Journal of Neural Transmission

, Volume 104, Issue 4–5, pp 469–481 | Cite as

Desferrioxamine and vitamin E protect against iron and MPTP-induced neurodegeneration in mice

  • J. Lan
  • D. H. Jiang
Parkinson's Disease and Allied Conditions


To elucidate the neuroprotective effects of the iron chelator desferrioxamine (DFO) and the antioxidant vitamin E on excessive iron-induced free radical damage, a chronic iron-loaded mice model was established. The relationship between striatal iron content, oxidized to reduced glutathione ratio, hydroxyl radical (.OH) levels and dopamine concentrations were observed in DFO or vitamin E pretreated iron-loaded/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57BL/6 mice. The results demonstrated that both DFO and vitamin E inhibit the iron accumulation and thus reverses the increase in oxidized glutathione (GSSG), oxidized to reduced glutathione ratios, .OH and lipid peroxidation levels. The striatal dopamine concentration was elevated to normal value. Our data suggested that: (1) iron may induce neuronal damage and thus excessive iron in the brain may contribute to the neuronal loss in PD; (2) iron chelators and antioxidants may serve as potential therapeutic agents in retarding the progression of neurodegeneration.


Iron MPTP DFO vitamin E neurodegeneration 


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  1. Akai F, Maeda M, Hashimoto S, Taneda M, Takagi H (1995) A new animal model of cerebral infarction: magnetic embolization with carbonyl iron particles. Neurosci Lett 194: 139–141PubMedGoogle Scholar
  2. Althaus JS, Andrus PK, Williams CM, Von Voigtlander PF, Cazers AR, Hall ED (1993) The use of salicylate hydroxylation to detect hydroxyl radical generation in ischemic and traumatic brain injury: reversal by tirilazad mesylate (U-74006F). Mol Chem Neuropath 20: 147–162Google Scholar
  3. Andreoli SP, Cohen M (1989) Intraperitoneal desferrioxamine therapy for iron overload in children undergoing CAPD. Kidney Int 35: 1330–1335PubMedGoogle Scholar
  4. Arendash GW, Sengstock GJ, Olanow CW, Barone S Jr, Dunn AJ (1994) Intranigral iron infusion as a model for Parkinson's disease. In: Woodruff ML, Nonneman AJ (eds) Toxin-induced models of neurological disorders. Plenum Press, New York, pp 175–212Google Scholar
  5. Ben-Shachar D, Youdim MBH (1991a) Intranigral iron injection induces behavioral and biochemical parkinsonism in rats. J Neurochem 57: 2133–2135PubMedGoogle Scholar
  6. Ben-Schachar D, Eshel G, Finberg JPM, Youdim MBH (1991b) The iron chelator desferrioxamine (desferal) retards 6-hydroxydopamine-induced degeneration of nigrostriatal dopamine neurons. J Neurochem 56: 1441–1444PubMedGoogle Scholar
  7. Ben-Schachar D, Eshel G, Riederer P, Youdim MBH (1992) Role of iron and iron chelation in dopaminergic-induced neurodegeneration: implication for PD. Ann Neurol 32: S105–111PubMedGoogle Scholar
  8. Cadet JL, Katz M, Jackson-Lewis V, Fahn S (1989) Vitamin E attenuates the toxic effects of intrastriatal injection of 6-hydroxydopamine (6-OHDA) in rats: behavioral and biochemical evidence. Brain Res 476: 10–15PubMedGoogle Scholar
  9. Ceccarelli D, Gallesi D, Giovannini F, Ferrali M, Masini A (1995) Relationship between free iron level and rat liver mitochondrial dysfunction in experimental dietary iron overload. Biochem Biophy Res Commun 209: 53–59Google Scholar
  10. Cohen A (1990) Current status of iron chelation therapy with desferrioxamine. Semin Hematol 27: 86–90PubMedGoogle Scholar
