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Drug Res (Stuttg) 2024; 74(06): 280-289
DOI: 10.1055/a-2317-7578
Original Article

Concomitant Effects of Metformin and Vitamin C on Indomethacin-Induced Gastric Ulcer in Rats: Biochemical and Histopathological Approach

Mohammad Rafi Khezri
1   Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
,
Reza Varzandeh
1   Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
,
Morteza Ghasemnejad-Berenji 
2   Experimental & Applied Pharmaceutical Sciences Research Center, Urmia University of Medical Sciences, Urmia, Iran
3   Department of Pharmacology and Toxicology, School of Pharmacy, Urmia University of Medical Sciences,Urmia, Iran
› Author Affiliations Funding Information Urmia University of Medical Sciences — http://dx.doi.org/10.13039/501100016286; 10470 This work was supported by the Urmia University of Medical Sciences under Grant [number 10470.
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Abstract

Introduction Gastric ulcer is one of the most common and serious conditions in the gastrointestinal tract. One of the main causes of gastric ulcers is using of non-steroidal anti-inflammatory drugs (NSAIDs) which have limited their use in clinical practice. Several studies have revealed that metformin and Vitamin C (Vit C) exhibit protective effects against gastric mucosal damage in different animal models. However, no studies indicate their combination's effect on gastric ulcer models. Therefore, this study aims to investigate the protective effects of metformin and Vit C combination on indomethacin-induced gastric ulcers.

Material and methods In total, thirty rats were divided into six groups, including the control group, rats received indomethacin (50 mg/kg, i.p.), rats received indomethacin and pretreated with ranitidine (100 mg/kg), metformin (100 mg/kg, i.p.), Vit C (100 mg/kg), or metformin combined with Vit C. Four hours after indomethacin administration, rats were euthanized, and gastric tissues were removed for macroscopic, histopathologic, and biochemical examinations.

Results All therapeutics used in this study were found to alleviate gastric mucosal injury caused by indomethacin, as observed in histopathologic and macroscopic evaluations. Both Vit C and metformin were observed to significantly decrease lipid peroxidation and enhance the activity of anti-oxidative enzymes, SOD, GPx, and catalase. However, a more significant effectiveness was observed in catalase and GPx activities when Vit C was co-administered with metformin.

Conclusions In conclusion, the present study revealed that metformin and Vit C combination therapy could potentially treat gastric ulcers associated with indomethacin.

Keywords

indomethacin - metformin - gastric ulcer - vitamin C - oxidative stress


Publication History

Received: 26 December 2023

Accepted: 16 April 2024

Article published online:
05 July 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
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  • References

