COMT Inhibition in the Treatment of Parkinson’S Disease: Neuroprotection and Future Perspectives

  • Vladimir S. Kostić
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 541)


Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects about 1 to 2% of the elderly population (aged > 65 years). It remains that from the clinical point of view, PD’s cardinal features are limited to four — tremor, rigidity, akinesia, and postural instability — and that customarily the unambiguous observation of at least two of the first three suffices to pose the clinical diagnosis of PD. Although the progression of PD is slow compared to other degenerative parkinsonian disorders, the annual rate of motor function decline is most rapid early in the course of the disease (during the first 4 to 9 years). This pattern of progression may be correlated with the underlying nigral pathology.1


Plasma Homocysteine Motor Fluctuation Levodopa Therapy Motor Complication Nigrostriatal Pathway 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    M. Guttman, J. Burkholder J, S.J. Kish, D. Hussey, A. Wilson, J. DaSitva, and S. Houle, [11C]RTI-32 PET studies of the dopamine transporter in early dopa-naive Parkinson’s disease: implications for the symptomatic threshold, Neurology 48, 1578–1583 (1997).PubMedCrossRefGoogle Scholar
  2. 2.
    A. Björ klund, and O. Lindvall, Dopamine-containing systems in the CNS, in: Handbook of chemical neuroanatomy. Classical transmitters in the CNS. Part, edited by A. Björklund, and T. Hökfelt (El-sevier, Amsterdam, 1984), pp. 55–122.Google Scholar
  3. 3.
    B. Scatton, T. Dennis, R. L’Heureux, J.C. Monfort, C. Duyckaerts, and F. Javoy-Agid, Degeneration of noradrenergic and serotonergic but not dopaminergic neurones in the lumbar spinal cord of parkinsonian patients, Brain Res. 380, 181–185 (1986).PubMedCrossRefGoogle Scholar
  4. 4.
    CD. Marsden, Neuromelanin and Parkinson’s disease. J. Neural. Transm. 19, 121–141 (1983).Google Scholar
  5. 5.
    L.S. Forno, Pathology of Parkinson’s disease: the importance of the substantia nigra and Lewy bodies, in: Parkinson’s disease, edited by G M. Stern (The Johns Hopkins University Press, Baltimore, 1990), pp. 185–238.Google Scholar
  6. 6.
    O. Hornykiewicz, and S.J. Kish, Biochemical pathophysiology of Parkinson’s disease, in: Parkinson’s disease, edited by M. Yahr, and K.J. Bergmann Raven Press, New York, 1987), pp. 19–34.Google Scholar
  7. 7.
    K.O. Lloyd, L. Davidson, and O. Hornykiewicz, The neurochemistry of Parkinson’s disease: effect of Levodopa therapy, J. Pharmacol. Exp. Ther. 195, 453–464 (1975).PubMedGoogle Scholar
  8. 8.
    T. Nagatsu, Changes of tyrosine hydroxylase in parkinsonian brains and in the brains of MPTP-treated mice, Adv. Neurol. 53, 207–214 (1990).PubMedGoogle Scholar
  9. 9.
    X.-H. Zhong, J.W. Haycock, K. Shannak, Y. Robitaille, J. Fratkin, AH. Koeppen, O. Hornykiewicz, and S.J. Kish, Striatal dihydroxyphenylalanine decarboxylase and tyrosine hydroxylase protein in idiopathic Parkinson’s disease and dominantly inherited olivopontocerebellar atrophy, Mov. Disord. 10, 10–17 (1995).PubMedCrossRefGoogle Scholar
  10. 10.
    J.M. Wilson, A.I. Levey, A. Rajput, L. Ang, M. Guttman, K. Shannak, H.B. Niznik, O. Hornykiewicz, C. Pifl, and S.J. Kish, Differential changes in neurochemical markers of striatal dopamine nerve terminals in idiopathic Parkinson’s disease, Neurology 47, 718–726 (1996).PubMedCrossRefGoogle Scholar
  11. 11.
