Targets for neuroprotection in Parkinson's disease

Biochimica et Biophysica Acta - Molecular Basis of Disease

Volumn 1792, Issue 7, 2009, Pages 676-687

  Yacoubian, Talene A ^a   Standaert, David G ^a  

^a UNIVERSITY OF ALABAMA AT BIRMINGHAM   (United States)

Author keywords

Alpha synuclein; Apoptosis; Clinical trial; Excitotoxicity; Neuroinflammation; Oxidative stress; Trophic factor

Indexed keywords

ACETYLSALICYLIC ACID; ALPHA TOCOPHEROL; AMANTADINE; CAFFEINE; CEP 1347; CREATINE; DIHYDROPYRIDINE DERIVATIVE; DOPAMINE RECEPTOR STIMULATING AGENT; GLIAL CELL LINE DERIVED NEUROTROPHIC FACTOR; GPI 1485; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; ISRADIPINE; ISTRADEFYLLINE; LEVODOPA; MINOCYCLINE; N METHYL DEXTRO ASPARTIC ACID RECEPTOR BLOCKING AGENT; NEURTURIN; NONSTEROID ANTIINFLAMMATORY AGENT; PARVOVIRUS VECTOR; PLACEBO; PRAMIPEXOLE; RASAGILINE; RILUZOLE; ROPINIROLE; SELEGILINE; SELENIUM; SIMVASTATIN; UBIDECARENONE; UNINDEXED DRUG; URIC ACID;

ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; APOPTOSIS; CLINICAL TRIAL; DISORDERS OF MITOCHONDRIAL FUNCTIONS; DOSE RESPONSE; DRUG EFFICACY; DRUG MEGADOSE; DRUG POTENCY; DRUG SAFETY; DRUG TARGETING; DRUG TOLERABILITY; EXCITOTOXICITY; HUMAN; HYPERTENSION; INFLAMMATION; NEUROPROTECTION; NONHUMAN; OXIDATIVE STRESS; PARKINSON DISEASE; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN FOLDING; QUALITY OF LIFE; REVIEW; RISK REDUCTION; VIRAL GENE THERAPY;

ANIMALS; ANTIOXIDANTS; ANTIPARKINSON AGENTS; CARBAZOLES; CLINICAL TRIALS AS TOPIC; DOPAMINE AGONISTS; HUMANS; LEVODOPA; NERVE GROWTH FACTORS; NEUROPROTECTIVE AGENTS; OXEPINS; PARKINSON DISEASE;

EID: 68649126582     PISSN: 09254439     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bbadis.2008.09.009     Document Type: Review

References (244)

