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Vol. 65 No. 1: Issue 1

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Chronic copper exposure elicit neurotoxic responses in rat brain: Assessment of 8-hydroxy-2-deoxyguanosine activity, oxidative stress and neurobehavioral parameters

https://doi.org/10.14715/cmb/2019.65.1.5
Jayant Kumar
National Institute of Pharmaceutical Education and Research (NIPER-R), New Transit Campus, Bijnor Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow (UP)- 226002, India
Kshirod Bihari Sathua
National Institute of Pharmaceutical Education and Research (NIPER-R), New Transit Campus, Bijnor Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow (UP)- 226002, India
S. J. S. Flora
National Institute of Pharmaceutical Education and Research (NIPER-R), New Transit Campus, Bijnor Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow (UP)- 226002, India

Corresponding Author(s) : S. J. S. Flora

director@niperraebareli.edu.in

Cellular and Molecular Biology, Vol. 65 No. 1: Issue 1

Abstract

Copper (Cu), one of the essential transition metal acts as a prosthetic group for variety of proteins and metalloenzymes. However, it may be hazardous when administered in excess. Copper induced memory impairment and progression of neurodegenerative diseases have not yet been fully elucidated. The aim of the present study was to investigate the effect of exposure to copper sulphate (10mg/kg and 20mg/kg body weight, daily for 16 weeks) on brain copper concentration, few biochemical parameters indicative of oxidative stress and on different neurobehavioral functions in male Sprague Dawley rats. Copper-administered animals showed significant increase in brain copper concentration and a depleted Ceruloplasmin level. Different neurobehavioral studies revealed impaired memory and motor coordination in copper exposed rat. Spontaneous locomotors activity and depression symptoms were also noted in copper intoxicated rats. 8-hydroxy-2' -deoxyguanosine (8-OHdG) level, one of the predominant forms of free radical-induced oxidative lesions, and has been widely used as a biomarker for oxidative stress, increased in copper treated group. Copper induced oxidative stress in the brain was also evident from the increased lipid per oxidation (LPO) and nitrite level, depletion of reduced glutathione (GSH), and reduced activities of the antioxidant enzymes such as superoxide dismutase (SOD), and catalase. The present study thus suggests a significant correlation between copper induced oxidative stress and changes in neurobehavioral function in rats. The changes were more pronounced in animals exposed to a higher dose of copper (20mg/kg) than the lower dose.

