CNS Drugs

, Volume 17, Issue 10, pp 729–762

Neuroprotective Strategies in Parkinson’s Disease

An Update on Progress
  • Silvia Mandel
  • Edna Grünblatt
  • Peter Riederer
  • Manfred Gerlach
  • Yona Levites
  • Moussa B. H. Youdim
Review Article


In spite of the extensive studies performed on postmortem substantia nigra from Parkinson’s disease patients, the aetiology of the disease has not yet been established. Nevertheless, these studies have demonstrated that, at the time of death, a cascade of events had been initiated that may contribute to the demise of the melanin-containing nigro-striatal dopamine neurons. These events include increased levels of iron and monoamine oxidase (MAO)-B activity, oxidative stress, inflammatory processes, glutamatergic excitotoxicity, nitric oxide synthesis, abnormal protein folding and aggregation, reduced expression of trophic factors, depletion of endogenous antioxidants such as reduced glutathione, and altered calcium homeostasis. To a large extent, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) animal models of Parkinson’s disease confirm these findings. Furthermore, neuroprotection can be afforded in these models with iron chelators, radical scavenger antioxidants, MAO-B inhibitors, glutamate antagonists, nitric oxide synthase inhibitors, calcium channel antagonists and trophic factors.

Despite the success obtained with animal models, clinical neuroprotection is much more difficult to accomplish. Although the negative studies obtained with the MAO-B inhibitor selegiline (deprenyl) and the antioxidant tocopherol (vitamin E) may have resulted from an inappropriate choice of drug (selegiline) or an inadequate dose (tocopherol), the niggling problem that still remains is why these drugs, and others, do work in animals while they fail in the clinic. One reason for this may be related to the fact that in normal human brains the number of dopaminergic neurons falls by around 3–5% every decade, while in Parkinson’s disease this decline is greater. Brain autopsy studies have shown that by the time the disease is identified, some 70–75% of the dopamine-containing neurons have been lost. More sensitive reliable methods and clinical correlative markers are required to discern between confoundable symptomatic effects versus a possible neuroprotective action of drugs, namely, the ability to delay or forestall disease progression by protecting or rescuing the remaining dopamine neurons or even restoring those that have been lost.

A number of other possibilities for the clinical failure of potential neuroprotectants also exist. First, the animal models of Parkinson’s disease may not be totally reflective of the disease and, therefore, the chemical pathologies established in the animal models may not cause, or contribute to, the progression of the disease clinically. Second, because of the series of events occurring in neurode-generation and our ignorance about which of these factors constitutes the primary event in the pathogenic process, a single drug may not be adequate to induce neuroprotection and, as a consequence, use of a cocktail of drugs may be more appropriate. The latter concept receives support from recent complementary DNA (cDNA) microarray gene expression studies, which show the existence of a gene cascade of events occurring in the nigrostriatal pathway of MPTP, 6-OHDA and methamphetamine animal models of Parkinson’s disease.

Even with the advent of powerful new tools such as genomics, proteomics, brain imaging, gene replacement therapy and knockout animal models, the desired end result of neuroprotection is still beyond our current capability.


  1. 1.
    Marsden CD, Parkes JD. Success and problems of long-term levodopa therapy in Parkinson’s disease. Lancet 1977; I(8007): 345–9CrossRefGoogle Scholar
  2. 2.
    Lindvall O, Backlund EO, Farde L, et al. Transplantation in Parkinson’s disease: two cases of adrenal medullary grafts to the putamen. Ann Neurol 1987; 22(4): 457–68PubMedCrossRefGoogle Scholar
  3. 3.
    Freeman TB, Olanow CW, Hauser RA, et al. Bilateral fetal nigral transplantation into the postcommissural putamen in Parkinson’s disease. Ann Neurol 1995; 38(3): 379–88PubMedCrossRefGoogle Scholar
  4. 4.
    Barker RA. Prospects for the treatment of Parkinson’s disease using neural grafts. Expert Opin Pharmacother 2000; 1(5): 889–902PubMedCrossRefGoogle Scholar
  5. 5.
    Freed CR, Greene PE, Breeze RE, et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med 2001; 344(10): 710–9PubMedCrossRefGoogle Scholar
  6. 6.
    Parboosingh JS, Rousseau M, Rogan F, et al. Absence of mutations in superoxide dismutase and catalase genes in patients with Parkinson’s disease. Arch Neurol 1995; 52(12): 1160–3PubMedCrossRefGoogle Scholar
  7. 7.
    Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 1997; 276(5321): 2045–7PubMedCrossRefGoogle Scholar
  8. 8.
    Polymeropoulos MH. Autosomal dominant Parkinson’s disease and alpha-synuclein. Ann Neurol 1998; 44(3 Suppl. 1): S63–4PubMedGoogle Scholar
  9. 9.
    Conway KA, Harper JD, Lansbury PT. Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat Med 1998; 4(11): 1318–20PubMedCrossRefGoogle Scholar
  10. 10.
    Spillantini MG, Schmidt ML, Lee VM, et al. Alpha-synuclein in Lewy bodies. Nature 1997; 388(6645): 839–40PubMedCrossRefGoogle Scholar
  11. 11.
    Chung KK, Dawson VL, Dawson TM. The role of the ubiquitin-proteasomal pathway in Parkinson’s disease and other neuro-degenerative disorders. Trends Neurosci 2001; 24(11 Suppl.): S7–14PubMedCrossRefGoogle Scholar
  12. 12.
    Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998; 392(6676): 605–8PubMedCrossRefGoogle Scholar
  13. 13.
    Shimura H, Hattori N, Kubo S, et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 2000; 25(3): 302–5PubMedCrossRefGoogle Scholar
  14. 14.
    Polymeropoulos MH. Genetics of Parkinson’s disease. Ann N Y Acad Sci 2000; 920: 28–32PubMedCrossRefGoogle Scholar
  15. 15.
    Linazasoro G. Neuroprotection in Parkinson’s disease: love story or mission impossible? Exp Rev Neurotherapeutics 2002; 2(3): 403–16CrossRefGoogle Scholar
  16. 16.
    McNaught KS, Belizaire R, Jenner P, et al. Selective loss of 20S proteasome alpha-subunits in the substantia nigra pars compacta in Parkinson’s disease. Neurosci Lett 2002; 326(3): 155–8PubMedCrossRefGoogle Scholar
  17. 17.
    Riederer P, Sofic E, Rausch WD, et al. Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem 1989; 52(2): 515–20PubMedCrossRefGoogle Scholar
  18. 18.
    Youdim MB, Ben-Shachar D, Riederer P. The possible role of iron in the etiopathology of Parkinson’s disease. Mov Disord 1993; 8(1): 1–12PubMedCrossRefGoogle Scholar
  19. 19.
    Gotz ME, Kunig G, Riederer P, et al. Oxidative stress: free radical production in neural degeneration. Pharmacol Ther 1994; 63(1): 37–122PubMedCrossRefGoogle Scholar
  20. 20.
    Jenner P, Olanow CW. Oxidative stress and the pathogenesis of Parkinson’s disease. Neurology 1996; 47(0028-3878): 161–70CrossRefGoogle Scholar
  21. 21.
    Olanow CW, Youdim MB. Iron and neurodegeneration: prospects for neuroprotection. In: Olanow CW, Jenner P, Youdim MB, editors. Neurodegeneration and neuroprotection in Parkinson’s disease. London: Academic Press, 1996: 55–69CrossRefGoogle Scholar
  22. 22.
    Youdim MBH, Riederer P. Understanding Parkinson’s disease. Sci Am 1999; 276(1): 52–9CrossRefGoogle Scholar
  23. 23.
    Jenner P. Oxidative mechanisms in nigral cell death in Parkinson’s disease. Mov Disord 1998; 13(0885-3185): 24–34PubMedGoogle Scholar
  24. 24.
    Mandel S, Grunblatt E, Youdim MBH. cDNA microarray to study gene expression of dopaminergic neurodegeneration and neuroprotection in MPTP and 6-hydroxydopamine models: implications for idiopathic Parkinson’s disease. J Neural Transm Suppl 2000; 60: 117–24PubMedGoogle Scholar
  25. 25.
    Mendez JS, Finn BW. Use of 6-hydroxydopamine to create lesions in catecholamine neurons in rats. J Neurosurg 1975; 42(2): 166–73PubMedCrossRefGoogle Scholar
  26. 26.
    Kostrzewa RM, Harper JW. Effect of 6-hydroxydopa on cat-echolamine-containing neurons in brains of newborn rats. Brain Res 1974; 69(1): 174–81PubMedCrossRefGoogle Scholar
  27. 27.
    Burns RS, Chiueh CC, Markey SP, et al. A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci U S A 1983; 80(14): 4546–50PubMedCrossRefGoogle Scholar
  28. 28.
    Chiueh CC, Miyake H, Peng MT. Role of dopamine autoxidation, hydroxyl radical generation, and calcium overload in underlying mechanisms involved in MPTP-induced parkinsonism. Adv Neurol 1993; 60: 251–8PubMedGoogle Scholar
  29. 29.
    Davis GC, Williams AC, Markey SP, et al. Chronic parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res 1979; 1(3): 249–54PubMedCrossRefGoogle Scholar
  30. 30.
    Heikkila RE, Manzino L, Cabbat FS, et al. Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine by monoamine oxidase inhibitors. Nature 1984; 311(5985): 467–9PubMedCrossRefGoogle Scholar
  31. 31.
    Tatton WG. Selegiline can mediate neuronal rescue rather than neuronal protection. Mov Disord 1993; 8Suppl. 1: S20–30PubMedCrossRefGoogle Scholar
  32. 32.
    Santiago M, Matarredona ER, Granero L, et al. Neuroprotective effect of the iron chelator desferrioxamine against MPP+ toxicity on striatal dopaminergic terminals. J Neurochem 1997; 68(2): 732–8PubMedCrossRefGoogle Scholar
  33. 33.
    Lan J, Jiang DH. Desferrioxamine and vitamin E protect against iron and MPTP-induced neurodegeneration in mice. J Neural Transmission 1997; 104(4-5): 469–81CrossRefGoogle Scholar
  34. 34.
    Matarredona ER, Santiago M, Cano J, et al. Involvement of iron in MPP+ toxicity in substantia nigra: protection by desferrioxamine. Brain Res 1997; 773(1-2): 76–81PubMedCrossRefGoogle Scholar
  35. 35.
    Ben-Shachar D, Eshel G, Finberg JP, et al. The iron chelator desferrioxamine (Desferal) retards 6-hydroxydopamine-induced degeneration of nigrostriatal dopamine neurons. J Neurochem 1991; 56(4): 1441–4PubMedCrossRefGoogle Scholar
  36. 36.