    Y. Agid, F. Javoy-Agid, and M. Ruberg, Biochemistry of neurotransmitters in Parkinson’s disease, in: Movement Disorders 2, edited by CD. Marsden, and S. Fahn (Butterworths, London, 1987), pp. 166–230.Google Scholar
  12. 12.
    C.R. Gerfen, and C.J. Wilson, The basal ganglia, in: Handbook of chemical neuroanatomy. Integrated systems of the CNS, Part III, edited by L.W. Swanson, A. Björklund, and T. Hökfelt (El-sevier, New York, 1996), pp. 371–468.Google Scholar
  13. 13.
    M.R. DeLong, Primate models of movement disorders of basal ganglia origin, Trends Neurosci. 13, 281–285 (1990).Google Scholar
  14. 14.
    R.L. Albin, A.B. Young, and J.B. Penney, The functional anatomy of disorders of the basal ganglia, Trends Neurosci. 18, 63–64 (1995).PubMedCrossRefGoogle Scholar
  15. 15.
    M.J. Zigmond, E.D. Abercrombie, T.W. Berger, A.A. Grace, and E.M. Stricker, Compensations after lesions of the central dopaminergic neurons: some clinical and basic implications, Trends Neurosci. 13, 290–296 (1990).PubMedCrossRefGoogle Scholar
  16. 16.
    G.F. Wooten, Pharmacokinetics of levodopa, in: Movement disorders 2, edited by CD. Marsden, and S. Fahn (Butterworths, London, 1987), pp. 231–248.Google Scholar
  17. 17.
    U. Trendelenburg, The interaction of transport mechanisms and intracellular enzymes in metabolizing systems, J. Neural. Transm. 32, 3–18 (1990).Google Scholar
  18. 18.
    P.T. Männistö, and S. Kaakkola, Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors, Pharmacol. Rev. 51, 593–628 (1999).PubMedGoogle Scholar
  19. 19.
    J.G. Nutt, Effect of COMT inhibition on the pharmacokinetics and pharmacodynamics of levodopa in parkinsonian patients, Neurology 55(suppl 4), S33–S37 (2000).PubMedGoogle Scholar
  20. 20.
    V.Glover, Sandler M, Owen F, Dopamine is a monoamine oxidase B substrate in man. Nature 1977;265:80–81.PubMedCrossRefGoogle Scholar
  21. 21.
    H.C. Guldberg, and C.A. Marsden, Catechol-O-methyl transferase: pharmacological aspects and physiological role, Pharmacol. Rev. 27, 135–206 (1975).PubMedGoogle Scholar
  22. 22.
    T. Karhunen, C. Tilgmann, I. Ulmanen, and P. Panula, Catechol-O-methyltransferase (COMT) in rat brain: immunoelectron microscopic study with an antiserum against rat recombinant COMT protein, Neurosci. Lett. 187, 57–60 (1995).PubMedCrossRefGoogle Scholar
  23. 23.
    A. Kastner, P. Anglade, C. Bounaix, P. Damier, F. Javoy-Agid, N. Bromet, and Y. Agid, Immunohistochemical study of catechol-O-methyltransferase in the human mesostriatal system, Neuroscience 62, 449–457 (1994).PubMedCrossRefGoogle Scholar
  24. 24.
    M.H. Grossman, B.S. Emanuel, and M.L. Budarf, Chromosomal mapping of the human catechol-O-methyltransferase gene to 22q11.1-q11.2, Genomics 12, 822–825 (1992).PubMedCrossRefGoogle Scholar
  25. 25.
    J. Tenhunen, and I. Ulmanen, Production of rat soluble and membrane-bound catechol-O-methyltransferase forms from bifunctional mRNAs, Biochem. J. 296, 595–600 (1993).PubMedGoogle Scholar
  26. 26.
    B. Boudikova, C. Szumlanski, B. Maidak, and R. Weinshilboum, Human liver catechol-O-methyltransferase pharmacogenetics, Clin. Pharmacol. Ther. 48, 381–389 (1990).PubMedCrossRefGoogle Scholar
  27. 27.
