Skip to main content Accessibility help
×
Home
  • Print publication year: 2005
  • Online publication date: August 2010

42 - Current and potential treatments of Parkinson's disease

from Part VII - Parkinson's and related movement disorders

Summary

Parkinson's disease (PD) is a progressive, degenerative neurological disorder characterized by rest tremor, bradykinesia, cogwheel rigidity and postural instability (Lang & Lozano, 1998). In the later stages of the illness approximately 30–40% of patients will develop cognitive compromise. The cardinal pathological features of PD are loss of neurons on the substantia nigra pars compacta (SNpc) and the presence of eosinophilic, intracytoplasmic inclusions, and Lewy bodies (Braak & Braak, 2000). The neurons of the SNpc project primarily to the caudate and putamen, which are referred to collectively as the striatum, and utilize the neurotransmitter dopamine. Dopamine is severely reduced in the SNpc and striatum in parkinsonian brains (Hornykiewicz, 2002). Although the loss of neurons is most conspicuous in the SNpc, neuronal loss and Lewy bodies are found in a number of brain regions, e.g. locus ceruleus, entorhinal region and amygdala (Braak & Braak, 2000). The neuronal loss and the presence of Lewy bodies in regions other than the SNpc suggest that although treatments that target only the nigrostriatal dopaminergic system may substantially benefit patients, they are unlikely to completely resolve the deficits of PD.

The following review presents a strategic framework through which to consider targets for therapies of PD. In some of the areas we are just beginning to have treatments, e.g. slowing the progression of the disease, and in others we have well-established therapies, e.g. augmentation of the function of the remaining dopaminergic system.

Related content

Powered by UNSILO
REFERENCES
Aarsland, D., Laake, K., Larsen, J. P. & Janvin, C. (2002). Donepezil for cognitive impairment in Parkinson's disease: a randomised controlled study. J. Neurol., Neurosurg. Psychiatr., 72, 708–12
Aarsland, D., Andersen, K., Larsen, J. P., Lolk, A. & Kragh-Sorensen, P. (2003). Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch. Neurol., 60, 387–92
Adler, C. H., Singer, C., O'Brien, C. et al. (1998). Randomized, placebo-controlled study of tolcapone in patients with fluctuating Parkinson disease treated with levodopacarbidopa. Tolcapone Fluctuator Study Group III. Arch. Neurol., 55, 1089–95
Alam, Z. I., Daniel, S. E., Lees, A. J.et al. (1997). A generalized increase in protein carbonyls in the brain in Parkinson's but not incidental Lewy body disease. J. Neurochemi., 69 (3), 1326–9
Andersen, J. K. (2001). Does neuronal loss in Parkinson's disease involve programmed cell death?Bioessays, 23 (7), 640–6
Barone, P., Bravi, D., Bermejo-Pareja, F.et al. (1999). Pergolide monotherapy in the treatment of early PD. A randomized controlled study. Neurology, 53, 573–9
Beal, M. F. (2002). Oxidatively modified proteins in aging and disease. Free Radic. Biol. Med., 32 (9), 797–803
Björklund, A. (2000). Cell replacement strategies for neurodegenerative disorders. Novartis Foundation Symposium, 231, 7–15; discussion 16–20
Braak, H. & Braak, E. (2000). Pathoanatomy of Parkinson's disease. J. Neurol.) 247 (2), II3–10
Brooks, D. J., Abbott, R. J., Lees, A. J.et al. (1998). A placebo-controlled evaluation of ropinirole, a novel D2 agonist, as sole dopaminergic therapy in Parkinson's disease. Clin. Neuropharmacol., 21, 101–7
Burchiel, K. J., Anderson, V. C., Favre, J.et al. (1999). Comparison of pallidal and subthalamic nucleus deep brain stimulation for advanced Parkinson's disease: results of a randomized, blinded pilot study. Neurosurgery, 45 (6), 1375–82
Butzer, J. F., Silver, D. E. & Sans, A. L. (1975). Amantadine in Parkinson's disease. A double-blind, placebo-controlled, crossover study with long-term follow-up. Neurology, 25, 603–6