    Cadet JL, Katz M, Jackson-Lewis V, et al. Vitamin E attenuates the toxic effects of intrastriatal injection of 6-hydroxydopamine (6-OHDA) in rats: behavioral and biochemical evidence. Brain Res 1989; 476(1): 10–5PubMedCrossRefGoogle Scholar
  37. 37.
    Perumal AS, Gopal VB, Tordzro WK, et al. Vitamin E attenuates the toxic effects of 6-hydroxydopamine on free radical scavenging systems in rat brain. Brain Res Bull 1992; 29(5): 699–701PubMedCrossRefGoogle Scholar
  38. 38.
    Gassen M, Gross A, Youdim MB. Apomorphine enantiomers protect cultured pheochromocytoma (PC1 2) cells from oxidative stress induced by H2O2 and 6-hydroxydopamine. Mov Disord 1998; 13(2): 242–8PubMedCrossRefGoogle Scholar
  39. 39.
    Grunblatt E, Mandel S, Berkuzki T, et al. Apomorphine protects against MPTP-induced neurotoxicity in mice. Mov Disord 1999; 14(4): 612–8PubMedCrossRefGoogle Scholar
  40. 40.
    Grunblatt E, Mandel S, Maor G, et al. Effects of R-apomorphine and S-apomorphine on MPTP-induced nigro-striatal doamine neuronal loss. J Neurochem 2001; 77(1): 146–56PubMedCrossRefGoogle Scholar
  41. 41.
    Muralikrishnan D, Mohanakumar KP. Neuroprotection by bromocriptine against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in mice. FASEB J 1998; 12(10): 905–12PubMedGoogle Scholar
  42. 42.
    Di Monte D, Sandy MS, Smith MT. Increased efflux rather than oxidation is the mechanism of glutathione depletion by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Biochem Biophys Res Commun 1987; 148(1): 153–60PubMedCrossRefGoogle Scholar
  43. 43.
    Przedborski S, Jackson-Lewis V, Yokoyama R, et al. Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6-tetrahy-dropyridine (MPTP)-induced dopaminergic neurotoxicity. Proc Natl Acad Sci U S A 1996; 93(10): 4565–71PubMedCrossRefGoogle Scholar
  44. 44.
    Schulz JB, Matthews RT, Muqit MM, et al. Inhibition of neuronal nitric oxide synthase by 7-nitroindazole protects against MPTP-induced neurotoxicity in mice. J Neurochem 1995; 64(2): 936–9PubMedCrossRefGoogle Scholar
  45. 45.
    DeRisi J, Penland L, Brown PO, et al. Use of a cDNA microarray to analyse gene expression patterns in human cancer. Nat Genet 1996; 14(4): 457–60PubMedCrossRefGoogle Scholar
  46. 46.
    Lee CK, Klopp RG, Weindruch R, et al. Gene expression profile of aging and its retardation by caloric restriction. Science 1999; 285(5432): 1390–3PubMedCrossRefGoogle Scholar
  47. 47.
    Lockhart DJ, Winzeler EA. Genomics, gene expression and DNA arrays. Nature 2000; 405(6788): 827–36PubMedCrossRefGoogle Scholar
  48. 48.
    Mandel S, Grunblatt E, Maor G, et al. Early and late gene changes in MPTP mice model of Parkinson’s disease employing cDNA microarray. Neurochem Res 2002; 27(10): 1231–43PubMedCrossRefGoogle Scholar
  49. 49.
    Grunblatt E, Mandel S, Maor G, et al. Gene expression analysis in MPTP mice model of Parkinson’s disease using cDNA microarray. J Neurochem 2001; 78: 1–12PubMedCrossRefGoogle Scholar
  50. 50.
    Cadet JL, Jayanthi S, McCoy MT, et al. Temporal profiling of methamphetamine-induced changes in gene expression in the mouse brain: evidence from cDNA array. Synapse 2001; 41(1): 40–8PubMedCrossRefGoogle Scholar
  51. 51.
    Xie T, Tong L, Barrett T, et al. Changes in gene expression linked to methamphetamine-induced dopaminergic neurotoxicity. J Neurosci 2002; 22(1): 274–83PubMedGoogle Scholar
  52. 52.
    Berding G, Odin P, Brooks DJ, et al. Resting regional cerebral glucose metabolism in advanced Parkinson’s disease studied in the off and on conditions with [(18)F]FDG-PET. Mov Disord 2001; 16(6): 1014–22PubMedCrossRefGoogle Scholar
  53. 53.
    Napolitano M, Centonze D, Calce A, et al. Experimental Parkinsonism modulates multiple genes involved in the transduction of dopaminergic signals in the striatum. Neurobiol Dis 2002; 10(3): 387–95PubMedCrossRefGoogle Scholar
  54. 54.
    Smyth PG, Berman SA. Markers of apoptosis: methods for elucidating the mechanism of apoptotic cell death from the nervous system. Biotechniques 2002; 32(3): 648–50, 652, 654 passimPubMedGoogle Scholar
  55. 55.
    Mattson MP. Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 2000; 1(2): 120–9PubMedCrossRefGoogle Scholar
  56. 56.
    Blum D, Torch S, Lambeng N, et al. Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson’s disease. Prog Neurobiol 2001; 65(2): 135–72PubMedCrossRefGoogle Scholar
  57. 57.
    Jimenez Del Rio M, Velez Pardo C. Apoptosis in neurodegenerative diseases: facts and controversies. Rev Neurol 2001; 32(9): 851–60Google Scholar
  58. 58.
    Johnston JP. Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem Pharmacol 1968; 17(7): 1285–97PubMedCrossRefGoogle Scholar
  59. 59.
    Youdim MBH, Gross A, Finberg JPM. Rasagiline [N-propargyl-1R (+)-aminoindant], a selective and potent inhibitor of mitochondrial monoamine oxidase B. Br J Pharmacol 2001; 132: 500–6PubMedCrossRefGoogle Scholar
  60. 60.
    Riederer P, Youdim MBH, Rausch WD, et al. On the mode of action of L-deprenyl in the human central nervous system. J Neural Transm 1978; 43(3–4): 217–26PubMedCrossRefGoogle Scholar
  61. 61.
    Sonsalla PK, Golbe LI. Deprenyl as prophylaxis against Parkinson’s disease? Clin Neuropharmacol 1988; 11(6): 500–11PubMedCrossRefGoogle Scholar
  62. 62.
    Knoll J, Ecseri Z, Kelemen K, et al. Phenylisopropylmethyl-propinylamine (E-250), a new spectrum psychic energizer. Arch Int Pharmacodyn Ther 1965; 155: 154–64PubMedGoogle Scholar
  63. 63.
    Magyar K, Vizi ES, Ecseri Z, et al. Comparative pharmacological analysis of the optical isomers of phenyl-isopropyl-methylpropinylamine (E-250). Acta Physiol Acad Sci Hung 1967; 32(4): 377–87PubMedGoogle Scholar
  64. 64.
    Varga E, Tringer L. Clinical trial of a new type promptly acting psychoenergetic agent (phenyl-isopropyl-methylpropinyl-HCl, “E-250”). Acta Med Acad Sci Hung 1967; 23(3): 289–95PubMedGoogle Scholar
  65. 65.
    Birkmayer W, Riederer P, Youdim MBH, et al. The potentiation of the anti akinetic effect after L-dopa treatment by an inhibitor of MAO-B, deprenil. J Neural Transm 1975; 36(3–4): 303–26PubMedCrossRefGoogle Scholar
  66. 66.
    Presthus J, Hajba A. Deprenyl (selegiline) combined with levodopa and a decarboxylase inhibitor in the treatment of Parkinson’s disease. Acta Neurol Scand Suppl 1983; 95: 127–33PubMedCrossRefGoogle Scholar
  67. 67.
    Robertson DR, George CF. Drug therapy for Parkinson’s disease in the elderly. Br Med Bull 1990; 46(1): 124–46PubMedGoogle Scholar
  68. 68.
    Mendlewicz J, Youdim MBH. A selective MAO-B inhibitor (L-deprenyl) and 5-HTP as antidepressant therapy. In: Youdim MBH, Paykel ES, editor. Monoamine oxidase inhibitors: the state of the art. London: John Wiley & Sons Ltd, 1981: 177–88Google Scholar
  69. 69.
    Golbe LI. Deprenyl as symptomatic therapy in Parkinson’s disease. Clin Neuropharmacol 1988; 11(5): 387–400PubMedCrossRefGoogle Scholar
  70. 70.
    Birkmayer W, Knoll J, Riederer P, et al. Increased life expectancy resulting from addition of L-deprenyl to madopar treatment in Parkinson’s disease: a longterm study. J Neural Transm 1985; 64(2): 113–27PubMedCrossRefGoogle Scholar
  71. 71.
    Cohen G, Spina MB. Deprenyl suppresses the oxidant stress associated with increased dopamine turnover. Ann Neurol 1989; 26(5): 689–90PubMedCrossRefGoogle Scholar
  72. 72.
    Oreland L, Gottfries CG. Brain and brain monoamine oxidase in aging and in dementia of Alzheimer’s type. Prog Neuropsy-chopharmacol Biol Psychiatry 1986; 10(3–5): 533–40CrossRefGoogle Scholar
  73. 73.
    Fowler CJ, Wiberg A, Oreland L, et al. The effect of age on the activity and molecular properties of human brain monoamine oxidase. J Neural Transm 1980; 49(1-2): 1–20PubMedCrossRefGoogle Scholar
  74. 74.
    Glover V, Gibb C, Sandler M. The role of MAO in MPTP toxicity: a review. J Neural Transm Suppl 1986; 20: 65–76PubMedGoogle Scholar
  75. 75.
    Knoll J. The pharmacological basis of the beneficial effects of (−)deprenyl (selegiline) in Parkinson’s and Alzheimer’s diseases. J Neural Transm Suppl 1993; 40: 69–91PubMedGoogle Scholar
  76. 76.
    Carrillo MC, Minami C, Kitani K, et al. Enhancing effect of rasagiline on superoxide dismutase and catalase activities in the dopaminergic system in the rat. Life Sci 2000; 67(5): 577–85PubMedCrossRefGoogle Scholar
  77. 77.
    Kitani K, Minami C, Isobe K, et al. Why (−)deprenyl prolongs survivals of experimental animals: increase of anti-oxidant enzymes in brain and other body tissues as well as mobilization of various humoral factors may lead to systemic anti-aging effects. Mech Ageing Dev 2002; 123(8): 1087–100PubMedCrossRefGoogle Scholar
  78. 78.
    Lai CT, Zuo DM, Yu PH. Is brain superoxide dismutase activity increased following chronic treatment with 1-deprenyl? J Neural Transm Suppl 1994; 41: 221–9PubMedGoogle Scholar
  79. 79.
    Langston JW. Selegiline as neuroprotective therapy in Parkinson’s disease: concepts and controversies. Neurology 1990; 40 (10Suppl. 3): Suppl. 61–6Google Scholar
  80. 80.
