Trimetazidine Prevents Oxidative Changes Induced in a Rat Model of Sporadic Type Of Alzheimer's Disease

  • Gholamreza Hassanzadeh Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. AND Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
  • Amir Hosseini Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
  • Parichehr Pasbakhsh Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
  • Mohammad Akbari Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
  • Massoud Ghaffarpour Iranian Research Organizations for Science and Technology (IROST), Tehran, Iran.
  • Nasrin Takzare Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
  • Maryam Zahmatkesh Mail Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Keywords:
Alzheimers disease, Streptozotocin, Trimetazidine, Oxidative stress

Abstract

Oxidative stress plays a major role in the pathogenesis of Alzheimer's disease (AD) of sporadic origin. The expression of DHCR24 (Seladin-1), marker for neuronal oxidative stress and degeneration, has been reported to be altered in the brains of AD patients. In the present study, we investigated the effect of trimetazidine (TMZ) on the hippocampal oxidative parameters and the expression of DHCR24 (Seladin-1) in an animal model of sporadic AD. Male rats were pre-treated with TMZ (25 mg/kg) after which injected with intracerebroventricular-streptozotocin (ICV-STZ)/Saline. Following 2, 7 and 14 days, animals of different groups were sacrificed with their brain excised to detect the hippocampal lipid peroxidation, superoxide dismutase (SOD), catalase activity, DHCR24 (Seladin-1) expression and possible histopathological changes. ICV-STZ administration induced significant oxidative changes in the hippocampus. Meanwhile, TMZ pre-treatment showed to ameliorate the oxidative stress, which was demonstrated by a significant rise in the hippocampal SOD and catalase activity, as well as a significant decrease in the malondialdehyde (MDA) level. TMZ administration also increased the expression of DHCR24 (Seladin-1) gene in the hippocampus. In conclusion, our findings indicated a neuroprotective effect of TMZ possibly related to its antioxidant activity resulting in the up-regulation of DHCR24 (Seladin-1). Such TMZ effects may be beneficial in minimizing oxidative stress in sporadic Alzheimer's disease and possible prevention of disease progression.

References

Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med 2010;362(4):329-44.

de la Torre JC. A turning point for Alzheimer's disease? Biofactors 2012;38(2):78-83.

Nunomura A, Castellani RJ, Zhu X, et al. Involvement of oxidative stress in Alzheimer disease. J Neuropathol Exp Neurol 2006;65(7):631-41.

Zhu X, Lee HG, Casadesus G, Avila J, Drew K, Perry G, Smith MA. Oxidative imbalance in Alzheimer’s disease. Mol Neurobiol 2005; 31,205–17.

Zhu X, Smith MA, Honda K, et al. Vascular oxidative stress in Alzheimer disease. J Neurol Sci 2007;257(1-2):240-6.

Lecanu L, Greeson J, Papadopoulos V. Beta-Amyloid and Oxidative Stress Jointly Induce Neuronal Death, Amyloid Deposits, Gliosis, and Memory Impairment in the Rat Brain. Pharmacology 2006;76(1):19-33.

Floyd RA, Carney JM. Free radical damage to protein and DNA: Mechanism involved and relevant observations on brain undergoing oxidative stress. Ann Neurol 1992;32(Suupl):S22-7.

Rinaldi P, Polidori MC, Metastasio A, et al. Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer's disease. Neurobiol Aging 2003;24(7):915-9.

Choi DY, Lee YJ, Hong JT, et al. Antioxidant properties of natural polyphenols and their therapeutic potentials for Alzheimer's disease. Brain Res Bull 2012;87(2-3):144-53.

Aubert A, Bernard C, Clauser P, et al. Effect of phenazine methosulfate on electrophysiological activity of the semicircular canal: antioxidant properties of trimetazidine. Eur J Pharmacol 1989;174(2-3):215-25.

Guarnieri C, Muscari C. Effect of trimetazidine on mitochondrial function and oxidative damage during reperfusion of ischemic hypertrophied rat myocardium. Pharmacology 1993;46(6):324-31.

Kantor PF, Lucien A, Kozak R, et al. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res 2000;86(5):580-8.

Baltalarli A, Coskun E, Ortac R, et al. Protective effects of trimetazidine in transient spinal cord ischemia. Res Exp Med (Berl) 2000;200(1):43-51.

Ikizler M, Dernek S, Sevin B, et al. Trimetazidine improves recovery during reperfusion in isolated rat hearts after prolonged ischemia. Anadolu Kardiyol Derg 2003;3(4):303-8.

Veitch K, Maisin L, Hue L. Trimetazidine effects on the damage to mitochondrial functions caused by ischemia and reperfusion. Am J Cardiol 1995;76(6):25B-30B.

