Skip to main content
Log in

Excessive iron accumulation in the brain: A possible potential risk of neurodegeneration in Parkinson's disease

  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Summary

In this study a chronic cerebral iron-loaded model was established by feeding mice with high iron diet. Data indicated that brain iron concentrations were significantly increased in iron-fed mice compared with those of controls. A significant increase in oxidized glutathione (GSSG), decrease in total glutathione (oxidized and reduced glutathione, GSSG + GSH), and therefore increase in the GSSG/(GSSG + GSH) ratios were observed in iron-loaded mice. Hydroxyl radical (.OH) levels in striatum and brainstem were also significantly increased. Excessive iron alone did not change either dopamine (DA) or lipid peroxidation (LPO) concentrations in striatum. However, a single injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30mg/kg, i.p.) into the iron-loaded mice caused a great enhancement in all these biochemical abnormalities. These findings suggest that iron does induce oxidative stress, but not severely injury neurons per se. Excessive iron accumulation in the brain, however, is a potential risk for neuronal damage, which may promote by triggering factor(s). This supports the hypothesis that excessive cerebral iron may contribute to the aetiology of Parkinson's disease (PD).

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Adams JD, Lauterberg BH, Mitchell JR (1983) Plasma glutathione and glutathione dissulfide in the rat: regulation and response to oxidative stress. J Pharmacol Exp Ther 227: 749–754

    Google Scholar 

  • Aebi HE (1983) Catalase. In: Burgmeyer HU (ed) Methods of enzymatic analysis, 3rd ed, vol 3. Academic Press, New York, pp 273–286

    Google Scholar 

  • 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: reveal by tirilazad mesylate (U74006F). Mol Chem Neuropathol 20: 147–162

    Google Scholar 

  • Ambani LM, Van Woert MH, Murphy S (1975) Brain peroxidase and catalase in Parkinson's disease. Arch Neurol 32: 114–118

    Google Scholar 

  • Ben-Shachar D, Youdim MBH (1991) Intranigral iron injection induces behavioral and biochemical parkinsonism in rats. J Neurochem 57: 2133–2135

    Google Scholar 

  • Braughler JM, Chase RL, Pregenzer JF (1987) Oxidation of ferrous iron during peroxidation of lipid substrates. Biochem Biophys Acta 921: 457–464

    Google Scholar 

  • Cooper AJL, Pulsinelli WA, Duffy TE (1980) Glutathione and ascorbate during ischemia and postischemic reperfusion in rat brain. J Neurochem 35: 1242–1245

    Google Scholar 

  • Dexter DT, Wells FR, Lees AJ, Agid F, Agid Y, Jenner P, Marsden CD (1989a) Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson's disease. J Neurochem 52: 1830–1836

    Google Scholar 

  • Dexter DT, Jenner P, Marsden CD (1989b) Oxyferriscorbone elevates the total iron content of blood but not brain. Mov Disord 4: 176–182

    Google Scholar 

  • Dexter DT, Cater CJ, Wells FR, Javoy-Agid F, Agid Y, Lees A, Jenner P, Marsden CD (1989c) Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease. J Neurochem 52: 381–389

    Google Scholar 

  • Di Monte DA, Chan P, Sandy MS (1992) Glutathione in Parkinson's disease: a link between oxidative stress and mitochondria damage? Ann Neurol 32: S111–115

    Google Scholar 

  • Earle KM (1968) Studies in Parkinson's disease including x-ray fluorescent spectroscopy of formalin fixed tissue. J Neuropathol Exp Neurol 27: 1–14

    Google Scholar 

  • Flohe L, Gunzler WA (1984) Assays of glutathione peroxidase. In: Packer L (ed) Methods in enzymology, vol 105. Oxygen radicals in biological systems. Academic Press, New York, pp 114–121

    Google Scholar 

  • 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: 221–235

    Google Scholar 

  • Gerlach M, Riederer P, Przuntek H, Youdim MBH (1991) MPTP mechanisms of neurotoxicity and their implications for Parkinson's disease. Eur J Pharmacol (Mol Pharmacol Sect) 208: 273–286

    Google Scholar 

  • Gerlach M, Ben-Shachar D, Riederer P, Youdim MBH (1994) Altered brain metabolism of iron as a cause of neurodegenerative disease? J Neurochem 63: 793–807

    Google Scholar 

  • Gerlach M, Götz M, Dirr A, Kupsch A, Janetzky B, Oertel W, Sautter J, Schwarz J, Reichmann H, Riederer P (1996) Acute MPTP treatment produces no changes in mitochondrial complex activities and indices of oxidative damage in the common marmoset ex vivo one week after exposure to the toxin. Neurochem Int 28: 41–49

    Google Scholar 

  • Götz ME, Künig G, Riederer P, Youdim MBH (1994) Oxidative stress: free radical production in neural degeneration. Pharmacol Ther 63: 37–122

    Google Scholar 

  • Hallgren B, Sourander P (1958) The effect of age on the nonhaemin iron in the human brain. J Neurochem 3: 41–51

    Google Scholar 

  • Halliwell B (1992) Reactive oxygen species and the central nervous system. J Neurochem 59: 1609–1623

    Google Scholar 

  • Heales SJ, Davies SE, Bates TE, Clark JB (1995) Depletion of brain glutathione is accompanied by impaired mitochondrial function and decreased N-acetyl aspartate concentration. Neurochem Res 20: 31–38