    Magyar K. Behaviour of (−)-deprenyl and its analogues. J Neural Transm Suppl 1994; 41: 167–75PubMedGoogle Scholar
  81. 81.
    Lamensdorf I, Porat S, Simantov R, et al. Effect of low-dose treatment with selegiline on dopamine transporter (DAT) expression and amphetamine-induced dopamine release in vivo. Br J Pharmacol 1999; 126(4): 997–1002PubMedCrossRefGoogle Scholar
  82. 82.
    Tatton WG, Wadia JS, Ju WY, et al. (−)-Deprenyl reduces neuronal apoptosis and facilitates neuronal outgrowth by altering protein synthesis without inhibiting monoamine oxidase. J Neural Transm Suppl 1996; 48: 45–59PubMedGoogle Scholar
  83. 83.
    Maruyama W, Naoi M. Neuroprotection by (−)-deprenyl and related compounds. Mech Ageing Dev 1999; 111(2–3): 189–200PubMedCrossRefGoogle Scholar
  84. 84.
    Maruyama W, Yamamoto T, Kitani K, et al. Mechanism underlying anti-apoptotic activity of a (−) deprenyl-related propargylamine, rasagiline. Mech Ageing Dev 2000; 116(2–3): 181–91PubMedCrossRefGoogle Scholar
  85. 85.
    Mizuta I, Ohta M, Ohta K, et al. Selegiline and desmethyl-selegiline stimulate NGF, BDNF, and GDNF synthesis in cultured mouse astrocytes. Biochem Biophys Res Commun 2000; 279(3): 751–5PubMedCrossRefGoogle Scholar
  86. 86.
    Group TPS. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 1993; 328(3): 176–83CrossRefGoogle Scholar
  87. 87.
    Olanow CW, Hauser RA, Gauger L, et al. The effect of deprenyl and levodopa on the progression of Parkinson’s disease. Ann Neurol 1995; 38(5): 771–7PubMedCrossRefGoogle Scholar
  88. 88.
    Chiba K, Trevor A, Castagnoli Jr N. Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem Biophys Res Commun 1984; 120(2): 574–8PubMedCrossRefGoogle Scholar
  89. 89.
    Finnegan KT, Skratt JJ, Irwin I, et al. Protection against DSP-4-induced neurotoxicity by deprenyl is not related to its inhibition of MAO B. Eur J Pharmacol 1990; 184(1): 119–26PubMedCrossRefGoogle Scholar
  90. 90.
    Wu RM, Murphy DL, Chiueh CC. Neuronal protective and rescue effects of deprenyl against MPP+ dopaminergic toxicity. J Neural Transm Gen Sect 1995; 100(1): 53–61PubMedCrossRefGoogle Scholar
  91. 91.
    Salonen T, Haapalinna A, Heinonen E, et al. Monoamine oxidase B inhibitor selegiline protects young and aged rat peripheral sympathetic neurons against 6-hydroxydopamine-induced neurotoxicity. Acta Neuropathol (Berl) 1996; 91(5): 466–74CrossRefGoogle Scholar
  92. 92.
    Sprague JE, Nichols DE. The monoamine oxidase-B inhibitor L-deprenyl protects against 3,4-methylenedioxymetham-phetamine-induced lipid peroxidation and long-term serotonergic deficits. J Pharmacol Exp Ther 1995; 273(2): 667–73PubMedGoogle Scholar
  93. 93.
    Chiueh CC, Huang SJ, Murphy DL. Enhanced hydroxyl radical generation by 2?-methyl analog of MPTP: suppression by clorgyline and deprenyl. Synapse 1992; 11(4): 346–8PubMedCrossRefGoogle Scholar
  94. 94.
    Wu RM, Murphy DL, Chiueh CC. Suppression of hydroxyl radical formation and protection of nigral neurons by l-deprenyl (selegiline). Ann N Y Acad Sci 1996; 786: 379–90PubMedCrossRefGoogle Scholar
  95. 95.
    Carrillo MC, Kitani K, Kanai S, et al. (−)Deprenyl increases activities of superoxide dismutase and catalase in certain brain regions in old male mice. Life Sci 1994; 54(14): 975–81PubMedCrossRefGoogle Scholar
  96. 96.
    Tatton WG, Olanow CW. Apoptosis in neurodegenerative diseases: the role of mitochondria. Biochim Biophys Acta 1999; 1410(2): 195–213PubMedCrossRefGoogle Scholar
  97. 97.
    Knoll J, Dallo J, Yen TT. Striatal dopamine, sexual activity and lifespan: longevity of rats treated with (−)deprenyl. Life Sci 1989; 45(6): 525–31PubMedCrossRefGoogle Scholar
  98. 98.
    Kitani K, Kanai S, Sato Y, et al. Chronic treatment of (−)deprenyl prolongs the life span of male Fischer 344 rats: further evidence. Life Sci 1993; 52(3): 281–8PubMedCrossRefGoogle Scholar
  99. 99.
    Birkmayer W, Birkmayer GD. Effect of (−)deprenyl in long-term treatment of Parkinson’s disease: a 10-years experience. J Neural Transm Suppl 1986; 22: 219–25PubMedGoogle Scholar
  100. 100.
    Group PS. Cerebrospinal fluid homovanillic acid in the DATATOP study on Parkinson’s disease. Arch Neurol 1995; 52(3): 237–45CrossRefGoogle Scholar
  101. 101.
    Group PS. Mortality in DATATOP: a multicenter trial in early Parkinson’s disease. Ann Neurol 1998; 43(3): 318–25CrossRefGoogle Scholar
  102. 102.
    Kalir A, Sabbagh A, Youdim MBH. Selective acetylenic ‘suicide’ and reversible inhibitors of monoamine oxidase types A and B. Br J Pharmacol 1981; 73(1): 55–64PubMedCrossRefGoogle Scholar
  103. 103.
    Finberg JPM, Tenne M, Youdim MBH. Selective irreversible propargyl derivative inhibitors of monoamine oxidase (MAO) without the cheese effect. In: Youdim MBH, Peykel ES, editors. Monoamine oxidase inhibitors: the state of the art. Chichester: Wiley, 1981: 31–41Google Scholar
  104. 104.
    Finberg JP, Lamensdorf I, Weinstock M, et al. Pharmacology of rasagiline (N-propargyl-1R-aminoindan). Adv Neurol 1999; 80: 495–9PubMedGoogle Scholar
  105. 105.
    Maruyama W, Akao Y, Youdim MBH, et al. Neurotoxins induce apoptosis in dopamine neurons: protection by N-propargylamine-1 (R)-and (S)-aminoindan, rasagiline and TV1022. J Neural Transm Suppl 2000; 60: 171–86PubMedGoogle Scholar
  106. 106.
    Maruyama W, Akao Y, Youdim MBH, et al. 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 2001; 78: 727–35PubMedCrossRefGoogle Scholar
  107. 107.
    Huang W, Chen Y, Shohami E, et al. Neuroprotective effect of rasagiline, a selective monoamine oxidase-B inhibitor, against closed head injury in the mouse. Eur J Pharmacol 1999; 366(2-3): 127–35PubMedCrossRefGoogle Scholar
  108. 108.
    Youdim MBH, Wadia JS, Tatton NA. Neuroprotective properties of the antiparkinson drug rasagiline and its optical S-isomer [letter]. Neurosci Lett 1999; 54: S45Google Scholar
  109. 109.
    Goggi J, Theofilopoulos S, Riaz SS,et al. The neuronal survival effects of rasagiline and deprenyl on fetal human and rat ventral mesencephalic neurones in culture. Neuroreport 2000; 11(18): 3937–41PubMedCrossRefGoogle Scholar
  110. 110.
    Oh C, Murray B, Bhattacharya N, et al. (−)-Deprenyl alters the survival of adult murine facial motoneurons after axotomy: increases in vulnerable C57BL strain but decreases in motor neuron degeneration mutants. J Neurosci Res 1994; 38(1): 64–74PubMedCrossRefGoogle Scholar
  111. 111.
    Abu-Raya S, Tabakman R, Blaugrund E, et al. Neuroprotective and neurotoxic effects of monoamine oxidase-B inhibitors and derived metabolites under ischemia in PC12 cells. Eur J Pharmacol 2002; 434(3): 109–16PubMedCrossRefGoogle Scholar
  112. 112.
    Youdim MBH, Wadia A, Tatton NA, et al. 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 2001; 939: 450–8PubMedCrossRefGoogle Scholar
  113. 113.
    Yogev-Falach M, Amit T, Bar-Am O, et al. The involvement of MAP kinase in the regulation of amyloid precursor protein processing by novel cholinesterase inhibitors derived from rasagiline. FASEB J 2002; 16: 1674–6PubMedGoogle Scholar
  114. 114.
    Youdim MBH, Weinstock M. Molecular basis of neuroprotective activities of rasagline and the anti-Alzheimer drug TV3326, [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate]. Cell Mol Neurobiol 2002; 21(6): 555–73CrossRefGoogle Scholar
  115. 115.
    Maruyama W, Weinstock M, Youdim MB, et al. Anti-apoptotic action of anti-Alzheimer drug, TV3326 [(N-propargyl)-3(R)-aminoindan-5-yl]-ethyl methyl carbamate, a novel cholinesterase-monoamine oxidase inhibitor. Neurosci Lett 2003 May 8; 341(3): 233–6PubMedCrossRefGoogle Scholar
  116. 116.
    Maruyama W, Akao Y, Carrillo MC, et al. Neuroprotection by propargylamines in Parkinson’s disease: suppression of apoptosis and induction of prosurvival genes. Neurotoxicol Teratol 2002; 24(5): 675–82PubMedCrossRefGoogle Scholar
  117. 117.
    Rabey JM, Sagi I, Huberman M, et al. Rasagiline mesylate, a new MAO-B inhibitorfor the treatment of Parkinson’s disease: a double-blind study as adjunctive therapy to levodopa. Clin Neuropharmacol 2000; 23(6): 324–30PubMedCrossRefGoogle Scholar
  118. 118.
    Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol 2002; 59(12): 1937–43CrossRefGoogle Scholar
  119. 119.
    Shoulson I. Results of the TEMPO trial. Efficacy and safety of rasagiline as monotherapy: 12 month data. Parkinson Study Group. The 7th International Congress of Parkinson’s Disease and Movement Disorders; 2002 Nov 10; MiamiGoogle Scholar
  120. 120.
    Uitti RJ, Alskog JE. Comparative review of dopamine receptor agonists in Parkinson’s disease. CNS Drugs 1996; 5(5): 369–88CrossRefGoogle Scholar
  121. 121.
    Gerlach M, Ben-Shachar D, Riederer P, et al. Altered brain metabolism of iron as a cause of neurodegenerative diseases? J Neurochem 1994; 63(3): 793–807PubMedCrossRefGoogle Scholar
  122. 122.