Serarslan Y, Bal R, Altug ME, et al. Effects of trimetazidine on crush injury of the sciatic nerve in rats: A biochemical and stereological study. Brain Res 2009;1247:11-20.

Sharma M, Gupta YK. Intracerebroventricular injection of streptozotocin in rats produces both oxidative stress in the brain and cognitive impairment. Life Sci 2001;68(9):1021-9.

Labak M, Foniok T, Kirk D, et al. Metabolic Changes in Rat Brain Following Intracerebroventricular Injections of Streptozotocin: A Model of Sporadic Alzheimer’s Disease. Acta Neurochir Suppl 2010;106:177-81.

Duelli R, Schröck H, Kuschinsky W, et al. Intracerebroventricular injection of streptozotocin induces discrete local changes in cerebral glucose utilization in rats. Int J Dev Neurosci 1994;12(8):737-43.

Plaschke K, Hoyer S. Action of the diabetogenic drug streptozotocin on glycolytic and glycogenolytic metabolism in adult rat brain cortex and hippocampus. Int J Dev Neurosci 1993;11(4):477-83.

Lannert H, Hoyer S. Intracerebroventricular Administration of Streptozotocin Causes Long-Term Diminutions in Learning and Memory Abilities and in Cerebral Energy Metabolism in Adult Rats. Behav Neurosci 1998;112(5):1199-208.

Shoham S, Bejar C, Kovalev E, et al. Ladostigil prevents gliosis, oxidative-nitrative stress and memory deficits induced by intracerebroventricular injection of streptozotocin in rats. Neuropharmacology 2007;52(3):836-43.

Sapcanin A, Sofic E, Tahirovic I, et al. Antioxidant capacity in rat brain after intracerebroventricular treatment with streptozotocin and alloxan--a preliminary study. Neurotox Res 2008;13(2):97-104.

Benvenuti S, Saccardi R, Luciani P, et al. Neuronal differentiation of human mesenchymal stem cells: changes in the expression of the Alzheimer's disease-related gene seladin-1. Exp Cell Res 2006;312(13):2592-604.

Liang WS, Dunckley T, Thomas G, et al. Altered neuronal gene expression in brain regions differentially affected by Alzheimer’s disease: a reference data set. Physiol Genomics. 2008;33(2):240-56.

Greeve I, Hermans-Borgmeyer I, Brellinger C, et al. The human DIMINUTO/DWARF1 homolog Seladin-1 confers resistance to Alzheimer's disease-associated neurodegeneration and oxidative stress. J Neurosci 2000;20(19):7345-52.

Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates, New York: Academic Press; 2007.

Satoh K. Serum lipid peroxide in cerebrovascular disorders determined by a new colorimetric method. Clin Chim Acta 1978;90(1):37-43.

Misra HP, Fridovich I. Superoxide dismutase: "positive" spectrophotometric assays. Anal Biochem 1977;79(1-2):553-60.

Aebi H. Catalase in vitro. Methods Enzymol 1984;105:121-6.

Dhote V, Balaraman R. Anti-oxidant activity mediated neuroprotective potential of trimetazidine on focal cerebral ischaemia-reperfusion injury in rats. Clin Exp Pharmacol Physiol 2008;35(5-6):630-7.

Iqbal S, Baziany A, Hussain M, et al. Trimetazidine as a potential neuroprotectant in transient global ischemia in gerbils: a behavioral and histological study. Brain Res 2002;928(1-2):1-7.

Hosseinzadeh S, Zahmatkesh M, Zarrindast MR, et al. Elevated CSF and plasma microparticles in a rat model of streptozotocin-induced cognitive impairment. Behav Brain Res 2013;256:503-11.

Wu Q, Qi B, Liu Y, Cheng B, et al. Mechanisms underlying protective effects of trimetazidine on endothelial progenitor cells biological functions against H2O2-induced injury: involvement of antioxidation and Akt/eNOS signaling pathways. Eur J Pharmacol 2013;707(1-3):87-94.

Iivonen S, Hiltunen M, Alafuzoff I, et al. Seladin-1 transcription is linked to neuronal degeneration in Alzheimer's disease. Neuroscience 2002;113(2):301-10.

Crameri A, Biondi E, Kuehnle K, et al. The role of seladin- 1/DHCR24 in cholesterol biosynthesis, APP processing and Abeta generation in vivo. EMBO J 2006;25(2):432-43.

How to Cite
1.
Hassanzadeh G, Hosseini A, Pasbakhsh P, Akbari M, Ghaffarpour M, Takzare N, Zahmatkesh M. Trimetazidine Prevents Oxidative Changes Induced in a Rat Model of Sporadic Type Of Alzheimer’s Disease. Acta Med Iran. 53(1):17-24.
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