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Zinc Improves Cognitive and Neuronal Dysfunction During Aluminium-Induced Neurodegeneration

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Abstract

Metals are considered as important components of a physiologically active cell, and imbalance in their levels can lead to various diseased conditions. Aluminium (Al) is an environmental neurotoxicant, which is etiologically related to several neurodegenerative disorders like Alzheimer’s, whereas zinc (Zn) is an essential trace element that regulates a large number of metabolic processes in the brain. The objective of the present study was to understand whether Zn provides any physiological protection during Al-induced neurodegeneration. Male Sprague Dawley rats weighing 140–160 g received either aluminium chloride (AlCl3) orally (100 mg/kg b.wt./day), zinc sulphate (ZnSO4) in drinking water (227 mg/L) or combined treatment of aluminium and zinc for 8 weeks. Al treatment resulted in a significant decline in the cognitive behaviour of rats, whereas zinc supplementation caused an improvement in various neurobehavior parameters. Further, Al exposure decreased (p ≤ 0.001) the levels of neurotransmitters, acetylcholinesterase activity, but increased (p ≤ 0.001) the levels of l-citrulline as well as activities of nitric oxide and monoamine oxidase in the brain. However, zinc administration to Al-treated animals increased the levels of neurotransmitters and regulated the altered activities of brain markers. Western blot of tau, amyloid precursor protein (APP), glial fibrillary acidic protein (GFAP), ubiquitin, α-synuclein and Hsp 70 were also found to be elevated after Al exposure, which however were reversed following Zn treatment. Al treatment also revealed alterations in neurohistoarchitecture in the form of loss of pyramidal and Purkinje cells, which were improved upon zinc co-administration. Therefore, the present study demonstrates that zinc improves cognitive functions by regulating α-synuclein and APP-mediated molecular pathways during aluminium-induced neurodegeneration.

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References

  1. Yumoto S, Kakimi S, Ohsaki A, Ishikawa A (2009) Demonstration of aluminum in amyloid fibers in the cores of senile plaques in the brains of patients with Alzheimer's disease. J Inorg Biochem 103:1579–1584

    Article  CAS  PubMed  Google Scholar 

  2. Yokel RA, Hicks CL, Florence RL (2008) Aluminium bioavailability from basic sodium aluminium phosphate, an approved food additive emulsifying agent, incorporated in cheese. Food Chem Toxicol 46:2261–2266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Exley C (2011) Aluminium-based adjuvants should not be used as placebos in clinical trials. Vaccine 29:9289

    Article  PubMed  Google Scholar 

  4. Golub MS, Han B, Keen CL (1999) Aluminum uptake and effects on transferrin mediated iron uptake in primary cultures of rat neurons, astrocytes and oligodendrocytes. Neurotoxicology 20:961–970

    CAS  PubMed  Google Scholar 

  5. Aremu DA, Meshitsuka S (2005) Accumulation of aluminum by primary cultured astrocytes from aluminum amino acid complex and its apoptotic effect. Brain Res 1031:284–296

    Article  CAS  PubMed  Google Scholar 

  6. Singla N, Dhawan DK (2013) Zinc, a neuroprotective agent against aluminum-induced oxidative DNA injury. Mol Neurobiol 48:1–12

    Article  CAS  PubMed  Google Scholar 

  7. Lakshmi BV, Sudhakar M, Anisha M (2014) Neuroprotective role of hydroalcoholic extract of Vitis vinifera against aluminium-induced oxidative stress in rat brain. Neurotoxicology 41C:73–79

    Article  Google Scholar 

  8. Kandimalla R, Vallamkondu J, Corgiat EB, Gill KD (2015) Understanding aspects of aluminum exposure in Alzheimer's disease development. Brain Pathol

  9. Kawahara M, Kato-Negishi M (2011) Link between aluminum and the pathogenesis of Alzheimer's disease: the integration of the aluminum and amyloid cascade hypotheses. Int J Alzheimers Dis 2011:276393