Keywords

Copper Toxicity 8-OHdG Oxidative Stress Neurobehavioral Rat.
Kumar, J., Sathua, K. B., & Flora, S. J. S. (2019). Chronic copper exposure elicit neurotoxic responses in rat brain: Assessment of 8-hydroxy-2-deoxyguanosine activity, oxidative stress and neurobehavioral parameters. Cellular and Molecular Biology, 65(1), 27–35. https://doi.org/10.14715/cmb/2019.65.1.5
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References
  1. Lu J, Zheng YL, Wu DM, Sun DX, Shan Q, Fan SH (2006). Trace amounts of copper induce neurotoxicity in the cholesterol-fed mice through apoptosis. FEBS letters 580(28-29): 6730-6740.
  2. Hegde ML, Bharathi P, Suram A, Venugopal C, Jagannathan R, Poddar P, et al. (2009). Challenges associated with metal chelation therapy in Alzheimer's disease. Journal of Alzheimer's disease : JAD 17(3): 457-468.
  3. Mathys ZK, White AR (2017). Copper and Alzheimer's Disease. Advances in neurobiology 18: 199-216.
  4. Kumar V, Kalita J, Misra UK, Bora HK (2015). A study of dose response and organ susceptibility of copper toxicity in a rat model. Journal of trace elements in medicine and biology: organ of the Society for Minerals and Trace Elements (GMS) 29: 269-274
  5. G. Georgopoulos ARMJY-LREOPJLP (2001). ENVIRONMENTAL COPPER: ITS DYNAMICS AND HUMAN EXPOSURE ISSUES. Journal of Toxicology and Environmental Health, Part B 4(4): 341-39
  6. Halatek T, Lutz P, Krajnow A, Stetkiewicz J, Domeradzka K, Swiercz R, et al. (2011). Assessment of neurobehavioral and biochemical effects in rats exposed to copper smelter dusts. Journal of environmental science and health. Part A, Toxic/hazardous substances & environmental engineering 46(3): 230-241.
  7. Arnal N, Dominici L, de Tacconi MJ, Marra CA (2014). Copper-induced alterations in rat brain depends on route of overload and basal copper levels. Nutrition (Burbank, Los Angeles County, Calif.) 30(1): 96-106.
  8. Hozumi I, Hasegawa T, Honda A, Ozawa K, Hayashi Y, Hashimoto K, et al. (2011). Patterns of levels of biological metals in CSF differ among neurodegenerative diseases. Journal of the neurological sciences 303(1-2): 95-99.
  9. Gamez P, Caballero AB (2015). Copper in Alzheimer's disease: Implications in amyloid aggregation and neurotoxicity. AIP Advances 5(9): 092503.
  10. Tokuda E, Furukawa Y (2016). Copper Homeostasis as a Therapeutic Target in Amyotrophic Lateral Sclerosis with SOD1 Mutations. International journal of molecular sciences 17(5).
  11. Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA, et al. (2001). Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron 30(3): 665-676.
  12. Bush AI (2003). The metallobiology of Alzheimer's disease. Trends in neurosciences 26(4): 207-214.
  13. Lu J, Wu DM, Zheng YL, Sun DX, Hu B, Shan Q, et al. (2008). Trace amounts of copper exacerbate beta amyloid-induced neurotoxicity in the cholesterol-fed mice through TNF-mediated inflammatory pathway. Brain, behavior, and immunity 23(2): 193-203.
  14. Kalita J, Kumar V, Misra UK, Bora HK (2017). Memory and Learning Dysfunction Following Copper Toxicity: Biochemical and Immunohistochemical Basis. Molecular neurobiology.
  15. Schosinsky KH, Lehmann HP, Beeler MF (1974). Measurement of ceruloplasmin from its oxidase activity in serum by use of o-dianisidine dihydrochloride. Clinical chemistry 20(12): 1556-1563.
  16. Kushwaha P, Yadav A, Samim M, Flora SJS (2018). Combinatorial drug delivery strategy employing nano-curcumin and nano-MiADMSA for the treatment of arsenic intoxication in mouse. Chemico-Biological Interactions 286: 78-87.
  17. Carter RJ, Morton J, Dunnett SB (2001). Motor coordination and balance in rodents. Current protocols in neuroscience 15(1): 8.12. 11-18.12. 14.
  18. Yu L, Jiang X, Liao M, Ma R, Yu T (2011). Antidepressant-Like Effect of Tetramethylpyrazine in Mice and Rats. Neuroscience and Medicine Vol.02No.02: 7.
  19. Sarkaki A, Rezaiei M, Gharib Naseri M, Rafieirad M (2013). Improving active and passive avoidance memories deficits due to permanent cerebral ischemia by pomegranate seed extract in female rats. The Malaysian journal of medical sciences : MJMS 20(2): 25-34.
