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Characterization of the Neuroprotective Potential of Derivatives of the Iron Chelating Drug Deferiprone

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Abstract

There is growing evidence for alterations in iron homeostasis during aging that are exacerbated in neurodegenerative diseases such as Alzheimer’s disease. However, since essentially all neurodegenerative diseases are multi-factorial in the sense that there are a large number of mechanisms that can be identified as contributing to nerve cell death, iron chelators that have additional activities might be the most useful for the treatment of age-related CNS diseases. We have described a series of cell culture-based assays that define molecular toxicity pathways relevant to neurodegenerative diseases and have used these assays to identify potential therapeutic compounds for the treatment of these diseases. Deferiprone is a blood brain barrier permeable, low molecular weight iron chelator that has been used for many years to treat systemic iron disease. In this study, we describe the use of our cell culture-based screening assays to identify deferiprone derivatives with the greatest therapeutic potential for the treatment of CNS diseases. We show that several derivatives are much more potent than deferiprone at reducing oxidative stress and preventing nerve cell death induced by multiple, age-related insults. In addition, we show that both deferiprone and the derivatives modulate several distinct signaling pathways associated with neuroprotection. All of the compounds were able to both inhibit the activation of p38 MAP kinase and JNK kinase and prevent the loss of PI3 kinase activity in response to a toxic stress. These results strongly suggest that these compounds have significant potential for the treatment of CNS diseases.

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References

  1. Ayton S, Lei P, Bush AI (2013) Metallostasis in Alzheimer’s disease. Free Radic Biol Med 62:76–89

    Article  CAS  PubMed  Google Scholar 

  2. Raven EP, Lu PH, Tishler TA, Heydari P, Bartzokis G (2013) Increased iron levels and decreased tissue integrity in hippocampus of Alzheimer’s disease detected in vivo with magnetic resonance imaging. J Alzheimer’s Dis 37:127–136

    CAS  Google Scholar 

  3. Penke L, Valdes Hernandez MC, Maniega SM, Gow AJ, Murray C, Starr JM, Bastin ME, Deary IJ, Wardlaw JM (2012) Brain iron deposits are associated with general cognitive ability and cognitive aging. Neurobiol Aging 33:510–517

    Article  CAS  PubMed  Google Scholar 

  4. Waldvogel D, van Gelderen P, Hallett M (1999) Increased iron in the dentate nucleus of patients with Friedreich’s ataxia. Ann Neurol 46:123–125

    Article  CAS  PubMed  Google Scholar 

  5. Ward RJ, Dexter DT, Crichton RR (2012) Chelating agents for neurodegenerative diseases. Curr Med Chem 19:2760–2772

    Article  CAS  PubMed  Google Scholar 

  6. Weigel KJ, Lynch SG, Levine SM (2014) Iron chelation and multiple sclerosis. ASN Neuro 6:e00136

    Article  PubMed Central  PubMed  Google Scholar 

  7. Kontoghiorghes GJ, Jackson MJ, Lunec J (1986) In vitro screening of iron chelators using models of free radical damage. Free Radic Res Commun 2:115–124

    Article  CAS  PubMed  Google Scholar 

  8. Kontoghiorghes GJ (2009) Prospects for introducing deferiprone as potent pharmaceutical antioxidant. Front Biosci (Elite Ed) 1:161–178

    Google Scholar 

  9. Kupershmidt L, Amit T, Bar-Am O, Weinreb O, Youdim MB (2012) Multi-target, neuroprotective and neurorestorative M30 improves cognitive impairment and reduces Alzheimer’s-like neuropathology and age-related alterations in mice. Mol Neurobiol 46:217–220

    Article  CAS  PubMed  Google Scholar 

  10. Schubert D, Maher P (2012) An alternative approach to drug discovery for Alzheimer’s disease dementia. Future Med Chem 4:1681–1688

    Article  CAS  PubMed  Google Scholar 

  11. Prior M, Chiruta C, Currais A, Goldberg J, Ramsey J, Dargusch R, Maher PA, Schubert D (2014) Back to the future with phenotypic screening ACS. Chem Neurosci 5:503–514

  12. Liu Y, Dargusch R, Maher P, Schubert D (2008) A broadly neuroprotective derivative of curcumin. J Neurochem 105:1336–1345