    PubMed  PubMed Central  Google Scholar 

  10. Kumar S (2002) Aluminium-induced changes in the rat brain serotonin system. Food Chem Toxicol 40:1875–1880

    Article  CAS  PubMed  Google Scholar 

  11. Abu-Taweel GM, Ajarem JS, Ahmad M (2012) Neurobehavioral toxic effects of perinatal oral exposure to aluminum on the developmental motor reflexes, learning, memory and brain neurotransmitters of mice offspring. Pharmacol Biochem Behav 101:49–56

    Article  CAS  PubMed  Google Scholar 

  12. Singla N, Dhawan DK (2012) Regulatory role of zinc during aluminium-induced altered carbohydrate metabolism in rat brain. J Neurosci Res 90:698–705

    Article  CAS  PubMed  Google Scholar 

  13. Prakash D, Gopinath K, Sudhandiran G (2013) Fisetin enhances behavioral performances and attenuates reactive gliosis and inflammation during aluminium chloride-induced neurotoxicity. Neuromolecular Med 15:192–208

    Article  CAS  PubMed  Google Scholar 

  14. Ali HA, Afifi M, Abdelazim AM, Mosleh YY (2014) Quercetin and omega 3 ameliorate oxidative stress induced by aluminium chloride in the brain. J Mol Neurosci 53:654–660

    Article  PubMed  Google Scholar 

  15. Walton JR (2009) Brain lesions comprised of aluminum-rich cells that lack microtubules may be associated with the cognitive deficit of Alzheimer's disease. Neurotoxicology 30:1059–1069

    Article  CAS  PubMed  Google Scholar 

  16. Takeda A (2004) Essential trace metals and brain function. Yakugaku Zasshi 124:577–585

    Article  CAS  PubMed  Google Scholar 

  17. Gower-Winter SD, Corniola RS, Morgan TJ Jr, Levenson CW (2013) Zinc deficiency regulates hippocampal gene expression and impairs neuronal differentiation. Nutr Neurosci 16:174–182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ryu JM, Lee MY, Yun SP, Han HJ (2009) Zinc chloride stimulates DNA synthesis of mouse embryonic stem cells: involvement of PI3K/Akt, MAPKs, and mTOR. J Cell Physiol 218:558–567

    Article  CAS  PubMed  Google Scholar 

  19. Omata Y, Salvador GA, Supasai S, Keenan AH, Oteiza PI (2013) Decreased zinc availability affects glutathione metabolism in neuronal cells and in the developing brain. Toxicol Sci 133:90–100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sensi SL, Paoletti P, Koh JY, Aizenman E, Bush AI, Hershfinkel M (2011) The neurophysiology and pathology of brain zinc. J Neurosci 31:16076–16085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Szewczyk B (2013) Zinc homeostasis and neurodegenerative disorders. Front Aging Neurosci 5:33

    Article  PubMed  PubMed Central  Google Scholar 

  22. Goel A, Chauhan DP, Dhawan DK (2000) Protective effects of zinc in chlorpyrifos induced hepatotoxicity: a biochemical and trace elemental study. Biol Trace Elem Res 74:171–183

    Article  CAS  PubMed  Google Scholar 

  23. An WL, Pei JJ, Nishimura T, Winblad B, Cowburn RF (2005) Zinc-induced anti-apoptotic effects in SH-SY5Y neuroblastoma cells via the extracellular signal-regulated kinase 1/2. Brain Res Mol Brain Res 135:40–47

    Article  CAS  PubMed  Google Scholar 

  24. Joshi M, Akhtar M, Najmi AK, Khuroo AH, Goswami D (2012) Effect of zinc in animal models of anxiety, depression and psychosis. Hum Exp Toxicol 31:1237–1243

    Article  CAS  PubMed  Google Scholar 

  25. Takeda A, Nakamura M, Fujii H, Tamano H (2013) Synaptic Zn(2+) homeostasis and its significance. Metallomics 5:417–423

    Article  CAS  PubMed  Google Scholar 

  26. Song Y, Xue Y, Liu X, Wang P, Liu L (2008) Effects of acute exposure to aluminum on blood-brain barrier and the protection of zinc. Neurosci Lett 445:42–46

