Neurotoxicity Research

, Volume 17, Issue 1, pp 15–27 | Cite as

Restoration of Nigrostriatal Dopamine Neurons in Post-MPTP Treatment by the Novel Multifunctional Brain-Permeable Iron Chelator-Monoamine Oxidase Inhibitor Drug, M30

  • Shunit Gal
  • Hailin Zheng
  • Mati Fridkin
  • Moussa B. H. Youdim
Article

Abstract

The anti-Parkinson iron chelator-monoamine oxidase inhibitor M30 [5-(N-methyl-N-propargyaminomethyl)-8-hydroxyquinoline] was shown to possess neuroprotective activities in vitro and in vivo, against several insults applicable to several neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and ALS. In the present study we sought to examine the effect of M30 on a pre-existing lesion induced by the parkinsonism-inducing toxin, MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). In this neurorescue paradigm, M30 orally administered to mice for 14 days (2.5 mg/kg/day) following MPTP was shown to significantly elevate striatal dopamine levels, reduce its metabolism, and elevate tyrosine-hydroxylase protein levels (from 25.86 ± 5.10 to 68.35 ± 10.67% of control) and activity (from 7.52 ± 0.98 to 16.33 ± 2.92 pmol/mg protein/min). Importantly, M30 elevated MPTP-reduced dopaminergic (from 62.8 ± 4.1 to 84.2 ± 5.9% of control) and transferrin receptor (from 31.3 ± 2.6 to 80.4 ± 7.6% of control) cell count in the SNpc. Finally, M30 was shown to decrease mitosis, thus providing additional protection. These findings suggest that brain-permeable M30 may clearly be of clinical importance for the treatment of PD.

Keywords

Parkinson’s disease Alzheimer’s disease Multifunctional drugs Monoamine oxidase-A and -B inhibitor Iron chelator Neurorestoration Dopamine Serotonin 

References

  1. Akao Y, Maruyama W, Shimizu S, Yi H, Nakagawa Y, Shamoto-Nagai M, Youdim MB, Tsujimoto Y, Naoi M (2002) Mitochondrial permeability transition mediates apoptosis induced by N-methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl-2 and rasagiline, N-propargyl-1(R)-aminoindan. J Neurochem 82:913–923CrossRefPubMedGoogle Scholar
  2. Amit T, Avramovich-Tirosh Y, Youdim MB, Mandel S (2007) Targeting multiple Alzheimer’s disease etiologies with multimodal neuroprotective and neurorestorative iron chelators. Faseb JGoogle Scholar
  3. Avramovich-Tirosh Y, Amit T, Bar-Am O, Zheng H, Fridkin M, Youdim MB (2007) Therapeutic targets and potential of the novel brain- permeable multifunctional iron chelator-monoamine oxidase inhibitor drug, M-30, for the treatment of Alzheimer’s disease. J Neurochem 100:490–502CrossRefPubMedGoogle Scholar
  4. Bar-Am O, Yogev-Falach M, Amit T, Sagi Y, Youdim MBH (2004) Regulation of protein kinase C by the anti-Parkinson drug, MAO-B inhibitor, rasagiline and its derivatives, in vivo. J Neurochem 89:1119–1125CrossRefPubMedGoogle Scholar
  5. Bar-Am O, Weinreb O, Amit T, Youdim MB (2005) Regulation of Bcl-2 family proteins, neurotrophic factors, and APP processing in the neurorescue activity of propargylamine. Faseb J 19:1899–1901PubMedGoogle Scholar
  6. Ben-Shachar D, Youdim MBH (1990) Selectivity of melaninized nigra-striatal dopamine neurons to degeneration in Parkinson’s disease may depend on iron-melanin interaction. J Neural Transm Suppl 29:251–258PubMedGoogle Scholar