    Gassen M, Glinka Y, Pinchasi B, et al. Apomorphine is a highly potent free radical scavenger in rat brain mitochondrial fraction. Eur J Pharmacol 1996; 308(2): 219–25PubMedCrossRefGoogle Scholar
  123. 123.
    Nishibayashi S, Asanuma M, Kohno M, et al. Scavenging effects of dopamine agonists on nitric oxide radicals. J Neurochem 1996; 67(5): 2208–11PubMedCrossRefGoogle Scholar
  124. 124.
    Cassarino DS, Fall CP, Smith TS, et al. Pramipexole reduces reactive oxygen species production in vivo and in vitro and inhibits the mitochondrial permeability transition produced by the parkinsonian neurotoxin methylpyridinium ion. J Neurochem 1998; 71(1): 295–301PubMedCrossRefGoogle Scholar
  125. 125.
    Youdim MB, Gassen M, Gross A, et al. Iron chelating, antioxidant and cytoprotective properties of dopamine receptor agonist; apomorphine. J Neural Transm Suppl 2000; 58: 83–96PubMedGoogle Scholar
  126. 126.
    Olanow CW, Jenner P, Brooks D. Dopamine agonists and neuroprotection in Parkinson’s disease. Ann Neurol 1998; 44(3 Suppl. 1): S167–74PubMedGoogle Scholar
  127. 127.
    Zou L, Jankovic J, Rowe DB, et al. Neuroprotection by pramipexole against dopamine- and levodopa-induced cytotoxicity. Life Sci 1999; 64(15): 1275–85PubMedCrossRefGoogle Scholar
  128. 128.
    Bennett JP, Carvey PM, Hinds TR, et al. Mechanisms of action of pramipexole putative neuroprotective effects. In: Johnson S, Johnson FN, editors. Contemporary pharmacotherapy. Lancashire: Marius Press, 2001: 33–57Google Scholar
  129. 129.
    Mena MA, Davila V, Bogaluvsky J, et al. A synergistic neuro-trophic response to l-dihydroxyphenylalanine and nerve growth factor. Mol Pharmacol 1998; 54(4): 678–86PubMedGoogle Scholar
  130. 130.
    Ohta M, Mizuta I, Ohta K, et al. Apomorphine up-regulates NGF and GDNF synthesis in cultured mouse astrocytes. Biochem Biophys Res Commun 2000; 272(1): 18–22PubMedCrossRefGoogle Scholar
  131. 131.
    Hall ED, Andrus PK, Oostveen JA, et al. Neuroprotective effects of the dopamine D2/D3 agonist pramipexole against postischemic or methamphetamine-induced degeneration of nigrostriatal neurons. Brain Res 1996; 742(1–2): 80–8PubMedCrossRefGoogle Scholar
  132. 132.
    Kondo T, Ito T, Sugita Y. Bromocriptine scavenges methamphetamine-induced hydroxyl radicals and attenuates dopamine depletion in mouse striatum. Ann N Y Acad Sci 1994; 738: 222–9PubMedCrossRefGoogle Scholar
  133. 133.
    Linazasoro G. Subcutaneous apomorphine in the treatment of Parkinson’s disease. Neurologia 1994; 9(1): 1–3PubMedGoogle Scholar
  134. 134.
    Fornai F, Battaglia G, Gesi M, et al. Dose-dependent protective effects of apomorphine against methamphetamine-induced nigrostriatal damage. Brain Res 2001; 898(1): 27–35PubMedCrossRefGoogle Scholar
  135. 135.
    Iida M, Miyazaki I, Tanaka K, et al. Dopamine D2 receptor-mediated antioxidant and neuroprotective effects of ropinirole, a dopamine agonist. Brain Res 1999; 838(1–2): 51–9PubMedCrossRefGoogle Scholar
  136. 136.
    Zou L, Xu J, Jankovic J, et al. Pramipexole inhibits lipid peroxidation and reduces injury in the substantia nigra induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in C57BL/6 mice. Neurosci Lett 2000; 281(2-3): 167–70PubMedCrossRefGoogle Scholar
  137. 137.
    Iida M, Miyazaki I, Tanaka K, et al. Dopamine D2 receptor-mediated antioxidant and neuroprotective effects of ropinirole, a dopamine agonist. Brain Res 1999; 838 (1–2): 51–9Google Scholar
  138. 138.
    Sam EE, Verbeke N. Free radical scavenging properties of apomorphine enantiomers and dopamine: possible implication in their mechanism of action in parkinsonism. J Neural Transm Park Dis Dement Sect 1995; 10(2–3): 115–27PubMedGoogle Scholar
  139. 139.
    Ubeda A, Montesinos C, Paya M, et al. Iron-reducing and free-radical-scavenging properties of apomorphine and some related benzylisoquinolines. Free Radic Biol Med 1993; 15(2): 159–67PubMedCrossRefGoogle Scholar
  140. 140.
    Gassen M, Youdim MBH. Free radical scavengers: chemical concepts and clinical relevance. J Neural Transm Suppl 1999; 56: 193–210PubMedCrossRefGoogle Scholar
  141. 141.
    Sawada H, Ibi M, Kihara T, et al. Dopamine D2-type agonists protect mesencephalic neurons from glutamate neurotoxicity: mechanisms of neuroprotective treatment against oxidative stress. Ann Neurol 1998; 44(1): 110–9PubMedCrossRefGoogle Scholar
  142. 142.
    Takashima H, Tsujihata M, Kishikawa M, et al. Bromocriptine protects dopaminergic neurons from levodopa-induced toxicity by stimulating D(2) receptors. Exp Neurol 1999; 159(1): 98–104PubMedCrossRefGoogle Scholar
  143. 143.
    Carvey PM, Ling ZD, Sortwell CE, et al. A clonal line of mesencephalic progenitor cells converted to dopamine neurons by hematopoietic cytokines: a source of cells for transplantation in Parkinson’s disease. Exp Neurol 2001; 171(1): 98–108PubMedCrossRefGoogle Scholar
  144. 144.
    Le W, Jankovic J, Xie W, et al. Antioxidant property of pramipexole independent of dopamine receptor activation in neuroprotection. J Neural Transm 2000; 107(10): 1165–73PubMedCrossRefGoogle Scholar
  145. 145.
    Kitamura Y, Kosaka T, Kakimura JI, et al. Protective effects of the antiparkinsonian drugs talipexole and pramipexole against 1-methyl-4-phenylpyridinium-induced apoptotic death in human neuroblastoma SH-SY5Y cells. Mol Pharmacol 1998; 54(6): 1046–54PubMedGoogle Scholar
  146. 146.
    Abramova NA, Cassarino DS, Khan SM, et al. Inhibition by R (+) or S (−) pramipexole of caspase activation and cell death induced by methylpyridinium ion or beta amyloid peptide in SH-SY5Y neuroblastoma. J Neurosci Res 2002; 67(4): 494–500PubMedCrossRefGoogle Scholar
  147. 147.
    Weinreb O, Mandel S, Youdim MBH. cDNA gene expression profile homology of antioxidants and their anti-apoptotic and pro-apoptotic activities in human neuroblastoma cells. FASEB J 2003; 17: 935–7PubMedGoogle Scholar
  148. 148.
    Marek K, Seibyl J, Shoulson I, et al. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002; 287(13): 1653–61CrossRefGoogle Scholar
  149. 149.
    Whone A, Remy P, Davis MR, et al. The REAL-PET study: slower progression in early Parkinson’s disease treated with ropinirole compared with L-dopa [abstract]. Neurology 2002; 58: A82–3Google Scholar
  150. 150.
    Lees AJ, Stern GM. Sustained bromocriptine therapy in previously untreated patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 1981; 44(11): 1020–3PubMedCrossRefGoogle Scholar
  151. 151.
    Mizuno Y, Kondo T, Narabayashi H. Pergolide in the treatment of Parkinson’s disease. Neurology 1995; 45(3 Suppl. 3): S13–21PubMedCrossRefGoogle Scholar
  152. 152.
    Carlsson M, Carlsson A. Interactions between glutamatergic and monoaminergic systems within the basal ganglia: implications for schizophrenia and Parkinson’s disease. Trends Neurosci 1990; 13(7): 272–6PubMedCrossRefGoogle Scholar
  153. 153.
    Kornhuber J, Bormann J, Retz W, et al. Memantine displaces [3H]MK-801 at therapeutic concentrations in postmortem human frontal cortex. Eur J Pharmacol 1989; 166(3): 589–90PubMedCrossRefGoogle Scholar
  154. 154.
    Riederer P, Lange KW, Kornhuber J, et al. Glutamate receptor antagonism: neurotoxicity, anti-akinetic effects, and psychosis. J Neural Transm Suppl 1991; 34: 203–10PubMedGoogle Scholar
  155. 155.
    Starr MS. Glutamate/dopamine D1/D2 balance in the basal ganglia and its relevance to Parkinson’s disease. Synapse 1995; 19(4): 264–93PubMedCrossRefGoogle Scholar
  156. 156.
    Klockgether T, Turski L. Toward an understanding of the role of glutamate in experimental parkinsonism: agonist-sensitive sites in the basal ganglia. Ann Neurol 1993; 34(4): 585–93PubMedCrossRefGoogle Scholar
  157. 157.
    Choi DW. Excitotoxic cell death. J Neurobiol 1992; 23(9): 1261–76PubMedCrossRefGoogle Scholar
  158. 158.
    Small DL, Buchan AM. NMDA antagonists: their role in neuroprotection. Int Rev Neurobiol 1997; 40: 137–71PubMedCrossRefGoogle Scholar
  159. 159.
    McGeer PL, Itagaki S, McGeer EG. Expression of the histocompatibility glycoprotein HLA-DR in neurological disease. Acta Neuropathol 1988; 76(6): 550–7PubMedCrossRefGoogle Scholar
  160. 160.
    Jellinger K, Paulus W, Grundke-Iqbal I, et al. Brain iron and ferritin in Parkinson’s and Alzheimer’s diseases. J Neural Transm Park Dis Dement Sect 1990; 2: 327–40PubMedCrossRefGoogle Scholar
  161. 161.
    Mogi M, Harada M, Kondo T, et al. Interleukin-1 beta, interleukin-6, epidermal growth factor and transforming growth factor-alpha are elevated in the brain from parkinsonian patients. Neurosci Lett 1994; 180(2): 147–50PubMedCrossRefGoogle Scholar
  162. 162.
    Mogi M, Harada M, Kondo T, et al. Brain beta 2-microglobulin levels are elevated in the striatum in Parkinson’s disease. J Neural Transm Park Dis Dement Sect 1995; 9(1): 87–92PubMedCrossRefGoogle Scholar
  163. 163.
