Clioquinol Protects Against Cell Death in Parkinson’s Disease Models In Vivo and In Vitro

  • Simon Wilkins
  • Colin L. Masters
  • Ashley I. Bush
  • Robert A. Cherny
  • David I. Finkelstein
Conference paper
Part of the Advances in Behavioral Biology book series (ABBI, volume 58)


Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons located in the substantia nigra (SN). Data from our group and others indicate that metals, oxidative stress, and bioavailable reductants provide a possible mechanism for the neurodegeneration observed in PD. 6-Hydroxydopamine (6-OHDA) injection into the nigra of mice resulted in quantified loss of dopaminergic neurons. Oral administration of the metal–protein binding compound clioquinol (CQ) commencing on the day of lesion led to a significant reduction in lesion size. This finding elaborates upon our previous study that long-term pre-treatment with CQ reduced the susceptibility of SN neurons to another neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrapyridine (MPTP) (Kaur et al. 2003), suggesting metals as a common pathway for propagation of these lesions. Human neuroblastoma M17 cells were susceptible to metal, 6-OHDA and dopamine-induced cell death that was partially recoverable by co-incubation with CQ or catalase. These results support the concept that CQ or a similar moderate-affinity transition metal ligand could modulate neuronal oxidative stress and therefore may be a novel class of drug that may be useful for the treatment of PD.


Substantia Nigra Substantia Nigra Neuron Substantia Nigra Cell Dopaminergic Substantia Nigra Neuron Striatal Tyrosine Hydroxylase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study was funded by Prana Biotechnology Ltd., Australian Brain Foundation as well as funds from the National Health and Medical Research Council.