    Google Scholar 

  • Hirsch EC, Graybiel AM, Agid Y (1988) Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease. Nature 334: 345–348

    Google Scholar 

  • Jellinger K, Kienzl E, Rumperlmair G, Riederer P, Stachelberger H, Ben-Shachar D, Youdim MBH (1992) Iron-melanin complex in substantia nigra of parkinsonian brains: an x-ray microanalysis. J Neurochem 59: 1168–1171

    Google Scholar 

  • Jenner P (1991) Oxidative stress as a cause of Parkinson's disease. Acta Neurol Scand [Suppl] 136: 6–15

    Google Scholar 

  • Jenner P (1993) Altered mitochondria function, iron metabolism and glutathione levels in Parkinson's disease. Acta Neurol Scand [Suppl] 146: 6–13

    Google Scholar 

  • Kass GEN, Wright JM, Nicoatera P, Orrenius S (1988) The mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity: role of intracellular calcium. Arch Biochem Biophys 260: 789–797

    Google Scholar 

  • 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: 25–35

    Google Scholar 

  • Kish SJ, Morito C, Hornykiewicz O (1985) Glutathione peroxidase activity in Parkinson's disease brain. Neurosci Lett 58: 343–346

    Google Scholar 

  • Langston JW, Ballard PA, Tetrud JW, Irwin I (1983) Chronic parkinsonism in human due to a product of meperidine-analog synthesis. Science 219: 979–980

    Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193: 265–275

    Google Scholar 

  • Nicklas WJ, Vyas I, Heikilla RE (1985) Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenylpyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetraphydrophyridine. Life Sci 36: 2503–2508

    Google Scholar 

  • Perry TL, Godin DV, Hansen S (1982) Parkinson's disease: a disorder due to nigral glutathione deficiency? Neurosci Lett 33: 305–310

    Google Scholar 

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

    Google Scholar 

  • Riederer P, Konradi C, Hebenstreit G, Youdim MBH (1989b) Neurochemical perspectives to the function of monoamine oxidase. Acta Neurol Scand 126: 41–45

    Google Scholar 

  • Sengstock GJ, Olanow CW, Dunn AJ, Arendash GW (1992) Iron induces degeneration of nigrostriatal neurons. Brain Res Bull 28: 645–649

    Google Scholar 

  • Sengstock GJ, Olanow CW, Menzies RA, Dunn AJ, Arendash GW (1993) Infustion of iron into the rat substantia nigra: nigral pathology and dose dependent loss of dopaminergic markers. J Neurosci Res 35: 67–82

    Google Scholar 

  • 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: 82–94

    Google Scholar 

  • Singer TP, Castagnoli N Jr, Ramsay RR, Treor AJ (1987) Biochemical events in the development of parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J Neurochem 49: 1–8

    Google Scholar 

  • Sofic E, Riederer P, Heinsen H, Beckmann H, Reynolds GP, Hebenstreit G, Youdim MBH (1988) Increase iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J Neural Transm 74: 199–205

    Google Scholar 

  • 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: 978–982

    Google Scholar 

  • Sofic E, Lange KW, Jellinger K, Riederer P (1992) Reduced and oxidized glutathione in the substantia nigra of patients with Parkinson's disease. Neurosci Lett 142: 128–130

    Google Scholar 

  • Spina MB, Cohen G (1989) Dopamine turnover and glutathione oxidation: implications for Parkinson disease. Proc Natl Acad Sci USA 86: 1398–1400

    Google Scholar 

  • Taylor E, Morgan E (1990) Developmental changes in transferrin and iron uptake by the brain in the rat. Dev Brain Res 55: 35–42

    Google Scholar 

  • Tietze F (1969) Enzymic method for quantitative determination of nanogram amount of total and oxidized glutathione. Anal Biochem 27: 502–522

    Google Scholar 

  • Uchiyama M, Mihara M (1978) Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 86: 271–278

    Google Scholar 

  • 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: 310–314

    Google Scholar 

  • Werner P, Cohen G (1991) Intramitochondrial formation of oxidized glutathione during oxidation of benzylamine by monoamine oxidase. FEES Lett 280: 44–46

    Google Scholar 

  • Young VW, Perry TL, Krisman AA (1986) Depletion of glutathione in brainstem of mice caused by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is prevented by antioxidant pretreatment. Neurosci Lett 63: 56–60

    Google Scholar 

  • Youdim MBH, Riederer P (1993) The role of iron in senescence of dopaminergic neurons in Parkinson's disease. J Neural Transm [Suppl] 40: 57–67

    Google Scholar 

  • Zaleska MM, Floyd RA (1985) Regional lipid peroxidation in rat brain in vitro: possible role of endogenous iron. Neurochem Res 10: 397–410

    Google Scholar 

  • 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: 1097–1101

    Google Scholar 

  • Zigmond MJ, Abercrombie ED, Berger TW, Grace AA, Stricker EM (1990) Compensations after lesions of central dopaminergic neurons: some clinical and basic implications. Trends Neurosci 13: 290–296

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lan, J., Jiang, D.H. Excessive iron accumulation in the brain: A possible potential risk of neurodegeneration in Parkinson's disease. J. Neural Transmission 104, 649–660 (1997). https://doi.org/10.1007/BF01291883

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01291883

Keywords

Navigation