    H. Kunugi, S. Nanko, A. Ueki, E. Otsuka, M. Hattori, F. Hoda, H.P. Vallada, M.J. Arranz, and D.A. Collier, High and low activity alleles of catechol-O-methyltransferase gene: ethnic difference and possible association with Parkinson’s disease, Neurosci. Lett. 221, 202–204 (1997).PubMedCrossRefGoogle Scholar
  28. 28.
    A. Yoritaka, N. Hattori, H. Yoshino, and Y. Mizuno, Catechol-O-methyltransferase genotype and susceptibility to Parkinson’s disease in Japan, J. Neural. Transm. 104, 1313–1317 (1997).PubMedCrossRefGoogle Scholar
  29. 29.
    E.L. Cavalieri, D.E. Stack, P.D. Devanesan, R. Todorovic, I. Dwivedy, S. Higginbotham, S.L. Johansson, K.D. Patil, M.L. Gross, J.K. Gooden, R. Ramanathan, R.L. Cerny, and E.G. Rogaen, Molecular origin of cancer: catechol estrogen-3,4-quinones as endogenous tumor initiators, Proc. Natl. Acad. Sci. USA 94, 10937–10942 (1997).PubMedCrossRefGoogle Scholar
  30. 30.
    S. Fahn, Adverse effects of levodopa in Parkinson’s disease, in: Handbook of experimental pharmacology, vol. 8, edited by D.B. Calne (Springer-Verlag, Berlin, 1989), pp. 386–409.Google Scholar
  31. 31.
    V.S. Kostić, S. Przedborski, E. Flaster, and N. Šternić, Early development of levodopa-induced dy-skinesias and response fluctuations in young-onset Parkinson’s disease, Neurology 41, 202–205 (1991).PubMedCrossRefGoogle Scholar
  32. 32.
    V.S. Kostic, J. Marinkovic, M. Svetel, E. Stefanova, and S. Przedborski, The effect of stage of Parkinson’s disease at the onset of levodopa therapy on development of motor complications, Eur. J. Neurol. 9, 9–14 (2002).PubMedCrossRefGoogle Scholar
  33. 33.
    J.G. Nutt, J.H. Carter, E.S. Lea, and G.J.Sexton, Evolution of the response to levodopa during the first 4 years of therapy, Ann. Neurology 51, 686–693 (2000).CrossRefGoogle Scholar
  34. 34.
    M.M. Mouradian, J.L. Juncos, G. Fabbrini, and T.N. Chase, Motor fluctuations in Parkinson’s disease: pathogenetic and therapeutic studies, Ann. Neurol. 22, 475–479 (1987).PubMedCrossRefGoogle Scholar
  35. 35.
    W. Schultz, Behavior-related activity of primate dopamine neurons, Rev. Neurol. (Paris) 150, 634–639 (1994).Google Scholar
  36. 36.
    T.N. Chase, and J.D. Oh, Striatal mechanisms and pathogenesis of parkinsonian signs and motor complications, Ann. Neurol. 47, S122–S129 (2000).PubMedCrossRefGoogle Scholar
  37. 37.
    S.M. Papa, T.M. Engber, A.M. Kask, and T.N. Chase, Motor fluctuations in levodopa treated parkinsonian rats: Relation to lesion extent and treatment duration, Brain Res. 662, 69–74 (1994).PubMedCrossRefGoogle Scholar
  38. 38.
    W.C. Koller, Levodopa in the treatment of Parkinson’s disease, Neurology 55(suppl 4), S2–S7 (2000).PubMedGoogle Scholar
  39. 39.
    C. Colosimo, M. Merello, A.J. Hughes, K. Sieradzan, and A.J. Lees, Motor response to acute dopaminergic challenge with apomorphine and levodopa in Parkinson’s disease: implications for the pathogenesis of the on-off phenomenon, J. Neurol. Neurosurg. Psychiatry 60, 634–637 (1996).PubMedCrossRefGoogle Scholar
  40. 40.
    A.E. Lang, and A.M. Lozano, Parkinson’s disease — Second of two parts, N. Engl. J. Med. 339, 1130–1143 (1998).PubMedCrossRefGoogle Scholar
  41. 41.