  7. Ben-Shachar D, Kahana N, Kampel V, Warshawsky A, Youdim MBH (2003) Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-hydroxydopamine lession in rats. NeuropharmacologyGoogle Scholar
  8. Ben-Shachar D, Kahana N, Kampel V, Warshawsky A, Youdim MB (2004) Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-hydroxydopamine lession in rats. Neuropharmacology 46:254–263CrossRefGoogle Scholar
  9. Berg D, Merz B, Reiners K, Naumann M, Becker G (2005) Five-year follow-up study of hyperechogenicity of the substantia nigra in Parkinson’s disease. Mov Disord 20:383–385CrossRefPubMedGoogle Scholar
  10. Berg D, Hochstrasser H, Schweitzer KJ, Riess O (2006) Disturbance of iron metabolism in Parkinson’s disease—ultrasonography as a biomarker. Neurotox Res 9:1–13CrossRefPubMedGoogle Scholar
  11. Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318:121–134CrossRefPubMedGoogle Scholar
  12. Carrillo MC, Minami C, Kitani K, Maruyama W, Ohashi K, Yamamoto T, Naoi M, Kanai S, Youdim MBH (2000) Enhancing effect of rasagiline on superoxide dismutase and catalase activities in the dopaminergic system in the rat. Life Sci 67:577–585CrossRefPubMedGoogle Scholar
  13. Coyle JT, Puttfarcken P (1993) Oxidative stress, glutamate, and neurodegenerative disorders. Science 262:689–695CrossRefPubMedGoogle Scholar
  14. Faiz M, Acarin L, Castellano B, Gonzalez B (2005) Proliferation dynamics of germinative zone cells in the intact and excitotoxically lesioned postnatal rat brain. BMC Neurosci 6:26Google Scholar
  15. Fornai F, Lenzi P, Gesi M, Ferrucci M, Lazzeri G, Busceti CL, Ruffoli R, Soldani P, Ruggieri S, Alessandri MG, Paparelli A (2003) Fine structure and biochemical mechanisms underlying nigrostriatal inclusions and cell death after proteasome inhibition. J Neurosci 23:8955–8966PubMedGoogle Scholar
  16. Friedlich AL, Tanzi RE, Rogers JT (2007) The 5′-untranslated region of Parkinson’s disease alpha-synuclein messengerRNA contains a predicted iron responsive element. Mol Psychiatry 12:222–223CrossRefPubMedGoogle Scholar
  17. Gal S, Zheng H, Fridkin M, Youdim MB (2005) Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases. In vivo selective brain monoamine oxidase inhibition and prevention of MPTP-induced striatal dopamine depletion. J Neurochem 95:79–88CrossRefPubMedGoogle Scholar
  18. Gal S, Fridkin M, Amit T, Zheng H, Youdim MB (2006) M30, a novel multifunctional neuroprotective drug with potent iron chelating and brain selective monoamine oxidase-ab inhibitory activity for Parkinson’s disease. J Neural Transm Suppl 70:447–456CrossRefPubMedGoogle Scholar
  19. Gilgun-Sherki Y, Melamed E, Offen D (2001) Oxidative stress induced-neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier. Neuropharmacology 40:959–975CrossRefPubMedGoogle Scholar
  20. Glinka YY, Youdim MB (1995) Inhibition of mitochondrial complexes I and IV by 6-hydroxydopamine. Eur J Pharmacol 292:329–332PubMedGoogle Scholar
  21. Glinka Y, Tipton KF, Youdim MB (1996) Nature of inhibition of mitochondrial respiratory complex I by 6-hydroxydopamine. J Neurochem 66:2004–2010PubMedGoogle Scholar
  22. Glinka Y, Tipton KF, Youdim MBH (1998) Mechanism of inhibition of mitochondrial respiratory complex I by 6-hydroxydopamine and its prevention by desferrioxamine. Eur J Pharmacol 351:121–129CrossRefPubMedGoogle Scholar