  1. Andrew R, Watson DG, Best SA, Midgley JM, Wenlong H and Petty RK (1993) The determination of hydroxydopamines and other trace amines in the urine of parkinsonian patients and normal controls. Neurochem Res 18: 1175–1177.CrossRefPubMedGoogle Scholar
  2. Barnham KJ, Haeffner F, Ciccotosto GD, Curtain CC, Tew D, Mavros C, Beyreuther K, Carrington D, Masters CL, Cherny RA, Cappai R and Bush AI (2004) Tyrosine gated electron transfer is key to the toxic mechanism of Alzheimer’s disease beta-amyloid. FASEB J 18: 1427–1429.PubMedGoogle Scholar
  3. Bensadoun JC, Mirochnitchenko O, Inouye M, Aebischer P and Zurn AD (1998) Attenuation of 6-OHDA-induced neurotoxicity in glutathione peroxidase transgenic mice. Eur J Neurosci 10: 3231–3236.CrossRefPubMedGoogle Scholar
  4. Ben-Shachar D and Youdim MB (1991) Intranigral iron injection induces behavioral and biochemical “parkinsonism” in rats. J Neurochem 57: 2133–2135.CrossRefPubMedGoogle Scholar
  5. Ben-Shachar D, Eshel G, Finberg JP and Youdim MB (1991) The iron chelator desferrioxamine (Desferal) retards 6-hydroxydopamine-induced degeneration of nigrostriatal dopamine neurons. J Neurochem 56: 1441–1444.CrossRefPubMedGoogle Scholar
  6. Berg D, Gerlach M, Youdim MB, Double KL, Zecca L, Riederer P and Becker G (2001) Brain iron pathways and their relevance to Parkinson’s disease. J Neurochem 79: 225–236.CrossRefPubMedGoogle Scholar
  7. Blum D, Torch S, Lambeng N, Nissou M, Benabid AL, Sadoul R and Verna JM (2001) Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson’s disease. Prog Neurobiol 65: 135–172.CrossRefPubMedGoogle Scholar
  8. Cadet JL, Katz M, Jackson-Lewis V and 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: 10–15.CrossRefPubMedGoogle Scholar
  9. Callio J, Oury TD and Chu CT (2005) Manganese superoxide dismutase protects against 6-hydroxydopamine injury in mouse brains. J Biol Chem 280: 18536–18542.CrossRefPubMedGoogle Scholar
  10. Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA, Barnham KJ, Volitakis I, Fraser FW, Kim Y, Huang X, Goldstein LE, Moir RD, Lim JT, Beyreuther K, Zheng H, Tanzi RE, Masters CL and Bush AI (2001) Treatment with a copper–zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron 30: 665–676.CrossRefPubMedGoogle Scholar
  11. Cohen G and Heikkila RE (1974) The generation of hydrogen peroxide, superoxide radical, and hydroxyl radical by 6-hydroxydopamine, dialuric acid, and related cytotoxic agents. J Biol Chem 249: 2447–2452.PubMedGoogle Scholar
  12. Ding WQ, Liu B, Vaught JL, Yamauchi H and Lind SE (2005) Anticancer activity of the antibiotic clioquinol. Cancer Res 65: 3389–3395.CrossRefPubMedGoogle Scholar
  13. Fahn S and Cohen G (1992) The oxidant stress hypothesis in Parkinson’s disease: evidence supporting it. Ann Neurol 32: 804–812.CrossRefPubMedGoogle Scholar
  14. Faucheux BA, Martin ME, Beaumont C, Hunot S, Hauw JJ, Agid Y and Hirsch EC (2002) Lack of up-regulation of ferritin is associated with sustained iron regulatory protein-1 binding activity in the substantia nigra of patients with Parkinson’s disease. J Neurochem 83: 320–330.CrossRefPubMedGoogle Scholar
  15. Finkelstein DI, Stanic D, Parish CL, Tomas D, Dickson K and Horne MK (2000) Axonal sprouting following lesions of the rat substantia nigra. Neuroscience 97: 99–112.CrossRefPubMedGoogle Scholar
  16. Franklin KBJ and Paxinos G (1997) The mouse brain in stereotaxic coordinates. San Diego: Academic Press.Google Scholar
  17. Fredriksson A, Schroder N, Eriksson P, Izquierdo I and Archer T (1999) Neonatal iron exposure induces neurobehavioural dysfunctions in adult mice. Toxicol Appl Pharmacol 159: 25–30.CrossRefPubMedGoogle Scholar
  18. Halliwell B (2003) Oxidative stress in cell culture: an under-appreciated problem? FEBS Lett 540: 3–6.CrossRefPubMedGoogle Scholar
  19. Halliwell B, Gutteridge JM and Cross CE (1992) Free radicals, antioxidants, and human disease: where are we now? J Lab Clin Med 119: 598–620.PubMedGoogle Scholar
  20. Hirsch EC (1993) Does oxidative stress participate in nerve cell death in Parkinson’s disease? Eur Neurol 33 Suppl 1: 52–59.CrossRefPubMedGoogle Scholar
  21. Izumi Y, Sawada H, Yamamoto N, Kume T, Katsuki H, Shimohama S and Akaike A (2005) Iron accelerates the conversion of dopamine-oxidized intermediates into melanin and provides protection in SH-SY5Y cells. J Neurosci Res 82: 126–137.CrossRefPubMedGoogle Scholar
  22. Jellinger K, Linert L, Kienzl E, Herlinger E and Youdim MB (1995) Chemical evidence for 6-hydroxydopamine to be an endogenous toxic factor in the pathogenesis of Parkinson’s disease. J Neural Transm Suppl 46: 297–314.PubMedGoogle Scholar