  11. Cooper AJL, Pulsinelli WA, Duffy TE (1980) Glutathione and ascorbate during ischemia and postischemic reperfusion in rat brain. J Neurochem 35: 1242–1245PubMedGoogle Scholar
  12. Crowe A, Morgan EH (1994) Effects of chelators on iron uptake and release by the brain in the rat. Neurochem Res 19: 71–76PubMedGoogle Scholar
  13. Crowe A, Morgan EH (1996) Iron and copper interact during their uptake and deposition in the brain and other organs of developing rats exposed to dietary excess of the two metals. J Nutr 126: 183–194PubMedGoogle Scholar
  14. Darley-Usmar VM, Hersey A, Garland LG (1989) A method for the comparative assessment of antioxidants as peroxyl radical scavengers. Biochem Pharmacol 38: 1465–1469PubMedGoogle Scholar
  15. Denicola A, Souza JM, Gatti RM, Augusto O, Radi R (1995) Desferrioxamine inhibition of the hydroxyl radical-like reactivity of peroxynitrite: role of the hydroxamic groups. Free Radic Biol Med 19: 11–19PubMedGoogle Scholar
  16. Dexter DT, Wells FR, Lees AJ, Agid F, Agid Y, Jenner P, Marsden CD (1989) Increased nigral iron content and alterations in other metal ions occurring brain in Parkinson's disease. J Neurochem 52: 1830–1836PubMedGoogle Scholar
  17. Dexter DT, Nanayakkara I, Goss-Sampson MA, Muller DPR, Harding AE, Marsden CD, Jenner P (1994) Nigral dopaminergic cell loss in vitamin E deficient rats. Neuroreport 5: 1773–1776PubMedGoogle Scholar
  18. Erin AN, Spirin MM, Tabidze LV, Kagan VE (1984) Formation of tocopherol with fatty acids; a hypothetical mechanism of stabilization of biomembrane by vitamin E. Biochem Biophys Acta 774: 96–102PubMedGoogle Scholar
  19. Fahn S (1992) A pilot trial of high-dose alpha-tocopherol and ascorbate in early Parkinson's disease. Ann Neurol 32 [Suppl]: 128–132Google Scholar
  20. Floyd RA, Watson JJ, Wong PK (1984) Sensitive assay of hydroxyl free radical formation utilizing high pressure liquid chromatography with electrochemical detection of phenol and salicylate hydroxylation products. J Biochem Biophys Methods 10: 221–235PubMedGoogle Scholar
  21. Gerlach M, Ben-Shachar D, Riederer P, Youdim MBH (1994) Altered brain metabolism of iron as a cause of neurodegenerative disease? J Neurochem 63: 793–807PubMedGoogle Scholar
  22. Götz ME, Künig G, Riederer P, Youdim MBH (1994) Oxidative stress: free radical production in neural degeneration. Pharmacol Ther 63: 37–122PubMedGoogle Scholar
  23. Halliwell B (1987) Oxidants and human disease: some new concepts. FASEB J 1: 358–364PubMedGoogle Scholar
  24. Halliwell B (1989) Protection against tissue damage in vivo by desferrioxamine: what is mechanisms of action? Free Radic Biol Med 7: 645–651PubMedGoogle Scholar
  25. Halliwell B, Gutteridge JM (1984) Oxygen toxicity, oxygen radicals, transition metals and disease. Biochem J 219: 1–14PubMedGoogle Scholar
  26. Halliwell B, Gutteridge JM (1986) Oxygen free radicals and iron in relation to biology and medicine: some problems and concepts. Arch Biochem Biophys 246: 501–514PubMedGoogle Scholar
  27. Hartley A, Davies M, Rice-Evans C (1990) Desferrioxamine as a lipid chain-breaking antioxidant in sickle erythrocyte membranes. FEBS Lett 264: 145–148PubMedGoogle Scholar
  28. Ikeda Y, Ikeda K, Long DM (1989) Protective effect of the iron chelator deferoxamine on cold-induced brain edema. J Neurosurg 71: 233–238PubMedGoogle Scholar
  29. Jenner P (1993) Altered mitochondria function, iron metabolism and glutathione levels in Parkinson's disease. Acta Neurol Scand 87 [Suppl 46]: 6–13Google Scholar