    Article  CAS  PubMed  Google Scholar 

  13. Chen Q, Prior M, Dargusch R, Roberts A, Riek R, Eichmann C, Chiruta C, Akaishi T, Abe K, Maher P, Schubert D (2011) A novel neurotrophic drug for cognitive enhancement and Alzheimer’s disease. PLoS One 6:e27865

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Maher P, Salgado KF, Zivin JA, Lapchak PA (2007) A novel approach to screening for new neuroprotective compounds for the treatment of stroke. Brain Res 1173:117–125

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Biraboneye AC, Madonna S, Laras Y, Krantic S, Maher P, Kraus J-L (2009) Potential neuroprotective drugs in cerebral ischemia: new saturated and polyunsaturated lipids coupled to hydorphilic moieties: synthesis and biological activity. J Med Chem 52:4358–4369

    Article  CAS  PubMed  Google Scholar 

  16. Chiruta C, Schubert D, Dargusch R, Maher P (2012) Chemical modification of the multi-target neuroprotective compound fisetin. J Med Chem 55:378–389

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Wu A, Ying Z, Schubert D, Gomez-Pinilla F (2011) Brain and spinal cord interaction: a dietary curcumin derivative counteracts locomotor and cognitive deficits after brain trauma. Neurorehabil Neural Repair 25:332–342

    Article  PubMed Central  PubMed  Google Scholar 

  18. Maher P, Dargusch R, Bodai L, Gerard P, Purcell JM, Marsh JL (2011) ERK activation by the polyphenols fisetin and resveratrol provides neuroprotection in multiple models of Huntington’s disease. Hum Mol Genet 20:261–270

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Gelderblom M, Leypoldt F, Lewerenz J, Birkenmayer G, Orozco D, Ludewig P, Thundyil J, Arumugam TV, Gerloff C, Tolosa E, Maher P, Magnus T (2012) The flavonoid fisetin attenuates postischemic immune cell infiltration, activation and infarct size after transient cerebral middle artery occlusion in mice. J Cereb Blood Flow Metab 32:835–843

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Lapchak PA, Schubert DR, Maher PA (2011) Delayed treatment with a novel neurotrophic compound reduces behavioral deficits in rabbit ischemic stroke. J Neurochem 116:122–131

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Valera E, Dargusch R, Maher PA, Schubert D (2013) Modulation of 5-lipoxygenase in proteotoxicity and Alzheimer’s disease. J Neurosci 33:10512–10525

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Currais A, Prior M, Dargusch R, Armando A, Ehren J, Schubert D, Quehenberger O, Maher P (2014) Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer’s disease transgenic mice. Aging Cell 13:379–390

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Kontoghiorghes GJ, Barr J, Nortey P, Sheppard L (1993) Selection of a new generation of orally active alpha-ketohydroxypyridine iron chelators intended for use in the treatment of iron overload. Am J Hematol 42:340–349

    Article  CAS  PubMed  Google Scholar 

  24. Kontoghiorghes GJ, Efstathiou A, Kleanthous M, Michaelides Y, Kolnagou A (2009) Risk/benefit assessment, advantages over other drugs and targeting methods in the use of deferiprone as a pharmaceutical antioxidant in iron loading and non iron loading conditions. Hemoglobin 33:386–397

    Article  CAS  PubMed  Google Scholar 

  25. Kontoghiorghes GJ, Neocleous K, Kolnagou A (2003) Benefits and risks of deferiprone in iron overload in Thalassaemia and other conditions: comparison of epidemiological and therapeutic aspects with deferoxamine. Drug Saf 26:553–584

    Article  CAS  PubMed  Google Scholar 

  26. Kontoghiorghes GJ, Sheppard L (1987) Simple synthesis of the potent iron chelators 1-alkyl-3-hydroxy-2-methylpyrid-4-ones. Inorg Chim Acta 136:L11–L12

    Article  CAS  Google Scholar 

  27. Kontoghiorghes GJ, Sheppard L, Barr J (1988) Synthetic methods and in vitro iron binding studies of the novel 1-alkyl-2-ethyl-3-hydroxypyrid-4-one iron chelators. Inorg Chim Acta 152:195–199

