Skip to main content

Advertisement

SpringerLink
Log in

Hepatic and Hippocampus Iron Status is not Altered in Response to Increased Serum Ceruloplasmin and Serum “Free” Copper in Wistar Rat Model for Non-Wilsonian Brain Copper Toxicosis

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

Copper and iron dyshomeostasis has been implicated directly or indirectly in the pathogenesis of neurodegenerative diseases. Previously, we have shown the first in vivo evidence of significant increase in the hippocampus copper and zinc content with spatial memory impairments, astrocytes swelling (Alzheimer type-II cells) coupled with increase in the number of astrocytes, copper deposition in the choroid plexus, and degenerated neurons in copper-intoxicated Wistar rats. In continuation with our previous study, the aim of this study was to further investigate the effects of intraperitoneally injected copper lactate (0.15 mg Cu/100 g body weight) daily for 90 days on serum “free” copper levels, iron levels in the liver, and hippocampus by atomic absorption spectrophotometry and histopathological study of the liver and brain tissues of Wistar rats using Perls' Prussian blue (PPB) stain. A massive significant increase in serum “free” copper (79.48 % increase) along with strong correlation (r = 0.978) was found between serum copper and serum “free” copper in copper-intoxicated rats. No significant difference was detected in hepatic and hippocampus iron levels between control and copper-intoxicated rats. PPB stain demonstrated very few scattered grade 1 haemosiderin deposits within sinusoidal cells predominantly Kupffer cells; however, brain sections were negatively stained with PPB stain. In conclusion, the current study demonstrates that chronic copper toxicity causes increase in serum “free” copper, which may serve as predisposing factor for the development of neurodegeneration and memory deficits, and grade 1 haemosiderin deposition in Kupffer cells without altering hepatic and hippocampus iron levels in male Wistar rats.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Zheng W, Monnot AD (2012) Regulation of brain iron and copper homeostasis by brain barrier systems: implication in neurodegenerative diseases. Pharmacol Ther 133(2):177–188. doi:10.1016/j.pharmthera.2011.10.006

    Article  PubMed  CAS  Google Scholar 

  2. Georgopoulos PG, Roy A, Yonone-Lioy MJ, Opiekun RE, Lioy PJ (2001) Environmental copper: its dynamics and human exposure issues. J Toxicol Environ Health B Crit Rev 4(4):341–394. doi:10.1080/109374001753146207

    Article  PubMed  CAS  Google Scholar 

  3. Rivera-Mancia S, Perez-Neri I, Rios C, Tristan-Lopez L, Rivera-Espinosa L, Montes S (2010) The transition metals, copper, and iron in neurodegenerative diseases. Chem Biol Interact 186(2):184–199. doi:10.1016/j.cbi.2010.04.010

    Article  PubMed  CAS  Google Scholar 

  4. Gambling L, McArdle HJ (2004) Iron, copper, and fetal development. Proc Nutr Soc 63(4):553–562

    Article  PubMed  CAS  Google Scholar 

  5. Sharp P (2004) The molecular basis of copper and iron interactions. Proc Nutr Soc 63(4):563–569

    Article  PubMed  CAS  Google Scholar 

  6. Ranganathan PN, Lu Y, Jiang L, Kim C, Collins JF Serum ceruloplasmin protein expression and activity increases in iron-deficient rats and is further enhanced by higher dietary copper intake. Blood 118(11):3146–3153. doi:10.1182/blood-2011-05-352112

  7. Squitti R, Ventriglia M, Barbati G, Cassetta E, Ferreri F, Dal Forno G, Ramires S, Zappasodi F, Rossini PM (2007) 'Free' copper in serum of Alzheimer's disease patients correlates with markers of liver function. J Neural Transm 114(12):1589–1594. doi:10.1007/s00702-007-0777-6

    Article  PubMed  CAS  Google Scholar 

  8. Kristinsson J, Snaedal J, Torsdottir G, Johannesson T Ceruloplasmin and iron in Alzheimer's disease and Parkinson's disease: a synopsis of recent studies. Neuropsychiatr Dis Treat 8:515–521. doi:10.2147/NDT.S34729

  9. Brewer GJ, Kanzer SH, Zimmerman EA, Celmins DF, Heckman SM, Dick R Copper and ceruloplasmin abnormalities in Alzheimer's disease. Am J Alzheimers Dis Other Demen 25(6):490–497. doi:10.1177/1533317510375083

  10. Brewer GJ (2010) Risks of copper and iron toxicity during aging in humans. Chem Res Toxicol 23(2):319–326. doi:10.1021/tx900338d