  30. Keberle H (1964) The biochemistry of desferrioxamine and its relation to iron metabolism. Ann NY Acad Sci 119: 758–768PubMedGoogle Scholar
  31. Kim C, Speisky MB, Kharouba SN (1987) Rapid and sensitive method for measuring norepinephrine, dopamine, 5-hydroxytryptamine and their major metabolites in rat brain by high-performance liquid chromatography. J Chromatogr 386: 25–35PubMedGoogle Scholar
  32. Krause GS, Kumar K, Whilt BC, Aust SD, Wiegenstein JG (1986) Ischemia, resuscitation, and reperfusion: mechanisms of tissue injury and prospects for protection. Am Heart J 111: 768–780PubMedGoogle Scholar
  33. Lin XM, Waller SB, Dietz NJ (1995) Effects of deferoxamine and a diet deficient in vitamin E on isoelectric electroencephalographic responses associated with ischemia by the four vessel occlusion method. Life Sci 57: 989–996PubMedGoogle Scholar
  34. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193: 265–275PubMedGoogle Scholar
  35. Mizoi K, Suzuki J, Imazumi S, Yoshimoto T (1986) Development of new cerebral protective agents: the free radical scavengers. Neurol Res 8: 75–80PubMedGoogle Scholar
  36. Odunze IN, Klaidman LK, Adams JD Jr (1990) MPTP toxicity in the mouse brain and vitamin E. Neurosci Lett 108: 346–349PubMedGoogle Scholar
  37. Packer L, Landvik S (1990) Vitamin E in biological systems. Adv Exp Med Biol 264: 93–103PubMedGoogle Scholar
  38. Parkinson Study Group (1989a) Effect of deprenyl on the progression of disability in early Parkinson's disease. N Engl J Med 321: 1364–1371Google Scholar
  39. Parkinson Study Group (1989b) DATATOP: a multicenter controlled clinical trial in early Parkinson's disease. Arch Neurol 46: 1052–1060Google Scholar
  40. Parkinson Study Group (1993) Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. N Engl J Med 328: 176–183Google Scholar
  41. Perry TL, Yong VW, Clavier RM, Jones K, Wright JM, Foulks LG, Wall RA (1985) Partial protection from the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by four different antioxidants in the mouse. Neurosci Lett 60: 109–114PubMedGoogle Scholar
  42. Riederer P, Sofic E, Rausch WD, Schmidt B, Reynolds GP, Jellinger K, Youdim MBH (1989) Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem 52: 515–520PubMedGoogle Scholar
  43. Saunders RD, Dugan LL, Demediuk P, Means ED, Horrocks LA, Anderson DK (1987) Effects of methylprednisolone and the combination of α-tecopherol and selenium on arachidonic acid metabolism and lipid peroxidation in traumatized spinal cord tissue. J Neurochem 49: 24–31PubMedGoogle Scholar
  44. Sengstock GJ, Olanow CW, Dunn AJ, Arendash GW (1992) Iron induces degeneration of nigrostriatal neurons. Brain Res Bull 28: 645–649PubMedGoogle Scholar
  45. Sengstock GJ, Olanow CW, Menzies RA, Dunn AJ, Arendash GW (1993) Infusion of iron into the rat substantia nigra: nigral pathology and dose dependent loss of dopaminergic markers. J Neurosci Res 35: 67–82PubMedGoogle Scholar
  46. Sengstock GJ, Olanow CW, Dunn AJ, Barone S Jr, Arendash GW (1994) Progressive changes in striatal dopaminergic markers, nigral volume, and rotational behavior following iron infusion into the rat substantia nigra. Exp Neurol 130: 82–94PubMedGoogle Scholar
  47. Sharma BK, Bacon BR, Britton RS, Park CH, Magiera CJ, O'Neill R, Dalton N, Smanik P, Speroff T (1990) Prevention of hepatocyte injury and lipid peroxidation by iron chelators and α-tocopherol in isolated iron loaded rat hepatocytes. Hepatology 12: 31–39PubMedGoogle Scholar