    Article  CAS  PubMed  Google Scholar 

  27. Singla N, Dhawan DK (2013) Zinc protection against aluminium induced altered lipid profile and membrane integrity. Food Chem Toxicol 55:18–28

    Article  CAS  PubMed  Google Scholar 

  28. Singla N, Dhawan DK (2014) Influence of zinc on calcium-dependent signal transduction pathways during aluminium-induced neurodegeneration. Mol Neurobiol 50:613–625

    Article  CAS  PubMed  Google Scholar 

  29. Raddassi K, Berthon B, Petit JF, Lemaire G (1994) Role of calcium in the activation of mouse peritoneal macrophages, induction of NO synthase by calcium ionophores and thapsigargin. Cell Immunol 53:443–455

    Article  Google Scholar 

  30. Boyde TRC, Rahmatullah M (1980) Optimization of conditions for the colorimetric determination of citrulline, using diacetyl monoxime. Analytical Biochem J 107:424–431

    Article  CAS  Google Scholar 

  31. Ellman GL, Lourtney KD, Andres VJ (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95

    Article  CAS  PubMed  Google Scholar 

  32. McEwen CM, Cohen JD (1963) An amine oxidase in normal human serum. J Lab Clin Med 62:766–776

    CAS  PubMed  Google Scholar 

  33. Cox RH Jr, Perhach JL Jr (1973) A sensitive, rapid and simple method for the simultaneous spectro photo fluorometric determinations of norepinephrine, dopamine, 5-hydroxytryptamine and 5-hydroxy-indoleacetic acid in discrete areas of brain. J Neurochem 20:1777–1780

    Article  CAS  PubMed  Google Scholar 

  34. Humanson GL. In: Basic procedures—animal tissue technique. 1961; Part-1, 130–132.

  35. Mello NK (1975) Behavioral toxicology: a developing discipline. Fed Proc 34:1832–1834

    CAS  PubMed  Google Scholar 

  36. Bhalla P, Garg ML, Dhawan DK (2010) Protective role of lithium during aluminium-induced neurotoxicity. Neurochem Int 56:256–262

    Article  CAS  PubMed  Google Scholar 

  37. Takeda A, Tamano H, Tochigi M (2005) Zinc homeostasis in the hippocampus of zinc-deficient young adult rats. J Neuro Chem Int 46:221–225

    CAS  Google Scholar 

  38. Takeda A, Minami A, Seki Y, Oku N (2004) Differential effects of zinc on glutamatergic and GABAergic neurotransmitter systems in the hippocampus. J Neurosci Res 75:225–229

    Article  CAS  PubMed  Google Scholar 

  39. Sethi P, Jyoti A, Singh R, Hussain E, Sharma D (2008) Aluminium-induced electrophysiological, biochemical and cognitive modifications in the hippocampus of aging rats. Neurotoxicology 29:1069–1079

    Article  CAS  PubMed  Google Scholar 

  40. Takeda A, Tamano H, Kan F, Itoh H, Oku N (2007) Anxiety-like behavior of young rats after 2-week zinc deprivation. Behav Brain Res 177:1–6

    Article  CAS  PubMed  Google Scholar 

  41. Nowak G, Schlegel-Zawadzka M (1999) Alternations in serum and brain trace element levels after antidepressant treatment. Zinc Biol Trace Elem Res 67:85–92

    Article  CAS  PubMed  Google Scholar 

  42. Cope EC, Levenson CW (2010) Role of zinc in the development and treatment of mood disorders. Curr Opin Clin Nutr Metab Care 13:685–690

    Article  CAS  PubMed  Google Scholar 

  43. Ajjimaporn A, Shavali S, Ebadi M, Govitrapong P (2008) Zinc rescues dopaminergic SK-N-SH cell lines from methamphetamine-induced toxicity. Brain Res Bull 77:361–366