    Article  PubMed  CAS  Google Scholar 

  11. Desai V, Kaler SG (2008) Role of copper in human neurological disorders. Am J Clin Nutr 88(3):855S–858S

    PubMed  CAS  Google Scholar 

  12. Salustri C, Barbati G, Ghidoni R, Quintiliani L, Ciappina S, Binetti G, Squitti R (2010) Is cognitive function linked to serum free copper levels? A cohort study in a normal population. Clin Neurophysiol 121(4):502–507. doi:10.1016/j.clinph.2009.11.090

    Article  PubMed  CAS  Google Scholar 

  13. Sparks DL, Schreurs BG (2003) Trace amounts of copper in water-induce beta-amyloid plaques and learning deficits in a rabbit model of Alzheimer's disease. Proc Natl Acad Sci U S A 100(19):11065–11069. doi:10.1073/pnas.1832769100

    Article  PubMed  CAS  Google Scholar 

  14. 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 Lett 580(28–29):6730–6740. doi:10.1016/j.febslet.2006.10.072

    Article  PubMed  CAS  Google Scholar 

  15. Mao X, Ye J, Zhou S, Pi R, Dou J, Zang L, Chen X, Chao X, Li W, Liu M, Liu P (2012) The effects of chronic copper exposure on the amyloid protein metabolism associated genes' expression in chronic cerebral hypoperfused rats. Neurosci Lett. doi:10.1016/j.neulet.2012.04.030

    Google Scholar 

  16. An L, Liu S, Yang Z, Zhang T Cognitive impairment in rats induced by nano-CuO and its possible mechanisms. Toxicol Lett 213(2):220–227. doi:10.1016/j.toxlet.2012.07.007

  17. Pal A, Badyal RK, Vasishta RK, Attri SV, Thapa BR, Prasad R Biochemical, Histological, and Memory Impairment Effects of Chronic Copper Toxicity: A Model for Non-Wilsonian Brain Copper Toxicosis in Wistar Rat. Biol Trace Elem Res. doi:10.1007/s12011-013-9665-0

  18. Narasaki M (1980) Laboratory and histological similarities between Wilson's disease and rats with copper toxicity. Acta Med Okayama 34(2):81–90

    PubMed  CAS  Google Scholar 

  19. Scriver CR (1995) The Metabolic Basis of Inherited Disease. McGraw-Hill Information Services Company

  20. European Association for Study of L EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol 56 (3):671–685. doi:10.1016/j.jhep.2011.11.007

  21. Prasad R, Kaur G, Walia BN (1998) A critical evaluation of copper metabolism in Indian Wilson's disease children with special reference to their phenotypes and relatives. Biol Trace Elem Res 65(2):153–165. doi:10.1007/bf02784267

    Article  PubMed  CAS  Google Scholar 

  22. Bancroft JD, Gamble M (2008) Theory and Practice of Histological Techniques. Elsevier Science Health Science Division

  23. Hall AP, Davies W, Stamp K, Clamp I, Bigley A Comparison of Computerized Image Analysis with Traditional Semiquantitative Scoring of Perls' Prussian Blue Stained Hepatic Iron Deposition. Toxicol Pathol. doi:10.1177/0192623313476576

  24. Scheuer PJ, Williams R, Muir AR (1962) Hepatic pathology in relatives of patients with haemochromatosis. J Pathol Bacteriol 84:53–64

    Article  PubMed  CAS  Google Scholar 

  25. Barry M (1974) Liver iron concentration, stainable iron, and total body storage iron. Gut 15(5):411–415

    Article  PubMed  CAS  Google Scholar 

  26. Squitti R, Barbati G, Rossi L, Ventriglia M, Dal Forno G, Cesaretti S, Moffa F, Caridi I, Cassetta E, Pasqualetti P, Calabrese L, Lupoi D, Rossini PM (2006) Excess of nonceruloplasmin serum copper in AD correlates with MMSE, CSF [beta]-amyloid, and h-tau. Neurology 67(1):76–82. doi:10.1212/01.wnl.0000223343.82809.cf

    Article  PubMed  CAS  Google Scholar 

  27. Squitti R, Pasqualetti P, Dal Forno G, Moffa F, Cassetta E, Lupoi D, Vernieri F, Rossi L, Baldassini M, Rossini PM (2005) Excess of serum copper not related to ceruloplasmin in Alzheimer's disease. Neurology 64(6):1040–1046. doi:10.1212/01.wnl.0000154531.79362.23