  48. Sinaceur J, Ribiere C, Nordmann J, Nordmann R (1984) Desferrioxamine: a scavenger of superoxide radicals? Biochem Pharmacol 33: 1693–1694PubMedGoogle Scholar
  49. Sofic E, Paulus W, Jellinger K, Riederer P, Youdim MBH (1991) Selective increase of iron in substantia nigra zona compacta of parkinsonian brain. J Neurochem 56: 978–982PubMedGoogle Scholar
  50. Soriani M, Mazzuca S, Quaresima V, Minetti M (1993) Oxidation of desferrioxamine to nitroxide free radical by activited human neutrophils. Free Radic Biol Med 14: 589–599PubMedGoogle Scholar
  51. Spina MB, Cohen G (1989) Dopamine turnover and glutathione oxidation: implications for Parkinson's disease. Proc Natl Acad Sci USA 86: 1398–1400PubMedGoogle Scholar
  52. Taylor E, Morgan E(1990) Developmental changes in transferrin and iron uptake by the brain in the rat. Dev Brain Res 55: 35–42Google Scholar
  53. Tector AJ, Olynyk JK, Britton RS, Janney CG, O'Neill R, Bacon BR (1995) Hepatic mitochondrial oxidative metabolism and lipid peroxidation in iron-loaded rats fed ethanol. J Lab Clin Med 126: 597–602PubMedGoogle Scholar
  54. Tietze F (1969) Enzymic method for quantitative determination of nanogram amount of total and oxidized glutathione. Anal Biochem 27: 502–522PubMedGoogle Scholar
  55. Tsukamoto H, Horne W, Kamimura S, Niemelä O, Parkkila S, Ylä-Herttuala S (1995) Experimental liver cirrhosis induced by alcohol and iron. J Clin Invest 96: 620–630PubMedGoogle Scholar
  56. Uchiyama M, Mihara M (1978) Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 86: 271–278PubMedGoogle Scholar
  57. Uitti RJ, Rajput AH, Rozdilsky B, Bickis M, Wollin T, Yuen WK (1989) Regional metal concentrations in Parkinson's disease, other chronic neurological disease, and control brains. Can J Neurol Sci 16: 310–314PubMedGoogle Scholar
  58. Vatassery GT, Brin MF, Fahn S, Kayden HJ, Traber MG (1988) Effect of high doses of dietary vitamin E on the concentrations of vitamin E in several brain regions, plasma, liver, and adipose tissue of rats. J Neurochem 51: 621–623PubMedGoogle Scholar
  59. Ward RJ, Dexter D, Florence A, Aouad F, Hider R, Jenner P, Crichton R (1995) Brain iron in the ferrocene-loaded rat: its chelation and influence on dopamine metabolism. Biochem Pharmacol 49: 1821–1826PubMedGoogle Scholar
  60. Wolfe L, Olivier N, Sallau D (1985) Prevention of cardiac disease by subcutaneous desferrioxamine in patients with thalassemia major. N Engl J Med 312: 1600–1604PubMedGoogle Scholar
  61. Youdim MBH, Ben-Shachar D, Eshel G, Finberg JPM, Riederer P (1993) The neurotoxicity of iron and nitric oxide: relevance to the etiology of Parkinson's disease. In: Narabayashi H, Nagatsu T, Yanagisawa N, Mizuno Y (eds) Advances in neurology. Raven Press, New York, pp 259–266Google Scholar
  62. Zecca L, Pietra R, Goj C, Mecacci C, Radice D, Sabbioni E (1994) Iron and other metals in neuromelanin, substantia nigra, and putamen of human brain. J Neurochem 62: 1097–1101PubMedGoogle Scholar
  63. Zigmond MJ, Aberombie ED, Berger TW, Grace AA, Stricker EM (1990) Compensation after lesions of central dopaminergic neurons: some clinical and basic implications. Trends Neurosci 13: 290–295PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1997

Authors and Affiliations

  • J. Lan
    • 1
  • D. H. Jiang
    • 1
  1. 1.Tianjin Neurological InstituteTianjin Medical University HospitalP. R. China

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