  23. Goto K, Mochizuki H, Imai H, Akiyama H, Mizuno Y (1996) An immuno-histochemical study of ferritin in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced hemiparkinsonian monkeys. Brain Res 724:125–128CrossRefPubMedGoogle Scholar
  24. Grunblatt E, Mandel S, Jacob-Hirsch J, Zeligson S, Amariglo N, Rechavi G, Li J, Ravid R, Roggendorf W, Riederer P, Youdim MB (2004) Gene expression profiling of parkinsonian substantia nigra pars compacta; alterations in ubiquitin-proteasome, heat shock protein, iron and oxidative stress regulated proteins, cell adhesion/cellular matrix and vesicle trafficking genes. J Neural Transm 111:1543–1573CrossRefPubMedGoogle Scholar
  25. Hall S, Rutledge JN, Schallert T (1992) MRI, brain iron and experimental Parkinson’s disease. J Neurol Sci 113:198–208CrossRefPubMedGoogle Scholar
  26. Han J, Cheng FC, Yang Z, Dryhurst G (1999) Inhibitors of mitochondrial respiration, iron (II), and hydroxyl radical evoke release and extracellular hydrolysis of glutathione in rat striatum and substantia nigra: potential implications to Parkinson’s disease. J Neurochem 73:1683–1695CrossRefPubMedGoogle Scholar
  27. Hayley S, Crocker SJ, Smith PD, Shree T, Jackson-Lewis V, Przedborski S, Mount M, Slack R, Anisman H, Park DS (2004) Regulation of dopaminergic loss by Fas in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. J Neurosci 24:2045–2053CrossRefPubMedGoogle Scholar
  28. Herrup K, Yang Y (2007) Cell cycle regulation in the postmitotic neuron: oxymoron or new biology? Nat Rev Neurosci 8:368–378CrossRefPubMedGoogle Scholar
  29. Huang Y, Wernyj RP, Norton DD, Precht P, Seminario MC, Wange RL (2005) Modulation of specific protein expression levels by PTEN: identification of AKAP121, DHFR, G3BP, Rap1, and RCC1 as potential targets of PTEN. Oncogene 24:3819–3829CrossRefPubMedGoogle Scholar
  30. 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, Andersen JK (2003) Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson’s disease. Neuron 37:899–909CrossRefPubMedGoogle Scholar
  31. Kay JN, Blum M (2000) Differential response of ventral midbrain and striatal progenitor cells to lesions of the nigrostriatal dopaminergic projection. Dev Neurosci 22:56–67CrossRefPubMedGoogle Scholar
  32. Keilhoff G, Becker A, Grecksch G, Bernstein HG, Wolf G (2006) Cell proliferation is influenced by bulbectomy and normalized by imipramine treatment in a region-specific manner. Neuropsychopharmacology 31:1165–1176PubMedGoogle Scholar
  33. Kolb B, Pedersen B, Ballermann M, Gibb R, Whishaw IQ (1999) Embryonic and postnatal injections of bromodeoxyuridine produce age-dependent morphological and behavioral abnormalities. J Neurosci 19:2337–2346PubMedGoogle Scholar
  34. Kupershmidt L, Weinreb O, Mandel S, Amit T, Youdim MBH (2009) Involvement of HIF and VGEF in neuroprotective and neuritogenic activities of novel multimodal iron chelating drugs in motor neuron-like NSC-34 cells and transgenic mouse model of amyotrophic lateral sclerosis. FASEB J (in press)Google Scholar
  35. Lagace DC, Whitman MC, Noonan MA, Ables JL, DeCarolis NA, Arguello AA, Donovan MH, Fischer SJ, Farnbauch LA, Beech RD, DiLeone RJ, Greer CA, Mandyam CD, Eisch AJ (2007) Dynamic contribution of nestin-expressing stem cells to adult neurogenesis. J Neurosci 27:12623–12629CrossRefPubMedGoogle Scholar