    Article  PubMed  CAS  Google Scholar 

  28. Arnal N, Cristalli DO, de Alaniz MJ, Marra CA Clinical utility of copper, ceruloplasmin, and metallothionein plasma determinations in human neurodegenerative patients and their first-degree relatives. Brain Res 1319:118–130. doi:10.1016/j.brainres.2009.11.085

  29. Brewer GJ Metals in the causation and treatment of Wilson’s disease and Alzheimer’s disease, and copper lowering therapy in medicine. Inorg Chim Acta 393(0):135–141. doi:10.1016/j.ica.2012.06.014

  30. Texel SJ, Xu X, Harris ZL (2008) Ceruloplasmin in neurodegenerative diseases. Biochem Soc Trans 36(6):1277–1281. doi:10.1042/BST0361277

    Article  PubMed  CAS  Google Scholar 

  31. Sternlieb I, Morell AG, Tucker WD, Greene MW, Scheinberg IH (1961) The incorporation of copper into ceruloplasmin in vivo: studies with copper and copper. J Clin Invest 40(10):1834–1840. doi:10.1172/JCI104407

    Article  PubMed  CAS  Google Scholar 

  32. Matsuda I, Pearson T, Holtzman NA (1974) Determination of apoceruloplasmin by radioimmunoassay in nutritional copper deficiency, Menkes' kinky hair syndrome, Wilson's disease, and umbilical cord blood. Pediatr Res 8(10):821–824. doi:10.1203/00006450-197410000-00001

    Article  PubMed  CAS  Google Scholar 

  33. Multi-copper oxidases (1997). World Scientific, Singapore

  34. Holtzman NA, Elliott DA, Heller RH (1966) Copper intoxication. Report of a case with observations on ceruloplasmin. N Engl J Med 275(7):347–352

    Article  PubMed  CAS  Google Scholar 

  35. Monnot AD, Behl M, Ho S, Zheng W (2011) Regulation of brain copper homeostasis by the brain barrier systems: effects of Fe-overload and Fe-deficiency. Toxicol Appl Pharmacol 256(3):249–257. doi:10.1016/j.taap.2011.02.003

    Article  PubMed  CAS  Google Scholar 

  36. Choi BS, Zheng W (2009) Copper transport to the brain by the blood–brain barrier and blood–CSF barrier. Brain Res 1248:14–21. doi:10.1016/j.brainres.2008.10.056

    Article  PubMed  CAS  Google Scholar 

  37. Roberts EA, Cox DW (1998) Wilson disease. Baillieres Clin Gastroenterol 12(2):237–256

    Article  PubMed  CAS  Google Scholar 

  38. MacDonald RA (1967) Tissue iron and hemochromatosis. Comparative studies in Denver and Boston. Arch Pathol 84(5):543–551

    PubMed  CAS  Google Scholar 

  39. Macdonald RA, Pechet GS (1964) Liver and tissue iron: comparative studies and significance for hemochromatosis. Arch Pathol 77:348–353

    PubMed  CAS  Google Scholar 

  40. Weinfeld A, Lundin P, Lundvall O (1968) Significance for the diagnosis of iron overload of histochemical and chemical iron in the liver of control subjects. J Clin Pathol 21(1):35–40

    Article  PubMed  CAS  Google Scholar 

  41. Ding B, Chen KM, Ling HW, Sun F, Li X, Wan T, Chai WM, Zhang H, Zhan Y, Guan YJ (2009) Correlation of iron in the hippocampus with MMSE in patients with Alzheimer's disease. J Magn Reson Imaging 29(4):793–798. doi:10.1002/jmri.21730

    Article  PubMed  Google Scholar 

  42. Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR (1998) Copper, iron, and zinc in Alzheimer's disease senile plaques. J Neurol Sci 158(1):47–52

    Article  PubMed  CAS  Google Scholar 

  43. Barnham KJ, Haeffner F, Ciccotosto GD, Curtain CC, Tew D, Mavros C, Beyreuther K, Carrington D, Masters CL, Cherny RA, Cappai R, Bush AI (2004) Tyrosine gated electron transfer is key to the toxic mechanism of Alzheimer's disease beta-amyloid. FASEB J 18(12):1427–1429. doi:10.1096/fj.04-1890fje

    PubMed  CAS  Google Scholar 

  44. Huang X, Atwood CS, Hartshorn MA, Multhaup G, Goldstein LE, Scarpa RC, Cuajungco MP, Gray DN, Lim J, Moir RD, Tanzi RE, Bush AI (1999) The A beta peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry 38(24):7609–7616. doi:10.1021/bi990438f

