Drugs

, Volume 62, Issue 5, pp 775–786

Emerging Therapies in the Pharmacological Treatment of Parkinson’s Disease

  • Amos D. Korczyn
  • Miri Nussbaum
Review Article

Abstract

The pharmacological management of Parkinson’s disease is a complex and dynamic task; there is no one ‘right’ strategy indicating which drugs should be used at a particular stage of the disease. There are now many different drugs belonging to several classes that may be effective, and there are still differences of opinion among leading clinicians about the best course of treatment.

This review focuses on drug therapy for the motor impairment in Parkinson’s disease. Current and future research directions are summarised by taking inventory of recent and innovative areas of development in the field, representing each category with at least one of its featured treatments.

The main research efforts are being directed towards delaying the use of levodopa or finding therapies to be used as adjunct to it, in order to postpone motor complications and, in particular, dyskinesias. One of the recent trends is early employment of dopamine agonists. Additional efforts are being directed towards protecting and restoring dopamine neurons. Novel therapies actingon non-dopaminergic systems are also being researched.

References

  1. 1.
    Agid Y, Ahlskog E, Albanese A, et al. Levodopa in the treatment of Parkinson’s disease: a consensus meeting. Mov Disord 1999; 14: 911–3PubMedCrossRefGoogle Scholar
  2. 2.
    Korczyn AD. Parkinson’s disease. In: Bloom FE, Kupfer DJ, editors. Psychopharmacology: the fourth generation of propen. New York: Raven Press, 1994: 1479–85Google Scholar
  3. 3.
    Korczyn AD. Pathophysiology of drug-induced dyskinesias. Neuropharmacology 1973; 11: 601–7CrossRefGoogle Scholar
  4. 4.
    Marsden C, Parkes JD. ‘On-off’ effects in patients with Parkinson’s disease on chronic levodopa therapy. Lancet 1976; I(7954): 292–6CrossRefGoogle Scholar
  5. 5.
    Luquin MR, Scipioni O, Vaamonde J, et al. Levodopa-induced dyskinesias in Parkinson’s disease: clinical and pharmacological classification. Mov Disord 1992; 7: 117–24PubMedCrossRefGoogle Scholar
  6. 6.
    Rinne UK. Problems associated with long term levodopa treatment of Parkinson’s disease. Acta Neurol Scand Suppl. 1983; 95: 19–26PubMedCrossRefGoogle Scholar
  7. 7.
    Giladi N, Treves TA, Simon ES, et al. Freezing of gait in patients with advanced Parkinson’s disease. J Neural Transm 2001; 108: 53–61PubMedCrossRefGoogle Scholar
  8. 8.
    Mena MA, Pardo B, Casarejos MJ, et al. Neurotoxicity of levodopa on catecholamine-rich neurons. Mov Disord 1992; 7: 23–31PubMedCrossRefGoogle Scholar
  9. 9.
    Brucke T, Asenbaum S, Pirker W, et al. Measurement of the dopaminergic degeneration in Parkinson’s disease with [123]β-CIT and SPECT. Correlation with clinical findings and comparison with multiple system atrophy and progressive supranuclear palsy. J Neural Transm Suppl. 1997; 50: 9–24PubMedCrossRefGoogle Scholar
  10. 10.
    Brooks DJ. Advances in imaging Parkinson’s disease. Curr Opin Neurol 1997; 10: 327–31PubMedCrossRefGoogle Scholar
  11. 11.
    Nurmi E, Ruottinen HM, Kaasinen V, et al. Progression in Parkinson’s disease: a positron emission tomography study with a dopamine transporter ligand [18F]CFT. Ann Neurol 2000; 47: 804–8PubMedCrossRefGoogle Scholar
  12. 12.
    Trugman JM, Hubbard CA, Bennett Jr JP. Dose-related effects of continuous levodopa infusion in rats with unilateral lesions of the substantia nigra. Brain Res 1996; 725: 177–83PubMedGoogle Scholar
  13. 13.
    Korczyn AD, Nisipeanu P. Newer therapies for Parkinson’s disease. Neurol Neurochir Pol 1996; 30 Suppl. 2: 105–11PubMedGoogle Scholar
  14. 14.