    T.N. Chase, The significance of continuous dopaminergic stimulation in the treatment of Parkinson’s disease, Drugs 55(suppl 1), 1–9 (1998).PubMedCrossRefGoogle Scholar
  42. 42.
    J. Dingemanse, Issues important for rational COMT inhibition, Neurology 55(suppl 4), S24–S27 (2000).PubMedGoogle Scholar
  43. 43.
    M. Huotari, R. Gainetdinov, and P.T. Männistö, Microdialysis studies on the action of tolcapone on pharmacologically-elevated extracellular dopamine levels in conscious rats, Pharmacol. Toxicol. 85, 233–238 (1999).PubMedCrossRefGoogle Scholar
  44. 44.
    R. Ceravolo, P. Piccini, D.L. Bailey, K.M. Jorga, H. Bryson, and D.J. Brooks, 18F-Dopa PET evidence that tolcapone acts as a central COMT inhibitor in Parkinson’s disease, Synapse 43, 201–207 (2002).PubMedCrossRefGoogle Scholar
  45. 45.
    A. Napolitano, G. Bellini, E. Borroni, G. Zurcher, and U. Bonuccelli, Effects of peripheral and central catechol-O-methyltransferase inhibition on striatal ectracellular levels of dopamine: a microdialysis study in freely moveing rats, Parkinsonism. Relat. Dis. 9, 145–150 (2003).CrossRefGoogle Scholar
  46. 46.
    W. Kuhn, D. Woitalla, M. Gerlach, H. Russ, and T. Muller, Tolcapone and neurotoxicity in Parkinson’s disease, Lancet 352, 1313–1314 (1998).PubMedCrossRefGoogle Scholar
  47. 47.
    K.M. Jorga, COMT inhibitors: pharmacokinetic and pharmacodynamic comparisons, Clin. Neuropharmacol. 21(suppl 1), S9–S16 (1998).Google Scholar
  48. 48.
    M.C. Kurth, C.H. Adler, M.S. Hilaire, C. Singer, C. Waters, P. LeWitt, D.A. Chernik, E.E. Dorflinger, and K. Yoo, Tolcapone improves motor function and reduces levodopa requirement in patients with Parkinson’s disease experiencing motor fluctuations: a multicenter, double-blind, randomized, placebo-controlled trial, Neurology 48, 81–87 (1997).PubMedCrossRefGoogle Scholar
  49. 49.
    A.H. Rajput, W. Martin, M.G. Saint-Hilaire, E. Dorflinger, and S. Pedder, Tolcapone improves motor function in parkinsonian patients with the “wearing-off” phenomenon: a double-blind, placebocontrolled, multicenter trial, Neurology 49, 1066–1071 (1997).PubMedCrossRefGoogle Scholar
  50. 50.
    U.K. Rinne, J.P. Larsen, A. Siden, and J. Worm-Petersen, Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations, Neurology 51, 1309–1314 (1998).PubMedCrossRefGoogle Scholar
  51. 51.
    Group of authors, COMT inhibitors, Mov. Disord. 17(suppl 4), S45–S51 (2002).CrossRefGoogle Scholar
  52. 52.
    F. Assal, L. Spahr, A. Hadengue, L. Rubbici-Brandt, P.R. Burkhardt, Tolcapone and fulminant hepatitis, Lancel 352, 958 (1998).CrossRefGoogle Scholar
  53. 53.
    E. Nissinen, P. Kaheinen, K. Pentillä, J. Kaivola, I.B. Linden, Entacapone, a novel catechol-O-methyl transferase inhibitor of Parkinson’s disease, does not impair mitochondrial energy production, Eur. J. Pharmacol. 340, 287–294 (1997).PubMedCrossRefGoogle Scholar
  54. 54.
    K. Haasio, K. Lounatmaa, and A. Sukura, Entcapone does nor induce conformational changes in liver mitochondria or skeletal muscle in vivo, Exp. Toxic. Pathol. 54, 9–14 (2002).CrossRefGoogle Scholar
  55. 55.
