Antinociceptive and anti-inflammatory effect of metformin in experimental models conducted in mice
DOI:
https://doi.org/10.24265/horizmed.2019.v19n3.08Keywords:
Metformin, Inflammation, Pain, Carrageenan, Central nervous systemAbstract
Objective: To analyze the anti-inflammatory and antinociceptive activity of metformin in an acute event of inflammation-edema and pain induction in rodents. Materials and methods: One hundred ninety-eight (198) female mice were used. The anti-inflammatory effect was evaluated in 64 mice using the carrageenan-induced paw edema test, and the antinociceptive effect was assessed in 64 and 70 mice using the hot plate test and the tail immersion test, respectively. In both cases, there were control, placebo and experimental groups. For the analysis, the Shapiro-Wilk test, one-way ANOVA test, Tukey test and Pearsonian coefficient of correlation were used. Results: In the carrageenan-induced paw edema test, the metformin 50 and 150 mg/kg groups showed an anti- inflammatory effect at the second and third hours. In the hot plate test, the metformin 100, 200 and 250 mg/kg groups showed an antinociceptive effect at the second and fourth hours. In the tail immersion test, the metformin 100, 150, 200 and 250 mg/kg groups showed an antinociceptive effect from minute 15 until the end of the experiment. In addition, the metformin 150 mg/kg group had a statistically equivalent effect to the morphine 10 mg/kg control group. Conclusions: The acute anti-inflammatory and antinociceptive activity of metformin at different doses is demonstrated in experimental models conducted in mice.
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Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR, et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov. 2010; 9(3): 203-14.
Munos B. Lessons from 60 years of pharmaceutical innovation. Nat Rev Drug Discov. 2009; 8(12): 959–68.
Keiser MJ, Setola V, Irwin JJ, Laggner C, Abbas A, Hufeisen SJ, et al. Predicting new molecular targets for known drugs. Nature. 2009; 462(7270): 175–81.
Wolff T, Miller T, Ko S. Aspirin for the primary prevention of cardiovascular events: an update of the evidence for the U.S. preventive services task force. Ann Intern Med. 2009; 150(6): 405-10.
Sirven JI. New uses for older drugs: the tales of aspirin, thalidomide, and gabapentin. Mayo Clin Proc. 2010; 85(6): 508–11.
Cuzick J, Otto F, Baron JA, Brown PH, Burn J, Greenwald P, et al. Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. Lancet Oncol. 2009; 10(5): 501–7.
Mancera-Romero J, Hormigo-Pozo A, Fernández-Arquero J, Baca-Osorio A, Aparicio-Cervantes MJ, Muñoz-González L. Use of glucose-lowering drugs in a primary care setting in Malaga during the years 2008-2012. Semergen. 2014; 40(1): 4–11.
Scarpello JH, Howlett HC. Metformin therapy and clinical uses. Diab Vasc Dis Res. 2008; 5(3): 157–67.
Lamanna C, Monami M, Marchionni N, Mannucci E. Effect of metformin on cardiovascular events and mortality: a meta- analysis of randomized clinical trials. Diabetes Obes Metab. 2011; 13(3): 221–8.
Hoeger K, Davidson K, Kochman L, Cherry T, Kopin L, Guzick DS. The Impact of metformin, oral contraceptives, and lifestyle modification on polycystic ovary syndrome in obese adolescent women in two randomized, placebo-controlled clinical trials. J Clin Endocrinol Metab. 2008; 93(11): 4299–306.
Alexánderson-Rosas E, Martínez AJ, Ochoa-López JM, Calleja- Torres R, Sierra-Fernández C, Iñarra-Talboy F, et al. Efecto del tratamiento combinado con metformina/glimepirida sobre la función endotelial en pacientes con diabetes mellitus tipo 2 evaluados mediante PET. Arch Cardiol México. 2009; 79(4): 149–256.
Caballero AE, Delgado A, Aguilar-Salinas CA, Herrera AN, Castillo JL, Cabrera T, et al. The differential effects of metformin on markers of endothelial activation and inflammation in subjects with impaired glucose tolerance: a placebo-controlled, randomized clinical trial. J Clin Endocrinol Metab. 2004; 89(8): 3943–8.
Guppy A, Jamal-Hanjani M, Pickering L. Anticancer effects of metformin and its potential use as a therapeutic agent for breast cancer. Future Oncol. 2011; 7(6): 727–36.
Wiley J. Current Protocols in Pharmacology [Internet]. Disponible en: http://onlinelibrary.wiley.com/book/10.1002/0471141755/homepage/Archive.html
Montes J, Pacheco K, Figueroa J, Inga V, Ortega Y, Flores C, et al. Análisis de la actividad antiinflamatoria y analgésica aguda de la metformina mediante el Test de Formalina. Horiz Med. 2012; 12(2).
Galduf J, Gallego C, Escrivá J, Montserrat V. Ensayos clínicos: Elaboración de una lista-guía para la valoración de protocolos. Farm Hosp. 1995; 19(1): 17–23.
