Atorvastatin modulates the expression of aging-related genes in the brain of aging induced by D-galactose in mice

Document Type : Original Article

Authors

1 Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran

2 Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

3 Department of Clinical Biochemistry, Kerman University of Medical Sciences, Kerman, Iran

4 Department of Radiology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran

5 Research Center of Tropical and Infectious Diseases, Kerman University of Medical Sciences, Kerman, Iran

Abstract

Objective(s): Atorvastatin (AT), a competitive inhibitor of 3-hydroxymethyl-3-glutaryl-coenzyme-A reductase, is a cholesterol-lowering drug. AT has been shown to have neuroprotective, antioxidant, and anti-inflammatory properties. Previously, we have reported that AT could attenuate the behavioral, renal, and hepatic manifestations of aging. To clarify further the mechanisms involved, the present study was designed to evaluate the effect of AT on the expression of some aging-related genes in the brain of aging mice induced by D-galactose (DG).
Materials and Methods: For this purpose, AT (0.1 and 1 mg/kg/p.o.) was administrated daily in DG-received (500 mg/kg/p.o.) mice model of aging for six weeks. At the end of the experiment, mice were decapitated to remove the brains. Then, the expression profiles of sirtuin 1 (Sirt1), P53, P21, Bcl-2, Bax, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), interleukin 1 beta (IL1β), tumor necrosis factor-alpha (TNFα), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and brain-derived neurotrophic factor (BDNF) were assessed using the real-time PCR method.
Results: The present study shows that DG decreases the expression of Sirt1, Bcl-2, CAT, GPx, and BDNF while increasing the expression of P53, P21, Bax, IL-1β, iNOS, COX-2, and TNF-α. According to the findings of the present study, AT (more potentially at the dose of 1 mg/kg) modulates the expression of these aging-related genes in the brain of aging mice.
Conclusion: The results of the present study confirmed our previous reports on the anti-aging effects of AT at the gene level, the precise mechanisms and underlying pathways need further studies.