    Article  CAS  PubMed  Google Scholar 

  44. Tamano H, Kan F, Kawamura M, Oku N, Takeda A (2009) Behavior in the forced swim test and neurochemical changes in the hippocampus in young rats after 2-week zinc deprivation. Neurochem Int 55:536–541

    Article  CAS  PubMed  Google Scholar 

  45. Szutowicz A, Bielarczyk H, Kisielevski Y, Jankowska A, Madziar B, Tomaszewicz M (1998) Effects of aluminum and calcium on acetyl-CoA metabolism in rat brain mitochondria. J Neurochem 71:2447–2453

    Article  CAS  PubMed  Google Scholar 

  46. Zellner M, Baureder M, Rappold E, Bugert P, Kotzailias N, Babeluk R, Baumgartner R, Attems J et al (2012) Comparative platelet proteome analysis reveals an increase of monoamine oxidase-B protein expression in Alzheimer's disease but not in non-demented Parkinson's disease patients. J Proteomics 75:2080–2092

    Article  CAS  PubMed  Google Scholar 

  47. Shaban NZ, Ali AE, Masoud MS (2003) Effect of cadmium and zinc ethanolamine complexes on rat brain monoamine oxidase-B activity in vitro. J Inorg Biochem 95:141–148

    Article  CAS  PubMed  Google Scholar 

  48. Ravi SM, Prabhu BM, Raju TR, Bindu PN (2000) Long-term effects of postnatal aluminium exposure on acetylcholinesterase activity and biogenic amine neurotransmitters in rat brain. Indian J Physiol Pharmacol 44:473–478

    CAS  PubMed  Google Scholar 

  49. Cichy A, Sowa-Kućma M, Legutko B, Pomierny-Chamioło L, Siwek A, Piotrowska A, Szewczyk B, Poleszak E et al (2009) Zinc-induced adaptive changes in NMDA/glutamatergic and serotonergic receptors. Pharmacol Rep 61:1184–1191

    Article  CAS  PubMed  Google Scholar 

  50. Kim S, Nam J, Kim K (2007) Aluminum exposure decreases dopamine D1 and D2 receptor expression in mouse brain. Hum Exp Toxicol 26:741–746

    Article  CAS  PubMed  Google Scholar 

  51. Jaya Prasanthi RP, Hariprasad RG, Bhuvaneswari DC, Rajarami Reddy G (2005) Zinc and calcium reduce lead induced perturbations in the aminergic system of developing brain. Biometals 18:615–626

    Article  CAS  PubMed  Google Scholar 

  52. Eibl JK, Abdallah Z, Ross GM (2010) Zinc-metallothionein: a potential mediator of antioxidant defence mechanisms in response to dopamine-induced stress. Can J Physiol Pharmacol 88:305–312

    Article  CAS  PubMed  Google Scholar 

  53. Kaur A, Gill KD (2005) Disruption of neuronal calcium homeostasis after chronic aluminium toxicity in rats. Basic Clin Pharmacol Toxicol 96:118–122

    Article  CAS  PubMed  Google Scholar 

  54. Zhao HH, Di J, Liu WS, Liu HL, Lai H, Lü YL (2013) Involvement of GSK3 and PP2A in ginsenoside Rb1's attenuation of aluminum-induced tau hyperphosphorylation. Behav Brain Res 241:228–234

    Article  CAS  PubMed  Google Scholar 

  55. Bharathi, Vasudevaraju P, Govindaraju M, Palanisamy AP, Sambamurti K, Rao KS (2008) Molecular toxicity of aluminium in relation to neurodegeneration. Indian J Med Res 128:545–556

    CAS  Google Scholar 

  56. Davis CD, Milne DB, Nielsen FH (2000) Changes in dietary zinc and copper affect zinc-status indicators of postmenopausal women, notably, extracellular superoxide dismutase and amyloid precursor proteins. Am J Clin Nutr 71:781–788

    CAS  PubMed  Google Scholar 

  57. Hashimoto M, Hsu LJ, Xia Y, Takeda A, Sisk A, Sundsmo M, Masliah E (1999) Oxidative stress induces amyloid-like aggregate formation of NACP/α-synuclein in vitro. Neuroreport 10:717–721