  • 1 El-Ashmawy NE, Khedr EG, El-Bahrawy HA. et al Nebivolol prevents indomethacin-induced gastric ulcer in rats. J Immunotoxicol 2016; 13: 580-589
    CrossrefPubMedGoogle Scholar
  • 2 Watanabe T, Higuchi K, Tanigawa T. et al Mechanisms of peptic ulcer recurrence: role of inflammation. InflammoPharmacology 2002; 10: 291-302
    CrossrefPubMedGoogle Scholar
  • 3 Coruzzi G, Menozzi A, Dobrilla G. Novel non-steroidal anti-inflammatory drugs: what we have learned from animal studies. Curr Drug Targets Inflamm Allergy 2004; 3: 43-61
    CrossrefPubMedGoogle Scholar
  • 4 Tai FWD, McAlindon ME. Non-steroidal anti-inflammatory drugs and the gastrointestinal tract. Clinical Medicine 2021; 21: 131
    CrossrefPubMedGoogle Scholar
  • 5 Bhattacharya S, Banerjee D, Bauri AK. et al Healing property of the Piper betel phenol, allylpyrocatechol against indomethacin-induced stomach ulceration and mechanism of action. World J Gastroenterol 2007; 13: 3705-3713
    CrossrefPubMedGoogle Scholar
  • 6 Simmons DL, Botting RM, Hla T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev 2004; 56: 387-437
    CrossrefPubMedGoogle Scholar
  • 7 Tamaddonfard E, Erfanparast A, Farshid AA. et al Safranal, a constituent of saffron, exerts gastro-protective effects against indomethacin-induced gastric ulcer. Life sciences 2019; 224: 88-94
    CrossrefPubMedGoogle Scholar
  • 8 Danisman B, Cicek B, Yildirim S. et al Carnosic Acid Ameliorates Indomethacin-Induced Gastric Ulceration in Rats by Alleviating Oxidative Stress and Inflammation. Biomedicines 2023; 11: 829
    CrossrefPubMedGoogle Scholar
  • 9 Ma N, Sun Y, Yi J. et al Chinese sumac (Rhus chinensis Mill.) fruits alleviate indomethacin-induced gastric ulcer in mice by improving oxidative stress, inflammation and apoptosis. J Ethnopharmacol 2022; 284: 114752
    CrossrefPubMedGoogle Scholar
  • 10 AbdelAziz EY, Tadros MG, Menze ET. The effect of metformin on indomethacin-induced gastric ulcer: Involvement of nitric oxide/Rho kinase pathway. Eur J Pharmacol 2021; 892: 173812
    CrossrefPubMedGoogle Scholar
  • 11 Morsy MA, Ashour OM, Fouad AA. et al Gastroprotective effects of the insulin sensitizers rosiglitazone and metformin against indomethacin-induced gastric ulcers in Type 2 diabetic rats. Clin Exp Pharmacol Physiol 2010; 37: 173-177
    CrossrefPubMedGoogle Scholar
  • 12 DeFronzo R, Fleming GA, Chen K. et al Metformin-associated lactic acidosis: Current perspectives on causes and risk. Metabolism 2016; 65: 20-29
    CrossrefPubMedGoogle Scholar
  • 13 Heistad DD. Oxidative stress and vascular disease: 2005 Duff lecture. Arterioscler Thromb Vasc Biol 2006; 26: 689-695
    CrossrefPubMedGoogle Scholar
  • 14 Budin SB, Han KJ, Jayusman PA. et al Antioxidant Activity of Tocotrienol Rich Fraction Prevents Fenitrothion-induced Renal Damage in Rats. J Toxicol Pathol 2013; 26: 111-118
    CrossrefPubMedGoogle Scholar
  • 15 Shireen KF, Pace RD, Mahboob M. et al Effects of dietary vitamin E, C and soybean oil supplementation on antioxidant enzyme activities in liver and muscles of rats. Food Chem Toxicol 2008; 46: 3290-3294
    CrossrefPubMedGoogle Scholar
  • 16 Sauberlich HE. Pharmacology of vitamin C. Annu Rev Nutr 1994; 14: 371-391
    CrossrefPubMedGoogle Scholar
  • 17 Naidu KA. Vitamin C in human health and disease is still a mystery? An overview. Nutr J 2003; 2: 7
    CrossrefPubMedGoogle Scholar
  • 18 Carr A, Frei B. Does vitamin C act as a pro-oxidant under physiological conditions?. Faseb j 1999; 13: 1007-1024
    CrossrefPubMedGoogle Scholar
  • 19 Djeffal A, Messarah M, Boumendjel A. et al Protective effects of vitamin C and selenium supplementation on methomyl-induced tissue oxidative stress in adult rats. Toxicol Ind Health 2015; 31: 31-43
    CrossrefPubMedGoogle Scholar
