Abstract
Parkinson’s disease is a chronic progressive condition that causes disability and reduction of quality of life. Symptomatic treatments are effective in the early disease; however, with time, most patients develop motor complications. Neuroprotective therapies are those that can slow disease progression; unfortunately, these agents are not available. Advances in the knowledge of the possible pathogenic events that can lead to nigral cell death have increased dramatically. These mechanisms include oxidative stress, mitochondrial dysfunction, inflammation, excitotoxicity, alterations in protein degradation, and ultimately apoptosis. Based on these laboratory scientific findings, a number of agents have been studied in clinical trials. However, how to assess disease evolution and establish reliable endpoints is still an unresolved issue. The monoamine oxidase inhibitors selegiline and rasagiline have been shown to be neuroprotective in vitro and in animal models, but so far this property was not demonstrated in clinical trials. Other agents have been studied and still others are undergoing clinical investigation. These include antiexcitotoxicity drugs like riluzole, the bioenergetic agent coenzyme Q10, trophic factors, and antiapoptotic drugs. Laboratory and clinical data suggest that dopamine agonists may have a neuroprotective action, but this has yet to be proven. However, as our basic and clinical knowledge on Parkinson’s disease increases, it is likely that a neuroprotective drug will be found.
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References and Recommended Reading
Olanow CW, Watt RL, Koller WC: An algorithm (decision tree) for the management of Parkinson’s disease: treatment guideline. Neurology 2001, 56(suppl 5):51–88.
Rajput AH, Rajput A, Rajput M: Epidemiology for Parkinsonism. In Handbook of Parkinson’s Disease, edn 3. Edited by Pahwa R, Lyons KE, Koller WC. New York: Marcel Dekker; 2003:17–42.
Gibb WR, Lee AJ: Anatomy, pigmentation, ventral and dorsal subpopulation of the substantia nigra and differential cell death in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1991, 54:388–396.
McNaught K, Olanow CW: Proteolytic stress: a unifying concept for the etiopathogenesis of Parkinson’s disease. Ann Neurol 2003, 53(suppl 3):573–586. This paper reviews the role of protein aggregation and degradation in PD. Dysfunction of the ubiquitin-proteasome system and the genesis of Lewy bodies are discussed.
Hoehn MM, Yahr MD: Parkinsonism: onset, progression and mortality. Neurology 1967, 17:427–442.
Marsden CD, Olanow CW: Neuroproctection in Parkinson’s disease. The causes of Parkinson’s disease are being unraveled and rational neuroprotective therapy is close to reality. Ann Neurol 1998, 44:189–196.
Stocchi FS, Olanow CW: Neuroprotection in Parkinson’s disease: clinical trials. Ann Neurol 2003, 53(suppl 3):587–599.
Warner T, Schapira AV: Genetics and environmental factors in the cause of Parkinson’s disease. Ann Neurol 2003, 53(suppl 3):516–525.
Fahn S, Sulzer D: Neurodegeneration and neuroprotection in Parkinson’s disease. Neuro Rx 2003, 1:139–154.
Koller WC, Vetere-Overfield B, Gray C, et al.: Environmental risk factors in Parkinson’s disease. Neurology 1990, 40:1218–1221.
Betarbet R, Sherer TB, MacKenzie G, et al.: Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 2000, 3:1301–1306.
Tanner CM, Ohman R, Goldman SM, et al.: Parkinson’s disease in twins: an etiologic study. JAMA 1999, 281:341–346.
Jenner P: Oxidative stress in Parkinson’s disease. Ann Neurol 2003, 53(suppl 3):526–538. Data implicating oxidative stress in the pathogenesis of PD are reviewed.
Jenner P: Oxidative damage in neurodegenerative disease. Lancet 1994, 344:796–798.
Sian J, Dexter DJ, Less AJ, et al.: Glutathione-related enzymes in brains of Parkinson’s disease. Ann Neurol 1994, 36:356–361.