    Article  CAS  PubMed  Google Scholar 

  58. Hsu LJ, Sagara Y, Arroyo A, Rockenstein E, Sisk A, Mallory M, Wong J, Takenouchi T (2000) α-Synuclein promotes mitochondrial deficit and oxidative stress. Am J Pathol 157:401–410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Uversky VN, Li J, Fink AL (2001) Metal-triggered structural transformations, aggregation, and fibrillation of human alpha-synuclein. A possible molecular NK between Parkinson's disease and heavy metal exposure. J Biol Chem 276:44284–44296

    Article  CAS  PubMed  Google Scholar 

  60. Milanese M, Lkhayat MI, Zatta P (2001) Inhibitory effect of aluminum on dopamine beta-hydroxylase from bovine adrenal gland. J Trace Elem Med Biol 15:139–141

    Article  CAS  PubMed  Google Scholar 

  61. Yokel RA, O'Callaghan JP (1998) An aluminum-induced increase in GFAP is attenuated by some chelators. Neurotoxicol Teratol 20:55–60

    Article  CAS  PubMed  Google Scholar 

  62. Penkowa M, Giralt M, Thomsen PS, Carrasco J, Hidalgo J (2001) Zinc or copper deficiency-induced impaired inflammatory response to brain trauma may be caused by the concomitant metallothionein changes. J Neurotrauma 18:447–463

    Article  CAS  PubMed  Google Scholar 

  63. Campbell A, Kumar A, La Rosa FG, Prasad KN, Bondy SC (2000) Aluminum increases levels of beta-amyloid and ubiquitin in neuroblastoma but not in glioma cells. Proc Soc Exp Biol Med 223:397–402

    Article  CAS  PubMed  Google Scholar 

  64. Sood PK, Nahar U, Nehru B (2012) Stress proteins and glial cell functions during chronic aluminium exposures: protective role of curcumin. Neurochem Res 37:639–646

    Article  CAS  PubMed  Google Scholar 

  65. Wu C, Zhang W, Mai K, Xu W, Zhong X (2011) Effects of dietary zinc on gene expression of antioxidant enzymes and heat shock proteins in hepatopancreas of abalone Haliotis discus hannai. Comp Biochem Physiol C Toxicol Pharmacol 154:1–6

    Article  PubMed  Google Scholar 

  66. Pan R, Qiu S, Lu DX, Dong J (2008) Curcumin improves learning and memory ability and its neuroprotective mechanism in mice. Chin Med J (Engl) 121:832–839

    CAS  Google Scholar 

  67. Platt B, Fiddler G, Riedel G, Henderson Z (2001) Aluminium toxicity in the rat brain: histochemical and immunocytochemical evidence. Brain Res Bull 55:257–267

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are thankful to Department of Biophysics, Panjab University, Chandigarh, India, for providing various facilities during this study. The authors are also grateful to Mr. Damodar Dass, Senior Technician in the Department of Biophysics, for providing valuable suggestions during staining procedures.

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  1. Department of Biophysics, Sector-14, Panjab University, Chandigarh, 160014, India

    Neha Singla & D. K. Dhawan

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  1. Neha Singla
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Correspondence to D. K. Dhawan.

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We are grateful to University Grants Commission (UGC-34-294/2008 SR), New Delhi, India, and Department of Science and Technology (DST-INSPIRE-IF10380), New Delhi, India, for their financial support. Due to the financial support, we were able to procure various chemicals, kits, glassware and instruments to carry out this study.

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The authors declare that they have no competing interests.

Authors’ Contributions

NS and DKD have designed this study as well as drafted this manuscript. Both the authors have critically reviewed the content of this manuscript. NS has performed various experiments and did analysis of data.

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Singla, N., Dhawan, D.K. Zinc Improves Cognitive and Neuronal Dysfunction During Aluminium-Induced Neurodegeneration. Mol Neurobiol 54, 406–422 (2017). https://doi.org/10.1007/s12035-015-9653-9

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