    Mogi M, Harada M, Narabayashi H, et al. Interleukin (IL)-1 beta, IL-2, IL-4, IL-6 and transforming growth factor-alpha levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson’s disease. Neurosci Lett 1996; 211(0304-3940): 13–6PubMedCrossRefGoogle Scholar
  164. 164.
    Mogi M, Harada M, Riederer P, et al. Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci Lett 1994; 165(1-2): 208–10PubMedCrossRefGoogle Scholar
  165. 165.
    Blum-Degen D, Muller T, Kuhn W, et al. Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients. Neurosci Lett 1995; 202(1–2): 17–20PubMedCrossRefGoogle Scholar
  166. 166.
    Katsuura G, Gottschall PE, Dahl RR, et al. Interleukin-1 beta increases prostaglandin E2 in rat astrocyte cultures: modulatory effect of neuropeptides. Endocrinology 1989; 124(6): 3125–7PubMedCrossRefGoogle Scholar
  167. 167.
    Bezzi P, Carmignoto G, Pasti L, et al. Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 1998; 391(6664): 281–5PubMedCrossRefGoogle Scholar
  168. 168.
    Robinson MB, Djali S, Buchhalter JR. Inhibition of glutamate uptake with L-trans-pyrrolidine-2,4-dicarboxylate potentiates glutamate toxicity in primary hippocampal cultures. J Neurochem 1993; 61(6): 2099–103PubMedCrossRefGoogle Scholar
  169. 169.
    Rothstein JD, Jin L, Dykes-Hoberg M, et al. Chronic inhibition of glutamate uptake produces a model of slow neurotoxicity. Proc Natl Acad Sci U S A 1993; 90(14): 6591–5PubMedCrossRefGoogle Scholar
  170. 170.
    Schwab RS, England Jr AC, Poskanzer DC, et al. Amantadine in the treatment of Parkinson’s disease. JAMA 1969; 208(7): 1168–70PubMedCrossRefGoogle Scholar
  171. 171.
    Davies WL, Grunert RR, Haff RF, et al. Antiviral activity of l-adamantanamine (amantadine). Science 1964; 144: 862–3PubMedCrossRefGoogle Scholar
  172. 172.
    Nastuk WL, Su P, Doubilet P. Anticholinergic and membrane activities of amantadine in neuromuscular transmission. Nature 1976; 264(5581): 76–9PubMedCrossRefGoogle Scholar
  173. 173.
    Gianutsos G, Chute S, Dunn JP. Pharmacological changes in dopaminergic systems induced by long-term administration of amantadine. Eur J Pharmacol 1985; 110(3): 357–61PubMedCrossRefGoogle Scholar
  174. 174.
    Kornhuber J, Mack-Burkhardt F, Riederer P, et al. [3H]MK-801 binding sites in postmortem brain regions of schizophrenic patients. J Neural Transm 1989; 77(2-3): 231–6PubMedCrossRefGoogle Scholar
  175. 175.
    Chen HS, Pellegrini JW, Aggarwal SK, et al. Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity. J Neurosci 1992; 12(11): 4427–36PubMedGoogle Scholar
  176. 176.
    Lustig HS, Ahern KV, Greenberg DA. Antiparkinsonian drugs and in vitro excitotoxicity. Brain Res 1992; 597(1): 148–50PubMedCrossRefGoogle Scholar
  177. 177.
    Rojas P, Altagracia M, Kravsov J, et al. Partially protective effect of amantadine in the MPTP model of Parkinson’s disease. Proc West Pharmacol Soc 1992; 35: 33–5PubMedGoogle Scholar
  178. 178.
    Schwab RS, Poskanzer DC, England Jr AC, et al. Amantadine in Parkinson’s disease: review of more than two years’ experience. JAMA 1972; 222(7): 792–5PubMedCrossRefGoogle Scholar
  179. 179.
    Dallos V, Heathfield K, Stone P, et al. Use of amantadine in Parkinson’s disease: results of a double-blind trial. BMJ 1970; 4(726): 24–6PubMedCrossRefGoogle Scholar
  180. 180.
    Mann DC, Pearce LA, Waterbury LD. Amantadine for Parkinson’s disease. Neurology 1971; 21(9): 958–62PubMedCrossRefGoogle Scholar
  181. 181.
    Parkes JD, Baxter RC, Curzon G, et al. Treatment of Parkinson’s disease with amantadine and levodopa: a one-year study. Lancet 1971; I (7709): 1083–6Google Scholar
  182. 182.
    Fahn S, Isgreen WP. Long-term evaluation of amantadine and levodopa combination in parkinsonism by double-blind crossover analyses. Neurology 1975; 25(8): 695–700PubMedCrossRefGoogle Scholar
  183. 183.
    Savery F. Amantadine and a fixed combination of levodopa and carbidopa in the treatment of Parkinson’s disease. Dis Nerv Syst 1977; 38(8): 605–8PubMedGoogle Scholar
  184. 184.
    Luginger E, Wenning GK, Bosch S, et al. Beneficial effects of amantadine on L-dopa-induced dyskinesias in Parkinson’s disease. Mov Disord 2000; 15(5): 873–8PubMedCrossRefGoogle Scholar
  185. 185.
    Snow BJ, Macdonald L, McAuley D, et al. The effect of amantadine on levodopa-induced dyskinesias in Parkinson’s disease: a double-blind, placebo-controlled study. Clin Neuro-pharmacol 2000; 23(2): 82–5Google Scholar
  186. 186.
    Del Dotto P, Pavese N, Gambaccini G, et al. Intravenous amantadine improves levadopa-induced dyskinesias: an acute double-blind placebo-controlled study. Mov Disord 2001; 16(3): 515–20PubMedCrossRefGoogle Scholar
  187. 187.
    Paci C, Thomas A, Onofrj M. Amantadine for dyskinesia in patients affected by severe Parkinson’s disease. Neurol Sci 2001; 22(1): 75–6PubMedCrossRefGoogle Scholar
  188. 188.
    Gerlach M, Riederer PF. Time sequences of dopaminergic cell death in Parkinson’s disease: indications for neuroprotective studies. Adv Neurol 1999; 80: 219–25PubMedGoogle Scholar
  189. 189.
    Wilson JA, Farquhar DL, Primrose WR, et al. Long term amantadine treatment: the danger of withdrawal. Scott Med J 1987; 32(5): 135PubMedGoogle Scholar
  190. 190.
    Danielczyk W. Therapy of akinetic crises. Med Welt 1973; 24(33): 1278–82PubMedGoogle Scholar
  191. 191.
    Uitti RJ. More recent lessons from amantadine [letter]. Neurology 1999; 52(3): 676PubMedCrossRefGoogle Scholar
  192. 192.
    Seif el Nasr M, Peruche B, Rossberg C, et al. Neuroprotective effect of memantine demonstrated in vivo and in vitro. Eur J Pharmacol 1990; 185(1): 19–24PubMedCrossRefGoogle Scholar
  193. 193.
    Kornhuber J, Bormann J, Hubers M, et al. Effects of the 1-amino-adamantanes at the MK-801-binding site of the NMDA-receptor-gated ion channel: a human postmortem brain study. Eur J Pharmacol 1991; 206(4): 297–300PubMedCrossRefGoogle Scholar
  194. 194.
    Erdo SL, Schafer M. Memantine is highly potent in protecting cortical cultures against excitotoxic cell death evoked by glutamate and N-methyl-D-aspartate. Eur J Pharmacol 1991; 198(2–3): 215–7PubMedCrossRefGoogle Scholar
  195. 195.
    Marvanova M, Lakso M, Pirhonen J, et al. The neuroprotective agent memantine induces brain-derived neurotrophic factor and trkB receptor expression in rat brain. Mol Cell Neurosci 2001; 18(3): 247–58PubMedCrossRefGoogle Scholar
  196. 196.
    Storch A, Burkhardt K, Ludolph AC, et al. Protective effects of riluzole on dopamine neurons: involvement of oxidative stress and cellular energy metabolism. J Neurochem 2000; 75(6): 2259–69PubMedCrossRefGoogle Scholar
  197. 197.
    Araki T, Muramatsu Y, Tanaka K, et al. Riluzole (2-amino-6-trifluoromethoxy benzothiazole) attenuates MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity in mice. Neurosci Lett 2001; 312(1): 50–4PubMedCrossRefGoogle Scholar
  198. 198.
    Obinu MC, Reibaud M, Blanchard V, et al. Neuroprotective effect of riluzole in a primate model of Parkinson’s disease: behavioral and histological evidence. Mov Disord 2002; 17(1): 13–9PubMedCrossRefGoogle Scholar
  199. 199.
    Jankovic J, Hunter C. A double-blind, placebo-controlled and longitudinal study of riluzole in early Parkinson’s disease. Parkinsonism Relat Disord 2002; 8(4): 271–6PubMedCrossRefGoogle Scholar
  200. 200.
    Riederer P, Sofic E, Rausch W, et al. Dopaminforschung heute und morgen-L-dopa in der zukunft. In: Riederer PUH, editor. L-dopa-substitution der Parkinson-krankheit. Vienna: Springer-Verlag, 1985: 127–44CrossRefGoogle Scholar
  201. 201.
    Dexter DT, Carter CJ, Wells FR, et al. Basal lipid peroxidation in substantia nigra is increased in Parkinson’s disease. J Neurochem 1989; 52(2): 381–9PubMedCrossRefGoogle Scholar
  202. 202.
    Sofic E, Paulus W, Jellinger K, et al. Selective increase of iron in substantia nigra zona compacta of parkinsonian brains. J Neurochem 1991; 56(3): 978–82PubMedCrossRefGoogle Scholar
  203. 203.
    Ostrerova-Golts N, Petrucelli L, Hardy J, et al. The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. J Neurosci 2000; 20(16): 6048–54PubMedGoogle Scholar
  204. 204.
    Uversky VN, Li J, Fink AL. Evidence for a partially folded intermediate in alpha-synuclein fibril formation. J Biol Chem 2001; 276(14): 10737–44PubMedCrossRefGoogle Scholar
  205. 205.
    Turnbull S, Tabner BJ, El-Agnaf OM, et al. alpha-Synuclein implicated in Parkinson’s disease catalyses the formation of hydrogen peroxide in vitro. Free Radic Biol Med 2001; 30(10): 1163–70PubMedCrossRefGoogle Scholar
  206. 206.
    Ebadi M, Govitrapong P, Sharma S, et al. Ubiquinone (coenzyme q10) and mitochondria in oxidative stress of Parkinson’s disease. Biol Signals Recept 2001; 10(3–4): 224–53PubMedCrossRefGoogle Scholar
  207. 207.
    Monteiro HP, Winterbourn CC. 6-Hydroxydopamine releases iron from ferritin and promotes ferritin-dependent lipid peroxidation. Biochem Pharmacol 1989; 38(23): 4177–82PubMedCrossRefGoogle Scholar
  208. 208.