Schapira AV: Evidence for mitochondrial dysfunction in Parkinson’s disease-a critical appraisal. Mov Disord 1994, 9:123–138.
Schapira AV, Cooper JM, Dexter D, et al.: Mitchondrial complex I deficiency in Parkinson’s disease. J Neurochem 1990, 54:823–827.
Nicklas WJ, Vyas I, Heikkila RE: Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. Life Sci 1985, 36:2503–2508.
Parker WP, Boyson SJ, Parks JK: Abnormalities of the electron transport chain in idiopathic Parkinson’s disease. Ann Neurol 1989, 26:719–723.
Beal MF: Bioenergetic approaches for neuroprotection in Parkinson’s disease. Ann Neurol 2003, 53(suppl 3):539–548.
Hunot S, Hirsch EC: Neuroinflammatory processes in Parkinson’s disease. Ann Neurol 2003, 53(suppl 3):549–560.
McGeer PL, Itagaki S, Boyes BE, McGeer EG: Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurol 1988, 38:1285–1291.
Langston JW, Forno LS, Tetrud J, et al.: 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 1999, 46:598–605.
Iravani MM, Kashefi K, Mander P, et al.: Involvement of inducible nitric oxide synthetase in inflammation-induced dopaminergic neurogeneration. Neurol Sci 2002, 110:49–58. Potential neuroprotective drugs and clinical assessment are reviewed.
Rodriguez MC, Obeso JA, Olanow CW: Subthalamic nucleus mediated excitotoxicity in Parkinson’s disease: a target for neuroprotection. Ann Neurol 1998, 44:175–188.
Feger J, Hassani LN, Mouroux M: The subthalamic nucleus and its connections new electrophysiological and pharmacological data. Adv Neurol 1997, 74:31–44.
Uitti RJ, Rajput AH, Ahlskog JE, et al.: Amantadine treatment is an independent predictor of improved survival in Parkinson’s disease. Neurology 1996, 46:1551–1556.
McNaught K, Shashidharan P, Perl DP, et al.: Aggresomerelated biogenesis of Lewy bodies. Eur J Neurosci 2002, 16:2136–2148.
Olanow CW, Tatton WG: Etiology and pathogenesis of Parkinson’s disease. Ann Rev Neurosci 1999, 22:123–144.
McNaught KS, Jenner P: Proteasomal function is impaired in substantia nigra in Parkinson’s disease. Neurosci Lett 2001, 297:191–194.
Masliah E, Rockenstein E, Veinbergs I, et al.: Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 2000, 287:1265–1269.
Tatton WG, Chalmer-Redman R, Brown D, Tatton N: Apoptosis in Parkinson’s disease: Signals for neuronal degradation. Ann Neurol 2003, 53(suppl 3):561–572.
Przedborksi S, Vila M: MPTP: a review of its mechanism of neurotoxicity. Clin Neurosci Res 2001, 407–418.
Ravina BM, Fagan SC, Hart RG, et al.: Neuroprotective agents for clinical trials in Parkinson’s disease: a systematic assessment. Neurology 2003, 60:1234–1240.
Kieburtz K: Designing neuroprotection trials in Parkinson’s disease. Ann Neurol 2003, 53(suppl 3):S100-S109.
Brooks D: Imaging end points for monitoring neuroprotection in Parkinson’s disease. Ann Neurol 2003, 53(suppl 3):S110-S119.
Jenner P, Olanow CW: Understanding cell death in Parkinson’s disease. Ann Neurol 1998, 44:S72-S84.
Finberg JP, Takeshima T, Johnston JM, Commissiong JW: Increased survival of dopaminergic neurons by rasagiline, a monoamine oxidase B inhibitor. Neuro-Report 1998, 9:703–707.
Fineberg JP, Lamensdorf I, Commission JW, Youdim MD: Pharmacology and neuroproctective properties of rasagiline. J Neural Transm 1996, 48(suppl):95–101.
Parkinson Study Group: Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 1993, 328:176–183.