  • 20 Heo HJ, Lee CY. Protective effects of quercetin and vitamin C against oxidative stress-induced neurodegeneration. J Agric Food Chem 2004; 52: 7514-7517
    CrossrefPubMedGoogle Scholar
  • 21 Doğan MF, Kaya K, Demirel HH. et al The effect of vitamin C supplementation on favipiravir-induced oxidative stress and proinflammatory damage in livers and kidneys of rats. Immunopharmacol Immunotoxicol 2023; 45: 521-526
    CrossrefPubMedGoogle Scholar
  • 22 Nishikawa Y, Minenaka Y, Ichimura M. et al Effects of astaxanthin and vitamin C on the prevention of gastric ulcerations in stressed rats. J Nutr Sci Vitaminol (Tokyo) 2005; 51: 135-141
    CrossrefPubMedGoogle Scholar
  • 23 Turkyilmaz IB, Coskun ZM, Bolkent S. et al The effects of antioxidant combination on indomethacin-induced gastric mucosal injury in rats. Cellular and Molecular Biology 2019; 65: 76-83
    CrossrefPubMedGoogle Scholar
  • 24 İpek BE, Yüksel M, Cumbul A. et al The Effect of Metformin on Ethanol- and IndomethacinInduced Gastric Ulcers in Rats. Turk J Gastroenterol 2022; 33: 767-776
    CrossrefPubMedGoogle Scholar
  • 25 Tveden-Nyborg P, Bergmann TK, Jessen N. et al BCPT policy for experimental and clinical studies. Basic Clin Pharmacol Toxicol 2021; 128: 4-8
    CrossrefPubMedGoogle Scholar
  • 26 Hegab II, Abd-Ellatif RN, Sadek MT. The gastroprotective effect of N-acetylcysteine and genistein in indomethacin-induced gastric injury in rats. Can J Physiol Pharmacol 2018; 96: 1161-1170
    CrossrefPubMedGoogle Scholar
  • 27 Koc M, Imik H, Odabasoglu F. Gastroprotective and anti-oxidative properties of ascorbic acid on indomethacin-induced gastric injuries in rats. Biological trace element research 2008; 126: 222-236
    CrossrefPubMedGoogle Scholar
  • 28 Jafari A, Andishfar N, Esmaeilzadeh Z. et al Gastroprotective effect of topiramate on indomethacin-induced peptic ulcer in rats: Biochemical and histological analyses. Basic & Clinical Pharmacology & Toxicology 2022; 130: 559-568
    CrossrefPubMedGoogle Scholar
  • 29 Li W, Wang X, Zhang H. et al Anti-ulcerogenic effect of cavidine against ethanol-induced acute gastric ulcer in mice and possible underlying mechanism. International immunopharmacology 2016; 38: 450-459
    CrossrefPubMedGoogle Scholar
  • 30 Silva RO, Santana APM, Carvalho NS. et al A sulfated-polysaccharide fraction from seaweed Gracilaria birdiae prevents naproxen-induced gastrointestinal damage in rats. Marine drugs 2012; 10: 2618-2633
    CrossrefPubMedGoogle Scholar
  • 31 Di S, An X, Pang B. et al Yiqi Tongluo Fang could preventive and delayed development and formation of diabetic retinopathy through antioxidant and anti-inflammatory effects. Biomedicine & Pharmacotherapy 2022; 148: 112254
    CrossrefPubMedGoogle Scholar
  • 32 Jafari A, Ghasemnejad-Berenji H, Nemati M. et al Topiramate: A novel protective agent against ischemia reperfusion-induced oxidative injury after testicular torsion/detorsion. The American journal of emergency medicine 2021; 44: 257-261
    CrossrefPubMedGoogle Scholar
  • 33 Ghasemnejad-Berenji M, Ghazi-Khansari M, Pashapour S. et al Synergistic effect of rapamycin and metformin against germ cell apoptosis and oxidative stress after testicular torsion/detorsion-induced ischemia/reperfusion in rats. Biomedicine & Pharmacotherapy 2018; 105: 645-651
    CrossrefPubMedGoogle Scholar
  • 34 Huang R, Zhong T, Wu H. Quercetin protects against lipopolysaccharide-induced acute lung injury in rats through suppression of inflammation and oxidative stress. Archives of medical science: AMS. 2015. 11. 427
    Google Scholar
  • 35 Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical biochemistry 1979; 95: 351-358
    CrossrefPubMedGoogle Scholar
  • 36 Sen S, Chakraborty R, Sridhar C. et al Free radicals, antioxidants, diseases and phytomedicines: current status and future prospect. International journal of pharmaceutical sciences review and research 2010; 3: 91-100