    Jenner P. The rationale for the use of dopamine agonists in Parkinson’s disease. Neurology 1995; 45 (3 Suppl. 3): s6–12PubMedCrossRefGoogle Scholar
  15. 15.
    Watts RL. The role of dopamine agonists in early Parkinson’s disease. Neurology 1997; 49: S34–48PubMedCrossRefGoogle Scholar
  16. 16.
    Montastruc JL, Rascol O, Senard JM. Treatment of Parkinson’s disease should begin with a dopamine agonist. Mov Disord 1999; 14: 725–30PubMedCrossRefGoogle Scholar
  17. 17.
    Rascol O, Brooks DJ, Korczyn AD, et al. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000; 342(20): 1484–91PubMedCrossRefGoogle Scholar
  18. 18.
    Hubble JP, Koller WC, Cutler NR, et al. Pramipexole in patients with early Parkinson’s disease. Clin Neuropharmacol 1995; 18: 338–47PubMedCrossRefGoogle Scholar
  19. 19.
    Korczyn AD, Brunt ER, Larsen JP, et al. A 3-year randomized trial of ropinirole and bromocriptine in early Parkinson’s disease. Neurology 1999; 53: 364–70PubMedCrossRefGoogle Scholar
  20. 20.
    Bodde HE, Van Laar T, Van der Geest R, et al. An integrated pharmacokinetic-pharmacodynamic approach to optimization of R-apomorphine delivery in Parkinson’s disease. Adv Drug Deliv Rev 1998; 33: 253–63PubMedCrossRefGoogle Scholar
  21. 21.
    Ondo W, Hunter C, Almaguer M, et al. A novel sublingual apomorphine treatment for patients with fluctuating Parkinson’s disease. Mov Disord 1999; 14: 664–8PubMedCrossRefGoogle Scholar
  22. 22.
    Montastruc JL, Rascol O, Senard JM, et al. Sublingual apomorphine: a new pharmacological approach in Parkinson’s disease? J Neural Transm Suppl. 1995; 45: 157–61PubMedGoogle Scholar
  23. 23.
    Ikechukwu Ugwoke M, Kaufmann G, Verbeke N, et al. Intranasal bioavailability of apomorphine from carboxymethylcellulose-based drug delivery systems. Int J Pharm 2000; 202: 125–31PubMedCrossRefGoogle Scholar
  24. 24.
    Corboy DL, Wagner ML, Sage JI. Apomorphine for motor fluctuations and freezing in Parkinson’s disease. Ann Pharmacother 1995; 29: 282–8PubMedGoogle Scholar
  25. 25.
    Korczyn AD. Autonomic nervous system disturbances in Parkinson’s disease. In: MB Streifler, AD Korczyn, E Melamed, et al. editors. Advances in neurology: Parkinson’s disease: anatomy, pathology, therapy. New York: Raven Press, 1990: 463–68Google Scholar
  26. 26.
    Kujawa KA, Leurgans S, Raman R, et al. Dopamine agonists and orthostatic hypotension in Parkinson’s disease [abstract]. Neurology 1999; 52 Suppl. 2: A407Google Scholar
  27. 27.
    Moskovitz C, Moses H, Klawans HL. Levodopa-induced psychosis: a kindling phenomenon. Am J Psychiatry 1978; 135: 669–75PubMedGoogle Scholar
  28. 28.
    Saint-Cyr JA, Taylor AE, Lang AE. Neuropsychological and psychiatric side effects in the treatment of Parkinson’s disease. Neurology 1993; 43: S47–52PubMedGoogle Scholar
  29. 29.
    Goetz CG, Vogel C, Tanner CM, et al. Early dopaminergic druginduced hallucinations in parkinsonian patients. Neurology 1998; 51: 811–4PubMedCrossRefGoogle Scholar
  30. 30.
    Nausieda PA, Weiner WJ, Kaplan LR, et al. Sleep disruption in the course of chronic levodopa therapy: an early feature of the levodopa psychosis. Clin Neuropharmacol 1982; 5: 183–94PubMedCrossRefGoogle Scholar
  31. 31.
