potential of metformin as a therapeutic agent in an experimental hemorrhoid model using Sprague-Dawley rats.
Methods: Rats were assigned to six groups: normal control, negative control (hemorrhoid-induced without treatment), positive control (hemorrhoid-induced and treated with aspirin), and three metformin-treated groups receiving 3 mg/kg, 9 mg/kg, and 15 mg/kg body weight doses. Metformin's effects were assessed through macroscopic observation, qPCR analysis of IL-6, TNF-α, IL-10, and COX-2 gene expression, and histopathological examination of leukocyte infiltration and venule diameter.
Results: qPCR analysis revealed significant reductions in IL-6 and TNF-α expression in metformin-treated groups compared to the negative control. Specifically, the 9 mg/kg dose achieved a 99% reduction in IL-6 and over 98% reduction in TNF-α expression. COX-2 expression was also significantly decreased in metformin-treated groups (p<0.0001), while IL-10 expression remained unchanged (p=0.3973). Histopathological analysis showed a dose-dependent reduction in leukocyte infiltration, with the 15 mg/kg dose exhibiting the most significant decrease (p<0.0001). Additionally, metformin treatment resulted in a significant reduction in venule diameter, particularly at the 15 mg/kg dose (p<0.0001).
Conclusion: These results suggest that metformin, especially at higher doses, has significant anti-inflammatory effects in experimental hemorrhoid models, indicating its potential as a promising therapeutic option for hemorrhoid treatment.
References
Gupta S, Singh TG, Baishnab S, Garg N, Kaur K, Satija S, editors. Recent management of hemorrhoids: a pharmacological and surgical perspective; 2020.
Ray Offor E, Amadi S. Hemorrhoidal disease: predilection sites, pattern of presentation, and treatment. Ann Afr Med. 2019;18(1):12-6. doi: 10.4103/aam.aam_4_18, PMID 30729927, PMCID PMC6380113.
Al-Masoudi RO, Shosho R, Alquhra D, Alzahrani M, Hemdi M, Alshareef L. Prevalence of hemorrhoids and the associated risk factors among the general adult population in Makkah, Saudi Arabia. Cureus. 2024;16(1):e51612. doi: 10.7759/cureus.51612, PMID 38318578, PMCID PMC10840063.
Sardinas C, Arreaza DD, Osorio H. Changes in the proportions of types I and III collagen in hemorrhoids: the sliding anal lining theory. J Coloproctol. 2016;36(3):124-9. doi: 10.1016/j.jcol.2016.04.003.
Sun Z, Migaly J. Review of hemorrhoid disease: presentation and management. Clin Colon Rect Surg. 2016;29(1):22-9. doi: 10.1055/s-0035-1568144, PMID 26929748.
Sanchez C, Chinn BT. Hemorrhoids. Clin Colon Rect Surg. 2011;24(1):5-13. doi: 10.1055/s-0031-1272818, PMID 22379400, PMCID PMC3140328.
Lohsiriwat V. Hemorrhoids: from basic pathophysiology to clinical management. World J Gastroenterol. 2012;18(17):2009-17. doi: 10.3748/wjg.v18.i17.2009. PMID 22563187, PMCID PMC3342598.
Porwal A, Gandhi P, Kulkarni D. Laser hemorrhoidopexy: an observational study of 1088 patients treated at a single center. Indian J Colo Rect Surg. 2022;5(3):61-7. doi: 10.4103/ijcs.ijcs_28_21, PMID 02234691.
Ng KS, Holzgang M, Young C. Still a case of “no pain, no gain”? An updated and critical review of the pathogenesis, diagnosis, and management options for hemorrhoids in 2020. Ann Coloproctol. 2020;36(3):133-47. doi: 10.3393/ac.2020.05.04, PMID 32674545, PMCID PMC7392573.
Altomare DF, Giuratrabocchetta S. Conservative and surgical treatment of haemorrhoids. Nat Rev Gastroenterol Hepatol. 2013;10(9):513-21. doi: 10.1038/nrgastro.2013.91, PMID 23752820.