Keywords


1. Sander M, Oxlund B, Jespersen A, Krasnik A, Mortensen EL, Westendorp RG, et al. The challenges of human population ageing. Age Ageing 2015; 44: 185-187.
2. Khan SS, Singer BD, Vaughan DE. Molecular and physiological manifestations and measurement of aging in humans. Aging cell 2017; 16: 624-633.
3. Strong R. Neurochemical changes in the aging human brain: Implications for behavioral impairment and neurodegenerative disease. Geriatrics 1998; 53: S9.
4. Hakimizadeh E, Kaeidi A, Taghipour Z, Mehrzadi S, Allahtavakoli M, Shamsizadeh A, et al. Ceftriaxone improves senile neurocognition damages induced by D-galactose in mice. Iran J Basic Med Sci 2020; 23: 368-375.
5. Zakeri M, Fatemi I, Kaeidi A, Zakeri MA, Hakimizadeh E, Hassanipour M, et al. Pro-neurocognitive and Anti-sarcopenic benefits of one-year Metformin therapy in ovariectomized aged mice. Clin Exp Pharmacol Physiol 2019; 46:1133-1140.
6. Kennedy BK and Pennypacker JK. Drugs that modulate aging: The promising yet difficult path ahead. Transl Res 2014; 163: 456-465.
7. Fatemi I, Khaluoi A, Kaeidi A, Shamsizadeh A, Heydari S, and Allahtavakoli MA. Protective effect of metformin on D-galactose-induced aging model in mice. Iran J Basic Med Sci 2018; 21: 19-25.
8. Hakimizadeh E, Hassanshahi J, Kaeidi A, Nematollahi MH, Taghipour Z, Rahmani M, et al. Ceftriaxone improves hepatorenal damages in mice subjected to D-galactose-induced aging. Life Sci 2020; 258: 118119.
9. Xu F. Sub-acute toxicity of d-galactose in Proceedings of the Second National Conference on Aging Research. Herbin China. 1985.
10. Hakimizadeh E, Zamanian M, Giménez-Llort L, Sciorati C, Nikbakhtzadeh M, Kujawska M, et al. Calcium dobesilate reverses cognitive deficits and anxiety-like behaviors in the D-galactose-induced aging mouse model through modulation of oxidative stress. Antioxidants (Basel) 2021; 10: 649.
11. Ho SC, Liu JH, and Wu RY. Establishment of the mimetic aging effect in mice caused by D-galactose. Biogerontology 2003; 4: 15-18.
12. Fatemi I, Heydari S, Kaeidi A, Shamsizadeh A, Hakimizadeh E, Khaluoi A, et al. Metformin ameliorates the age-related changes of d-galactose administration in ovariectomized mice. Fundam Clin Pharmacol 2018; 32: 392-399.
13. Athyros V, Mikhailidis D, Papageorgiou A, Symeonidis A, Pehlivanidis A, Bouloukos V, et al. The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study. J clin Pathol 2004; 57: 728-734.
14. Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: An update. Fundam Clin Pharmacol 2005; 19: 117-125.
15. Bedi O, Dhawan V, Sharma PL, Kumar P. Pleiotropic effects of statins: New therapeutic targets in drug design. Naunyn Schmiedebergs Arch Pharmacol 2016; 389: 695-712.
16. 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.
17. Taghipour Z, Kaviani E, Kaeidi A, Shamsizadeh A, Hassanshahi J, Fatemi I. Atorvastatin attenuates D-galactose-induced hepatorenal toxicity in mice: An experimental study with histopathological evaluations. Physiol Pharmacol 2019; 23: 36-43.
18. Ludka FK, Constantino LC, Dal-Cim T, Binder LB, Zomkowski A, Rodrigues ALS, et al. Involvement of PI3K/Akt/GSK-3β and mTOR in the antidepressant-like effect of atorvastatin in mice. J Psychiatric Res 2016; 82: 50-57.
19. Xu Y, Wu T, Jin Y, Fu Z. Effects of age and jet lag on D-galactose induced aging process. Biogerontol 2009; 10: 153-161.
20. Li W, Wei F, Fan M, Zhang J, Zhang B, Ma X, et al. Mimetic brain aging effect induced by D-galactose in mice. Chinese J Pharmacol Toxicol 1994; 9: 93-95.
21. Ghanbari S, Yonessi M, Mohammadirad A, Gholami M, Baeeri M, Khorram-Khorshid HR, et al. Effects of IMOD and angipars on mouse D-galactose-induced model of aging. Daru 2012; 20: 68.
22. Li Q, Zeng J, Su M, He Y, Zhu B. Acetylshikonin from Zicao attenuates cognitive impairment and hippocampus senescence in d-galactose-induced aging mouse model via upregulating the expression of SIRT1. Brain Res Bull 2018; 137: 311-318.
23. Ng F, Wijaya L, Tang BL.SIRT1 in the brain-connections with aging-associated disorders and lifespan. Front Cell Neurosci 2015; 9: 64.
24. Gao J, Zhou R, You X, Luo F, He H, Chang X, et al. Salidroside suppresses inflammation in a D-galactose-induced rat model of Alzheimer’s disease via SIRT1/NF-kappaB pathway. Metab Brain Dis 2016; 31: 771-778.
25. Chang C, Su H, Zhang D, Wang Y, Shen Q, Liu B, et al. AMPK-dependent phosphorylation of GAPDH triggers Sirt1 activation and is necessary for autophagy upon glucose starvation. Mol Cell 2015; 60: 930-940.
26. Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, et al. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. Embo J 2007; 26: 3169-3179.
27. Rodier F, Campisi J, Bhaumik D. Two faces of p53: aging and tumor suppression. Nucleic Acids Res 2007; 35: 7475-7484.
28. Gu B and Zhu WG. Surf the post-translational modification network of p53 regulation. Int J Biol Sci 2012; 8: 672-684.
29. Deschenes M and Chabot B. The emerging role of alternative splicing in senescence and aging. Aging Cell 2017; 16: 918-933.
30. Ong ALC and Ramasamy TS. Role of Sirtuin1-p53 regulatory axis in aging, cancer and cellular reprogramming. Ageing Res Rev 2018; 43: 64-80.
31. Karimian A, Ahmadi Y, Yousefi B. Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage. DNA Repair (Amst) 2016; 42: 63-71.