    C.W. Olanow, The role of dopamine agonists in the treatment of early Parkinson’s disease, Neurology 58(suppl 1), S33–S41 (2002).PubMedCrossRefGoogle Scholar
  56. 56.
    W. Olanow, and J.A. Obeso, Pulsatile stimulation of dopamine receptors and levodopa-induced motor complications in Parkinson’s disease: implications for the early use of COMT inhibitors, Neurology 55(Suppl 4), S72–S77 (2000).PubMedGoogle Scholar
  57. 57.
    P. Jenner, G. Al-Bargouthy, L. Smith, M. Kuoppamaki, M. Jackson, S. Rose, and W. Olanow, Initiation of entacapone with L-dopa further improves antiparkinsonian activity and avoids dyskinesia in the MPTP primate model of Parkinson’s disease, Neurology 58(Suppl 3), A374 (2002).Google Scholar
  58. 58.
    V.S. Kostic, S.R. Filipovic, D. Lecic, D. Momcilovic, D. Sokic, and N. Sternic, Effect of age at onset on frequency of depression in Parkinson’s disease, J. Neurol. Neurosurg. Psychiatry 57, 1265–1267 (1994).PubMedCrossRefGoogle Scholar
  59. 59.
    V.S. Kostić, B.M. Djurićić, N. Šternić, Lj. Bumbaširević, M. Nikolić, and B.B. Mršulja, Depression and Parkinson’s disease: possible role of serotonergic mechanisms, J. Neurol. 234, 94–96 (1987).PubMedCrossRefGoogle Scholar
  60. 60.
    E. Melamed, Neurobehavioral abnormalities in Parkinson’s disease, in: Movement disorders: neurologic principles and practice, edited by R.L. Watts, and W.C. Koller (McGraw-Hill, New York, 1997) pp. 257–262.Google Scholar
  61. 61.
    S.A. Cole, J.L. Woodard, J.L. Juncos, J.L. Kogos, E.A. Youngstrom, and R.L. Watts, Depression and disability in Parkinson’s disease, J. Neuropsychiatry Clin. Neurosci. 8, 20–25 (1996).PubMedGoogle Scholar
  62. 62.
    S.E. Starkstein, H.S. Mayberg, R. Leiguarda, T.J. Preziosi, and R.G. Robinson, A prospective longitudinal study of depression, cognitive decline, and physical impairments in patients with Parkinson’s disease, J. Neurol. Neurosurg. Psychiatry. 55, 377–382 (1992).PubMedCrossRefGoogle Scholar
  63. 63.
    T. Tom, and J.L. Cummings, Depression in Parkinson’s disease: pharmacological characteristics and treatment, Drugs & Aging 12, 55–74 (1998).Google Scholar
  64. 64.
    K. Marder, M.X. Tang, L. Cote, Y. Stern, and R. Mayeux, The frequency and associated risk factors for dementia in patients with Parkinson’s disease, Arch. Neurol. 52, 695–701 (1995).PubMedCrossRefGoogle Scholar
  65. 65.
    K.H. Karlsen, J.P. Larsen, E. Tandberg, and J.G. Maeland, Influence of clinical and demographic variables on quality of life in patients with Parkinson’s disease, J. Neurol. Neurosurg. Psychiatry. 66, 431–435 (1999).PubMedCrossRefGoogle Scholar
  66. 66.
    A.-M. Kuopio, R.J. Martilla, H. Helenius, M. Toivonen, and U.K. Rinne, The quality of life in Parkinson’s disease, Mov. Disord. 15, 216–223 (2000).PubMedCrossRefGoogle Scholar
  67. 67.
    T. Bottiglieri, and K. Hyland, S-adenosyl-methionine levels in psychiatric and neurologic disorders, Acta Neurol Scand 154(suppl), 19–26 (1994).CrossRefGoogle Scholar
  68. 68.
    C.W. Fetrow, and J.R. Avila, Efficacy of the dietary supplement S-adenosyl-L-methionine, Ann. Pharmacother. 35, 1414–1425 (2001).PubMedCrossRefGoogle Scholar
  69. 69.