    Mochizuki H, Imai H, Endo K, et al. Iron accumulation in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced hemiparkinsonian monkeys. Neurosci Lett 1994; 168(1–2): 251–3PubMedCrossRefGoogle Scholar
  209. 209.
    Oestreicher E, Sengstock GJ, Riederer P, et al. Degeneration of nigrostriatal dopaminergic neurons increases iron within the substantia nigra: a histochemical and neurochemical study. Brain Res 1994; 660(1): 8–18PubMedCrossRefGoogle Scholar
  210. 210.
    Temlett JA, Landsberg JP, Watt F, et al. Increased iron in the substantia nigra compacta of the MPTP-lesioned hemiparkinsonian African green monkey: evidence from proton microprobe elemental microanalysis. J Neurochem 1994; 62(1): 134–46PubMedCrossRefGoogle Scholar
  211. 211.
    Ben-Shachar D, Youdim MB. Intranigral iron injection induces behavioral and biochemical ‘parkinsonism’ in rats. J Neurochem 1991; 57(6): 2133–5PubMedCrossRefGoogle Scholar
  212. 212.
    Levites Y, Weinreb O, Maor G, et al. Green tea polyphenol (−)-epigallocatechin-3-gallate prevents N-methyl-4-phenyl-1,2,-3,6-tetrahydropyridine-induced dopaminergic neurodegeneration. J Neurochem 2001; 78: 1073–82PubMedCrossRefGoogle Scholar
  213. 213.
    LaVaute T, Smith S, Cooperman S, et al. Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. Nat Genet 2001; 27(2): 209–14PubMedCrossRefGoogle Scholar
  214. 214.
    Bruehlmeier M, Leenders KL, Vontobel P, et al. Increased cerebral iron uptake in Wilson’s disease: a 52Fe-citrate PET study. J Nucl Med 2000; 41(5): 781–7PubMedGoogle Scholar
  215. 215.
    Curtis AR, Fey C, Morris CM, et al. Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet 2001; 28(4): 350–4PubMedCrossRefGoogle Scholar
  216. 216.
    Zhou B, Westaway SK, Levinson B, et al. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat Genet 2001; 28(4): 345–9PubMedCrossRefGoogle Scholar
  217. 217.
    Miyajima H, Takahashi Y, Kamata T, et al. Use of desferriox-amine in the treatment of aceruloplasminemia. Ann Neurol 1997; 41(3): 404–7PubMedCrossRefGoogle Scholar
  218. 218.
    Guo Q, Zhao B, Li M, et al. ESR study on the structure-antioxidant activity relationship of tea catechins and their epimers. Biochim Biophys Acta 1996; 1304(3): 210–22PubMedCrossRefGoogle Scholar
  219. 219.
    Suganuma M, Okabe S, Oniyama M, et al. Wide distribution of [3H](−)-epigallocatechin gallate, a cancer preventive tea polyphenol, in mouse tissue. Carcinogenesis 1998; 19: 1771–6PubMedCrossRefGoogle Scholar
  220. 220.
    Vatassery GT, Bauer T, Dysken M. High doses of vitamin E in the treatment of disorders of the central nervous system in the aged. Am J Clin Nutr 1999; 70(5): 793–801PubMedGoogle Scholar
  221. 221.
    McCay PB. Vitamin E: interactions with free radicals and ascorbate. Annu Rev Nutr 1985; 5: 323–40PubMedCrossRefGoogle Scholar
  222. 222.
    Hall ED, Yonkers PA, Andrus PK, et al. Biochemistry and pharmacology of lipid antioxidants in acute brain and spinal cord injury. J Neurotrauma 1992; 9Suppl. 2: S425–42PubMedGoogle Scholar
  223. 223.
    Packer L, Tritschler HJ, Wessel K. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic Biol Med 1997; 22(1-2): 359–78PubMedCrossRefGoogle Scholar
  224. 224.
    Behl C. Vitamin E protects neurons against oxidative cell death in vitro more effectively than 17-beta estradiol and induces the activity of the transcription factor NF-kappaB. J Neural Transm 2000; 107(4): 393–407PubMedCrossRefGoogle Scholar
  225. 225.
    Kilander L, Ohrvall M. Alpha-tocopherol and Alzheimer’s disease. N Engl J Med 1997; 337(8): 572–3PubMedCrossRefGoogle Scholar
  226. 226.
    Dufresne C, Farnworth E. A review of latest research findings on the health promotion properties of tea. J Nutr Biochem 2001; 12(7): 404–21PubMedCrossRefGoogle Scholar
  227. 227.
    Schroeter H, Williams RJ, Matin R, et al. Phenolic antioxidants attenuate neuronal cell death following uptake of oxidized low-density lipoprotein. Free Radic Biol Med 2000; 29(12): 1222–33PubMedCrossRefGoogle Scholar
  228. 228.
    Hibatallah J, Carduner C, Poelman MC. In-vivo and in-vitro assessment of the free-radical-scavenger activity of ginkgo flavone glycosides at high concentration. J Pharm Pharmacol 1999; 51(12): 1435–40PubMedCrossRefGoogle Scholar
  229. 229.
    Bastianetto S, Ramassamy C, Dore S, et al. The ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by beta-amyloid. Eur J Neurosci 2000; 12(6): 1882–90PubMedCrossRefGoogle Scholar
  230. 230.
    Bastianetto S, Zheng WH, Quirion R. Neuroprotective abilities of resveratrol and other red wine constituents against nitric oxide-related toxicity in cultured hippocampal neurons. Br J Pharmacol 2000; 131(4): 711–20PubMedCrossRefGoogle Scholar
  231. 231.
    Joseph JA, Shukitt-Hale B, Denisova NA, et al. Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. J Neurosci 1999; 19(18): 8114–21PubMedGoogle Scholar
  232. 232.
    Pratico D, Delanty N. Oxidative injury in diseases of the central nervous system: focus on Alzheimer’s disease. Am J Med 2000; 109(7): 577–85PubMedCrossRefGoogle Scholar
  233. 233.
    Clostre F. Ginkgo biloba extract (EGb 761): state of knowledge in the dawn of the year 2000 [French]. Ann Pharm Fr 1999; 57Suppl. 1: 18–88Google Scholar
  234. 234.
    Wang ZY, Huang MT, Lou YR, et al. Inhibitory effects of black tea, green tea, decaffeinated black tea, and decaffeinated green tea on ultraviolet B light-induced skin carcinogenesis in 7,12-dimethylbenz[a]anthracene-initiated SKH-1 mice. Cancer Res 1994; 54(13): 3428–55PubMedGoogle Scholar
  235. 235.
    Haqqi TM, Anthony DD, Gupta S, et al. Prevention of collagen-induced arthritis in mice by a polyphenolic fraction from green tea. Proc Natl Acad Sci U S A 1999; 96(8): 4524–9PubMedCrossRefGoogle Scholar
  236. 236.
    Pan MH, Lin-Shiau SY, Ho CT, et al. Suppression of lypo-polysaccharide-induced nuclear factor kappaB activity by theaflavin-3,3t?-digallate from black tea and other polyphenols through down-regulation of IkappaB kinase activity in macrophages. 2000; 59(12): 357–67Google Scholar
  237. 237.
    Lin YL, Tsai SH, Lin-Shiau SY, et al. Theaflavin-3,3t?-digallate from black tea blocks the nitric oxide synthase by down-regulating the activation of NF-kappaB in macrophages. Eur J Pharmacol 1999; 367(2–3): 379–88PubMedCrossRefGoogle Scholar
  238. 238.
    Salah N, Miller NJ, Paganga G, et al. Polyphenolic flavanols as scavengers of aqueous phase radicals and as chain-breaking antioxidants. Arch Biochem Biophy 1995; 322(2): 339–46CrossRefGoogle Scholar
  239. 239.
    Nanjo F, Goto K, Seto R, et al. Scavenging effects of tea catechins and their derivatives on 1,1-diphenyl-2-picrylhydrazyl radical. Free Radic Biol Med 1996; 21(6): 895–902PubMedCrossRefGoogle Scholar
  240. 240.
    Morel I, Lescoat G, Cogrel P, et al. Antioxidant and iron-chelating activities of the flavonoids catechin, quercetin and diosmetin on iron-loaded rat hepatocyte cultures. Biochem Pharmacol 1999; 45(1): 13–9CrossRefGoogle Scholar
  241. 241.
    Guo Q, Zhao B, Li M, et al. Studies on protective mechanisms of four components of green tea polyphenols against lipid peroxidation in synaptosomes. Biochim Biophys Acta 1996; 1304(3): 210–22PubMedCrossRefGoogle Scholar
  242. 242.
    Grinberg LN, Newmark H, Kitrossky N, et al. Protective effects of tea polyphenols against oxidative damage to red blood cells. Biochem Pharmacol 1997; 54(9): 973–8PubMedCrossRefGoogle Scholar
  243. 243.
    Levites Y, Youdim MBH, Maor G, et al. Attenuation of 6-hydroxydopamine (6-OHDA)-induced nuclear factor-kappaB (NF-kappaB) activation and cell death by tea extracts in neuronal cultures. Biochem Pharmacol 2002; 63(1): 21–9PubMedCrossRefGoogle Scholar
  244. 244.
    Levites Y, Amit T, Youdim MB, et al. Involvement of protein kinase C activation and cell survival/cell cycle genes in green tea polyphenol, (−)-epigallocatechin-3-gallate neuroprotective action. J Biol Chem 2002 Aug 23; 277(34): 30574–80PubMedCrossRefGoogle Scholar
  245. 245.
    Matsuoka Y, Hasegawa H, Okuda S, et al. Ameliorative effects of tea catechins on active oxygen-related nerve cell injuries. J Pharmacol Exp Ther 1995; 274(2): 602–8PubMedGoogle Scholar
  246. 246.
    Lee S, Suh S, Kim S. Protective effects of the green tea polyphenol (−)-epigallocatechin gallate against hippocampal neuronal damage after transient global ischemia in gerbils. Neurosci Lett 2000; 287(3): 191–4PubMedCrossRefGoogle Scholar
  247. 247.
    van Acker SA, van den Berg DJ, Tromp MN, et al. Structural aspects of antioxidant activity of flavonoids. Free Radic Biol Med 1996; 20(3): 331–42PubMedCrossRefGoogle Scholar
  248. 248.
    Checkoway H, Powers K, Smith-Weller T, et al. Parkinson’s disease risks associated with cigarette smoking, alcohol consumption, and caffeine intake. Am J Epidemiol 2002; 155(8): 732–8PubMedCrossRefGoogle Scholar
  249. 249.
    Hirsch EC, Hunot S, Damier P, et al. Glial cells and inflammation in Parkinson’s disease: a role in neurodegeneration? Ann Neurol 1998; 44 (3 Suppl. 1): S1 15–20Google Scholar
  250. 250.