Calne, D. B., Techenne, P. F., Claveria, L. E.et al. (1974). Bromocriptine in Parkinsonism. Br. Med. J., 4, 442–4
Cantello, R., Riccio, A., Gilli, M.et al. (1986). Bornaprine vs placebo in Parkinson disease: double-blind controlled cross-over trial in 30 patients. Ital. J. Neurol. Sci., 7, 139–43
Chung, K. K., Dawson, V. L. & Dawson, T. M. (2001). The role of the ubiquitin-proteasomal pathway in Parkinson's disease and other neurodegenerative disorders. Trends Neurosci., 24 (11 Suppl), S7–14
Cotzias, G. C., Papavasiliou, P. S. & Gellene, R. (1969). Modification of Parkinsonism-chronic treatment with L-dopa. N. Engl. J. Med., 280, 337–45
Bie, R. M., Haan, R. J., Nijssen, P. C.et al. (1999). Unilateral pallidotomy in Parkinson's disease: a randomised, single-blind, multicentre trial. Lancet, 354 (9191), 1665–9
Bie, R. M., Haan, R. J., Schuurman, P. R.et al. (2002). Morbidity and mortality following pallidotomy in Parkinson's disease: a systematic review. Neurology, 58 (7), 1008–12
Dexter, D. T., Carter, C. J., Wells, F. R.et al. (1989). Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease. J. Neurochem., 52 (2), 381–9
Drukarch, B. & Muiswinkel, F. L. (2000). Drug treatment of Parkinson's disease. Time for phase II. Biochem. Pharmacol., 59 (9), 1023–31
Du, Y., Ma, Z., Lin, S.et al. (2001). Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. Proc. Natl Acad. Sci. USA, 98 (25), 14669–74
Dupont, E., Anderson, A., Boqs, J.et al. (1996). Sustained-release Madopar HBS compared with standard Madopar in the long-term treatment of de novo parkinsonian patients. Acta Neurol. Scand., 93, 14–20
Eberling, J. L., Pivirotto, P., Bringas, J.et al. (2002). The immunophilin ligand GPI-1046 does not have neuroregenerative effects in MPTP-treated monkeys. Exp. Neurol., 178 (2), 236–42
Etminan, M., Samii, A., Takkouche, B.et al. (2001). Increased risk of somnolence with the new dopamine agonists in patients with Parkinson's disease: a meta-analysis of randomised controlled trials. Drug Safety, 24 (11), 863–8
Freed, C. R., Greene, P. E., Breeze, R. E.et al. (2001). Transplantation of embryonic dopamine neurons for severe Parkinson's disease. New Engl. J. Med., 344 (10), 710–19
Furukawa, Y., Vigouroux, S., Wong, H.et al. (2002). Brain proteasomal function in sporadic Parkinson's disease and related disorders. Ann. Neurol., 51 (6), 779–82
Galvin, J. E., Lee, V. M., Schmidt, M. L.et al. (1999). Pathobiology of the Lewy body. Adv. Neurol., 80, 313–24
Giasson, B. I. & Lee, V. M. (2001). Parkin and the molecular pathways of Parkinson's disease. Neuron, 31 (6), 885–8
Giasson, B. I., Duda, J. E., Murray, I. V.et al. (2000). Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science, 290 (5493), 985–9
Gill, S. S., Patel, N. K., Hotton, G. R., O'Sullivan, K., et al. (2003). Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat. Med., 9 (5), 589–95
Goetz, C. G., Blasucci, L. M., Leurgans, S. & Pappert, E. J. (2000). Olanzapine and clozapine: comparative effects on motor function in hallucinating PD patients. Neurology, 55, 789–94
Gold, B. G. & Nutt, J. G. (2002). Neuroimmunophilin ligands in the treatment of Parkinson's disease. Curr. Opin. Pharmacol., 2 (1), 82–6
Guttman, M. and the International Pramipexole-Bromocriptine Study Group (1997). Double-blind comparison of pramipexole and bromocriptine treatment with placebo in advanced Parkinson's disease. Neurology, 49, 1060–5
Haas, R. H., Nasirian, F., Nakano, K., Ward, D.et al. (1995). Low platelet mitochondrial Complex I and Complex II/III activity in early untreated Parkinson's disease. Ann. Neurol., 37, 714–22
Hallett, M. & Litvan, I. (1999). Evaluation of surgery for Parkinson's disease: a report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. The Task Force on Surgery for Parkinson's Disease. Neurology, 53 (9), 1910–21