    G.M. Bressa, S-adenosyl-L-methionine as antidepressant: a meta analysis of clinical studies, Acta Neurol. Scand. 154(suppl 1), 7–14 (1994).CrossRefGoogle Scholar
  70. 70.
    M. Da Prada, J. Borgulya, A. Napolitano, and G. Zucher, Improved therapy for Parkinson’s disease with tolcapone: a central and peripheral COMT inhibitor with an S-adenosylmethionine sparing effect, Clin. Neuropharmacol. 17(suppl 3), 26–27 (1994).CrossRefGoogle Scholar
  71. 71.
    R.J. Wurtman, S. Rose, S. Matthyse, J. Stephenson, and R. Baldessarini, L-dihydroxyphenilalanine: effect on S-adenosyl-methionine in the brain, Science 169, 395–397 (1970).PubMedCrossRefGoogle Scholar
  72. 72.
    R. Surtees, K. Hyland, L-dihydroxyphenilalanine (levodopa) lowers central nervous system Sadenosylmethionine concentrations in humans, J. Neurol. Neurosurg. Psychiatry 53, 569–572 (1990).PubMedCrossRefGoogle Scholar
  73. 73.
    A. Stock, S. Clarke, C. Clarke, and J. Stock, N-terminal methylation of proteins: structure, function and specificity, FEBS Lett. 220, 8–14 (1987).PubMedCrossRefGoogle Scholar
  74. 74.
    I. Bellido, A. Gomez-Luque, A. Plaza, F. Ruiz, P. Ortiz, and F. Sanchez de la Cuesta, S-Adenosyl-L-methionine prevents 5-HT(l°) receptors up-regulation induced by acute imipramine in the frontal cortex of the rat, Neurosci. Lett. 321, 110–114 (2002).PubMedCrossRefGoogle Scholar
  75. 75.
    A. Di Rocco, J.D. Rogers, R. Brown, P. Werner, and T. Bottiglieri, S-Adenosyl-methionine improves depression in patients with Parkinson’s disease in an open-label clinical trial, Mov. Disord. 15, 1225–1229 (2000).PubMedCrossRefGoogle Scholar
  76. 76.
    J.L. Moreau, J. Borgulya, F. Jenck, and J.R. Martin, Tolcapone: a potential new antidepressant detected in a novel animal model of depression, Behav. Pharmacol. 5, 344–350 (1994).PubMedCrossRefGoogle Scholar
  77. 77.
    M. Fava, J.F. Rosenbaum, A.R. Kolsky, J.E. Alpert, A.A. Nierenberg, M. Spillmann, P. Rensshaw, T. Bottiglieri, G. Moroz, and G. Magni, Open study of the catechol-O-methyltransferase inhibitor tolacapone in major depressive disorder, J. Clin. Psychopharmacol. 19, 329–335 (1999).PubMedCrossRefGoogle Scholar
  78. 78.
    S. Przedborski, and V. Jackson-Lewis, Experimental developments in movement disorders: update on proposed free radical mechanisms, Curr. Opm. Neurol. 11, 335–339 (1998).CrossRefGoogle Scholar
  79. 79.
    H.M. Swartz, T. Sarna, and L. Zecca, Modulation by neuromelanin of the availability and reactivity of metal ions, Ann. Neurol. 32 (Suppl.), S69–S75 (1992).PubMedCrossRefGoogle Scholar
  80. 80.
    Y. Agid, E. Ahlskog, A. Albanese A, D. Calne, T. Chase, J. De Yebenes, S. Factor, S. Fahn, O. Gershanik, C. Goetz, W. Koller, M. Kurth, A. Lang, A. Lees, CD. Marsden, E. Melamed, P.P. Michel, Y. Mizuno, J. Obeso, W. Oertel, W. Olanow, W. Poewe, Pollak P, and E. Tolosa, Levodopa in the treatment of Parkinson’s disease: a consensus meeting, Mov. Disord. 14, 911–913 (1999).Google Scholar
  81. 81.