  20. Masuo Y, Matsumoto Y, Morita S, Noguchi J (1997). A novel method for counting spontaneous motor activity in the rat. Brain research. Brain research protocols 1(4): 321-326.
  21. Walf AA, Frye CA (2007). The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nature protocols 2(2): 322-328.
  22. Leger M, Quiedeville A, Bouet V, Haelewyn B, Boulouard M, Schumann-Bard P, et al. (2013). Object recognition test in mice. Nature protocols 8(12): 2531-2537.
  23. Ohkawa H, Ohishi N, Yagi K (1979). Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical biochemistry 95(2): 351-358.
  24. Gupta R, Flora SJ (2006). Effect of Centella asiatica on arsenic induced oxidative stress and metal distribution in rats. Journal of applied toxicology : JAT 26(3): 213-222.
  25. Giustarini D, Rossi R, Milzani A, Dalle-Donne I (2008). Nitrite and nitrate measurement by Griess reagent in human plasma: evaluation of interferences and standardization. Methods in enzymology 440: 361-380.
  26. Góth L (1991). A simple method for determination of serum catalase activity and revision of reference range. Clinica Chimica Acta 196(2): 143-151.
  27. Flora SJS, Bhadauria S, Pant SC, Dhaked RK (2005). Arsenic induced blood and brain oxidative stress and its response to some thiol chelators in rats. Life Sciences 77(18): 2324-2337.
  28. Dwivedi DK, Jena GB (2018). Glibenclamide protects against thioacetamide-induced hepatic damage in Wistar rat: investigation on NLRP3, MMP-2, and stellate cell activation. Naunyn-Schmiedeberg's archives of pharmacology.
  29. Waggoner DJ, Bartnikas TB, Gitlin JD (1999). The role of copper in neurodegenerative disease. Neurobiology of disease 6(4): 221-230.
  30. Osredkar J, Sustar N (2011). Copper and zinc, biological role and significance of copper/zinc imbalance. J. Clinic. Toxicol. S 3: 2161-0495.
  31. Turski ML, Thiele DJ (2009). New roles for copper metabolism in cell proliferation, signaling, and disease. The Journal of biological chemistry 284(2): 717-721.
  32. Pal A (2014). Copper toxicity induced hepatocerebral and neurodegenerative diseases: an urgent need for prognostic biomarkers. Neurotoxicology 40: 97-101.
  33. Mostafa HE, Alaa-Eldin EA, El-Shafei DA, Abouhashem NS (2017). Alleviative effect of licorice on copper chloride-induced oxidative stress in the brain: biochemical, histopathological, immunohistochemical, and genotoxic study. Environmental science and pollution research international 24(22): 18585-18595.
  34. Pal A, Badyal RK, Vasishta RK, Attri SV, Thapa BR, Prasad R (2013). Biochemical, histological, and memory impairment effects of chronic copper toxicity: a model for non-Wilsonian brain copper toxicosis in Wistar rat. Biological trace element research 153(1-3): 257-268.
  35. Cisternas FA, Tapia G, Arredondo M, Cartier-Ugarte D, Romanque P, Sierralta WD, et al. (2005). Early histological and functional effects of chronic copper exposure in rat liver. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 18(5): 541-551.
  36. Narang R, Gupta K, Narang A, Singh R (1991). Levels of copper and zinc in depression. Indian J Physiol Pharmacol 35(4): 272-274.
  37. Crayton JW, Walsh WJ (2007). Elevated serum copper levels in women with a history of post-partum depression. Journal of Trace Elements in Medicine and Biology 21(1): 17-21.
  38. SÅ‚upski J, CubaÅ‚a WJ, Górska N, GaÅ‚uszko-Wć™gielnik M, Wiglusz MS (2018). Role of copper in depression. Relationship with ketamine treatment. Medical Hypotheses 119: 14-17.
  39. Russo A (2011). Analysis of plasma zinc and copper concentration, and perceived symptoms, in individuals with depression, post zinc and anti-oxidant therapy. Nutrition and metabolic insights 4: NMI. S6760.
  40. Moser VC (2011). Functional assays for neurotoxicity testing. Toxicologic pathology 39(1): 36-45.
  41. Przybyłkowski A, Gromadzka G, Wawer A, Bulska E, Jabłonka-Salach K, Grygorowicz T, et al. (2013). Neurochemical and Behavioral Characteristics of Toxic Milk Mice: An Animal Model of Wilson's Disease. Neurochemical Research 38(10): 2037-2045.
  42. Ma Q, Ying M, Sui X, Zhang H, Huang H, Yang L, et al. (2015). Chronic copper exposure causes spatial memory impairment, selective loss of hippocampal synaptic proteins, and activation of PKR/eIF2alpha pathway in mice. Journal of Alzheimer's disease : JAD 43(4): 1413-1427.