    Ferreira JJ, Thalamas C, Montastruc JL, et al. Levodopa monotherapy can induce ‘sleep attacks’ in Parkinson’s disease patients. J Neurol 2001; 248: 426–7PubMedCrossRefGoogle Scholar
  32. 32.
    Frucht S, Rogers JD, Greene PE, et al. Falling asleep at the wheel: motor vehicle mishaps in persons taking pramipexole and ropinirole. Lancet 2000; 355: 1332–3CrossRefGoogle Scholar
  33. 33.
    Olanow CW, Schapira AH, Roth T. Waking up to sleep episodes in Parkinson’s disease. Mov Disord 2000; 15: 212–5PubMedCrossRefGoogle Scholar
  34. 34.
    Ryan M, Slevin JT, Wells A. Non-ergot dopamine agonists-induced sleep attacks. Pharmacotherapy 2000; 6: 724–6CrossRefGoogle Scholar
  35. 35.
    Ling LH, Ahlskog JE, Munger TM, et al. Constrictive pericarditis and pleuropulmonary disease linked to ergot dopamine agonist therapy (cabergoline) for Parkinson’s disease. Mayo Clin Proc 1999; 74: 371–5PubMedCrossRefGoogle Scholar
  36. 36.
    Bressman SB, Shulman LM, Tanner CM, et al. Long-term safety and efficacy of pramipexole in early Parkinson’s disease [abstract]. Neurology 1999; 52 Suppl. 2: A261Google Scholar
  37. 37.
    Roberts JW, Maral Mouradian M, Ho Sohn Y, et al. D2 agonist N-0923 treatment of Parkinson’s disease [abstract]. Neurology 1994; 44 Suppl. 2: 244Google Scholar
  38. 38.
    Hutton JT, Chase T, Verhagen L, et al. Transdermal dopamine D2 receptor agonist therapy with N-0923 TDS in Parkinson’s isease: a double-blind, placebo-controlled study [abstract]. Mov Disord 1988; 13 Suppl. 2: 62Google Scholar
  39. 39.
    Djaldetti R, Melamed E. Levodopa ethylester: a novel rescue therapy for response fluctuations in Parkinson’s disease. Ann Neurol 1996; 39: 400–4PubMedCrossRefGoogle Scholar
  40. 40.
    Djaldetti R, Giladi N, Peretz-Aharon Y, et al. Oral levodopa ethylester (LDEE) for treatment of response fluctuations in patients with advanced Parkinson’s disease: results of a double-blind controlled study [abstract]. Mov Disord 1998; 13 Suppl. 2: 58Google Scholar
  41. 41.
    Rascol O, Blin O, Thalamas C, et al. ABT-431, a Dl receptor agonist prodrug has efficacy in Parkinson’s disease. Ann Neurol 1999; 45: 736–41PubMedCrossRefGoogle Scholar
  42. 42.
    Uchiumi M, Ochiai K, Nakano T, et al. Phase I study of BAM-1110: single and repeated administration [abstract]. Mov Disord 1996; 11 Suppl. 1: 163Google Scholar
  43. 43.
    Doll MK, Nichols DE, Kilts JD, et al. Synthesis and dopaminergic properties ofbenzo-fused analogues of quinpirole and quinelorane. J Med Chem 1999; 42(5): 935–40PubMedCrossRefGoogle Scholar
  44. 44.
    Ghosh D, Snyder SE, Watts VJ, et al. 9-Dihydroxy-2,3,7,11btetrahydro-1H-naph [l,2,3-de]isoquinoline: a potent full dopamine D1 agonist containing a rigid-beta-phenyldopamine pharmacophore. J Med Chem 1996; 39(2): 549–55PubMedCrossRefGoogle Scholar
  45. 45.
    Kaakkola S. Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson’s disease. Drugs 2000; 59(6): 1233–50PubMedCrossRefGoogle Scholar
  46. 46.
    Bonifati V, Meco G. New, selective catechol-O-methyltransferase inhibitors as therapeutic agents in Parkinson’s disease. Pharmacol Ther 1999; 81(1): 1–36PubMedCrossRefGoogle Scholar
  47. 47.
    Kurth MC, Adler CH. COMT inhibition: a new treatment strategy for Parkinson’s disease. Neurology 1998; 50 (5 Suppl. 5): S3–14PubMedCrossRefGoogle Scholar
  48. 48.
