Experimental study of the effect of metformin on corneal burn ulcer healing in rabbit

Document Type : Full Research Paper

Authors

1 Department of Veterinary Surgery, Science and Research Branch, Islamic Azad University, Tehran, Iran

2 Veterinary Graduate Student, Science and Research Branch, Islamic Azad University, Tehran, Iran

3 Department of Veterinary Pathobiology, Science and Research Branch, Islamic Azad University, Tehran, Iran;

Abstract

This study was conducted to examine the effect of metformin on corneal burn wound healing in rabbit. In this study, 20 adult healthy male New Zealand rabbits were used with an average weight of 2.5-3 kg. After general anesthesia, corneal ulcer in the left eye of the all animals was induced. After returning from anesthesia, the rabbits were randomly divided into 4 groups of 5 numbers. Then the first group was gavaged with 50 mg/kg of metformin, the second group with 100 mg/kg and the third group with 200 mg/kg while the fourth group was gavaged with water for 21 days. In the day 21 after making a corneal ulcer, tissue samples were taken and evaluated histopathologically. According to the pathological results, the vascularization, inflammation and edema of matrix of cornea significantly diminished while the epithelium of cornea increased in metformin-treated rabbits compared to control group (P<0.05). Also, administration of metformin significantly improved the natural structure of cornea collagen fibers (P<0.05). Based on the results, it seems metformin has favorable effect on the healing process in rabbit’s corneal ulcer.