1. Braak H., Del Tredici K., Rub U., de Vos R.A., Jansen Steur E.N., and Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24 (2003) 197-211
2. Alam Z.I., Jenner A., Daniel S.E., Lees A.J., Cairns N., Marsden C.D., Jenner P., and Halliwell B. Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra. J. Neurochem. 69 (1997) 1196-1203
3. Dexter D.T., Holley A.E., Flitter W.D., Slater T.F., Wells F.R., Daniel S.E., Lees A.J., Jenner P., and Marsden C.D. Increased levels of lipid hydroperoxides in the parkinsonian substantia nigra: an HPLC and ESR study. Mov. Disord. 9 (1994) 92-97
4. Dexter D.T., Sian J., Rose S., Hindmarsh J.G., Mann V.M., Cooper J.M., Wells F.R., Daniel S.E., Lees A.J., Schapira A.H., et al. Indices of oxidative stress and mitochondrial function in individuals with incidental Lewy body disease. Ann. Neurol. 35 (1994) 38-44
5. Hastings T.G., Lewis D.A., and Zigmond M.J. Reactive dopamine metabolites and neurotoxicity: implications for Parkinson's disease. Adv. Exp. Med. Biol. 387 (1996) 97-106
6. Sulzer D., and Zecca L. Intraneuronal dopamine-quinone synthesis: a review. Neurotox. Res. 1 (2000) 181-195
7. Schapira A.H., Cooper J.M., Dexter D., Jenner P., Clark J.B., and Marsden C.D. Mitochondrial complex I deficiency in Parkinson's disease. Lancet 1 (1989) 1269
8. Betarbet R., Sherer T.B., MacKenzie G., Garcia-Osuna M., Panov A.V., and Greenamyre J.T. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat. Neurosci. 3 (2000) 1301-1306
9. Langston J.W., Ballard P., Tetrud J.W., and Irwin I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219 (1983) 979-980
10. Langston J.W., Forno L.S., Rebert C.S., and Irwin I. Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyrine (MPTP) in the squirrel monkey. Brain Res. 292 (1984) 390-394
11. Wooten G.F., Currie L.J., Bennett J.P., Harrison M.B., Trugman J.M., and Parker Jr. W.D. Maternal inheritance in Parkinson's disease. Ann. Neurol. 41 (1997) 265-268
12. Schapira A.H. Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurol. 7 (2008) 97-109
13. Cantuti-Castelvetri I., Lin M.T., Zheng K., Keller-McGandy C.E., Betensky R.A., Johns D.R., Beal M.F., Standaert D.G., and Simon D.K. Somatic mitochondrial DNA mutations in single neurons and glia. Neurobiol. Aging 26 (2005) 1343-1355
14. Dexter D.T., Wells F.R., Lees A.J., Agid F., Agid Y., Jenner P., and Marsden C.D. Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson's disease. J. Neurochem. 52 (1989) 1830-1836
15. Riederer P., Sofic E., Rausch W.D., Schmidt B., Reynolds G.P., Jellinger K., and Youdim M.B. Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J. Neurochem. 52 (1989) 515-520
16. Perry T.L., and Yong V.W. Idiopathic Parkinson's disease, progressive supranuclear palsy and glutathione metabolism in the substantia nigra of patients. Neurosci. Lett. 67 (1986) 269-274
17. Sian J., Dexter D.T., Lees A.J., Daniel S., Agid Y., Javoy-Agid F., Jenner P., and Marsden C.D. Alterations in glutathione levels in Parkinson's disease and other neurodegenerative disorders affecting basal ganglia. Ann. Neurol. 36 (1994) 348-355
18. Sofic E., Lange K.W., Jellinger K., and Riederer P. Reduced and oxidized glutathione in the substantia nigra of patients with Parkinson's disease. Neurosci. Lett. 142 (1992) 128-130
19. Clark I.E., Dodson M.W., Jiang C., Cao J.H., Huh J.R., Seol J.H., Yoo S.J., Hay B.A., and Guo M. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441 (2006) 1162-1166
20. Kim R.H., Smith P.D., Aleyasin H., Hayley S., Mount M.P., Pownall S., Wakeham A., You-Ten A.J., Kalia S.K., Horne P., Westaway D., Lozano A.M., Anisman H., Park D.S., and Mak T.W. Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc. Natl. Acad. Sci. U. S. A. 102 (2005) 5215-5220