Halliwell, B. (2001). Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. Drugs Aging, 18 (9), 685–716
Hely, M. A., Morris, J. G. L. & Reid, W. G. J. (1994). The Sydney multicentre study of Parkinson's disease: a randomized, prospective five year study comparing low dose bromocriptine with low dose levodopa-carbidopa. J. Neurol., Neurosurg., Psychiatr., 57, 903–10
Hirsch, E.., Hunot, S., Damier, P.et al. (1998). Glial cells and inflammation in Parkinson's disease: a role in neurodegeneration?Ann. Neurol., 44 (3 Suppl 1), S115–20
Hornykiewicz, O. (2002). Dopamine miracle: from brain homogenate to dopamine replacement. Movement Disord., 17 (3), 501–8
Hutton, J. T., Morris, J. L., Bush, D. F.et al. (1989). Multicenter controlled study of Sinemet CR vs Sinemet (25/100) in advanced Parkinson's disease. Neurology, 39, 67–72
Isacson, O. (2002). Models of repair mechanisms for future treatment modalities of Parkinson's disease. Brain Res. Bull., 57 (6), 839–46
Kingsbury, A. E., Mardsen, C. D. & Foster, O. J. (1998). DNA fragmentation in human substantia nigra: apoptosis or perimortem effect?Movement Disord., 13 (6), 877–84
Kitada, T., Asakawa, S., Hattori, N.et al. (1998). Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature, 392, 605–8
Koller, W. C., Hutton, J. T., Tolosa, E.et al. (1999). Immediate-release and controlled-release carbidopa/levodopa in PD: a 5-year randomized multicenter study. Neurology, 53, 1012–19
Kordower, J. H., Palfi, S., Chen, E. Y.et al. (1999). Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson's disease. Ann. Neurol., 46 (3), 419–24
Kordower, J. H., Emborg, M. E., Bloch, J.et al. (2000). Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science, 290 (5492), 767–73
Kumar, S., Bhatia, M. & Behari, M. (2002). Sleep disorders in Parkinson's disease. Movement Disord., 17 (4), 775–81
Laitinen, L. V., Bergenheim, A. T. & Hariz, M. I. (1992). Leksell's posteroventral pallidotomy in the treatment of Parkinson's disease. J. Neurosurg., 76 (1), 53–61
Lang, A. E. (2000). Surgery for Parkinson disease: A critical evaluation of the state of the art. Arch. Neurol., 57 (8), 1118–25
Lang, A. E. & Lozano, A. M. (1998). Parkinson's disease. First of two parts. N. Engl. J. Med., 339 (15), 1044–53
Langston, J. W., Ballard, P., Tetrud, J. W. & Irwin, I. (1983). Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science, 219, 979–80
Langston, J. W., Forno, L. S., Tetrud, J.et al. (1999). Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann. Neurol., 46 (4), 598–605
Lieberman, A., Ranhosky, A. & Korts, D. (1997). Clinical evaluation of pramipexole in advanced Parkinson's disease: results of a double-blind, placebo controlled, parallel-group study. Neurology, 49, 162–8
Limousin, P., Krack, P., Pollak, P.et al. (1998). Electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease. N. Engl. J. Med., 339 (16), 1105–11
Lindvall, O. & Hagell, P. (2001). Cell therapy and transplantation in Parkinson's disease. Clin. Chem. Laborat. Med., 39 (4), 356–61
Luginger, E., Wenning, G. K., Bosch, S. & Poewe, W. (2000). Beneficial effects of amantadine on L-dopa-induced dyskinesias in Parkinson's disease. Movement Disord., 15, 873–8
Matthews, R. T., Klivenyi, P., Mueller, G.et al. (1999). Novel free radical spin traps protect against malonate and MPTP neurotoxicity. Exp. Neurol., 157 (1), 120–6
McGeer, E. G. & McGeer, P. L. (1997). The role of the immune system in neurodegenerative disorders. Movement Disord., 12 (6), 855–8
McNaught, K. S., Olanow, C. W., Halliwell, B.et al. (2001). Failure of the ubiquitin-proteasome system in Parkinson's disease. Nat. Rev. Neurosci., 2 (8), 589–94
Mizuno, Y., Hattori, N., Mori, H.et al. (2001). Parkin and Parkinson's disease. Curr. Opin. Neurol., 14 (4), 477–82
