Iron chelating, antioxidant and cytoprotective properties of dopamine receptor agonist; apomorphine

  • M. B. H. Youdim
  • M. Gassen
  • A. Gross
  • S. Mandel
  • E. Grünblatt
Conference paper


There have been many attempts to discover neuroprotective drugs for the treatment of Parkinson’s disease (PD). Many ofthese compounds either do not cross the blood brain barrier or are not very effective in the 6-hydroxydopamine or MPTP (N-methyl-4-phenyl-1,2,3,6-terahydropyridine) models of PD. We have examined several compounds including dopamine receptor agonist bromocritine, lisuride, pergolide and R-apomorphine for their neuroprotective action against the above neurotoxins in PC12 and dopamine neuroblastoma cell lines in culture and in vivo. R-apomorphine exhibited relatively potent neuroprotective action in vitro, cell culture and in vivo as a radical scavenger and iron chelator, because of its catechol structure. The recent clinical trials with apomorphine, where parkinsonian subjects can be weaned off L-dopa would suggest that this drug either exerts a neuroprotective action or that continuous sustained stimulation of dopamine receptor may be responsible for its unusual pharmacological activity. Apomorphine has a far more broad neuroprotective activity in the various models as compared with 1-selegiline and may therefore be an ideal drug to study neuroprotection in parkinsonian subjects with the use of PET or SPECT.