  36. Lan J, Jiang DH (1997a) Desferrioxamine and vitamin E protect against iron and MPTP-induced neurodegeneration in mice. J Neural Transm 104:469–481CrossRefPubMedGoogle Scholar
  37. Lan J, Jiang DH (1997b) Excessive iron accumulation in the brain: a possible potential risk of neurodegeneration in Parkinson’s disease. J Neural Transm 104:649–660CrossRefPubMedGoogle Scholar
  38. Levites Y, Weinreb O, Maor G, Youdim MBH, Mandel S (2001) Green tea polyphenol (-)-Epigallocatechin-3-gallate prevents N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration. J Neurochem 78:1073–1082CrossRefPubMedGoogle Scholar
  39. Lin YL, Lin JK (1997) (-)-Epigallocatechin-3-gallate blocks the induction of nitric oxide synthase by down-regulating lipopolysaccharide-induced activity of transcription factor nuclear factor-kappaB. Mol Pharmacol 52:465–472PubMedGoogle Scholar
  40. Lin M, Rippe RA, Niemela O, Brittenham G, Tsukamoto H (1997) Role of iron in NF-kappa B activation and cytokine gene expression by rat hepatic macrophages. Am J Physiol 272:G1355–G1364PubMedGoogle Scholar
  41. Mandel S, Grunblatt E, Riederer P, Gerlach M, Levites Y, Youdim MB (2003) Neuroprotective strategies in Parkinson’s disease: an update on progress. CNS Drugs 17:729–762CrossRefPubMedGoogle Scholar
  42. Maruyama W, Youdim MBH, Naoi M (2001a) Antiapoptotic properties of rasagiline, N-propargylamine-1(R)-aminoindan, and its optical (S)-isomer, TV1022. Ann N Y Acad Sci 939:320–329PubMedGoogle Scholar
  43. Maruyama W, Akao Y, Youdim MBH, Boulton AA, Davis BA, Naoi M (2001b) Transfection-enforced Bcl-2 overexpression and an anti-Parkinson drug, rasagiline, prevent nuclear accumulation of glyceraldehyde-3 phosphate dehydrogenase induced by an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol. J Neurochem 78:727–735CrossRefPubMedGoogle Scholar
  44. Maruyama W, Takahashi T, Youdim MBH, Naoi M (2002) The anti-Parkinson drug, rasagiline, prevents apoptotic DNA damage induced by peroxynitrite in human dopaminergic neuroblastoma SH-SY5Y cells. J Neural Transm 109:467–481CrossRefPubMedGoogle Scholar
  45. Maruyama W, Nitta A, Shamoto-Nagai M, Hirata Y, Akao Y, Youdim MBH, Furukawa S, Nabeshima T, Naoi M (2004) N-Propargyl-1 (R)-aminoindan, rasagiline, increases glial cell line-derived neurotrophic factor (GDNF) in neuroblastoma SH-SY5Y cells through activation of NF-kappaB transcription factor. Neurochem Int 44:393–400CrossRefPubMedGoogle Scholar
  46. McNaught KS, Olanow CW (2006) Protein aggregation in the pathogenesis of familial and sporadic Parkinson’s disease. Neurobiol Aging 27:530–545CrossRefPubMedGoogle Scholar
  47. Mochizuki H, Imai H, Endo K, Yokomizo K, Murata Y, Hattori N, 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 168:251–253CrossRefPubMedGoogle Scholar
  48. Morrish PK, Rakshi JS, Bailey DL, Sawle GV, Brooks DJ (1998) Measuring the rate of progression and estimating the preclinical period of Parkinson’s disease with [18F]dopa PET. J Neurol Neurosurg Psychiatry 64:314–319CrossRefPubMedGoogle Scholar
  49. Munoz M, Rodriguez A, Diez C, Caamano JN, Fernandez-Sanchez MT, Perez-Gomez A, De Frutos C, Facal N, Gomez E (2009) Tyrosine kinase A, C and fibroblast growth factor-2 receptors in bovine embryos cultured in vitro. Theriogenology 71(6):1005–1010Google Scholar
