Protective effect of metformin on D-galactose-induced aging model in mice

Document Type : Original Article

Authors

1 Physiology-Pharmacology Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

2 Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

Abstract

Objective(s): Metformin (Met), an antidiabetic biguanide, reduces hyperglycemia via improving glucose utilization and reducing the gluconeogenesis. Met has been shown to exert neuroprotective, antioxidant and anti-inflammatory properties. The present study investigated the possible effect of Met on the D-galactose (D-gal)-induced aging in mice.
Materials and Methods: Met (1 and 10 mg/kg/p.o.), was administrated daily in D-gal-received (500 mg/kg/p.o.) mice model of aging for six weeks. Anxiety-like behavior, cognitive function, and physical power were evaluated by the elevated plus-maze, novel object recognition task (NORT), and forced swimming capacity test, respectively. The brains were analyzed for the level of superoxide dismutase (SOD) and brain-derived neurotrophic factor (BDNF).
Results: Met decreased the anxiety-like behavior in D-gal-treated mice. Also, Met treated mice showed significantly improved learning and memory ability in NORT compared to the D-gal-treated mice. Furthermore, Met increased the physical power as well as the activity of SOD and BDNF level in D-gal-treated mice.
Conclusion: Our results suggest that the use of Met can be an effective strategy for prevention and treatment of D-gal-induced aging in animal models. This effect seems to be mediated by attenuation of oxidative stress and enhancement of the neurotrophic factors.