    Article  PubMed  CAS  Google Scholar 

  45. Schubert D, Chevion M (1995) The role of iron in beta amyloid toxicity. Biochem Biophys Res Commun 216(2):702–707

    Article  PubMed  CAS  Google Scholar 

  46. Riederer P, Sofic E, Rausch WD, Schmidt B, Reynolds GP, Jellinger K, Youdim MB (1989) Transition metals, ferritin, glutathione, and ascorbic acid in Parkinsonian brains. J Neurochem 52(2):515–520

    Article  PubMed  CAS  Google Scholar 

  47. Tiffany-Castiglioni E, Hong S, Qian Y (2011) Copper handling by astrocytes: insights into neurodegenerative diseases. Int J Dev Neurosci 29(8):811–818. doi:10.1016/j.ijdevneu.2011.09.004

    Article  PubMed  CAS  Google Scholar 

  48. Allaman I, Belanger M, Magistretti PJ Astrocyte-neuron metabolic relationships: for better and for worse. Trends Neurosci 34(2):76–87. doi:10.1016/j.tins.2010.12.001

  49. Gibbs ME, Hutchinson D, Hertz L (2008) Astrocytic involvement in learning and memory consolidation. Neurosci Biobehav Rev 32(5):927–944. doi:10.1016/j.neubiorev.2008.02.001

    Article  PubMed  Google Scholar 

  50. Huang X, Cuajungco MP, Atwood CS, Hartshorn MA, Tyndall JD, Hanson GR, Stokes KC, Leopold M, Multhaup G, Goldstein LE, Scarpa RC, Saunders AJ, Lim J, Moir RD, Glabe C, Bowden EF, Masters CL, Fairlie DP, Tanzi RE, Bush AI (1999) Cu(II) potentiation of Alzheimer abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem 274(52):37111–37116

    Article  PubMed  CAS  Google Scholar 

  51. White AR, Reyes R, Mercer JF, Camakaris J, Zheng H, Bush AI, Multhaup G, Beyreuther K, Masters CL, Cappai R (1999) Copper levels are increased in the cerebral cortex and liver of APP and APLP2 knockout mice. Brain Res 842(2):439–444

    Article  PubMed  CAS  Google Scholar 

  52. Duce JA, Tsatsanis A, Cater MA, James SA, Robb E, Wikhe K, Leong SL, Perez K, Johanssen T, Greenough MA, Cho HH, Galatis D, Moir RD, Masters CL, McLean C, Tanzi RE, Cappai R, Barnham KJ, Ciccotosto GD, Rogers JT, Bush AI Iron-export ferroxidase activity of beta-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell 142(6):857–867. doi:10.1016/j.cell.2010.08.014

  53. Behnke S, Berg D, Becker G (2003) Does ultrasound disclose a vulnerability factor for Parkinson's disease? J Neurol 250 Suppl 1:I24-27. doi:10.1007/s00415-003-1104-0 [doi]

  54. Matyash V, Kettenmann H Heterogeneity in astrocyte morphology and physiology. Brain Res Rev 63(1–2):2–10. doi:10.1016/j.brainresrev.2009.12.001

Download references

Acknowledgments

The authors acknowledge the financial assistance provided by the Indian Council of medical Research (ICMR, New Delhi) as JRF to Mr. Amit Pal [3/1/3/JRF-2009/MPD-13 (11279)]. Special thanks to Dr. J.K. Pradhan of Jaypee University, Solan for providing facilities and guidance to carry out tissue Fe estimations. Authors also acknowledge the support of Mr. Charan Singh (for staining studies) and Mr. Rakesh Mohindra (for statistics).

Conflict of interest

Authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Biochemistry, PGIMER, Chandigarh, 160012, India

    Amit Pal & Rajendra Prasad

  2. Department of Histopathology, PGIMER, Chandigarh, India

    Rakesh kumar Vasishta

Authors
  1. Amit Pal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rakesh kumar Vasishta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rajendra Prasad
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rajendra Prasad.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pal, A., kumar Vasishta, R. & Prasad, R. Hepatic and Hippocampus Iron Status is not Altered in Response to Increased Serum Ceruloplasmin and Serum “Free” Copper in Wistar Rat Model for Non-Wilsonian Brain Copper Toxicosis. Biol Trace Elem Res 154, 403–411 (2013). https://doi.org/10.1007/s12011-013-9753-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-013-9753-1

Keywords

Search

Navigation