  50. Oestreicher E, Sengstock GJ, Riederer P, Olanow CW, Dunn AJ, Arendash GW (1994) Degeneration of nigrostriatal dopaminergic neurons increases iron within the substantia nigra: a histochemical and neurochemical study. Brain Res. 660:8–18CrossRefPubMedGoogle Scholar
  51. Offen D, Beart PM, Cheung NS, Pascoe CJ, Hochman A, Gorodin S, Melamed E, Bernard R, Bernard O (1998) Transgenic mice expressing human Bcl-2 in their neurons are resistant to 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity. Proc Natl Acad Sci USA 95:5789–5794CrossRefPubMedGoogle Scholar
  52. Ostrerova-Golts N, Petrucelli L, Hardy J, Lee JM, Farer M, Wolozin B (2000) The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. J Neurosci 20:6048–6054PubMedGoogle Scholar
  53. Peng J, Xie L, Jin K, Greenberg DA, Andersen JK (2008) Fibroblast growth factor 2 enhances striatal and nigral neurogenesis in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. Neuroscience 153:664–670CrossRefPubMedGoogle Scholar
  54. Perier C, Bove J, Wu DC, Dehay B, Choi DK, Jackson-Lewis V, Rathke-Hartlieb S, Bouillet P, Strasser A, Schulz JB, Przedborski S, Vila M (2007) Two molecular pathways initiate mitochondria-dependent dopaminergic neurodegeneration in experimental Parkinson’s disease. Proc Natl Acad Sci USA 104:8161–8166CrossRefPubMedGoogle Scholar
  55. Ramsay RR, Kowal AT, Johnson MK, Salach JI, Singer TP (1987) The inhibition site of MPP+, the neurotoxic bioactivation product of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is near the Q-binding site of NADH dehydrogenase. Arch Biochem Biophys 259:645–649CrossRefPubMedGoogle Scholar
  56. Sagi Y, Weinstock M, Youdim MBH (2003) Attenuation of MPTP-induced dopaminergic neurotoxicity by TV3326, a cholinesterase-monoamine oxidase inhibitor. J Neurochem 2:290–297CrossRefGoogle Scholar
  57. Sagi Y, Mandel S, Amit T, Youdim MB (2007) Activation of tyrosine kinase receptor signaling pathway by rasagiline facilitates neurorescue and restoration of nigrostriatal dopamine neurons in post-MPTP-induced parkinsonism. Neurobiol Dis 25:35–44CrossRefPubMedGoogle Scholar
  58. Sangchot P, Sharma S, Chetsawang B, Porter J, Govitrapong P, Ebadi M (2002) Deferoxamine attenuates iron-induced oxidative stress and prevents mitochondrial aggregation and alpha-synuclein translocation in SK-N-SH cells in culture. Dev Neurosci 24:143–153CrossRefPubMedGoogle Scholar
  59. Semkova I, Wolz P, Schilling M, Krieglstein J (1996) Selegiline enhances NGF synthesis and protects central nervous system neurons from excitotoxic and ischemic damage. Eur J Pharmacol 315:19–30CrossRefPubMedGoogle Scholar
  60. Siddiq A, Ayoub IA, Chavez JC, Aminova L, Shah S, LaManna JC, Patton SM, Connor JR, Cherny RA, Volitakis I, Bush AI, Langsetmo I, Seeley T, Gunzler V, Ratan RR (2005) Hypoxia-inducible factor prolyl 4-hydroxylase inhibition. A target for neuroprotection in the central nervous system. J Biol Chem 280:41732–41743CrossRefPubMedGoogle Scholar
  61. Tatton WG, Chalmers-Redman RM, Ju WJ, Mammen M, Carlile GW, Pong AW, Tatton NA (2002) Propargylamines induce antiapoptotic new protein synthesis in serum- and nerve growth factor (NGF)-withdrawn, NGF-differentiated PC-12 cells. J Pharmacol Exp Ther 301:753–764CrossRefPubMedGoogle Scholar