    Article  CAS  Google Scholar 

  28. Tan S, Schubert D, Maher P (2001) Oxytosis: a novel form of programmed cell death. Curr Top Med Chem 1:497–506

    Article  CAS  PubMed  Google Scholar 

  29. Currais A, Maher P (2013) Functional consequences of age-dependent changes in glutathione status in the brain. Antioxid Redox Signal 19:813–822

    Article  CAS  PubMed  Google Scholar 

  30. Sonnen JA, Breitne JC, Lovell MA, Markesbery WR, Quinn JF, Montine TJ (2008) Free radical-mediated damage to brain in Alzheimer’s disease and its transgenic mouse models. Free Radic Biol Med 45:219–230

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Davis JB, Maher P (1994) Protein kinase c activation inhibits glutamate-induced cytotoxicity in a neuronal cell lines. Brain Res 652:169–173

    Article  CAS  PubMed  Google Scholar 

  32. Ishige K, Chen Q, Sagara Y, Schubert D (2001) The activation of dopamine D4 receptors inhibits oxidative stress-induced nerve cell death. J Neurosci 21:6069–6076

    CAS  PubMed  Google Scholar 

  33. Lewerenz J, Albrecht P, Tien ML, Henke N, Karumbayaram S, Kornblum HI, Wiedua-Pazos M, Schubert D, Maher P, Methner A (2009) Induction of Nrf2 and xCT and involved in the action of the neuroprotective antibiotic ceftriaxone in vitro. J Neurochem 111:332–343

    Article  CAS  PubMed  Google Scholar 

  34. Saxena U (2012) Bioenergetics failure in neurodegenerative diseases: back to the future. Expert Opin Ther Targets 16:351–354

    Article  CAS  PubMed  Google Scholar 

  35. Winkler BS, Sauer MW, Starnes CA (2003) Modulation of the Pasteur effect in retinal cells: implications for understanding compensatory metabolic mechanisms. Exp Eye Res 76:715–723

    Article  CAS  PubMed  Google Scholar 

  36. Wyss-Coray T, Rogers J (2012) Inflammation in Alzheimer’s disease—a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med 2:a006346

    Article  PubMed Central  PubMed  Google Scholar 

  37. Keegan K, Halegoua S (1993) Signal transduction pathways in neuronal differentiation. Curr Opin Neurobiol 3:14–19

    Article  CAS  PubMed  Google Scholar 

  38. Greene L, Tischler AS (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci USA 73:2424–2428

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Sagara Y, Vahnnasy J, Maher P (2004) Induction of PC12 cell differentiation by flavonoids is dependent upon extracellular signal-regulated kinase activation. J Neurochem 90:1144–1155

    Article  CAS  PubMed  Google Scholar 

  40. Ehren JL, Maher P (2013) Concurrent regulation of the transcription factors Nrf2 and ATF4 mediates the enhancement of glutathione levels by the flavonoid fisetin. Biochem Pharmacol 85:1816–1826

    Article  CAS  PubMed  Google Scholar 

  41. Tietze F (1969) Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal Biochem 106:207–212

    Google Scholar 

  42. Ishige K, Schubert D, Sagara Y (2001) Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms. Free Radic Biol Med 30:433–446

    Article  CAS  PubMed  Google Scholar 

  43. Maher P (2006) A comparison of the neurotrophic activities of the flavonoid fisetin and some of its derivatives. Free Radic Res 40:1105–1111

    Article  CAS  PubMed  Google Scholar 

  44. Li Y, Maher P, Schubert D (1997) Requirement for cGMP in nerve cell death caused by glutathione depletion. J Cell Biol 139:1317–1324

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Jeremy JY, Kontoghiorghes GJ, Hoffbrand AV, Dandona P (1988) The iron chelators desferrioxamine and 1-alkyl-2-methyl-3-hydroxypyrid-4-ones inhibit vascular prostacyclin synthesis in vitro. Biochem J 254:239–244

    PubMed Central  CAS  PubMed  Google Scholar 

  46. Rai BL, Dekhordi LS, Khodr H, Jin Y, Liu Z, Hider RC (1998) Synthesis, physiochemical properties, and evaluation of N-substituted-2-alkyl-3-hydorxy-4(1H)-pyridinones. J Med Chem 41:3347–3359