    PubMedGoogle Scholar
  • 37 Kwiecien S, Brzozowski T, Konturek S. Effects of reactive oxygen species action on gastric mucosa in various models of mucosal injury. Journal of physiology and pharmacology 2002; 53: 39-50
    PubMedGoogle Scholar
  • 38 Kataoka H, Horie Y, Koyama R. et al Interaction between NSAIDs and steroid in rat stomach: safety of nimesulide as a preferential COX-2 inhibitor in the stomach. Dig Dis Sci 2000; 45: 1366-1375
    CrossrefPubMedGoogle Scholar
  • 39 Bilici D, Süleyman H, Banoğlu ZN. et al Melatonin prevents ethanol-induced gastric mucosal damage possibly due to its antioxidant effect. Digestive Diseases and Sciences 2002; 47: 856-861
    CrossrefPubMedGoogle Scholar
  • 40 Mahmoud MF, Abdo W, Nabil M. et al Apple (Malus domestica Borkh) leaves attenuate indomethacin-induced gastric ulcer in rats. Biomedicine & Pharmacotherapy 2023; 160: 114331
    CrossrefPubMedGoogle Scholar
  • 41 Mehta A, Verma RS, Srivastava N. Chlorpyrifos induced alterations in the levels of hydrogen peroxide, nitrate and nitrite in rat brain and liver. Pesticide biochemistry and physiology 2009; 94: 55-59
    CrossrefPubMedGoogle Scholar
  • 42 Uzunhisarcikli M, Kalender Y. Protective effects of vitamins C and E against hepatotoxicity induced by methyl parathion in rats. Ecotoxicology and environmental safety 2011; 74: 2112-2118
    CrossrefPubMedGoogle Scholar
  • 43 Celik I, Suzek H. Effects of subacute exposure of dichlorvos at sublethal dosages on erythrocyte and tissue antioxidant defense systems and lipid peroxidation in rats. Ecotoxicology and environmental safety 2009; 72: 905-908
    CrossrefPubMedGoogle Scholar
  • 44 Pérez Y, Oyárzabal A, Mas R. et al Protective effect of D-002, a mixture of beeswax alcohols, against indomethacin-induced gastric ulcers and mechanism of action. Journal of natural medicines 2013; 67: 182-189
    CrossrefPubMedGoogle Scholar
  • 45 Sabiu S, Garuba T, Sunmonu T. et al Indomethacin-induced gastric ulceration in rats: Protective roles of Spondias mombin and Ficus exasperata. Toxicology reports 2015; 2: 261-267
    CrossrefPubMedGoogle Scholar
  • 46 Matés JM, Pérez-Gómez C, Núñez de Castro I. Antioxidant enzymes and human diseases. Clinical biochemistry 1999; 32: 595-603
    CrossrefPubMedGoogle Scholar
  • 47 Islam MN, Rauf A, Fahad FI. et al Superoxide dismutase: an updated review on its health benefits and industrial applications. Critical Reviews in Food Science and Nutrition 2022; 62: 7282-7300
    CrossrefPubMedGoogle Scholar
  • 48 Sepand MR, Soodi M, Hajimehdipoor H. et al Comparison of neuroprotective effects of Melissa officinalis total extract and its acidic and non-acidic fractions against a β-induced toxicity. Iranian journal of pharmaceutical research: IJPR 2013; 12: 415
    PubMedGoogle Scholar
  • 49 Duvoix A, Blasius R, Delhalle S. et al Chemopreventive and therapeutic effects of curcumin. Cancer letters 2005; 223: 181-190
    CrossrefPubMedGoogle Scholar
  • 50 Ashakumary L, Vijayammal P. Additive effect of alcohol and nicotine on lipid peroxidation and antioxidant defence mechanism in rats. Journal of Applied Toxicology 1996; 16: 305-308
    CrossrefPubMedGoogle Scholar
  • 51 Bebe FN, Panemangalore M. Exposure to low doses of endosulfan and chlorpyrifos modifies endogenous antioxidants in tissues of rats. Journal of Environmental Science and Health, Part B 2003; 38: 349-363
    CrossrefPubMedGoogle Scholar
  • 52 Abbas AM, Sakr HF. Effect of selenium and grape seed extract on indomethacin-induced gastric ulcers in rats. Journal of physiology and biochemistry 2013; 69: 527-537
    CrossrefPubMedGoogle Scholar
  • 53 Odabasoglu F, Cakir A, Suleyman H. et al Gastroprotective and antioxidant effects of usnic acid on indomethacin-induced gastric ulcer in rats. Journal of ethnopharmacology 2006; 103: 59-65