21. Park J., Lee S.B., Lee S., Kim Y., Song S., Kim S., Bae E., Kim J., Shong M., Kim J.M., and Chung J. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441 (2006) 1157-1161
22. Yokota T., Sugawara K., Ito K., Takahashi R., Ariga H., and Mizusawa H. Down regulation of DJ-1 enhances cell death by oxidative stress, ER stress, and proteasome inhibition. Biochem. Biophys. Res. Commun. 312 (2003) 1342-1348
23. Athanassiadou A., Voutsinas G., Psiouri L., Leroy E., Polymeropoulos M.H., Ilias A., Maniatis G.M., and Papapetropoulos T. Genetic analysis of families with Parkinson disease that carry the Ala53Thr mutation in the gene encoding alpha-synuclein. Am. J. Hum. Genet. 65 (1999) 555-558
24. Kruger R., Kuhn W., Muller T., Woitalla D., Graeber M., Kosel S., Przuntek H., Epplen J.T., Schols L., and Riess O. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat. Genet. 18 (1998) 106-108
25. Polymeropoulos M.H., Lavedan C., Leroy E., Ide S.E., Dehejia A., Dutra A., Pike B., Root H., Rubenstein J., Boyer R., Stenroos E.S., Chandrasekharappa S., Athanassiadou A., Papapetropoulos T., Johnson W.G., Lazzarini A.M., Duvoisin R.C., Di Iorio G., Golbe L.I., and Nussbaum R.L. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276 (1997) 2045-2047
26. Zarranz J.J., Alegre J., Gomez-Esteban J.C., Lezcano E., Ros R., Ampuero I., Vidal L., Hoenicka J., Rodriguez O., Atares B., Llorens V., Gomez Tortosa E., del Ser T., Munoz D.G., and de Yebenes J.G. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann. Neurol. 55 (2004) 164-173
27. Irizarry M.C., Growdon W., Gomez-Isla T., Newell K., George J.M., Clayton D.F., and Hyman B.T. Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson's disease and cortical Lewy body disease contain alpha-synuclein immunoreactivity. J. Neuropathol. Exp. Neurol. 57 (1998) 334-337
28. Spillantini M.G., Schmidt M.L., Lee V.M., Trojanowski J.Q., Jakes R., and Goedert M. Alpha-synuclein in Lewy bodies. Nature 388 (1997) 839-840
29. Singleton A.B., Farrer M., Johnson J., Singleton A., Hague S., Kachergus J., Hulihan M., Peuralinna T., Dutra A., Nussbaum R., Lincoln S., Crawley A., Hanson M., Maraganore D., Adler C., Cookson M.R., Muenter M., Baptista M., Miller D., Blancato J., Hardy J., and Gwinn-Hardy K. alpha-Synuclein locus triplication causes Parkinson's disease. Science 302 (2003) 841
30. El-Agnaf O.M., Jakes R., Curran M.D., and Wallace A. Effects of the mutations Ala30 to Pro and Ala53 to Thr on the physical and morphological properties of alpha-synuclein protein implicated in Parkinson's disease. FEBS Lett. 440 (1998) 67-70
31. Narhi L., Wood S.J., Steavenson S., Jiang Y., Wu G.M., Anafi D., Kaufman S.A., Martin F., Sitney K., Denis P., Louis J.C., Wypych J., Biere A.L., and Citron M. Both familial Parkinson's disease mutations accelerate alpha-synuclein aggregation. J. Biol. Chem. 274 (1999) 9843-9846
32. Conway K.A., Harper J.D., and Lansbury P.T. Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat. Med. 4 (1998) 1318-1320
33. Conway K.A., Lee S.J., Rochet J.C., Ding T.T., Williamson R.E., and Lansbury Jr. P.T. Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson's disease: implications for pathogenesis and therapy. Proc. Natl. Acad. Sci. U. S. A. 97 (2000) 571-576
34. Masliah E., Rockenstein E., Veinbergs I., Mallory M., Hashimoto M., Takeda A., Sagara Y., Sisk A., and Mucke L. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 287 (2000) 1265-1269
35. Souza J.M., Giasson B.I., Chen Q., Lee V.M., and Ischiropoulos H. Dityrosine cross-linking promotes formation of stable alpha-synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies. J. Biol. Chem. 275 (2000) 18344-18349
36. Abeliovich A., Schmitz Y., Farinas I., Choi-Lundberg D., Ho W.H., Castillo P.E., Shinsky N., Verdugo J.M., Armanini M., Ryan A., Hynes M., Phillips H., Sulzer D., and Rosenthal A. Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25 (2000) 239-252