    Ruottinen HM, Rinne UK. COMT inhibition in the treatment of Parkinson’s disease. J Neurol 1998; 245 (11 Suppl. 3): 25–34CrossRefGoogle Scholar
  49. 49.
    Kurth MC, Adler CH, Saint Hilaire M-H, et al. Tolcapone improves motor function and reduces levodopa requirement in patients with Parkinson’s disease experiencing motor fluctuations: a multicenter, double-blind, randomized, placebocontrolled trial. Neurology 1997; 48: 81–7PubMedCrossRefGoogle Scholar
  50. 50.
    Rajput AH, Martin W, Saint-Hilaire MH, et al. Tolcapone improves motor function in parkinsonian patients with the ‘wearing off’ phenomenon: a double-blind, placebo-controlled, multicenter trial. Neurology 1997; 49: 1066–71PubMedCrossRefGoogle Scholar
  51. 51.
    Parkinson Study Group. Entacapone improves motor fluctuations in levodopa-treated Parkinson’s disease patients. Ann Neurol 1997; 42: 747–55CrossRefGoogle Scholar
  52. 52.
    Rinne UK, Larsen JP, Siden A, et al. Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations. Neurology 1998; 51: 1309–14PubMedCrossRefGoogle Scholar
  53. 53.
    Pearce RKB, Banerji T, Scheel-Kroauger J, et al. The dopamine reuptake blocker NS 2214 increases locomotor activity but does not produce dyskinesias in MPTP-treated common marmosets [abstract no. 304P]. Br J Pharmacol 1995; 116 (Proc Suppl.)Google Scholar
  54. 54.
    Brefel-Courbon C, Thalamas C, Peyro Saint Paul H, et al. Alpha-2 adrenoreceptor antagonists: a new approach to Parkinson’s disease? CNS Drugs 1998; 10: 189–207CrossRefGoogle Scholar
  55. 55.
    Grondin R, Tahar AH, Doan VD, et al. Noradrenoceptor antagonism with idazoxan improves 1-dopa-induced dyskinesia in MPTP monkeys. Naunyn Schmiedebergs Arch Pharmacol 2000; 361: 181–6PubMedCrossRefGoogle Scholar
  56. 56.
    Henry B, Fox SH, Peggs D, et al. Effect of the alpha-2 adrenoreceptor antagonist, idazoxan, on motor disabilities in MPTP-treated monkey. Prog Neuropsychopharmacol Biol Psychiatry 1999; 23: 1237–46CrossRefGoogle Scholar
  57. 57.
    Henry B, Fox SH, Peggs D, et al. The alpha-2-adrenergic receptor antagonist idazoxan reduces dyskinesia and enhances anti-parkinsonian actions of 1-dopa in the MPTP-lesioned primate model of Parkinson’s disease. Mov Disord 1999; 14: 744–53PubMedCrossRefGoogle Scholar
  58. 58.
    Manson AJ, Iakovidou E, Lees AJ. Idazoxan is ineffective for levodopa-induced dyskinesias in Parkinson’s disease. Mov Disord 2000; 15: 336–7PubMedCrossRefGoogle Scholar
  59. 59.
    Ross GW, Abbott RD, Petrovitch H, etal. Relationship between caffeine intake and parkinson disease. JAMA 2000; 284(11): 1378–9PubMedCrossRefGoogle Scholar
  60. 60.
    Abbracchio MP, Cattabeni F. Brain adenosine receptors as targets for therapeutic intervention in neurodegenerative diseases. Ann N Y Acad Sci 1999; 890: 79–92PubMedCrossRefGoogle Scholar
  61. 61.
    Kamada T, Tashiro T, Kuwama Y, et al. Adenosine A2A receptors modify motor fluctuations in MPTP-treated common marmosets. Neuroreport 1988; 9: 2857–60CrossRefGoogle Scholar
  62. 62.
    Kanda T, Jackson MJ, Smith LA, et al. Adenosine A2 antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in parkinsonian monkeys. Ann Neurol 1998; 43: 507–13PubMedCrossRefGoogle Scholar
  63. 63.