Montastruc, J. L., Rascol, O., Senard, J. M. & Rascol, A. (1994). A randomized controlled study comparing bromocriptine to which levodopa was later added, with levodopa alone in previously untreated patients with Parkinson's disease: a five year follow-up. J. Neurol., Neurosurg. Psychiatr., 57, 1034–8
Nijhawan, D., Honarpour, N. & Wang, X. (2000). Apoptosis in neural development and disease. Ann. Rev. Neurosci., 23, 73–87
Nutt, J. G., Burchiel, K. J., Comella, C. L.et al. and ICV GDNF Study Group (2003). Implanted intracerebroventricular glial cell line-derived neurotrophic factor. Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology, 60, 69–73
Oh, M. Y., Abosch, A., Kim, S. H.et al. (2002). Long-term hardware-related complications of deep brain stimulation. Neurosurgery, 50 (6), 1268–74; discussion 1274–6
Olanow, C. W., Fahn, S., Muenter, M.et al. (1994). A muticenter double-blind placebo-controlled trial of pergolide as an adjunct to Sinemet in Parkinson's disease. Movement Disord., 9, 40–7
Olanow, C. W., Hauser, R. A., Gauger, L.et al. (1995). The effect of deprenyl and levodopa on the progression of Parkinson's disease. Ann. Neurol., 38, 771–7
Olanow, C. W., Goetz, C. G., Kordower, J. H.et al. (2003). A doubleblind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease. Ann Neurol., 54, 403–14
Pålhagen, S., Heinonan, E. H., Hagglund, J.et al. (1998). Selegiline delays the onset of disability in de novo parkinsonian patients. Swedish Parkinson Study Group. Neurology, 51, 520–5
Parkinson Disease Research Group in the United Kingdom (1993). Comparisons of therapeutic effects of levodopa, levodopa and selegiline, and bromocriptine in patients with early, mild Parkinson's disease: three-year interim report. Br. Med. J., 307, 469–72
Parkinson Study Group. (1993). Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. N. Engl. J. Med., 328, 176–83
Parkinson Study Group. (1997a). Safety and efficacy of pramipexole in early Parkinson disease. A randomized dose-ranging study. Parkinson Study Group. J. Am. Med. Assoc., 278 (2), 125–30
Parkinson Study Group. (1997b). Entacapone improves motor fluctuations in levodopa-treated Parkinson's disease patients. Ann. Neurol., 42 (5), 747–55
Parkinson Study Group. (1999). Low-dose clozapine for the treatment of drug-induced psychoses in Parkinson's disease. N. Engl. J. Med., 340, 757–63
Parkinson Study Group. (2000). Pramipexole vs. levodopa as initial treatment for Parkinson's disease: a randomized controlled trial. J. Am. Med. Assoc., 284, 1931–8
Polymeropoulos, M. H., Lavedan, C., Leroy, E.et al. (1997). Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science, 276, 2045–7
Przedborski, S. & Jackson-Lewis, V. (1998). Mechanisms of MPTP toxicity. Movement Disord., 13 Suppl 1, 35–8
Rajput, A. H., Martin, W., Saint-Hilaire, M. H.et al. (1997). Tolcapone improves motor function in Parkinsonian patients with the “wearing-off” phenomenon: a double-blind, placebo-controlled, multicenter trial. Neurology, 49, 1066–71
Rascol, O., Brooks, D. J., Korczyn, A. D.et al. (2000). A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. N. Engl. J. Med., 342, 1484–91
Reed, J. C. (2002). Apoptosis-based therapies. Nat. Rev. Drug Discover., 1 (2), 111–21
Rinne, U. K., Larsen, J. P., Siden, A.et al. (1998). Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations. Neurology, 51, 1309–14
Riopelle, R. J. (1987). Bromocriptine and the clinical spectrum of Parkinson's disease. Can. J. Neurol. Sci., 14, 455–9
Sanchez-Ramos, J. R., Övervik, E. & Ames, B. N. (1994). A marker of oxyradical-mediated DNA damage (8-hydroxy-2′deoxyguanosine) is increased in nigro-striatum of Parkinson's disease brain. Neurodegeneration, 3, 197–204
Schapira, A. H. V., Mann, V. M., Cooper, J. M.et al. (1990). Anatomic disease specificity of NADH CoQ1 reductase complex I deficiency in Parkinson's disease. J. Neurochem., 55, 2142–5
Schuurman, P. R., Bosch, D. A., Bossuyt, P. M.et al. (2000). A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor. N. Engl. J. Med., 342 (7), 461–8