    Luo Y, Umegaki H, Wang X, et al. Dopamine induces apoptosis through an oxidation-involved SAPK/JNK activation pathway. J Biol Chem 1998; 273(6): 3756–64PubMedCrossRefGoogle Scholar
  251. 251.
    Oo TF, Henchcliffe C, James D, et al. Expression of c-fos, c-jun, and c-jun N-terminal kinase (JNK) in a developmental model of induced apoptotic death in neurons of the substantia nigra. J Neurochem 1999; 72(2): 557–64PubMedCrossRefGoogle Scholar
  252. 252.
    Perez-Otano I, Mandelzys A, Morgan JI. MPTP-Parkinsonism is accompanied by persistent expression of a delta-FosB-like protein in dopaminergic pathways. Brain Res Mol Brain Res 1998; 53(1-2): 41–52PubMedCrossRefGoogle Scholar
  253. 253.
    McGeer PL, McGeer EG. The inflammatory response system of brain: implications for therapy of Alzheimer and other neuro-degenerative diseases. Brain Res Brain Res Rev 1995; 21(2): 195–218PubMedCrossRefGoogle Scholar
  254. 254.
    Adams J, Collaco-Moraes Y, de Belleroche J. Cyclooxygenase-2 induction in cerebral cortex: an intracellular response to synaptic excitation. J Neurochem 1996; 66(1): 6–13PubMedCrossRefGoogle Scholar
  255. 255.
    Westwick JK, Weitzel C, Minden A, et al. Tumor necrosis factor alpha stimulates AP-1 activity through prolonged activation of the c-Jun kinase. J Biol Chem 1994; 269(42): 26396–401PubMedGoogle Scholar
  256. 256.
    Yamamoto K, Arakawa T, Ueda N, et al. Transcriptional roles of nuclear factor kappab and nuclear factor-interleukin-6 in the tumor necrosis factor alpha-dependent induction of cyclooxy-genase-2 in MC3T3-E1 cells. J Biol Chem 1995; 270(52): 31315–20PubMedCrossRefGoogle Scholar
  257. 257.
    Aubin N, Curet O, Deffois A, et al. Aspirin and salicylate protect against MPTP-induced dopamine depletion in mice. J Neurochem 1998; 71(4): 1635–42PubMedCrossRefGoogle Scholar
  258. 258.
    Ferger B, Teismann P, Earl CD, et al. Salicylate protects against MPTP-induced impairments in dopaminergic neurotransmission at the striatal and nigral level in mice. Naunyn Schmiedebergs Arch Pharmacol 1999; 360(3): 256–61PubMedCrossRefGoogle Scholar
  259. 259.
    Teismann P, Ferger B. Inhibition of the cyclooxygenase isoenzymes COX-1 and COX-2 provide neuroprotection in the MPTP-mouse model of Parkinson’s disease. Synapse 2001; 39(2): 167–74PubMedCrossRefGoogle Scholar
  260. 260.
    Grilli M, Pizzi M, Memo M, et al. Neuroprotection by aspirin and sodium salicylate through blockade of NF-kappaB activation. Science 1996; 274(5291): 1383–5PubMedCrossRefGoogle Scholar
  261. 261.
    Amin AR, Vyas P, Attur M, et al. The mode of action of aspirin-like drugs: effect on inducible nitric oxide synthase. Proc Natl Acad Sci U S A 1995; 92(17): 7926–30PubMedCrossRefGoogle Scholar
  262. 262.
    Casper D, Yaparpalvi U, Rempel N, et al. Ibuprofen protects dopaminergic neurons against glutamate toxicity in vitro. Neurosci Lett 2000; 289(3): 201–4PubMedCrossRefGoogle Scholar
  263. 263.
    Jackson LM, Hawkey CJ. COX-2 selective nonsteroidal anti-inflammatory drugs: do they really offer any advantages? Drugs 2000; 59(6): 1207–16PubMedCrossRefGoogle Scholar
  264. 264.
    Heinemann S, Boulter J, Connolly J, et al. The nicotinic receptor genes. Clin Neuropharmacol 1991; 14Suppl. 1: S45–61PubMedCrossRefGoogle Scholar
  265. 265.
    Anand R, Conroy WG, Schoepfer R, et al. Neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes have a pentameric quaternary structure. J Biol Chem 1991; 266(17): 11192–8PubMedGoogle Scholar
  266. 266.
    Wonnacott S, Irons J, Rapier C, et al. Presynaptic modulation of transmitter release by nicotinic receptors. Prog Brain Res 1989; 79: 157–63PubMedCrossRefGoogle Scholar
  267. 267.
    Rowell PP, Winkler DL. Nicotinic stimulation of [3H]acetylcholine release from mouse cerebral cortical synaptosomes. J Neurochem 1984; 43(6): 1593–8PubMedCrossRefGoogle Scholar
  268. 268.
    Quirion R, Richard J, Wilson A. Muscarinic and nicotinic modulation of cortical acetylcholine release monitored by in vivo microdialysis in freely moving adult rats. Synapse 1994; 17(2): 92–100PubMedCrossRefGoogle Scholar
  269. 269.
    Whitehouse PJ, Hedreen JC, White III CL, et al. Basal forebrain neurons in the dementia of Parkinson disease. Ann Neurol 1983; 13(3): 243–8PubMedCrossRefGoogle Scholar
  270. 270.
    Perry EK, Curtis M, Dick DJ, et al. Cholinergic correlates of cognitive impairment in Parkinson’s disease: comparisons with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1985; 48(5): 413–21PubMedCrossRefGoogle Scholar
  271. 271.
    Whitehouse PJ, Martino AM, Marcus KA, et al. Reductions in acetylcholine and nicotine binding in several degenerative diseases. Arch Neurol 1988; 45(7): 722–4PubMedCrossRefGoogle Scholar
  272. 272.
    Baron J. Epidemiology of smoking and Parkinson’s disease [abstract]. In: Clarke P, Quik M, Thurau K, et al., editors. Effects of nicotine on biological systems II. Boston: Birkhauser, 1994: s42Google Scholar
  273. 273.
    Allam MF. Transdermal nicotine in PD: a randomized, double-blind, placebo-controlled study [letter]. Neurology 2002; 58(7): 1133PubMedCrossRefGoogle Scholar
  274. 274.
    Mitsuoka T, Kaseda Y, Yamashita H, et al. Effects of nicotine chewing gum on UPDRS score and P300 in early-onset parkinsonism. Hiroshima J Med Sci 2002; 51(1): 33–9PubMedGoogle Scholar
  275. 275.
    Morens DM, Grandinetti A, Reed D, et al. Cigarette smoking and protection from Parkinson’s disease: false association or etiologic clue? Neurology 1995; 45(6): 1041–51PubMedCrossRefGoogle Scholar
  276. 276.
    Paulson GW. Addiction to nicotine is due to high intrinsic levels of dopamine. Med Hypotheses 1992; 38(3): 206–7PubMedCrossRefGoogle Scholar
  277. 277.
    Zheng JQ, Felder M, Connor JA, et al. Turning of nerve growth cones induced by neurotransmitters. Nature 1994; 368(6467): 140–4PubMedCrossRefGoogle Scholar
  278. 278.
    Hedin CA. Smoker’s melanosis may explain the lower hearing loss and lower frequency of Parkinson’s disease found among tobacco smokers: a new hypothesis. Med Hypotheses 1991; 35(3): 247–9PubMedCrossRefGoogle Scholar
  279. 279.
    Gresham LS, Molgaard CA, Smith RA. Induction of cytochrome P-450 enzymes via tobacco smoke: a potential mechanism for developing resistance to environmental toxins as related to parkinsonism and other neurologic diseases. Neuro-epidemiology 1993; 12(2): 114–6Google Scholar
  280. 280.
    Yong VW, Perry TL. Monoamine oxidase B, smoking, and Parkinson’s disease. J Neurol Sci 1986; 72(2–3): 265–72PubMedCrossRefGoogle Scholar
  281. 281.
    Quik M, Jeyarasasingam G. Nicotinic receptors and Parkinson’s disease. Eur J Pharmacol 2000; 393(1–3): 223–30PubMedCrossRefGoogle Scholar
  282. 282.
    Jeyarasasingam G, Tompkins L, Quik M. Stimulation of non-alpha7 nicotinic receptors partially protects dopaminergic neurons from 1-methyl-4-phenylpyridinium-induced toxicity in culture. Neuroscience 2002; 109(2): 275–85PubMedCrossRefGoogle Scholar
  283. 283.
    Soto-Otero R, Mendez-Alvarez E, Hermida-Ameijeiras A, et al. Effects of (−)-nicotine and (−)-cotinine on 6-hydroxy-dopamine-induced oxidative stress and neurotoxicity: relevance for Parkinson’s disease. Biochem Pharmacol 2002; 64(1): 125–35PubMedCrossRefGoogle Scholar
  284. 284.
    Janson AM, Meana JJ, Goiny M, et al. Chronic nicotine treatment counteracts the decrease in extracellular neostriatal dopamine induced by a unilateral transection at the mesodiencephalic junction in rats: a microdialysis study. Neurosci Lett 1991; 134(1): 88–92PubMedCrossRefGoogle Scholar
  285. 285.
    Janson AM, Fuxe K, Agnati LF, et al. Chronic nicotine treatment counteracts the disappearance of tyrosine-hydroxylase-immunoreactive nerve cell bodies, dendrites and terminals in the mesostriatal dopamine system of the male rat after partial hemitransection. Brain Res 1988; 455(2): 332–45PubMedCrossRefGoogle Scholar
  286. 286.
    Janson AM, Fuxe K, Sundstrom E, et al. Chronic nicotine treatment partly protects against the 1-methyl-4-phenyl-2,3,6-tetrahydropyridine-induced degeneration of nigrostriatal dopamine neurons in the black mouse. Acta Physiol Scand 1988; 132(4): 589–91PubMedCrossRefGoogle Scholar
  287. 287.
    Ryan RE, Ross SA, Drago J, et al. Dose-related neuroprotective effects of chronic nicotine in 6-hydroxydopamine treated rats, and loss of neuroprotection in alpha4 nicotinic receptor subunit knockout mice. Br J Pharmacol 2001; 132(8): 1650–6PubMedCrossRefGoogle Scholar
  288. 288.
    Bannon AW, Decker MW, Holladay MW, et al. Broad-spectrum, non-opioid analgesic activity by selective modulation of neuronal nicotinic acetylcholine receptors. Science 1998; 279(5347): 77–81PubMedCrossRefGoogle Scholar
  289. 289.
    Lloyd GK, Menzaghi F, Bontempi B, et al. The potential of subtype-selective neuronal nicotinic acetylcholine receptor agonists as therapeutic agents. Life Sci 1998; 62(17–18): 1601–6PubMedCrossRefGoogle Scholar
  290. 290.
    Kordower JH, Emborg ME, Bloch J, et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science 2000; 290(5492): 767–73PubMedCrossRefGoogle Scholar
  291. 291.