  62. Temlett JA, Landsberg JP, Watt F, 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 62:134–146PubMedGoogle Scholar
  63. Tonchev AB, Yamashima T, Chaldakov GN (2007) Distribution and phenotype of proliferating cells in the forebrain of adult macaque monkeys after transient global cerebral ischemia. Adv Anat Embryol Cell Biol 191:1–106CrossRefPubMedGoogle Scholar
  64. Van Kampen JM, Eckman CB (2006) Dopamine D3 receptor agonist delivery to a model of Parkinson’s disease restores the nigrostriatal pathway and improves locomotor behavior. J Neurosci 26:7272–7280CrossRefPubMedGoogle Scholar
  65. Vila M, Jackson-Lewis V, Vukosavic S, Djaldetti R, Liberatore G, Offen D, Korsmeyer SJ, Przedborski S (2001) Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Proc Natl Acad Sci USA 98:2837–2842CrossRefPubMedGoogle Scholar
  66. Warshawsky A, Youdim MB, Fridkin M, Zheng HL, Warshawsky R (2004) Preparation of neuroprotective iron chelators and pharmaceutical compositions comprising them. Int Publication Number WO 2004041151, A2Google Scholar
  67. Weinreb O, Bar-Am O, Amit T, Chillag-Talmor O, Youdim MB (2004) Neuroprotection via pro-survival protein kinase C isoforms associated with Bcl-2 family members. Faseb J 18:1471–1473PubMedGoogle Scholar
  68. Weinreb O, Amit T, Bar-Am O, Sagi Y, Mandel S, Youdim MB (2006) Involvement of multiple survival signal transduction pathways in the neuroprotective, neurorescue and APP processing activity of rasagiline and its propargyl moiety. J Neural Transm Suppl 70:457–465CrossRefPubMedGoogle Scholar
  69. Weinstock M, Gorodetsky E, Poltyrev T, Gross A, Sagi Y, Youdim MBH (2003) A novel cholinesterase and brain-selective monoamine oxidase inhibitor for the treatment of dementia comorbid with depression and Parkinson’s disease. Prog Neuro-Psychopharmacol Biol Psychiatry 27:555–561CrossRefGoogle Scholar
  70. Yang L, Matthews RT, Schulz JB, Klockgether T, Liao AW, Martinou JC, Penney J B Jr, Hyman BT, Beal MF (1998) 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyride neurotoxicity is attenuated in mice overexpressing Bcl-2. J Neurosci 18:8145–8152PubMedGoogle Scholar
  71. Yoshimi K, Ren YR, Seki T, Yamada M, Ooizumi H, Onodera M, Saito Y, Murayama S, Okano H, Mizuno Y, Mochizuki H (2005) Possibility for neurogenesis in substantia nigra of parkinsonian brain. Ann Neurol 58:31–40CrossRefPubMedGoogle Scholar
  72. Youdim MBH (2003) Rasagiline: an anti-Parkinson drug with neuroprotective activity. Future Drugs 3:737–749Google Scholar
  73. Youdim MBH, Wadia A, Tatton NA, Weinstock M (2001) The anti-Parkinson drug rasagiline and its cholinesterase inhibitor derivatives exert neuroprotection unrelated to MAO inhibition in cell culture and in vivo. Ann N Y Acad Sci 939:450–458PubMedCrossRefGoogle Scholar
  74. Youdim MBH, Stephenson G, Ben Shachar D (2004) Ironing iron out in Parkinson’s disease and other neurodegenerative diseases with iron chelator: a lesson from 6-hydroxopaime and iron chelatos desferal and VK-28. Ann N Y Acad Sci 1012:306–325Google Scholar
  75. Youdim MB, Bar Am O, Yogev-Falach M, Weinreb O, Maruyama W, Naoi M, Amit T (2005) Rasagiline: neurodegeneration, neuroprotection, and mitochondrial permeability transition. J Neurosci Res 79:172–179CrossRefPubMedGoogle Scholar