    Article  CAS  PubMed  Google Scholar 

  47. Prasanthi JRP, Schrag M, Dasari B, Marwarha G, Dickson A, Kirsch WM, Ghribi O (2012) Deferiprone reduces amyloid-beta and tau phosphorylation levels but not reactive oxygen species generation in hippocampus of rabbits fed a cholesterol-enriched diet. J Alzheimer’s Dis 30:167–182

    CAS  Google Scholar 

  48. Hodkova A, Cerna P, Kotyzova D, Eybl V (2010) The effect of iron (III) on the activity of selenoenzymes and oxidative damage in the liver of rats. Interaction with natural antioxidants and deferiprone. Hemoglobin 34:278–283

    Article  CAS  PubMed  Google Scholar 

  49. Eybl V, Caisova D, Koutensky J, Kontoghiorghes GJ (1991) Influence of iron chelators, 1,2-dialkyl-3-hydroxypyridin-4-ones, on the lipid peroxidation and glutathione level in the liver of mice. Arch Toxicol Suppl 14:185–187

    Article  CAS  PubMed  Google Scholar 

  50. Kakhlon O, Manning H, Breuer W, Melamed-Book N, Lu C, Cortopassi G, Munnich A, Cabantchik ZI (2008) Cell functions impaired by frataxin deficiency are restored by drug-mediated iron relocation. Blood 112:5219–5227

    Article  CAS  PubMed  Google Scholar 

  51. Hagemeier J, Geurts JJG, Zivadinov R (2012) Brain iron accumulation in aging and neurodegenerative disorders. Expert Rev Neurother 12:1467–1480

    Article  CAS  PubMed  Google Scholar 

  52. Hare D, Ayton S, Bush AI, Lei P (2013) A delicate balance: iron metabolism and diseases of the brain. Front Aging Neurosci 5:34

    Article  PubMed Central  PubMed  Google Scholar 

  53. Eskici G, Axelsen PH (2012) Copper and oxidative stress in the pathogenesis of Alzheimer’s disease. Biochemistry 51:6289–6311

    Article  CAS  PubMed  Google Scholar 

  54. Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames D, Harrison J, Masters CL, Targum S, Bush AI, Murdoch R, Wilson JX, Ritchie CW (2008) Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer’s diease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol 7:779–786

    Article  CAS  PubMed  Google Scholar 

  55. Bareggi SR, Cornelli U (2012) Clioquinol: review of its mechanisms of action and clinical uses in neurodegenerative disorders. CNS Neurosci Ther 18:41–46

    Article  CAS  PubMed  Google Scholar 

  56. Molina-Holgado F, Gaeta A, Francis PT, Williams RJ, Hider RC (2008) Neuroprotective actions of deferiprone in cultured cortical neurones and SHSY-5Y cells. J Neurochem 105:2466–2476

    Article  CAS  PubMed  Google Scholar 

  57. Dargusch R, Schubert D (2002) Specificity of resistance to oxidative stress. J Neurochem 81:1394–1400

    Article  CAS  PubMed  Google Scholar 

  58. Abbruzzese G, Cossu G, Balocco M, Marchese R, Murgia D, Melis M, Galanello R, Barella S, Matta G, Ruffinengo U, Bonuccelli U, Forni GL (2011) A pilot trial of deferiprone for neurodegeneration with brain iron accumulation. Haematologica 96:1708–1711

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Kontoghiorghes CN, Kolnagou A, Kontoghiorghes GJ (2013) Potential clinical applications of chelating drugs in diseases targeting transferrin-bound iron and other metals. Expert Opin Investig Drugs 22:591–618

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by a generous donation from Paul Slavik.

Conflict of interest

The authors have no conflicts of interest to declare.

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Authors and Affiliations

  1. The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA, 92037, USA

    Pamela Maher

  2. Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol, Cyprus

    George J. Kontoghiorghes

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  1. Pamela Maher
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  2. George J. Kontoghiorghes
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Correspondence to Pamela Maher.

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Maher, P., Kontoghiorghes, G.J. Characterization of the Neuroprotective Potential of Derivatives of the Iron Chelating Drug Deferiprone. Neurochem Res 40, 609–620 (2015). https://doi.org/10.1007/s11064-014-1508-7

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