Schwab, R. S., England, A. C. Jr., Poskancer, D. C.et al. (1969). Amantadine in the treatment of Parkinson's disease. J. Am. Med. Assoc., 208, 1168–70
Shimura, H., Hattori, N., Kubo,, S.et al. (2000). Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat. Genet., 25, 302–5
Shults, C. W. (1998). Neurotrophic factors in neurodegenerative disorder. In Parkinson's Disease and Movement Disorders, ed. J. Jankovic and E. Tolosa, pp. 105–18. 3rd edn. Williams and Wilkins
Shults, C. W., Haas, R. H., Passov, D. & Beal, M. F. (1997). Coenzyme Q10 levels correlate with the activities of complexes I and II/III in mitochondria from parkinsonian and nonparkinsonian subjects. Ann. Neurol., 42, 261–4
Shults, C. W., Oakes, D., Kieburtz, K.et al. (2002). Effects of coenzyme Q10 in early Parkinson disease-Evidence of slowing of the functional decline. Arch. Neurol., 59, 1541–50
Sian, J., Dexter, D. T., Lees, A. J.et al. (1994). Alterations in glutathione levels in Parkinson's disease and other neurodegenerative disorders affecting basal ganglia. Ann. Neurol., 36 (3), 348–55
Snow, B. J., MacDonald, L., Mcauley, D.et al. (2000). The effect of amantadine on levodopa-induced dyskinesias in Parkinson's disease: a double-blind, placebo-controlled study. Clin. Neuropharmacol., 23, 82–5
Spillantini, M. G., Schmidt, M. L., Lee, V. M.et al. (1997). Alpha-synuclein in Lewy bodies. Nature, 388 (6645), 839–40
Takeda, A., Mallory, M., Sundsmo, M.et al. (1998). Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders. Am. J. Pathol., 152 (2), 367–72
Tan, E. K., Lum, S. Y., Fook-Chong, S. M.et al. (2002). Evaluation of somnolence in Parkinson's disease: comparison with age- and sex-matched controls. Neurology, 58 (3), 465–8
Tarnopolsky, M. A. & Beal, M. F. (2001). Potential for creatine and other therapies targeting cellular energy dysfunction in neurological disorders. Ann. Neurol., 49 (5), 561–74
Teismann, P. & Ferger, B. (2001). Inhibition of the cyclooxygenase isoenzymes COX-1 and COX-2 provide neuroprotection in the MPTP-mouse model of Parkinson's disease. Synapse, 39 (2), 167–74
The Deep-Brain Stimulation for Parkinson's Disease Study Group (2001). Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson's disease. N. Engl. J. Med., 345, 956–63
The Parkinson Study Group (1999). Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson's disease. N. Engl. J. Med., 1340, 757–63
Trepanier, L. L., Kumar, R., Lozano, A. M.et al. (2000). Neuropsychological outcome of GPi pallidotomy and GPi or STN deep brain stimulation in Parkinson's disease. Brain Cogn., 42 (3), 324–47
Verhagen Metman, L. V., Del Dotto, P., LePoole, K.et al. (1999). Amantadine for levodopa-induced dyskinesias. A 1-year follow-up study. Arch. Neurol., 56, 1383–6
Wakabayashi, K., Matsumoto, K., Takayama, K.et al. (1997). NACP, a presynaptic protein, immunoreactivity in Lewy bodies in Parkinson's disease. Neurosci. Lett., 239 (1), 45–8
Wermuth, L. and the Danish Pramipexole Study Group (1998). A double-blind, placebo-controlled, randomized, multi-center study of pramipexole in advanced Parkinson's disease. Eur. J. Neurol., 5, 235–44
Wolters, E. C., Tesselaar, H. J. M. and the International (NL and UK) Sinemet CR Study Group (1996). International (NL–UK) double-blind study of Sinemet CR and standard Sinemet (25/100) in 170 patients with fluctuating Parkinson's disease. J. Neurol., 243, 235–40
Wu, D. C., Jackson-Lewis, V., Vila, M.et al. (2002). Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J. Neurosci., 22 (5), 1763–71
Zhang, C., Steiner, J. P., Hamilton, G. S.et al. (2001). Regeneration of dopaminergic function in 6-hydroxydopamine-lesioned rats by neuroimmunophilin ligand treatment. J. Neurosci., 21 (15), RC156
Zimmermann, K. C., Bonzon, C. & Green, D. R. (2001). The machinery of programmed cell death. Pharmacol. Therap., 92 (1), 57–70