Zagriadskii EA, Bogomazov AM, Golovko EB. Conservative treatment of hemorrhoids: results of an observational multicenter study. Adv Ther. 2018;35(11):1979-92. doi: 10.1007/s12325-018-0794-x, PMID 30276625, PMCID PMC6223991.
Shah I, Vyas J. Role of P-GP inhibitors on gut permeation of metformin: an ex-vivo study. Int J Pharm Pharm Sci. 2022;14(10):18-23. doi: 10.22159/ijpps.2022v14i10.45135.
Aleti R, Baratam SR, Jagirapu B, Kudamala S. Formulation and evaluation of metformin hydrochloride and gliclazide sustained release bilayer tablets: a combination therapy in management of diabetes. Int J Appl Pharm. 2021;13(5):343-50. doi: 10.22159/ijap.2021v13i5.41339.
Mussttaf GS, Habib A, Mahtook M. Drug prescribing pattern and cost-effectiveness analysis of oral antidiabetic drugs in patients with type-2 diabetes mellitus: real-world data from Indian population. Asian J Pharm Clin Res. 2021;14(7):45-9. doi: 10.22159/ajpcr.2021.v14i7.41677.
Tseng CH. Chronic metformin therapy is associated with a lower risk of hemorrhoid in patients with type 2 diabetes mellitus. Front Pharmacol. 2020;11:578831. doi: 10.3389/fphar.2020.578831, PMID 33664665, PMCID PMC7921735.
Zhou J, Massey S, Story D, Li L. Metformin: an old drug with new applications. Int J Mol Sci. 2018;19(10):2863. doi: 10.3390/ijms19102863, PMID 30241400, PMCID PMC6213209.
Saisho Y. Metformin and inflammation: its potential beyond glucose-lowering effect. Endocr Metab Immune Disord Drug Targets. 2015;15(3):196-205. doi: 10.2174/1871530315666150316124019, PMID 25772174.
Kelly B, Tannahill GM, Murphy MP, O’Neill LA. Metformin inhibits the production of reactive oxygen species from NADH: ubiquinone oxidoreductase to limit induction of interleukin-1β (IL-1β) and boosts interleukin-10 (IL-10) in lipopolysaccharide (LPS)-activated macrophages. J Biol Chem. 2015;290(33):20348-59. doi: 10.1074/jbc.M115.662114, PMID 26152715, PMCID PMC4536441.
Wang Q, Zhang M, Torres G, Wu S, Ouyang C, Xie Z. Metformin suppresses diabetes-accelerated atherosclerosis via the inhibition of Drp1-mediated mitochondrial fission. Diabetes. 2017;66(1):193-205. doi: 10.2337/db16-0915, PMID 27737949, PMCID PMC5204316.
Karimi H, Asghari A, Jahandideh A, Akbari G, Mortazavi P. Effects of metformin on experimental varicocele in rats. Arch Razi Inst. 2021;76(2):371-84. doi: 10.22092/ari.2020.128136.1406, PMID 34223735, PMCID PMC8410191.
Nurul Qurrota A, Kusmardi, Nurhuda BE. Anti-inflammation of soursop leaves (Annona muricata L.) against hemorrhoids in mice induced by croton oil. Pharmacogn J. 2020;12(4).
Hutagalung MS. Phlebotrophic effect of graptophyllum pictum (L.) griff on experimental wistar hemorrhoids. J Biomed Transl Res. 2019;5(1). doi: 10.14710/jbtr.v5i1.3704.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25(4):402-8. doi: 10.1006/meth.2001.1262, PMID 11846609.
Wanchaitanawong W, Thinrungroj N, Chattipakorn SC, Chattipakorn N, Shinlapawittayatorn K. Repurposing metformin as a potential treatment for inflammatory bowel disease: evidence from cell to the clinic. Int Immunopharmacol. 2022;112:109230. doi: 10.1016/j.intimp.2022.109230, PMID 36099786.