Keywords


. Akita, T., Mazaki, Y., Kobayashi, K., Koga, N. and Iwamura, H. 1995. Crystal Structures and Magnetic Properties of Nitronyl Nitroxide and Imino Nitroxide Radicals Attached to Thieno [3, 2-b]-and Thieno [2, 3-b] thiophene Rings. The Journal of Organic Chemistry, 60(7): 2092-2098.
2. Albertini, R., Passi, A., Abuja, P. and De Luca, G. 2000. The effect of glycosaminoglycans and proteoglycans on lipid peroxidation. International journal of molecular medicine, 6(2): 129-165.
3. Ambrish, C., Torgal, S.S., Patil, P.A., Malur, P.R. and Hiremath, S.V. 2009. Influence of oral anti-diabetic agents on wound healing in euglycemic male wistar rats. Pharmacologyonline, 1: 476-483
4. Bonnefont-Rousselot, D., Raji, B., Walrand, S., Gardes-Albert, M., Jore, D., Legrand, A., Peynet, J. and Vasson, M. 2003. An intracellular modulation of free radical production could contribute to the beneficial effects of metformin towards oxidative stress.
Metabolism, 52(5): 586-589.
5. Cejkova, J., Vejrazka, M., Plateník, J. and Stípek, S. 2004. Age-related changes in superoxide dismutase, glutathione peroxidase, catalase and xanthine oxidoreductase/xanthine oxidase activities in the rabbit cornea. Experimental gerontology, 39(10): 1537-1543.
6. Cheng, J., Truong, L. D., Wu, X., Kuhl, D., Lang, F. and Du, J. 2010. Serum-and glucocorticoid-regulated kinase 1 is upregulated following unilateral ureteral obstruction causing epithelial–mesenchymal transition. Kidney international, 78(7): 668-678.
7. Cicero, A., Tartagni, E. and Ertek, S. 2012a. Metformin and its clinical use: new insights for an old drug in clinical practice. Archives of medical science, 8(5): 907–917.
8. Cicero, A. F., Tartagni, E. and Ertek, S. 2012b. Metformin and its clinical use: new insights for an old drug in clinical practice. Archives of medical science: AMS, 8(5): 907.
9. Detaille, D., Guigas, B., Chauvin, C., Batandier, C., Fontaine, E., Wiernsperger, N. and Leverve, X. 2005. Metformin prevents high-glucose–induced endothelial cell death through a mitochondrial permeability transition-dependent process. Diabetes, 54(7): 2179-2187.
10. Esteghamati, A., Eskandari, D., Mirmiranpour, H., Noshad, S., Mousavizadeh, M., Hedayati, M. and Nakhjavani, M. 2013. Effects of metformin on markers of oxidative stress and antioxidant reserve in patients with newly diagnosed type 2 diabetes: a randomized clinical trial. Clinical Nutrition, 32(2): 179-185.
11. Etensel, B., Özkısacık, S., Özkara, E., Karul, A., Öztan, O. and Gürsoy, H. 2007. Dexpanthenol attenuates lipid peroxidation and testicular damage at experimental ischemia and reperfusion injury. Pediatric surgery international, 23(2): 177-181.
12. Gargiulo, P., Caccese, D., Pignatelli, P., Brufani, C., De Vito, F., Marino, R., Lauro, R., Violi, F., Di Mario, U. and Sanguigni, V. 2002. Metformin decreases platelet superoxide anion production in diabetic patients. Diabetes/metabolism research and reviews, 18(2): 156-159.
13. Hou, X., Song, J., Li, X.-N., Zhang, L., Wang, X., Chen, L. and Shen, Y. H. 2010. Metformin reduces intracellular reactive oxygen species levels by upregulating expression of the antioxidant thioredoxin via the AMPK-FOXO3 pathway. Biochemical and biophysical research communications, 396(2): 199-205.
14. Huang, N.-L., Chiang, S.-H., Hsueh, C.-H., Liang, Y.-J., Chen, Y.-J. and Lai, L.-P. 2009. Metformin inhibits TNF-α-induced IκB kinase phosphorylation, IκB-α degradation and IL-6 production in endothelial cells through PI3K-dependent AMPK phosphorylation. International journal of cardiology, 134(2): 169-175.
15. Inouye, K.A., Bisch, F.C., Elsalanty, M.E., Zakhary, I., Khashaba, R.M. and Borke, J.L. 2014. Effect of metformin on periimplant wound healing in a rat model of type 2 diabetes. Implant Dentistry, 223(3):319-27.
16. Isoda, K., Young, J. L., Zirlik, A., MacFarlane, L. A., Tsuboi, N., Gerdes, N., Schönbeck, U. and Libby, P. 2006. Metformin inhibits proinflammatory responses and nuclear factor-κB in human vascular wall cells. Arteriosclerosis, thrombosis, and vascular biology, 26(3): 611-617.
17. Jian, M.-Y., Alexeyev, M. F., Wolkowicz, P. E., Zmijewski, J. W. and Creighton, J. R. 2013. Metformin-stimulated AMPK-α1 promotes microvascular repair in acute lung injury. American Journal of Physiology-Lung Cellular and Molecular Physiology, 305(11): L844-L855.
18. Kasetsuwan, N., Wu, F. M., Hsieh, F., Sanchez, D. and McDonnell, P. J. 1999. Effect of topical ascorbic acid on free radical tissue damage and inflammatory cell influx in the cornea after excimer laser corneal surgery. Archives of ophthalmology, 117(5): 649-652.
19. Khaksar, E., Aldavood, S., Abedi, G., Sedaghat, R., Nekoui, O. and Zamani-ahmadmahmudi, M. 2013. The effect of sub-conjunctival platelet-rich plasma in combination with topical acetylcysteine on corneal alkali burn ulcer in rabbits. Comparative Clinical Pathology, 22(1):107-112.
20. Li, Y., Feng, G., Yi, Y. and Lin, J. 1999. The experimental investigation of epithelial healing in rabbit central corneal alkali wounds. Yan ke xue bao Eye science/" Yan ke xue bao" bian ji bu, 15(2): 74-77.
21. McKeag, D., Maini, R. and Taylor, H. 2002. The ocular surface toxicity of paraquat. British journal of ophthalmology, 86(3): 350-351.
22. Meller, D., Pires, R. T., Mack, R. J., Figueiredo, F., Heiligenhaus, A., Park, W. C., Prabhasawat, P., John, T., McLeod, S. D. and Steuhl, K. P. 2000. Amniotic membrane transplantation for acute chemical or thermal burns. Ophthalmology, 107(5): 980-989.
23. Petrali, J., Dick, E., Brozetti, J., Hamilton, T. and Finger, A. 2000. Acute ocular effects of mustard gas: ultrastructural pathology and immunohistopathology of exposed rabbit cornea†. Journal of Applied Toxicology, 20(S1): S173-S175.
24. Phillips, K., Arffa, R., Cintron, C., Rose, J., Miller, D., Kublin, C. L. and Kenyon, K. R. 1983. Effects of prednisolone and medroxyprogesterone on corneal wound healing, ulceration, and neovascularization. Archives of ophthalmology, 101(4): 640-643.
25. Podskochy, A., Gan, L. and Fagerholm, P. 2000. Apoptosis in UV-exposed rabbit corneas. Cornea, 19(1): 99-103.
26. Sarchahi, A. A., Maimandi, A., Khodakaram Tafti, A. and Amani, M. 2008. Effects of acetylcysteine and dexamethasone on experimental corneal wounds in rabbits. Ophthalmic research, 40(1): 41-48.
27. Shimazaki, J., Yang, H.-Y. and Tsubota, K. 1997. Amniotic membrane transplantation for ocular surface reconstruction in patients with chemical and thermal burns. Ophthalmology, 104(12): 2068-2076.
28. Shoham, A., Hadziahmetovic, M., Dunaief, J. L., Mydlarski, M. B. and Schipper, H. M. 2008. Oxidative stress in diseases of the human cornea. Free Radical Biology and Medicine, 45(8): 1047-1055.
29. Strubbe, D. T., Brooks, D. E., Schultz, G. S., Willis‐Goulet, H., Gelatt, K. N., Andrew, S. E., Kallberg, M. E., Mackay, E. O. and Collante, W. R. 2000. Evaluation of tear film proteinases in horses with ulcerative keratitis. Veterinary Ophthalmology, 3(2‐3): 111-119.
30. Taleb, S., Moghaddas, P., Balaei, M. R., Taleb, S., Rahimpour, S., Abbasi, A., Ejtemaei-Mehr, S. and Dehpour, A. R. 2014. Metformin improves skin flap survival through nitric oxide system. Journal of surgical research, 192(2): 686-691.
31. Tankova, T. 2002. Current indications for metformin therapy. Romanian journal of internal medicine Revue roumaine de medecine interne, 41(3): 215-225.
32. Wetzel, M. and Herndon, D. 2014. Celeste FinnertyMetformin down-regulates epithelial-mesenchymal transition (EMT) in fibroblasts from burned patients. Cancer & Metabolism, 2(Suppl 1): 84.