37. Murphy D.D., Rueter S.M., Trojanowski J.Q., and Lee V.M. Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J. Neurosci. 20 (2000) 3214-3220
38. Flower T.R., Chesnokova L.S., Froelich C.A., Dixon C., and Witt S.N. Heat shock prevents alpha-synuclein-induced apoptosis in a yeast model of Parkinson's disease. J. Mol. Biol. 351 (2005) 1081-1100
39. Saha A.R., Ninkina N.N., Hanger D.P., Anderton B.H., Davies A.M., and Buchman V.L. Induction of neuronal death by alpha-synuclein. Eur. J. Neurosci. 12 (2000) 3073-3077
40. Smith W.W., Jiang H., Pei Z., Tanaka Y., Morita H., Sawa A., Dawson V.L., Dawson T.M., and Ross C.A. Endoplasmic reticulum stress and mitochondrial cell death pathways mediate A53T mutant alpha-synuclein-induced toxicity. Hum. Mol. Genet. 14 (2005) 3801-3811
41. Volles M.J., and Lansbury Jr. P.T. Zeroing in on the pathogenic form of alpha-synuclein and its mechanism of neurotoxicity in Parkinson's disease. Biochemistry 42 (2003) 7871-7878
42. Cookson M.R., and van der Brug M. Cell systems and the toxic mechanism(s) of alpha-synuclein. Exp. Neurol. 209 (2008) 5-11
43. Kontopoulos E., Parvin J.D., and Feany M.B. Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum. Mol. Genet. 15 (2006) 3012-3023
44. Yacoubian T.A., Cantuti-Castelvetri I., Bouzou B., Asteris G., McLean P.J., Hyman B.T., and Standaert D.G. Transcriptional dysregulation in a transgenic model of Parkinson disease. Neurobiol. Dis. 29 (2008) 515-528
45. Benner E.J., Banerjee R., Reynolds A.D., Sherman S., Pisarev V.M., Tsiperson V., Nemachek C., Ciborowski P., Przedborski S., Mosley R.L., and Gendelman H.E. Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS ONE 3 (2008) e1376
46. S. Theodore, S. Cao, P.J. McLean, D.G. Standaert, Targeted overexpression of human alpha-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease, J. Neuropathol. Exp. Neurol. 67 (in press).
47. Leroy E., Boyer R., Auburger G., Leube B., Ulm G., Mezey E., Harta G., Brownstein M.J., Jonnalagada S., Chernova T., Dehejia A., Lavedan C., Gasser T., Steinbach P.J., Wilkinson K.D., and Polymeropoulos M.H. The ubiquitin pathway in Parkinson's disease. Nature 395 (1998) 451-452
48. Kitada T., Asakawa S., Hattori N., Matsumine H., Yamamura Y., Minoshima S., Yokochi M., Mizuno Y., and Shimizu N. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392 (1998) 605-608
49. Imai Y., Soda M., and Takahashi R. Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. J. Biol. Chem. 275 (2000) 35661-35664
50. Shimura H., Hattori N., Kubo S., Mizuno Y., Asakawa S., Minoshima S., Shimizu N., Iwai K., Chiba T., Tanaka K., and Suzuki T. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat. Genet. 25 (2000) 302-305
51. Zhang Y., Gao J., Chung K.K., Huang H., Dawson V.L., and Dawson T.M. Parkin functions as an E2-dependent ubiquitin-protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc. Natl. Acad. Sci. U. S. A. 97 (2000) 13354-13359
52. Chung K.K., Zhang Y., Lim K.L., Tanaka Y., Huang H., Gao J., Ross C.A., Dawson V.L., and Dawson T.M. Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat. Med. 7 (2001) 1144-1150
53. Shimura H., Schlossmacher M.G., Hattori N., Frosch M.P., Trockenbacher A., Schneider R., Mizuno Y., Kosik K.S., and Selkoe D.J. Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson's disease. Science 293 (2001) 263-269
54. Mori H., Kondo T., Yokochi M., Matsumine H., Nakagawa-Hattori Y., Miyake T., Suda K., and Mizuno Y. Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q. Neurology 51 (1998) 890-892
55. Takahashi H., Ohama E., Suzuki S., Horikawa Y., Ishikawa A., Morita T., Tsuji S., and Ikuta F. Familial juvenile parkinsonism: clinical and pathologic study in a family. Neurology 44 (1994) 437-441