Dey YN, Wanjari MM, Kumar D, Lomash V, Jadhav AD. Curative effect of Amorphophallus paeoniifolius tuber on experimental hemorrhoids in rats. J Ethnopharmacol. 2016;192:183-91. doi: 10.1016/j.jep.2016.07.042, PMID 27426509.
Fontem RF, Eyvazzadeh D. Internal hemorrhoid. Stat Pearls. Treasure Island, (FL); 2024.
Gallo G, Picciariello A, Tufano A, Camporese G. Clinical evidence and rationale of mesoglycan to treat chronic venous disease and hemorrhoidal disease: a narrative review. Update Surg. 2024;76(2):423-34. doi: 10.1007/s13304-024-01776-9, PMID 38356039, PMCID PMC10995001.
Kaidar Person O, Person B, Wexner SD. Hemorrhoidal disease: a comprehensive review. J Am Coll Surg. 2007;204(1):102-17. doi: 10.1016/j.jamcollsurg.2006.08.022, PMID 17189119.
Ahmadu AA, Zezi AU, Yaro AH. Anti-diarrheal activity of the leaf extracts of daniellia oliveri hutch and dalz (Fabaceae) and ficus sycomorus miq (Moraceae). Afr J Tradit Complement Altern Med. 2007;4(4):524-8. doi: 10.4314/ajtcam.v4i4.31246, PMID 20161921, PMCID PMC2816518.
Adikusuma W, Firdayani F, Irham LM, Darmawi D, Hamidy MY, Nopitasari BL. Integrated genomic network analysis revealed potential of a druggable target for hemorrhoid treatment. Saudi Pharm J. 2023;31(12):101831. doi: 10.1016/j.jsps.2023.101831, PMID 37965490, PMCID PMC10641558.
Kulkarni AS, Gubbi S, Barzilai N. Benefits of metformin in attenuating the hallmarks of aging. Cell Metab. 2020;32(1):15-30. doi: 10.1016/j.cmet.2020.04.001, PMID 32333835, PMCID PMC7347426.
Shi B, Hu X, He H, Fang W. Metformin suppresses breast cancer growth via inhibition of cyclooxygenase-2. Oncol Lett. 2021;22(2):615. doi: 10.3892/ol.2021.12876, PMID 34257723, PMCID PMC8243079.
Lin H, Ao H, Guo G, Liu M. The role and mechanism of metformin in inflammatory diseases. J Inflamm Res. 2023;16:5545-64. doi: 10.2147/JIR.S436147, PMID 38026260, PMCID PMC10680465.
Cameron AR, Morrison VL, Levin D, Mohan M, Forteath C, Beall C. Anti-inflammatory effects of metformin irrespective of diabetes status. Circ Res. 2016;119(5):652-65. doi: 10.1161/CIRCRESAHA.116.308445, PMID 27418629, PMCID PMC4990459.
Apostolova N, Iannantuoni F, Gruevska A, Muntane J, Rocha M, Victor VM. Mechanisms of action of metformin in type 2 diabetes: effects on mitochondria and leukocyte-endothelium interactions. Redox Biol. 2020;34:101517. doi: 10.1016/j.redox.2020.101517, PMID 32535544, PMCID PMC7296337.
Sigit Adi P, Parish B, Ignatius R. Ch. 3. Prolapsing hemorrhoids. In: Alberto V, Daniela Cornelia L, editors. Benign anorectal disorders. Rijeka: IntechOpen; 2022.
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Copyright (c) 2025 DARMAWI DARMAWI, MUHAMMAD YULIS HAMIDY, SORAYA SORAYA, NURUL AZIZAH, LALU MUHAMMAD IRHAM, BAIQ LENY NOPITASARI, INA F. RANGKUTI, A. A. MUHAMMAD NUR KASMAN, WIRAWAN ADIKUSUMA
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