    M. Gerlach, A.Y. Xiao, W. Kuhn, R. Lehnfeld, P. Waldmeier, K.H. Sontag, and P. Riederer, The central catechol-O-methyltransferase inhibitor tolcapone increases striatal hydroxyl radical production in L-dopa/carbidopa treated rats, J. Neural. Transm. 108, 189–204 (2001).PubMedCrossRefGoogle Scholar
  82. 82.
    L. Lyras, B.-Y. Zeng, G. McKenzie, R.K.B. Pearce, B. Halliwell, and P. Jenner, Chronic high dose L-dopa alone or in combination with the COMT inhibitor entacapone does not increase oxidative damage or impair the function of the nigro-striatal pathway in normal cynomologus monkeys, J. Neural. Transm. 109, 53–67 (2002).PubMedCrossRefGoogle Scholar
  83. 83.
    D. Offen, H. Panet, R. Galili-Mosberg, E. Melamed, Catechol-O-methyltransferase decreases levodopa toxicity in vitro, Clin. Neuropharmacol. 24, 27–30 (2001).CrossRefGoogle Scholar
  84. 84.
    E. Hansson, Enzymatic activities of monoamine oxidase, catechol-O-methyltransferase and gamma-aminobutyric acid transaminase in primary astroglial cultures and adult rat brain from different brain regions, Neurochem. Res. 9, 45–57 (1984).PubMedCrossRefGoogle Scholar
  85. 85.
    A. Storch, H. Blessing, M. Bareiss, S. Jankowski, Z.D. Ling, P. Carvey, and J. Schwarz, Catechol-O-methyltransferase inhibition attenuates levodopa toxicity in mesencephalic dopamine neurons, Mol. Pharm. 57, 589–594 (2002).Google Scholar
  86. 86.
    H. Blessing, M. Bareiss, H. Zettlmeisl, J. Schwarz, and A. Storch, Catechol-O-methyltransferase inhibition protects against 3,4-dihydroxyphenylalanine (DOPA) toxicity in primary mesencephalic cultures: new insights into levodopa toxicity, Neurochem. Int. 42, 139–151 (2003).PubMedCrossRefGoogle Scholar
  87. 87.
    S. Seshadri, A. Beiser, J, Selhub, P.F. Jacques, I.H. Rosenberg, R.B. D’A gostino, P.W.F. Wilson, and P.A. Wolf, Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease, N. Engl. J. Med. 345, 476–483 (2002).CrossRefGoogle Scholar
  88. 88.
    P. Allain, A. Le Bouil, E. Cordillet, L, Le Quay, H, Bagheri, and J.L. Montastruc, Sulfate and cysteine levels in the plasma of patients with Parkinson’s disease, Neurotoxicol. 16, 527–529 (1995).Google Scholar
  89. 89.
    W. Kuhn, R. Roebroek, H. Blom, D. van Oppenraaij, and T. Muller, Hyperhomocysteinemia in Parkinson’s disease, J. Neurol. 245, 811–812 (1998)PubMedCrossRefGoogle Scholar
  90. 90.
    K. Yasui, H. Kowa, K, Nakaso, T. Takeshima, and K. Nakashima, Plasma homocysteine and MTHFR C677T genotype on levodopa-treated patients with Parkinson’s disease, Neurology 55, 437–440 (2000).PubMedCrossRefGoogle Scholar
  91. 91.
    F. Blandini, R. Fancellu, E. Mortignoni, A. Mangiagalli, C. Pacchetti, A. Samuele, and G. Nappi, Plasma homocysteine and L-dopa metabolism in patients with Parkinson disease, Clin. Chem. 47, 1102–1104 (2001).PubMedGoogle Scholar
  92. 92.
    T. Muller, D. Woitalla, B. Hauptmann, B. Fowler, and W. Kuhn, Decrease in methionine and Sadenosylmethionine and increase of homocysteine in treated patients with Parkinson’s disease, Neurosci. Lett. 308, 54–56 (2001).PubMedCrossRefGoogle Scholar
  93. 93.
    T. Muller, D. Woitalla, B. Fowler, and W. Kuhn, 3-OMD and homocysteine plasma levels in parkinsonian patients. J. Neural. Transm. 109, 175–179 (2002).PubMedCrossRefGoogle Scholar
  94. 94.