32. Celik H, Karahan H, Kelicen-Ugur P. Effect of atorvastatin on Abeta1-42 -induced alteration of SESN2, SIRT1, LC3II and TPP1 protein expressions in neuronal cell cultures. J Pharm Pharmacol 2020; 72: 424-436.
33. Liu H, Yang J, Wang K, Niu T, Huang D. Moderate- and low-dose of atorvastatin alleviate cognition impairment induced by high-fat diet via sirt1 activation. Neurochem Res 2019; 44: 1065-1078.
34. Shen Q, Cao Y, Xia Y. Atorvastatin attenuates spinal cord injury by chronic fluorosis in rats. Neuroreport 2019; 30: 1256-1260.
35. McLean AJ and Le Couteur DG. Aging biology and geriatric clinical pharmacology. Pharmacol Rev 2004; 56: 163-184.
36. Liu H, Zhang X, Xiao J, Song M, Cao Y, Xiao H, et al. Astaxanthin attenuates d-galactose-induced brain aging in rats by ameliorating oxidative stress, mitochondrial dysfunction, and regulating metabolic markers. Food Funct 2020;11:4103-4113.
37. Mehrzadi S, Kamrava SK, Dormanesh B, Motevalian M, Hosseinzadeh A, Hosseini Tabatabaei SM, et al. Melatonin synergistically enhances protective effect of atorvastatin against gentamicin-induced nephrotoxicity in rat kidney. Can J Physiol Pharmacol 2016; 94: 265-271.
38. Haendeler J, Hoffmann J, Zeiher AM, Dimmeler S. Antioxidant effects of statins via S-nitrosylation and activation of thioredoxin in endothelial cells: a novel vasculoprotective function of statins. Circulation 2004; 110: 856-861.
39. Prajapati SK, Garabadu D, Krishnamurthy S. Coenzyme Q10 prevents mitochondrial dysfunction and facilitates pharmacological activity of atorvastatin in 6-OHDA Induced dopaminergic toxicity in rats. Neurotox Res 2017;31:478-492.
40. Cheng SM, Ho YJ, Yu SH, Liu YF, Lin YY, Huang CY, et al. Anti-apoptotic effects of diosgenin in D-Galactose-induced aging brain. Am J Chin Med 2020; 48: 391-406.
41. Buyuklu M, Kandemir FM, Ozkaraca M, Set T, Bakirci EM, Topal E. Protective effect of curcumin against contrast induced nephropathy in rat kidney: What is happening to oxidative stress, inflammation, autophagy and apoptosis? Eur Rev Med Pharmacol Sci 2014; 18: 461-470.
42. He X, Yang J, Li L, Tan H, Wu Y, Ran P, et al. Atorvastatin protects against contrast-induced nephropathy via anti-apoptosis by the upregulation of Hsp27 in vivo and in vitro. Mol Med Rep 2017; 15: 1963-1972.
43. Simani L, Naderi N, Khodagholi F, Mehrpour M, Nasoohi S. Association of long-term atorvastatin with escalated stroke-induced neuroinflammation in rats. J Mol Neurosci 2017; 61: 32-41.
44. Ali T, Badshah H, Kim TH, Kim MO. Melatonin attenuates D-galactose-induced memory impairment, neuroinflammation and neurodegeneration via RAGE/NF-K B/JNK signaling pathway in aging mouse model. J Pineal Res 2015; 58: 71-85.
45. Rehman SU, Shah SA, Ali T, Chung JI, Kim MO. Anthocyanins reversed D-Galactose-induced oxidative stress and neuroinflammation mediated cognitive impairment in adult rats. Mol Neurobiol 2017; 54: 255-271.
46. Xu L, He D, Bai Y. Microglia-mediated inflammation and neurodegenerative disease. Mol Neurobiol 2016; 53: 6709-6715.
47. Renno T, Krakowski M, Piccirillo C, Lin JY, Owens T. TNF-alpha expression by resident microglia and infiltrating leukocytes in the central nervous system of mice with experimental allergic encephalomyelitis. Regulation by Th1 cytokines. J Immunol 1995; 154: 944-953.
48. Salvemini D, Wang ZQ, Wyatt PS, Bourdon DM, Marino MH, Manning PT, et al. Nitric oxide: A key mediator in the early and late phase of carrageenan-induced rat paw inflammation. Br J Pharmacol 1996; 118: 829-838.
49. Taniguti EH, Ferreira YS, Stupp IJV, Fraga-Junior EB, Doneda DL, Lopes L, et al. Atorvastatin prevents lipopolysaccharide-induced depressive-like behaviour in mice. Brain Res Bull 2019; 146: 279-286.
50. Chu LW, Chen JY, Wu PC, Wu BN. Atorvastatin prevents neuroinflammation in chronic constriction injury rats through nuclear NFkappaB downregulation in the dorsal root ganglion and spinal cord. ACS Chem Neurosci 2015; 6: 889-898.
51. Beeri MS and Sonnen J. Brain BDNF expression as a biomarker for cognitive reserve against Alzheimer disease progression. Neurology 2016; 86: 702-703.
52. Buchman AS, Yu L, Boyle PA, Schneider JA, De Jager PL, Bennett DA. Higher brain BDNF gene expression is associated with slower cognitive decline in older adults. Neurology 2016; 86: 735-741.
53. Woo JY, Gu W, Kim KA, Jang SE, Han MJ, Kim DH. Lactobacillus pentosus var. plantarum C29 ameliorates memory impairment and inflammaging in a D-galactose-induced accelerated aging mouse model. Anaerobe 2014; 27: 22-26.
54. Vasconcelos-Moreno MP, Fries GR, Gubert C, Dos Santos BT, Fijtman A, Sartori J, et al. Telomere length, oxidative stress, inflammation and BDNF levels in siblings of patients with bipolar disorder: Implications for accelerated cellular aging. Int J Neuropsychopharmacol 2017;20: 445-454.
55. Chen J, Zhang C, Jiang H, Li Y, Zhang L, Robin A, et al. Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. J Cereb Blood Flow Metab 2005; 25: 281-290.
56. Zhang J, Mu X, Breker DA, Li Y, Gao Z, Huang Y. Atorvastatin treatment is associated with increased BDNF level and improved functional recovery after atherothrombotic stroke. Int J Neurosci 2017; 127: 92-97.