    Corsi C, Melani A, Bianchi L, et al. Striatal A2A adenosine receptor antagonism differentially modifies striatal glutamate outflow in vivo in young and aged rats. Neuroreport 2000; 11: 2591–5PubMedCrossRefGoogle Scholar
  64. 64.
    Schneider JS, Van Velson M, Menzaghi F, et al. Effects of the nicotinic acetylcholine receptor agonist SIB-1508Y on object retrieval performance in MPTP-treated monkeys: comparison with levodopa treatment. Ann Neurol 1998; 43: 311PubMedCrossRefGoogle Scholar
  65. 65.
    Lloyd GK, Rao TS, Sacaan A, et al. SIB-1508Y: a sub-type selective nicotinic agonist for treatment of motor and nonmotor dysfunction of Parkinson’s disease. Mov Disord 1996; 11: 605Google Scholar
  66. 66.
    Mogi M, Togari A, Kondo T, et al. Caspase activities and tumor necrosis factor receptor R1 (p55) level are elevated in the substantia nigra from parkinsonian brain. J Neural Transm 2000; 107: 335–41PubMedCrossRefGoogle Scholar
  67. 67.
    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 U S A 2000; 97: 2875–80PubMedCrossRefGoogle Scholar
  68. 68.
    Hastings TG, Lwis DA, Zigmond MJ. Role of oxidation in the neurotoxic effects of intrastriatal dopamine injections. Proc Natl Acad Sci U S A 1996; 93: 1956–61PubMedCrossRefGoogle Scholar
  69. 69.
    Delanty N, Dichter MA. Antioxidant therapy in neurologic disease. Arch Neurol 2000; 57: 1265–70PubMedCrossRefGoogle Scholar
  70. 70.
    Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 1993; 328: 176–83CrossRefGoogle Scholar
  71. 71.
    Vatassery GT. Vitamin E and other endogenous antioxidants in the central nervous system. Geriatrics 1998; 53 Suppl. 1: S25–7PubMedGoogle Scholar
  72. 72.
    Grundman M. Vitamin E and Alzheimer disease: the basis for additional clinical trials. Am J Clin Nutr 2000; 71: 630S–6SPubMedGoogle Scholar
  73. 73.
    Foley P, Gerlach M, Youdim MBH, et al. MAO-B inhibitors: multiple roles in the therapy of neurodegenerative disorders? Parkinsonism Relat Disord 2000; 6: 25–47PubMedCrossRefGoogle Scholar
  74. 74.
    Cohen G, Spina MB. Deprenyl supresses the oxidant stress associated with increased dopamine turnover. Ann Neurol 1989; 26: 689–90PubMedCrossRefGoogle Scholar
  75. 75.
    Seager H. Drug-delivery products and the Zydis fast-dissolving dosage form. J Pharm Pharmacol 1998; 50: 375–82PubMedCrossRefGoogle Scholar
  76. 76.
    Marek K, Friedman J, Hause R, et al. Phase II evaluation of rasagiline mesylate (TVP-1012), a novel anti-parkinsonian drug, in parkinsonian patients not using levodopa/carbidopa. Mov Disord 1997; 12: 838Google Scholar
  77. 77.
    Gotz ME, Breithaupt W, Sautter J, et al. Chronic TVP-1012 (rasagiline) dose-activity response of monoamine oxidase A and B in the brain of the common marmoset. J Neural Transm Suppl. 1998; 52: 271–8PubMedCrossRefGoogle Scholar
  78. 78.
    Finberg JP, Wang J, Bankiewicz K, et al. Increased striatal production from L-DOPA following selective inhibition of monoamine oxidase B by R(+)-N-propargyl-l-aminoindan (rasagiline) in the monkey. J Neural Transm Suppl 1998; 52: 279–85PubMedCrossRefGoogle Scholar
  79. 79.
    The Parkinson Study Group. Effect of lazabemide on the progression of disability in early Parkinson’s disease. Ann Neurol 1996; 40: 99–107CrossRefGoogle Scholar
  80. 80.
    Narabayashi H, Yamaguchi T, Sugi K, et al. Safety study of lazabemide (Ro 19–6327), anew MAO-B inhibitor, on cardiac arrhythmias and blood pressure of patients with Parkinson’s disease. Clin Neuropharmacol 1999; 22: 340–6PubMedGoogle Scholar
  81. 81.