    Palfi S, Leventhal L, Chu Y, et al. Lentivirally delivered glial cell line-derived neurotrophic factor increases the number of striatal dopaminergic neurons in primate models of nigrostriatal degeneration. J Neurosci 2002; 22(12): 4942–54PubMedGoogle Scholar
  292. 292.
    Kordower JH, Palfi S, Chen EY, et al. Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson’s disease. Ann Neurol 1999; 46(3): 419–24PubMedCrossRefGoogle Scholar
  293. 293.
    Gill SS, Patel NK, Hotton GR, et al. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med 2003; 9(5): 589–95PubMedCrossRefGoogle Scholar
  294. 294.
    Beal MF. Bioenergetic approaches for neuroprotection in Parkinson’s disease. Ann Neurol 2003; 53Suppl. 3: S39–47; discussion S47-8PubMedCrossRefGoogle Scholar
  295. 295.
    Kitamura Y, Itano Y, Kubo T, et al. Suppressive effect of FK-506, a novel immunosuppressant, against MPTP-induced dopamine depletion in the striatum of young C57BL/6 mice. J Neuroimmunol 1994; 50(2): 221–4PubMedCrossRefGoogle Scholar
  296. 296.
    Akao Y, Maruyama W, Shimizu S, et al. 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 2002; 82(4): 913–23PubMedCrossRefGoogle Scholar
  297. 297.
    Kaminski Schierle GS, Hansson O, Brundin P. Flunarizine improves the survival of grafted dopaminergic neurons. Neuroscience 1999; 94(1): 17–20PubMedCrossRefGoogle Scholar
  298. 298.
    Terland O, Flatmark T. Drug-induced parkinsonism: cinnarizine and flunarizine are potent uncouplers of the vacuolar H+-ATPase in catecholamine storage vesicles. Neuro-pharmacology 1999; 38(6): 879–82Google Scholar
  299. 299.
    Hartmann A, Hunot S, Michel PP, et al. Caspase-3: a vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson’s disease. Proc Natl Acad Sci USA 2000; 97(6): 2875–80PubMedCrossRefGoogle Scholar
  300. 300.
    Robertson GS, Crocker SJ, Nicholson DW, et al. Neuroprotection by the inhibition of apoptosis. Brain Pathol 2000; 10(2): 283–92PubMedCrossRefGoogle Scholar
  301. 301.
    Cheng EH, Wei MC, Weiler S, et al. BCL-2, BCL-X (L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell 2001; 8(3): 705–11PubMedCrossRefGoogle Scholar
  302. 302.
    Hartmann A, Troadec JD, Hunot S, et al. Caspase-8 is an effector in apoptotic death of dopaminergic neurons in Parkinson’s disease, but pathway inhibition results in neuronal necrosis. J Neurosci 2001; 21(7): 2247–55PubMedGoogle Scholar
  303. 303.
    Mechoulam R. The pharmacohistory of cannabis sativa. In: Mechoulam R, editor. Cannabinoids as therapeutic agents. Boca Raton: CRC, 1986: 1–19Google Scholar
  304. 304.
    Annas GJ. Reefer madness: the federal response to California’s medical-marijuana law. N Engl J Med 1997; 337(6): 435–9PubMedCrossRefGoogle Scholar
  305. 305.
    Mechoulam R, Vogel Z, Barg J. CNS cannabinoid receptors: role and therapeutic implications for CNS disorders. CNS Drugs 1994; 2(4): 255–60CrossRefGoogle Scholar
  306. 306.
    Devane WA. New dawn of cannabinoid pharmacology. Trends Pharmacol Sci 1994; 15(2): 40–1PubMedCrossRefGoogle Scholar
  307. 307.
    Devane WA, Dysarz III FA, Johnson MR, et al. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 1988; 34(5): 605–13PubMedGoogle Scholar
  308. 308.
    Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992; 258(5090): 1946–9PubMedCrossRefGoogle Scholar
  309. 309.
    Mechoulam R, Ben-Shabat S, Hanus L, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 1995; 50(1): 83–90PubMedCrossRefGoogle Scholar
  310. 310.
    Sugiura T, Kondo S, Sukagawa A, et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 1995; 215(1): 89–97PubMedCrossRefGoogle Scholar
  311. 311.
    Di Marzo V, Melck D, Bisogno T, et al. Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci 1998; 21(12): 521–8PubMedCrossRefGoogle Scholar
  312. 312.
    Herkenham M, Lynn AB, de Costa BR, et al. Neuronal localization of cannabinoid receptors in the basal ganglia of the rat. Brain Res 1991; 547(2): 267–74PubMedCrossRefGoogle Scholar
  313. 313.
    Glass M, Brotchie JM, Maneuf YP. Modulation of neurotransmission by cannabinoids in the basal ganglia. Eur J Neurosci 1997; 9(2): 199–203PubMedCrossRefGoogle Scholar
  314. 314.
    Romero J, Garcia L, Cebeira M, et al. The endogenous cannabinoid receptor ligand, anandamide, inhibits the motor behavior: role of nigrostriatal dopaminergic neurons. Life Sci 1995; 56(23–24): 2033–40PubMedCrossRefGoogle Scholar
  315. 315.
    Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 1997; 74(2): 129–80PubMedCrossRefGoogle Scholar
  316. 316.
    Jeon YJ, Yang KH, Pulaski JT, et al. Attenuation of inducible nitric oxide synthase gene expression by delta 9-tetrahydrocannabinol is mediated through the inhibition of nuclear factor-kappa B/Rel activation. Mol Pharmacol 1996; 50(2): 334–41PubMedGoogle Scholar
  317. 317.
    Skaper SD, Buriani A, Dal Toso R, et al. The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons. Proc Natl Acad Sci U S A 1996; 93(9): 3984–9PubMedCrossRefGoogle Scholar
  318. 318.
    Hampson AJ, Bornheim LM, Scanziani M, et al. Dual effects of anandamide on NMDA receptor-mediated responses and neurotransmission. J Neurochem 1998; 70(2): 671–6PubMedCrossRefGoogle Scholar
  319. 319.
    Shen M, Thayer SA. Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity. Mol Pharmacol 1998; 54(3): 459–62PubMedGoogle Scholar
  320. 320.
    Hampson AJ, Grimaldi M, Axelrod J, et al. Cannabidiol and (−)delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A 1998; 95(14): 8268–73PubMedCrossRefGoogle Scholar
  321. 321.
    Giuffrida A, Beltramo M, Piomelli D. Mechanisms of endocan-nabinoid inactivation: biochemistry and pharmacology. J Pharmacol Exp Ther 2001; 298(1): 7–14PubMedGoogle Scholar
  322. 322.
    Meschler JP, Howlett AC, Madras BK. Cannabinoid receptor agonist and antagonist effects on motor function in normal and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-treated non-human primates. Psychopharmacology (Berl) 2001; 156(1): 79–85CrossRefGoogle Scholar
  323. 323.
    Frankel JP, Hughes A, Lees AJ, et al. Marijuana for parkinsonian tremor [letter]. J Neurol Neurosurg Psychiatry 1990; 53(5): 436PubMedCrossRefGoogle Scholar
  324. 324.
    Commins DL, Vosmer G, Virus RM, et al. Biochemical and histological evidence that methylenedioxymethylamphetamine (MDMA) is toxic to neurons in the rat brain. J Pharmacol Exp Ther 1987; 241(1): 338–45PubMedGoogle Scholar
  325. 325.
    Schmidt CJ. Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. J Pharmacol Exp Ther 1987; 240(1): 1–7PubMedGoogle Scholar
  326. 326.
    Logan BJ, Laverty R, Sanderson WD, et al. Differences between rats and mice in MDMA (methylenedioxymethy-lamphetamine) neurotoxicity. Eur J Pharmacol 1988; 152(3): 227–34PubMedCrossRefGoogle Scholar
  327. 327.
    O’Callaghan JP, Miller DB. Neurotoxicity profiles of substituted amphetamines in the C57BL/6J mouse. J Pharmacol Exp Ther 1994; 270(2): 741–51PubMedGoogle Scholar
  328. 328.
    Stone DM, Stahl DC, Hanson GR, et al. The effects of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on monoaminergic systems in the rat brain. Eur J Pharmacol 1986; 128(1–2): 41–8PubMedCrossRefGoogle Scholar
  329. 329.
    Nash JF, Nichols DE. Microdialysis studies on 3,4-methylenedi-oxyamphetamine and structurally related analogues. Eur J Pharmacol 1991; 200(1): 53–8PubMedCrossRefGoogle Scholar
  330. 330.
    Ecstasy & agony [online]. Available from URL: [Accessed 10 April 2003]
  331. 331.
    Ricaurte GA, Yuan J, Hatzidimitriou G, et al. Severe dopaminergic neurotoxicity in primates after a common recreational dose regimen of MDMA (“Ecstasy”). Science 2002; 297(5590): 2260–3PubMedCrossRefGoogle Scholar
  332. 332.
    von Sydow K, Lieb R, Pfister H, et al. Use, abuse and dependence of ecstasy and related drugs in adolescents and young adults-a transient phenomenon? Results from a longitudinal community study. Drug Alcohol Depend 2002; 66(2): 147–59CrossRefGoogle Scholar
  333. 333.
    Youdim MB, Lavie L. Selective MAO-A and B inhibitors, radical scavengers and nitric oxide synthase inhibitors in Parkinson’s disease. Life Sci 1994; 55(25–26): 2077–82PubMedCrossRefGoogle Scholar
  334. 334.
    Colangelo V, Schurr J, Ball MJ, et al. Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and pro-inflammatory signaling. J Neurosci Res 2002; 70(3): 462–73PubMedCrossRefGoogle Scholar
  335. 335.
    Jin K, Mao XO, Eshoo MW, et al. Microarray analysis of hippocampal gene expression in global cerebral ischemia. Ann Neurol 2001; 50(1): 93–103PubMedCrossRefGoogle Scholar
  336. 336.
    Aronowski J, Strong R, Shirzadi A, et al. Ethanol plus caffeine (caffeinol) for treatment of ischemic stroke: preclinical experience. Stroke 2003; 34(5): 1246-51PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  • Silvia Mandel
    • 1
  • Edna Grünblatt
    • 2
  • Peter Riederer
    • 2
  • Manfred Gerlach
    • 2
  • Yona Levites
    • 1
  • Moussa B. H. Youdim
    • 1
  1. 1.Department of Pharmacology, Technion - Faculty of MedicineEve Topf and US National Parkinson’s Foundation Centers for Neurodegenerative Diseases, Bruce Rappaport Family Research InstituteHaifaIsrael
  2. 2.Department of NeurochemistryBayrische Julius-Maximilians-University of Wurzburg, Clinic, and Polyclinic of Psychiatry and PsychotherapyWürzburgGermany

Personalised recommendations