    CrossrefPubMedGoogle Scholar
  • 54 Bhatt K, Flora S. Oral co-administration of α-lipoic acid, quercetin and captopril prevents gallium arsenide toxicity in rats. Environmental toxicology and pharmacology 2009; 28: 140-146
    CrossrefPubMedGoogle Scholar
  • 55 Senthilkumar S, Ebenezar KK, Sathish V. et al Modulation of the tissue defense system by squalene in cyclophosphamide induced toxicity in rats. Archives of Medical Science 2006; 2: 94-100
    PubMedGoogle Scholar
  • 56 Subudhi U, Chainy GB. Expression of hepatic antioxidant genes in l-thyroxine-induced hyperthyroid rats: regulation by vitamin E and curcumin. Chemico-biological interactions 2010; 183: 304-316
    CrossrefPubMedGoogle Scholar
  • 57 İpek BE, Yüksel M, Cumbul A. et al. The Effect of Metformin on Ethanol-and Indomethacin-Induced Gastric Ulcers in Rats. Turk J Gastroenterol. 2022 33.
    PubMedGoogle Scholar
  • 58 Nolêto IR, Iles B, Alencar MS. et al Alendronate-induced gastric damage in normoglycemic and hyperglycemic rats is reversed by metformin. European Journal of Pharmacology 2019; 856: 172410
    CrossrefPubMedGoogle Scholar
  • 59 Mohammed I, Hollenberg MD, Ding H. et al A critical review of the evidence that metformin is a putative anti-aging drug that enhances healthspan and extends lifespan. Frontiers in endocrinology 2021; 12: 933
    CrossrefPubMedGoogle Scholar
  • 60 Khezri MR, Varzandeh R, Ghasemnejad-Berenji M. Protective effects of metformin against aluminum phosphide-induced acute hepato-renal damage in rats: An experimental approach. Pestic Biochem Physiol 2022; 188: 105258
    CrossrefPubMedGoogle Scholar
  • 61 Pandey A, Verma S, Kumar VL. Metformin maintains mucosal integrity in experimental model of colitis by inhibiting oxidative stress and pro-inflammatory signaling. Biomedicine & Pharmacotherapy 2017; 94: 1121-1128
    CrossrefPubMedGoogle Scholar
  • 62 Lutsenko EA, Cárcamo JM, Golde DW. Vitamin C prevents DNA mutation induced by oxidative stress. Journal of Biological Chemistry 2002; 277: 16895-16899
    CrossrefPubMedGoogle Scholar
  • 63 Kim D-O, Lee CY. Comprehensive study on vitamin C equivalent antioxidant capacity (VCEAC) of various polyphenolics in scavenging a free radical and its structural relationship. Critical reviews in food science and nutrition 2004; 44: 253-273
    CrossrefPubMedGoogle Scholar
  • 64 El-Beheiry KM, El-Sayad ME-S, El-Masry TA. et al Combination of metformin and hesperidin mitigates cyclophosphamide-induced hepatotoxicity. Emerging role of PPAR-γ/Nrf-2/NF-κB signaling pathway. International Immunopharmacology 2023; 117: 109891
    CrossrefPubMedGoogle Scholar
  • 65 Arab HH, Al-Shorbagy MY, Saad MA. Activation of autophagy and suppression of apoptosis by dapagliflozin attenuates experimental inflammatory bowel disease in rats: Targeting AMPK/mTOR, HMGB1/RAGE and Nrf2/HO-1 pathways. Chemico-biological interactions 2021; 335: 109368
    CrossrefPubMedGoogle Scholar
  • 66 Nishida N, Yano H, Nishida T. et al Angiogenesis in cancer. Vascular health and risk management 2006; 2: 213
    CrossrefPubMedGoogle Scholar
  • 67 Cuevas VM, Calzado YR, Guerra YP. et al. Effects of grape seed extract, vitamin C, and vitamin E on ethanol-and aspirin-induced ulcers. Adv Pharmacol Sci. 2011 740687..
    PubMedGoogle Scholar
  • 68 Gillani SW, Sulaiman SAS, Abdul MIM. et al Combined effect of metformin with ascorbic acid versus acetyl salicylic acid on diabetes-related cardiovascular complication; a 12-month single blind multicenter randomized control trial. Cardiovascular Diabetology 2017; 16: 103
    CrossrefPubMedGoogle Scholar
  • 69 Shivavedi N, Kumar M, Tej GNVC. et al Metformin and ascorbic acid combination therapy ameliorates type 2 diabetes mellitus and comorbid depression in rats. Brain Research 2017; 1674: 1-9
    CrossrefPubMedGoogle Scholar