    Patat A, Chaufour S, Gandon JM, et al. Safety and pharmacodynamic of single ascending doses of SL34.0026, a new reversible and selective MAO-B inhibitor in healthy subjects. Br J Clin Pharmacol 1999; 47: 584P–5PGoogle Scholar
  82. 82.
    Doble A. The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol Ther 1999;81: 163–221PubMedCrossRefGoogle Scholar
  83. 83.
    Parkinson Study Group. A multicenter randomized controlled trial of remacemide hydrochloride as monotherapy for PD. Neurology 2000; 54: 1583–8CrossRefGoogle Scholar
  84. 84.
    Shoulson I, Penney J, McDermott M, et al. A randomized, controlled trial of remacemide for motor fluctuations in Parkinson’s disease. Neurology 2001; 56(4): 455–62PubMedCrossRefGoogle Scholar
  85. 85.
    Eshel Y, Korczyn AD. Amantadine antagonism of oxotremorine effects. J Neural Transm 1979; 46: 79–83PubMedCrossRefGoogle Scholar
  86. 86.
    Korczyn AD, Keren O, Eshel Y. Effect of amantadine on pupillary diameter in mice. Israel J Med Sci 1982; 18: 145–7PubMedGoogle Scholar
  87. 87.
    Verhagen Metaman L, Del Dotto P, van den Munckhof P, et al. Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson’s disease. Neurology 1998; 50: 1323–6CrossRefGoogle Scholar
  88. 88.
    Factor SA, Molho ES. Transient benefit of amantadine in Parkinson’s disease: the facts about the myth. Mov Disord 1999; 14: 515–6PubMedCrossRefGoogle Scholar
  89. 89.
    Rabey JM, Korczyn AD. Efficacy of memantime, and NMDA receptor antagonist, in the treatment of Parkinson’s disease. J Neural Transm 1992; 4: 277–82CrossRefGoogle Scholar
  90. 90.
    Hunter C, Jankovic J. Double-blind, placebo-controlled study to assess safety and efficacy of riluzole as a neuro-protective drug in patients with early, untreated Parkinson’s disease. Neurology 1999; 52 Suppl. 2: 214–5Google Scholar
  91. 91.
    Merims D, Ziv I, Djaldetti R, et al. Riluzole for levodopa-induced dyskinesias in advanced Parkinson’s disease. Lancet 1999; 353: 1764–5PubMedCrossRefGoogle Scholar
  92. 92.
    Hirsch EC, Hunot S, Damier P, et al. Glial cells and inflammation in Parkinson’s disease: a role in neurodegeneration? Ann Neurol 1998; 44 Suppl. 1: S115–20PubMedGoogle Scholar
  93. 93.
    Obanion MK. COX-2 and Alzheimer’s disease: potential roles in inflammation and neurodegeneration. Expert Opin Investig Drugs 1999; 8: 1521–36CrossRefGoogle Scholar
  94. 94.
    Larousse C, Veyrac G. Clinical data on COX-1 and COX-2 inhibitors: what alerts in pharmacovigilance? Therapie 2000; 55: 21–8PubMedGoogle Scholar
  95. 95.
    Nagatsu T, Mogi M, Ichinose H, et al. Cytokines in Parkinson’s disease. J Neural Transm Suppl. 2000; (58): 143–51Google Scholar
  96. 96.
    Lindsay RM. Neurotrophic growth factors and neurodegenerative diseases: therapeutic potential of the neurotrophins and ciliary neurotrophic factor. Neurobiol Aging 1994; 15: 249–51PubMedCrossRefGoogle Scholar
  97. 97.
    Lingor P, Unsicker K, Krieglstein K. GDNF and NT-4 protect midbrain dopaminergic neurons from toxic damage by iron and nitric oxide. Exp Neurol 2000; 63: 55–62CrossRefGoogle Scholar
  98. 98.
    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: 767–73PubMedCrossRefGoogle Scholar
  99. 99.
    Espejo M, Cutillas B, Arenas TE, et al. Increased survival of dopaminergic neurons in striatal grafts of fetal ventral mesencephalic cells exposed to neurotrophin-3 or glial cell line-derived neurotrophic factor. Cell Transplant 2000; 9(1): 45–53PubMedGoogle Scholar
  100. 100.