  76. Youdim MB, Amit T, Bar-Am O, Weinreb O, Yogev-Falach M (2006) Implications of co-morbidity for etiology and treatment of neurodegenerative diseases with multifunctional neuroprotective-neurorescue drugs; ladostigil. Neurotox Res 10:181–192CrossRefPubMedGoogle Scholar
  77. Youdim MB, Grunblatt E, Mandel S (2007) The copper chelator, D-penicillamine, does not attenuate MPTP induced dopamine depletion in mice. J Neural Transm 114:205–209CrossRefPubMedGoogle Scholar
  78. Zaman K, Ryu H, Hall D, O’Donovan K, Lin KI, Miller MP, Marquis JC, Baraban JM, Semenza GL, Ratan RR (1999) Protection from oxidative stress-induced apoptosis in cortical neuronal cultures by iron chelators is associated with enhanced DNA binding of hypoxia-inducible factor-1 and ATF-1/CREB and increased expression of glycolytic enzymes, p21(waf1/cip1), and erythropoietin. J Neurosci 19:9821–9830PubMedGoogle Scholar
  79. Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR (2004) Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci 5:863–873CrossRefPubMedGoogle Scholar
  80. Zecca L, Berg D, Arzberger T, Ruprecht P, Rausch WD, Musicco M, Tampellini D, Riederer P, Gerlach M, Becker G (2005) In vivo detection of iron and neuromelanin by transcranial sonography: a new approach for early detection of substantia nigra damage. Mov Disord 20:1278–1285CrossRefPubMedGoogle Scholar
  81. Zhao M, Momma S, Delfani K, Carlen M, Cassidy RM, Johansson CB, Brismar H, Shupliakov O, Frisen J, Janson AM (2003) Evidence for neurogenesis in the adult mammalian substantia nigra. Proc Natl Acad Sci USA 100:7925–7930CrossRefPubMedGoogle Scholar
  82. Zheng H, Gal S, Weiner LM, Bar-Am O, Warshawsky A, Fridkin M, Youdim MB (2005a) Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases: in vitro studies on antioxidant activity, prevention of lipid peroxide formation and monoamine oxidase inhibition. J Neurochem 95:68–78CrossRefPubMedGoogle Scholar
  83. Zheng H, Weiner LM, Bar-Am O, Epsztejn S, Cabantchik ZI, Warshawsky A, Youdim MBH, Fridkin M (2005b) Design, synthesis, and evaluation of novel bifunctional iron-chelators as potential agents for neuroprotection in Alzheimer’s, Parkinson’s, and other neurodegenerative diseases. Bioorg Med Chem 13:773–783CrossRefPubMedGoogle Scholar
  84. Zhu W, Xie W, Pan T, Xu P, Fridkin M, Zheng H, Jankovic J, Youdim MB, Le W (2007) Prevention and restoration of lactacystin-induced nigrostriatal dopamine neuron degeneration by novel brain-permeable iron chelators. Faseb J 21:3835–3844CrossRefPubMedGoogle Scholar
  85. Zhu W, Xie W, Pan T, Jankovic J, Li J, Youdim MB, Le W (2008) Comparison of neuroprotective and neurorestorative capabilities of rasagiline and selegiline against lactacystin-induced nigrostriatal dopaminergic degeneration. J Neurochem 105:1970–1978CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Shunit Gal
    • 1
  • Hailin Zheng
    • 2
  • Mati Fridkin
    • 2
  • Moussa B. H. Youdim
    • 1
  1. 1.Department of Pharmacology, Technion-Rappaport Family Faculty of MedicineEve Topf and US National Parkinson Foundation Centers of Excellence for Neurodegenerative DiseasesHaifaIsrael
  2. 2.Department of ChemistryThe Weizmann InstituteRehovotIsrael

Personalised recommendations