Keywords

Main Subjects


1. Shin KR, Kim MY, Kim YH. Study on the lived experience of aging. Nurs Health Sci 2003; 5:245-252.
2. Kennedy BK, Pennypacker JK. Drugs that modulate aging: the promising yet difficult path ahead. Transl Res 2014; 163:456-465.
3. Forster MJ, Dubey A, Dawson KM, Stutts WA, Lal H, Sohal RS. Age-related losses of cognitive function and motor skills in mice are associated with oxidative protein damage in the brain. Proc Natl Acad Sci U S A 1996; 93:4765-4769.
4. Pak JW, Herbst A, Bua E, Gokey N, McKenzie D, Aiken JM. Mitochondrial DNA mutations as a fundamental mechanism in physiological declines associated with aging. Aging Cell 2003; 2:1-7.
5. van Velzen LS, Wijdeveld M, Black CN, van Tol MJ, van der Wee NJA, Veltman DJ, et al. Oxidative stress and brain morphology in individuals with depression, anxiety and healthy controls. Prog Neuropsychopharmacol Biol Psychiatry 2017; 76:140-144.
6. Joseph J, Cole G, Head E, Ingram D. Nutrition, brain aging, and neurodegeneration. J Neurosci 2009; 29:12795-12801.
7. Xu Y, Wu T, Jin Y, Fu Z. Effects of age and jet lag on D-galactose induced aging process. Biogerontology 2009; 10:153-161.
8. Wei H, Li L, Song Q, Ai H, Chu J, Li W. Behavioural study of the D-galactose induced aging model in C57BL/6J mice. Behav Brain Res 2005; 157:245-251.
9. Kothari V, Galdo JA, Mathews ST. Hypoglycemic agents and potential anti-inflammatory activity. J Inflamm Res 2016; 9:27-38.
10. Łabuzek K, Suchy D, Gabryel B, Bielecka A, Liber S, Okopień B. Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacological Reports 2010; 62:956-965.
11. Markowicz-Piasecka M, Sikora J, Szydlowska A, Skupien A, Mikiciuk-Olasik E, Huttunen KM. Metformin – a future therapy for neurodegenerative diseases. Pharm Res 2017; 34:1–14.
12. Zhao R-r, Xu X-c, Xu F, Zhang W-l, Zhang W-l, Liu L-m, et al. Metformin protects against seizures, learning and memory impairments and oxidative damage induced by pentylenetetrazole-induced kindling in mice. Biochem Biophys Res Commun 2014; 448:414-417.
13. Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, et al. Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol 2005; 40:685-693.
14. McCarty MF. Chronic activation of AMP-activated kinase as a strategy for slowing aging. Med Hypotheses 2004; 63:334-339.
15. Kaviani E, Rahmani M, Kaeidi A, Shamsizadeh A, Allahtavakoli M, Mozafari N, et al. Protective effect of atorvastatin on D-galactose-induced aging model in mice. Behav Brain Res 2017; 334:55-60.
16. Pellow S, Chopin P, File SE, Briley M. Validation of open - closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 1985; 14:149-167.
17. Fatemi I, Shamsizadeh A, Ayoobi F, Taghipour Z, Sanati MH, Roohbakhsh A, et al. Role of orexin-A in experimental autoimmune encephalomyelitis. J Neuroimmunol 2016; 291:101-109.
18. Roohbakhsh A, Shamsizadeh A, Arababadi MK, Ayoobi F, Fatemi I, Allahtavakoli M, et al. Tactile learning in rodents: neurobiology and neuropharmacology. Life Sci 2016; 147:1-8.
19. Ayoobi F, Fatemi I, Roohbakhsh A, Shamsizadeh A. Tactile learning within the early phase of experimental autoimmune encephalomyelitis in mice. Neurophysiology 2013; 45:306-311.
20. Zamanian M, Hajizadeh MR, Nadimi AE, Shamsizadeh A, Allahtavakoli M. Anti‐fatigue effects of troxerutin on exercise endurance capacity, oxidative stress and MMP‐9 levels in trained male rats. Fundam Clin Pharmacol 2017; 31:447-455.
21. Zhang XL, An LJ, Bao YM, Wang JY, Jiang B. D-galactose administration induces memory loss and energy metabolism disturbance in mice: protective effects of catalpol. Food Chem Toxicol 2008; 46:2888-2894.
22. Pourmemar E, Majdi A, Haramshahi M, Talebi M, Karimi P, Sadigh-Eteghad S. Intranasal cerebrolysin attenuates learning and memory impairments in D-galactose-induced senescence in mice. Exp Gerontol 2017; 87:16-22.
23. Ge XH, Zhu GJ, Geng DQ, Zhang HZ, He JM, Guo AZ, et al. Metformin protects the brain against ischemia/reperfusion injury through PI3K/Akt1/JNK3 signaling pathways in rats. Physiol Behav 2017; 170:115-123.
24. Oliveira WH, Nunes AK, Franca ME, Santos LA, Los DB, Rocha SW, et al. Effects of metformin on inflammation and short-term memory in streptozotocin-induced diabetic mice. Brain Res 2016; 1644:149-160.
25. Ashabi G, Sarkaki A, Khodagholi F, Zareh Shahamati S, Goudarzvand M, Farbood Y, et al. Subchronic metformin pretreatment enhances novel object recognition memory task in forebrain ischemia: behavioural, molecular, and electrophysiological studies. Can J Physiol Pharmacol 2016; 95:388-395.
26. Thangthaeng N, Rutledge M, Wong JM, Vann PH, Forster MJ, Sumien N. Metformin impairs spatial memory and visual acuity in old male mice. Aging Dis 2017; 8:17-30.
27. Takeda M, Takahashi M, Matsumoto S. Inflammation enhanced brain-derived neurotrophic factor-induced suppression of the voltage-gated potassium currents in small-diameter trigeminal ganglion neurons projecting to the trigeminal nucleus interpolaris/caudalis transition zone. Neuroscience 2014; 261:223-231.
28. Kumar A, Pareek V, Faiq MA, Kumar P, Raza K, Prasoon P, et al. Regulatory role of NGFs in neurocognitive functions. Rev Neurosci 2017; 28:649-673.
29. Ghadernezhad N, Khalaj L, Pazoki-Toroudi H, Mirmasoumi M, Ashabi G. Metformin pretreatment enhanced learning and memory in cerebral forebrain ischaemia: the role of the AMPK/BDNF/P70SK signalling pathway. Pharm Biol 2016; 54:2211-2219.
30. Smieszek A, Strek Z, Kornicka K, Grzesiak J, Weiss C, Marycz K. Antioxidant and anti-senescence effect of metformin on mouse olfactory ensheathing cells (mOECs) may be associated with increased brain-derived neurotrophic factor levels-an ex vivo study. Int J Mol Sci 2017; 18:872-891.
31. Yang X, Ding H, Qin Z, Zhang C, Qi S, Zhang H, et al. Metformin prevents renal stone formation through an antioxidant mechanism in vitro and in vivo. Oxid Med Cell Longev 2016; 2016:4156075-4156085.
32. El-Lakkany NM, Seif El-Din SH, Sabra AA, Hammam OA, Ebeid FA. Co-administration of metformin and N-acetylcysteine with dietary control improves the biochemical and histological manifestations in rats with non-alcoholic fatty liver. Res Pharm Sci 2016; 11:374-382.
33. Mansour HH, El Kiki SM, Galal SM. Metformin and low dose radiation modulates cisplatin-induced oxidative injury in rat via PPAR-gamma and MAPK pathways. Arch Biochem Biophys 2017; 616:13-19.
34. Garabadu D, Krishnamurthy S. Diazepam potentiates the antidiabetic, antistress and anxiolytic activities of metformin in type-2 diabetes mellitus with cooccurring stress in experimental animals. Biomed Res Int 2014; 2014:693074-693089.
35. Therrien Z, Hunsley J. Assessment of anxiety in older adults: a systematic review of commonly used measures. Aging Ment Health 2012; 16:1-16.
36. Haider S, Liaquat L, Shahzad S, Sadir S, Madiha S, Batool Z, et al. A high dose of short term exogenous D-galactose administration in young male rats produces symptoms simulating the natural aging process. Life Sci 2015; 124:110-119.
37. Damian JP, Acosta V, Da Cuna M, Ramirez I, Oddone N, Zambrana A, et al. Effect of resveratrol on behavioral performance of streptozotocin-induced diabetic mice in anxiety tests. Exp Anim 2014; 63:277-287.
38. Sarkaki A, Farbood Y, Badavi M, Khalaj L, Khodagholi F, Ashabi G. Metformin improves anxiety-like behaviors through AMPK-dependent regulation of autophagy following transient forebrain ischemia. Metab Brain Dis 2015; 30:1139-1150.
39. Chang L, Liu X, Liu J, Li H, Yang Y, Liu J, et al. D-galactose induces a mitochondrial complex I deficiency in mouse skeletal muscle: potential benefits of nutrient combination in ameliorating muscle impairment. J Med Food 2014; 17:357-364.
40. Boengler K, Kosiol M, Mayr M, Schulz R, Rohrbach S. Mitochondria and ageing: role in heart, skeletal muscle and adipose tissue. J Cachexia Sarcopenia Muscle 2017; 8:349-369.
41. Sun D, Yang F. Metformin improves cardiac function in mice with heart failure after myocardial infarction by regulating mitochondrial energy metabolism. Biochem Biophys Res Commun 2017; 486:329-335.
42. Izzo A, Nitti M, Mollo N, Paladino S, Procaccini C, Faicchia D, et al. Metformin restores the mitochondrial network and reverses mitochondrial dysfunction in Down syndrome cells. Hum Mol Genet 2017; 26:1056-1069.