Giladi N, McDermott MP, Fahn S, et al.: Freezing of gait in PD: prospective assessment in the DATATOP cohort. Neurology 2001, 56:1712–1721.
Olanow CW, Hauser RA, Gauger L, et al.: The effect of deprenyl and levodopa on the progression of signs and symptoms in Parkinson’s disease. Ann Neurol 1995, 38:771–777.
Tetrud JW, Langston JW: The effect of deprenyl (selegiline) on the natural history of Parkinson’s disease. Science 1989, 245:519–522.
Palhagen S, Heinonen EH, Hagglund J, et al.: Selegiline delays the onset of disability in he de novo parkinsonian patients. Swedish Parkinson Study Group. Neurology 1998, 51:520–525.
Myllylä VV, Sotaniemi KA, Vuorinen JA, Heinonen EH: Selegiline as a primary treatment of Parkinson’s disease. Acta Neurol Scand 1991, 136(suppl):70–72.
Parkinson’s Study Group: A controlled trial of rasagiline in early Parkinson’s disease, the TEMPO Study. Arch Neurol 2002, 59:1937–1943.
Rascol O, Olanow CW, Brooks D, et al.: A 2-year multicenter placebo-controlled, double-blind parallet group study of the effect of riluzole in Parkinson’s disease. Mov Disord 2002, 17:39.
Parkinson Study Group: A multicenter randomized controlled trial of remacemide hydrochloride as monotherapy for PD. Neurology 2000, 54:1583–1588.
Huntington’s Disease Study Goup: A randomized, placebocontrolled trial of coenzyme Q10 remacemide in Huntington’s disease. Neurology 2001, 57:397–404.
Schuls CW, Oakes D, Kieburtz K, et al.: Effect of coenzyme Q10 in early Parkinson’s disease: evidence of slowing of the functional decline. Arch Neurol 2002, 59:1541–1550. Initial pilot study of the bioenergetic drug coenzyme Q10 is reported.
Collier T, Sortwell CE: Therapeutic potential of nerve growth factors in Parkinson’s disease. Drugs Aging 1999, 14:261–287.
Hebert AA, Hoffer BJ, Zhang Z, et al.: Functional effects of GDNF in normal and parkinsonian rats and monkeys. In CNS Regeneration: Basic Science and Clinical Advances. Edited by Tuszynski M, Kordower JH. New York: Academic Press; 1999:419–436.
Nutt JG, Burchiel KJ, Comella CL, et al., for the ICV GDNF Study Group: Randomized double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 2002, 60:69–73.
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, 290:767–773. It is reported that lentivirus vector delivery of GDNF is effective in animal models of PD.
Gill SS, Patel NK, Hotton GR, et al.: Direct brain infusion of glial derived neurotrophic factor (GDNF) in Parkinson’s disease. Nature Med 2003, 9:589–595.
Olanow CW, Jenner P, Brooks P: Dopamine agonists and neuroprotection in Parkinson’s disease. Ann Neurol 1998, 44:5167–5174.
Parkinson Study Group: Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002, 287:1653–1661.
Whone AL, Remy P, Davis MR, et al.: The REAL-PET study: slower progression in early Parkinson’s disease treated with ropinirole compared with L-dopa. Neurology 2002, 58:82–83.
Kragten E, Lalande I, Zimmerman K, et al.: Glyceraldehyde-3-phosphate dehydrogenase, the putative target of the antiapopotic compounds CGP 3466 and R-(-)-deprenyl. J Biol Chem 1998, 273:5821–5828.
Schwid SR, for the Parkinson Study Group: CEP-1347 in Parkinson’s disease: a pilot study. Paper presented at the 7th International Congress of Parkinson’s disease and Movement Disorders. Miami, November 10–14, 2002.
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Koller, W.C., Cersosimo, M.G. Neuroprotection in parkinson’s disease: An elusive goal. Curr Neurol Neurosci Rep 4, 277–283 (2004). https://doi.org/10.1007/s11910-004-0052-2
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DOI: https://doi.org/10.1007/s11910-004-0052-2