    A controlled trial of recombinant methionyl human BDNF in ALS: the BDNF Study Group (Phase III). Neurology 1999; 52: 1427–33CrossRefGoogle Scholar
  101. 101.
    Shults CW, Kimber T, Martin D. Intrastriatal injection of GDNF attenuates the effects of 6-hydroxydopamine. Neuroreport 1996; 7: 627–31PubMedCrossRefGoogle Scholar
  102. 102.
    Tomac A, Lindquist E, Lin LFH, et al. Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature 1995; 373: 335–9PubMedCrossRefGoogle Scholar
  103. 103.
    Schapira AHV, Gu M, Taanman J-W, et al. Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. Ann Neurol 1998; 44 Suppl. 1: S89–98PubMedGoogle Scholar
  104. 104.
    Cassarino DS, Bennet JP. An evaluation of the role of mitochondria in neurodegenerative diseases: mitochondrial mutations and oxidative pathology, protective nuclear responses, and cell death in neurodegeneration. Brain Res Brain Res Rev 1999; 29(1): 1–25PubMedCrossRefGoogle Scholar
  105. 105.
    Steiner JP, Hamilton GS, Ross DT, et al. Neurotrophic immunophilin ligands stimulate structural and functional recovery in neurodegenerative animal models. Proc Natl Acad Sci U S A 1997; 94: 2019–24PubMedCrossRefGoogle Scholar
  106. 106.
    Gold BG. Neuroimmunophilin ligands: evaluation of their therapeutic potential for the treatment of neurological disorders. Expert Opin Investig Drugs 2000; 9: 2331–42PubMedCrossRefGoogle Scholar
  107. 107.
    Hurtig HI, Trojanowski IQ, Galvin J, et al. Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson’s disease. Neurology 2000; 54: 1916–21PubMedCrossRefGoogle Scholar
  108. 108.
    Trojanowski JQ, Lee VM. Aggregation of neurofilaments and alpha-synuclein proteins in Lewy bodies. Arch Neurol 1998; 55: 151–2PubMedCrossRefGoogle Scholar
  109. 109.
    Shoji M, Harigaya Y, Sasaki A, et al. Accumulation of NACP/alpha-synuclein in Lwey body disease and multiple system atrophy. J Neurol Neurosurg Psychiatry 2000; 68: 605–8PubMedCrossRefGoogle Scholar
  110. 110.
    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
  111. 111.
    Solano SM, Miller DW, Augood SJ, et al. Expression of alpha-synuclein, parkin, and ubiquitin carboxy-terminal hydrolase L1 mRNA in human brain: genes associated with familial Parkinson’s disease. Ann Neurol 2000; 47: 201–10PubMedCrossRefGoogle Scholar
  112. 112.
    Wagner J, Castro DS, Holm PC, et al. Induction of a midbrain dopaminergic phenotype in Nurrl-overexpressing neural stem cells by type 1 astrocytes. Nat Biotechnol 1999; 17: 653–9PubMedCrossRefGoogle Scholar
  113. 113.
    Piccini P, Brooks DJ, Bjorklund A, et al. Dopamine release for nigral transplants visualized in vivo in a Parkinson’s patient. Nat Neurosci 1999; 2: 1137–40PubMedCrossRefGoogle Scholar
  114. 114.
    Hallett M, Litvan I. Scientific position paper of the Movement Disorder Society evaluation of surgery for Parkinson’s disease. Task Force on Surgery for Parkinson’s Disease of the American Academy of Neurology Therapeutic and Technology Assessment Committee. Mov Disord 2000; 15(3): 436–8PubMedCrossRefGoogle Scholar
  115. 115.
    Rajerdan P. The use of alternative therapies by patients with Parkinson’s disease. The 52nd annual meeting of the American Academy of Neurology, 2000 May 5–10, San Diego, USA.Google Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  • Amos D. Korczyn
    • 1
  • Miri Nussbaum
    • 1
  1. 1.Department of Neurology, Sackler School of MedicineTel-Aviv University Medical SchoolRamat-AvivIsrael

Personalised recommendations