Mujica PY. Procesamiento de señales in vivo, edición audivisual y creación de un prototipo de software educativo para simulación de experimentos en farmacología [Tesis]. Universidad San Martín de Porres: Lima. Facultad de Medicina Humana; 2009.
Van Wilgenburg H. Microlabs for Pharmacologists [Internet]. Disponible en: https://norecopa.no/norina/microlabs-for-pharmacologists
National Research Council (US) Institute for Laboratory Animal Research. International Guiding Principles for Biomedical Research Involving Animals (1985: Washington (DC): National Academies Press US; 2004.
Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain. 1983; 16(2): 109–10.
Chi SC, Jun HW. Anti-inflammatory activity of ketoprofen gel on carrageenan-induced paw edema in rats. J Pharm Sci. 1990; 79(11): 974–7.
Matsumoto K, Obara S, Kuroda Y, Kizu J. Anti-inflammatory effects of linezolid on carrageenan-induced paw edema in rats. J Infect Chemother. 2015; 21(12): 889–91.
Li YY, Huang SS, Lee MM, Deng JS, Huang GJ. Anti-inflammatory activities of cardamonin from Alpinia katsumadai through heme oxygenase-1 induction and inhibition of NF-κB and MAPK signaling pathway in the carrageenan-induced paw edema. Int Immunopharmacol. 2015; 25(2): 332–9.
Necas J, Bartosikova L. Carrageenan: a review. Vet Med (Praha). 2013; 58(4): 187-205.
Gan TJ. Diclofenac: an update on its mechanism of action and safety profile. Curr Med Res Opin. 2010; 26(7): 1715–31.
Hattori Y, Suzuki K, Hattori S, Kasai K. Metformin inhibits cytokine-induced nuclear factor κb activation via AMP- activated protein kinase activation in vascular endothelial cells. Hypertension. 2006; 47(6): 1183–8.
Koh SJ, Kim JM, Kim IK, Ko SH, Kim JS. Anti-inflammatory mechanism of metformin and its effects in intestinal inflammation and colitis-associated colon cancer. J Gastroenterol Hepatol. 2014; 29(3): 502–10.
Arai M, Uchiba M, Komura H, Mizuochi Y, Harada N, Okajima K. Metformin, an antidiabetic agent, suppresses the production of tumor necrosis factor and tissue factor by inhibiting early growth response factor-1 expression in human monocytes in vitro. J Pharmacol Exp Ther. 2010; 334(1): 206–13.
Isoda K, Young JL, Zirlik A, MacFarlane LA, Tsuboi N, Gerdes N, et al. Metformin inhibits proinflammatory responses and nuclear factor-κb in human vascular wall cells. Arterioscler Thromb Vasc Biol. 2006; 26(3): 611–7.
Gómez-García A, Martínez Torres G, Ortega-Pierres LE, Rodríguez-Ayala E, Álvarez-Aguilar C. Rosuvastatina y metformina reducen la inflamación y el estrés oxidativo en pacientes con hipertensión y dislipemia. Rev Esp Cardiol. 2007; 60(12): 1242–9.
Deans KA, Sattar N. "Anti-inflammatory" drugs and their effects on type 2 diabetes. Diabetes Technol Ther. 2006; 8(1): 18–27.
Brunton LL, Lazo JS, Parket KL. Goodman & Gilman: Las bases farmacológicas de la terapéutica. 12da ed. McGraw Hill Mexico; 2012.
Hall JE. Guyton y Hall. Tratado de fisiología médica. 12da ed. Elsevier Health Sciences; 2011.
Le Bars D, Gozariu M, Cadden SW. Animal models of nociception. Pharmacol Rev. 2001; 53(4): 597–652.
Verma S, Mundkinajeddu D, Agarwal A, Chatterjee SS, Kumar V. Effects of turmeric curcuminoids and metformin against central sensitivity to pain in mice. J Tradit Complement Med. 2016; 7(2): 145-51.
Ortiz MI. Blockade of the antinociception induced by diclofenac, but not of indomethacin, by sulfonylureas and biguanides. Pharmacol Biochem Behav. 2011; 99(1): 1–6.
Ortiz MI. Metformin and phenformin block the peripheral antinociception induced by diclofenac and indomethacin on the formalin test. Life Sci. 2012; 90(1–2): 8–12.
Ananthakrishnan AN, Cagan A, Cai T, Gainer VS, Shaw SY, Churchill S, et al. Diabetes and the risk of infections with immunomodulator therapy in inflammatory bowel diseases. Aliment Pharmacol Ther. 2015; 41(11): 1141–8.
Dermanovic DV, Hrabac P, Skegro D, Smiljanic R, Dobrota S, Prkacin I, et al. The impact of neuropathic pain and other comorbidities on the quality of life in patients with diabetes. Health Qual Life Outcomes. 2014; 12(1): 171.
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