  43. Neifakh S, Monakhov N, Shaposhnikov A, Zubzhitski YN (1969). Localization of ceruloplasmin biosynthesis in human and monkey liver cells and its copper regulation. Experientia 25(4): 337-344.
  44. Gmitterova K, Heinemann U, Gawinecka J, Varges D, Ciesielczyk B, Valkovic P, et al. (2009). 8-OHdG in cerebrospinal fluid as a marker of oxidative stress in various neurodegenerative diseases. Neuro-degenerative diseases 6(5-6): 263-269.
  45. Kim GH, Kim JE, Rhie SJ, Yoon S (2015). The Role of Oxidative Stress in Neurodegenerative Diseases. Experimental Neurobiology 24(4): 325-340.
  46. Thannickal VJ, Fanburg BL (2000). Reactive oxygen species in cell signaling. American journal of physiology. Lung cellular and molecular physiology 279(6): L1005-1028.
  47. Bremner I (1998). Manifestations of copper excess. The American Journal of Clinical Nutrition 67(5): 1069S-1073S.
  48. Arnal N, Castillo O, de Alaniz MJ, Marra CA (2013). Effects of Copper and/or Cholesterol Overload on Mitochondrial Function in a Rat Model of Incipient Neurodegeneration. International journal of Alzheimer's disease 2013: 645379.
  49. Kasai H, Crain PF, Kuchino Y, Nishimura S, Ootsuyama A, Tanooka H (1986). Formation of 8-hydroxyguanine moiety in cellular DNA by agents producing oxygen radicals and evidence for its repair. Carcinogenesis 7(11): 1849-1851.
  50. Zhang S, Noordin M, Rahman S, Haron J (2000). Effects of copper overload on hepatic lipid peroxidation and antioxidant defense in rats. Veterinary and human toxicology 42(5): 261-264.
  51. Alam Z, Jenner A, Daniel S, Lees A, Cairns N, Marsden C, et al. (1997). Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8"hydroxyguanine levels in substantia nigra. Journal of neurochemistry 69(3): 1196-1203.
  52. Kikuchi Y, Yasuhara T, Agari T, Kondo A, Kuramoto S, Kameda M, et al. (2011). Urinary 8-OHdG elevations in a partial lesion rat model of Parkinson's disease correlate with behavioral symptoms and nigrostriatal dopaminergic depletion. Journal of cellular physiology 226(5): 1390-1398.
  53. Nielsen F, Mikkelsen BB, Nielsen JB, Andersen HR, Grandjean P (1997). Plasma malondialdehyde as biomarker for oxidative stress: reference interval and effects of life-style factors. Clinical chemistry 43(7): 1209-1214.
  54. Pan C, Chan C, Huang Y, Wu K (2008). Urinary 1-hydroxypyrene and malondialdehyde in male workers in Chinese restaurants. Occupational and Environmental Medicine 65(11): 732-735.
  55. Alexandrova A, Petrov L, Georgieva A, Kessiova M, Tzvetanova E, Kirkova M, et al. (2008). Effect of copper intoxication on rat liver proteasome activity: relationship with oxidative stress. Journal of biochemical and molecular toxicology 22(5): 354-362.
  56. Fridovich I (1995). Superoxide radical and superoxide dismutases. Annual review of biochemistry 64(1): 97-112.
  57. Ozturk P, Belge Kurutas E, Ataseven A (2013). Copper/zinc and copper/selenium ratios, and oxidative stress as biochemical markers in recurrent aphthous stomatitis. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) 27(4): 312-316.
  58. Singh D, Katiyar S, Verma A (2012). Role of copper sulphate on oxidative and metabolic enzymes of freshwater fish, Channa Punctatus. J. Environ. Analytic. Toxicol 2: 121.
  59. Jiang WD, Liu Y, Jiang J, Wu P, Feng L, Zhou XQ (2015). Copper exposure induces toxicity to the antioxidant system via the destruction of Nrf2/ARE signaling and caspase-3-regulated DNA damage in fish muscle: amelioration by myo-inositol. Aquatic toxicology (Amsterdam, Netherlands) 159: 245-255.
  60. Mirzaei F, Khazaei M (2017). Role of Nitric Oxide in Biological Systems:A Systematic Review. Journal of Mazandaran University of Medical Sciences 27(150): 192-222.
  61. Cuzzocrea S, Persichini T, Dugo L, Colasanti M, Musci G (2003). Copper induces type II nitric oxide synthase in vivo. Free Radical Biology and Medicine 34(10): 1253-1262.
  62. Ozcelik D, Uzun H (2009). Copper intoxication; antioxidant defenses and oxidative damage in rat brain. Biological trace element research 127(1): 45-52.
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