    J.D. Rogers, A. Sanchez-Saffon, A.B. Frol, and R. Diaz-Arastia, Elevated plasma homocysteine levels in patients with levodopa: association with vascular disease, Arch. Neurol. 60, 59–64 (2003).PubMedCrossRefGoogle Scholar
  95. 95.
    X.X. Liu, K. Wilson, and CG. Charlton, Effects of L-dopa treatment on methylation in mouse brain: implications for the side effects of L-dopa. Life Sci. 66, 2277–2288 (2000).PubMedCrossRefGoogle Scholar
  96. 96.
    P. Frosst, H.J. Blom, R. Milos, P. Goyette, C.A. Sheppard, R.G. Matthews, G.J. Boers, M. Den Heujer, L.A. Kluijtmans, and L.P. van den Heuvel, A candidate geneticd risk factor for vascular disease: a common mutation in methylentetrahydrofolate reductase, Nat. Genet 10, 111–113 (1995).PubMedCrossRefGoogle Scholar
  97. 97.
    W. Kuhn, T. Hummel, D. Woitalla, and T. Muller, Plasma homocysteine and MTHFR C667T genotype in levodopa-treated patients with PD (letter), Neurology 56, 281 (2001).PubMedCrossRefGoogle Scholar
  98. 98.
    D.S. Wald, M. Law, and J.K. Morris. Homocysteine and cardiovascular disease evidence on causality from a meta-analysis, Br. Med. J. 325, 1202–1206 (2002).CrossRefGoogle Scholar
  99. 99.
    S.E. Vermeer, T. Den Heijer, P.J. Koudstaal, M. Oudkerk, A. Hofman, and M.M. Breteler, Incidence and risk factors of silent brain infarcts in the population-based Rotterdam scan study, Stroke 34, 137–146 (2003).Google Scholar
  100. 100.
    T.G. Deloughery, Hyperhomocysteinemia in ischemic stroke, Sem. Cerebrovasc. Dis. Stroke 2, 111–119 (2002).CrossRefGoogle Scholar
  101. 101.
    G. Blundell, B.G. Jones, F.A. Rose, and N. Tudball, Homocysteine mediated endothelial cell toxicity and its amelioration, Atherosclerosis 122, 163–172 (1996).PubMedCrossRefGoogle Scholar
  102. 102.
    I.I. Kruman, C. Culmsee, S.L. Chan, Y. Kruman, Z. Guo, L. Penix, and M.P. Mattson, Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to ex-citotoxicity, J. Neurosci. 20, 6920–6926 (2000).PubMedGoogle Scholar
  103. 103.
    I.I. Kruman, T.S. Kumaravel, A. Lohani, W.A. Pedersen, R.G. Cutler, Y. Kruman, N. Haughey, J. Lee, M. Evans, and M.P. Mattson, Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental model of Alzheimer’s disease, J. Neurosci. 22, 1752–1762 (2002).PubMedGoogle Scholar
  104. 104.
    Q. Shi, J. Savage, S. Hufesein, L. Rauser, E. Grajkowski, P. Ernsberger, J. Wroblewski, J. Nadeau, and B.L. Roth, L-homocysteine sulfinic acid and other acidic homocysteine derivatives are potent and selective metabotropic glutamate receptor agonists, J. Pharmacol. Exp. Ther. 21, 2344–2348 (2003).Google Scholar
  105. 105.
    T.J. Montine, V. Amarnath, M.J. Picklo, K.R. Sidell, J. Zhang, and D.G. Graham, Dopamine mercapturate can augment dopaminergic neurodegeneration, Drugs Metabol. Rev. 32, 363–376 (2000).CrossRefGoogle Scholar
  106. 106.
    W. Duan, B. Ladenheim, R.G. Cutler, I.I. Kruman, J.L. Cadet, and M.P. Mattson, Diatery folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson’s disease, J. Neurosci. 80, 101–110 (2002).Google Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Vladimir S. Kostić
    • 1
  1. 1.Institute of Neurology CCSBelgrade, Serbia and Montenegro

Personalised recommendations