PC12 Cell Iron Chelator Dopamine Neuron Dopamine Receptor Agonist Cytoprotective Property 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Andrew R, Watson D.G., Best S.A., Midgley J.M., Wenlong H, Petty R.K. (1993) The determination of hydroxydopamines and other trace amines in the urine of parkinsonian patients and normal controls. Neurochem Res 18: 1175–1177PubMedCrossRefGoogle Scholar
  2. Ben Shachar D, Eshel G, Finberg J.P., You dim M.B. (1991a) The iron chelator desferrioxamine (Desferal) retards 6-hydroxydopamine-induced degeneration of nigrostriatal dopamine neurons. J Neurochem 56: 1441–1444PubMedCrossRefGoogle Scholar
  3. Ben Shachar D, Riederer P, Youdim M.B. (1991b) Iron-melanin interaction and lipid peroxidation: implications for Parkinson’s disease. J Neurochem 57: 1609–1614PubMedCrossRefGoogle Scholar
  4. Ben Shachar D, Zuk R, Glinka Y (1995) Dopamine neurotoxicity: inhibition of mitochondrial respiration. J Neurochem 64: 718–723PubMedCrossRefGoogle Scholar
  5. Dexter D.T., Jenner P, Schapira A.H., Marsden C.D. (1992) Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia. The Royal Kings and Queens Parkinson’s Disease Research Group. Ann Neurol 32 [Suppl]: S94-100Google Scholar
  6. Esterbauer H (1980) Aldehydes of lipid peroxidation. In: McBrien DCH, Slater TF (eds) Free radicals, peroxidation, and cancer. Academic Press, London, pp 101–122Google Scholar
  7. Glinka Y, Gasswen M, Youdim M.B.H. (1997) Mechanism of 6-hydroxydopamine neurotoxicity. J Neural Transm 50 [Suppl]: 55–66CrossRefGoogle Scholar
  8. Gancher S.T., Nutt J.G., Woodward W.R. (1995) Apomorphine infusional therapy in Parkinson’s disease: clinical utility and lack of tolerance. Mov Disord 10: 37–43PubMedCrossRefGoogle Scholar
  9. Gassen M, Glinka Y, Pinchasi B, You dim M.B. (1996) Apomorphine is a highly potent free radical scavenger in rat brain mitochondrial fraction. Eur J Pharmacol 308: 219–225PubMedCrossRefGoogle Scholar
  10. Gassen M, Gorss A, You dim M.B.H. (1998) Apomorphine enantiomers protect pheochromocytma (PC12) cells from oxidative stress induced by hydrogen peroxide and 6-hydroxydopamine. Mov Disord 13: 242–248PubMedCrossRefGoogle Scholar
  11. Gerlach M, Ben Shachar D, Riederer P, Youdim M.B. (1994) Altered brain metabolism of iron as a cause of neurodegenerative diseases? J Neurochem 63: 793–807PubMedCrossRefGoogle Scholar
  12. Glinka Y, Tipton K.F., You dim M.B. (1996) Nature of inhibition of mitochondrial respiratory complex I by 6-Hydroxydopamine. J Neurochem 66: 2004–2010PubMedCrossRefGoogle Scholar
  13. Grünblatt E, Mandel S, Berkuzki T, You dim M.B.H. (1999) Apomorphine protects against MPTP-induced neurotoxicity in mice. Mov Disord 14: 612–618PubMedCrossRefGoogle Scholar
  14. Jellinger K, Linert L, Kienzl E, Herlinger E, Youdim M.B., Ben Shachar D, Riederer P (1991) Chemical evidence for 6-hydroxydopamine to be an endogenous toxic factor in the pathogenesis of Parkinson’s disease Iron-melanin interaction and lipid peroxidation: implications for Parkinson’s disease. J Neural Transm 57 [Suppl]: 1609–1614Google Scholar
  15. Lees A.J. (1993) Dopamine agonists in Parkinson’s disease: a look at apomorphine. Fundam Clin Pharmacol 7: 121–128PubMedCrossRefGoogle Scholar
  16. Linert W, Herlinger E, Jameson R.F., Keizl E, Jellinger K, You dim M.B.H. (1996) Dopamine, 6-hydroxydopamine, iron and dioxygen, their mutal interaction and possible implications in the development of Parkinson’s disease. Biochim Biophyys Acta 131: 160–168CrossRefGoogle Scholar
  17. Liu J, Mori A (1993) Monoamine metabolism provides an antioxidant defense in the brain against oxidant- and free radical-induced damage. Arch Biochem Biophys 302:118–127PubMedCrossRefGoogle Scholar
  18. Monteiro H.P., Winterbourn C.C., Mytilineou C, Danias P (1989) 6-Hydroxydopamine releases iron from ferritin and promotes ferritin-dependent lipid peroxidation 6-Hydroxydopamine toxicity to dopamine neurons in culture: potentiation by the addition of superoxide dismutase and N-acetylcysteine. Biochem Pharmacol 38: 1872–1875CrossRefGoogle Scholar
  19. Riederer P, Sofie E, Rausch W.D., Jellinger K, Youdim M.B.H. (1989) Transition metals, ferritin, glutathione and ascorbic acid in parkinsonian brains. J Neurochem 52: 515–520PubMedCrossRefGoogle Scholar
  20. Riederer P, Dirr A, Goetz M, Sofie E, Jellinger K, Youdim M.B. (1992) Distribution of iron in different brain regions and subcellular compartments in Parkinson’s disease. Ann Neurol 32 [Suppl]: S101–104PubMedCrossRefGoogle Scholar
  21. Shoham S, Glinka Y, Tenne Z, Youdim M.B.H. (1996) Brain iron: function and dysfunction in relation to cognitive processes. In: Hallberg L, Asp NG (eds) Iron nutrition in health and disease. John Libbey, London, pp 205–218Google Scholar
  22. Sofie E, Paulus W, Jellinger K, Riederer P, Youdim M.B. (1991) Selective increase of iron in substantia nigra zona compacta of parkinsonian brains. J Neurochem 56: 978–982CrossRefGoogle Scholar
  23. Stadtman E.R. (1993) Oxidation of free amino acids and amino acid residues in proteins by radiolysis and by metal-catalyzed reactions. Annu Rev Biochem 62: 797–821PubMedCrossRefGoogle Scholar
  24. Vimard F, Nouvelot A, Duval D (1996) Cytotoxic effects of an oxidative stress on neuronal-like pheochromocytoma cells (PCI2). Biochem Pharmacol 51: 1389–1395PubMedCrossRefGoogle Scholar
  25. Yoritaka A, Hattori N, Uchida K, Tanaka M, Stadtman E.R., Mizuno Y (1996) Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease. Proc Natl Acad Sci USA 93: 2696–2701PubMedCrossRefGoogle Scholar
  26. Youdim M.B.H. (1990) Neuropharmacological and neurochemical aspects of iron deficiency. In: Dobbing J (ed) Brain, behaviour and iron in the infant brain. Springer, Berlin Heidelberg New York Tekyo, pp 83–132Google Scholar
  27. Youdim M.B.H., Riederer P (1997) Understanding Parkinson’s disease. Sci Am 267: 52–59CrossRefGoogle Scholar
  28. Youdim M.B.H., Ben-Shachar D, Riederer P (1993a) Iron-melanin interaction and Parkinson’s disease. NIPS 8: 45–49Google Scholar
  29. Youdim M.B.H., Ben-Shachar D, Riederer P (1993b) The possible role of iron in the etiopathology of Parkinson’s disease. Mov Disord 8: 1–12PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2000

Authors and Affiliations

  • M. B. H. Youdim
    • 1
  • M. Gassen
    • 2
  • A. Gross
    • 1
  • S. Mandel
    • 1
  • E. Grünblatt
    • 1
  1. 1.Department of PharmacologyEve Topf and National Parkinson’s Foundation Centers, Faculty of Medicine, TechnionHaifaIsrael
  2. 2.Merck GmbHBiomedical Research CNSDarmstadtFederal Pepublic of Germany

Personalised recommendations