  23. Jenner P (2003) Oxidative stress in Parkinson’s disease. Ann Neurol 53 Suppl 3: S26–S36; discussion S36–S28.CrossRefPubMedGoogle Scholar
  24. Jenner P and Olanow CW (1996) Oxidative stress and the pathogenesis of Parkinson’s disease. Neurology 47: S161–S170.PubMedGoogle Scholar
  25. Kaur D, Yantiri F, Rajagopalan S, Kumar J, Mo JQ, Boonplueang R, Viswanath V, Jacobs R, Yang L, Beal MF, DiMonte D, Volitaskis I, Ellerby L, Cherny RA, Bush AI and Andersen JK (2003) Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson’s disease. Neuron 37: 899–909.CrossRefPubMedGoogle Scholar
  26. Knoll J (1986) The pharmacology of (-)deprenyl. J Neural Transm Suppl 22: 75–89.PubMedGoogle Scholar
  27. Lang AE and Lozano AM (1998) Parkinson’s disease. First of two parts. N Engl J Med 339: 1044–1053.CrossRefPubMedGoogle Scholar
  28. Mochizuki H, Imai H, Endo K, Yokomizo K, Murata Y, Hattori N and Mizuno Y (1994) Iron accumulation in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced hemiparkinsonian monkeys. Neurosci Lett 168: 251–253.CrossRefPubMedGoogle Scholar
  29. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65: 55–63.CrossRefPubMedGoogle Scholar
  30. Paris I, Martinez-Alvarado P, Cardenas S, Perez-Pastene C, Graumann R, Fuentes P, Olea-Azar C, Caviedes P and Segura-Aguilar J (2005) Dopamine-dependent iron toxicity in cells derived from rat hypothalamus. Chem Res Toxicol 18: 415–419.CrossRefPubMedGoogle Scholar
  31. Parish CL, Finkelstein DI, Drago J, Borrelli E and Horne MK (2001) The role of dopamine receptors in regulating the size of axonal arbors. J Neurosci 21: 5147–5157.PubMedGoogle Scholar
  32. Perumal AS, Gopal VB, Tordzro WK, Cooper TB and Cadet JL (1992) Vitamin E attenuates the toxic effects of 6-hydroxydopamine on free radical scavenging systems in rat brain. Brain Res Bull 29: 699–701.CrossRefPubMedGoogle Scholar
  33. Ryu EJ, Harding HP, Angelastro JM, Vitolo OV, Ron D and Greene LA (2002) Endoplasmic reticulum stress and the unfolded protein response in cellular models of Parkinson’s disease. J Neurosci 22: 10690–10698.PubMedGoogle Scholar
  34. Schober A (2004) Classic toxin-induced animal models of Parkinson’s disease: 6-OHDA and MPTP. Cell Tissue Res 318: 215–224.CrossRefPubMedGoogle Scholar
  35. Stanic D, Finkelstein DI, Bourke DW, Drago J and Horne MK (2003) Timecourse of striatal re-innervation following lesions of dopaminergic SNpc neurons of the rat. Eur J Neurosci 18: 1175–1188.CrossRefPubMedGoogle Scholar
  36. Stanic D, Tripanichkul W, Drago J, Finkelstein DI and Horne MK (2004) Glial responses associated with dopaminergic striatal reinnervation following lesions of the rat substantia nigra. Brain Res 1023: 83–91.CrossRefPubMedGoogle Scholar
  37. Sziraki I, Mohanakumar KP, Rauhala P, Kim HG, Yeh KJ and Chiueh CC (1998) Manganese: a transition metal protects nigrostriatal neurons from oxidative stress in the iron-induced animal model of parkinsonism. Neuroscience 85: 1101–1111.CrossRefPubMedGoogle Scholar
  38. Takano K, Kitao Y, Tabata Y, Miura H, Sato K, Takuma K, Yamada K, Hibino S, Choshi T, Iinuma M, Suzuki H, Murakami R, Yamada M, Ogawa S and Hori O (2007) A dibenzoylmethane derivative protects dopaminergic neurons against both oxidative stress and endoplasmic reticulum stress. Am J Physiol Cell Physiol 293: C1884–C1894.CrossRefPubMedGoogle Scholar
  39. Temlett JA, Landsberg JP, Watt F and Grime GW (1994) Increased iron in the substantia nigra compacta of the MPTP-lesioned hemiparkinsonian African green monkey: evidence from proton microprobe elemental microanalysis. J Neurochem 62: 134–146.CrossRefPubMedGoogle Scholar
  40. Thompson KJ, Shoham S and Connor JR (2001) Iron and neurodegenerative disorders. Brain Res Bull 55: 155–164.CrossRefPubMedGoogle Scholar
  41. West MJ and Gundersen HJ (1990) Unbiased stereological estimation of the number of neurons in the human hippocampus. J Comp Neurol 296: 1–22.CrossRefPubMedGoogle Scholar
  42. Wu Y, Blum D, Nissou MF, Benabid AL and Verna JM (1996) Unlike MPP+, apoptosis induced by 6-OHDA in PC12 cells is independent of mitochondrial inhibition. Neurosci Lett 221: 69–71.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Simon Wilkins
    • 1
  • Colin L. Masters
    • 1
  • Ashley I. Bush
    • 1
  • Robert A. Cherny
    • 1
  • David I. Finkelstein
    • 1
  1. 1.The University of MelbourneMelbourneAustralia

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