56. Hayashi S., Wakabayashi K., Ishikawa A., Nagai H., Saito M., Maruyama M., Takahashi T., Ozawa T., Tsuji S., and Takahashi H. An autopsy case of autosomal-recessive juvenile parkinsonism with a homozygous exon 4 deletion in the parkin gene. Mov. Disord. 15 (2000) 884-888
57. Farrer M., Chan P., Chen R., Tan L., Lincoln S., Hernandez D., Forno L., Gwinn-Hardy K., Petrucelli L., Hussey J., Singleton A., Tanner C., Hardy J., and Langston J.W. Lewy bodies and parkinsonism in families with parkin mutations. Ann. Neurol. 50 (2001) 293-300
58. Klucken J., Shin Y., Masliah E., Hyman B.T., and McLean P.J. Hsp70 reduces alpha-synuclein aggregation and toxicity. J. Biol. Chem. 279 (2004) 25497-25502
59. Moore D.J., West A.B., Dikeman D.A., Dawson V.L., and Dawson T.M. Parkin mediates the degradation-independent ubiquitination of Hsp70. J. Neurochem. 105 (2008) 1806-1819
60. McNaught K.S., Mytilineou C., Jnobaptiste R., Yabut J., Shashidharan P., Jennert P., and Olanow C.W. Impairment of the ubiquitin-proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures. J. Neurochem. 81 (2002) 301-306
61. Chung K.K., Dawson V.L., and Dawson T.M. The role of the ubiquitin-proteasomal pathway in Parkinson's disease and other neurodegenerative disorders. Trends Neurosci. 24 (2001) S7-S14
62. Nishikawa K., Li H., Kawamura R., Osaka H., Wang Y.L., Hara Y., Hirokawa T., Manago Y., Amano T., Noda M., Aoki S., and Wada K. Alterations of structure and hydrolase activity of parkinsonism-associated human ubiquitin carboxyl-terminal hydrolase L1 variants. Biochem. Biophys. Res. Commun. 304 (2003) 176-183
63. Tansey M.G., McCoy M.K., and Frank-Cannon T.C. Neuroinflammatory mechanisms in Parkinson's disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp. Neurol. 208 (2007) 1-25
64. Esposito E., Di Matteo V., Benigno A., Pierucci M., Crescimanno G., and Di Giovanni G. Non-steroidal anti-inflammatory drugs in Parkinson's disease. Exp. Neurol. 205 (2007) 295-312
65. McGeer E.G., and McGeer P.L. The role of anti-inflammatory agents in Parkinson's disease. CNS Drugs 21 (2007) 789-797
66. McGeer P.L., Itagaki S., Boyes B.E., and McGeer E.G. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 38 (1988) 1285-1291
67. McGeer P.L., Schwab C., Parent A., and Doudet D. Presence of reactive microglia in monkey substantia nigra years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. Ann. Neurol. 54 (2003) 599-604
68. Orr C.F., Rowe D.B., Mizuno Y., Mori H., and Halliday G.M. A possible role for humoral immunity in the pathogenesis of Parkinson's disease. Brain 128 (2005) 2665-2674
69. Cicchetti F., Brownell A.L., Williams K., Chen Y.I., Livni E., and Isacson O. Neuroinflammation of the nigrostriatal pathway during progressive 6-OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging. Eur. J. Neurosci. 15 (2002) 991-998
70. Sherer T.B., Betarbet R., Kim J.H., and Greenamyre J.T. Selective microglial activation in the rat rotenone model of Parkinson's disease. Neurosci. Lett. 341 (2003) 87-90
71. Mogi M., Harada M., Kondo T., Riederer P., Inagaki H., Minami M., and Nagatsu T. Interleukin-1 beta, interleukin-6, epidermal growth factor and transforming growth factor-alpha are elevated in the brain from parkinsonian patients. Neurosci. Lett. 180 (1994) 147-150
72. Mogi M., Harada M., Riederer P., Narabayashi H., Fujita K., and Nagatsu T. Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci. Lett. 165 (1994) 208-210
73. Yamada T., McGeer P.L., and McGeer E.G. Lewy bodies in Parkinson's disease are recognized by antibodies to complement proteins. Acta Neuropathol. 84 (1992) 100-104
74. Goldknopf I.L., Sheta E.A., Bryson J., Folsom B., Wilson C., Duty J., Yen A.A., and Appel S.H. Complement C3c and related protein biomarkers in amyotrophic lateral sclerosis and Parkinson's disease. Biochem. Biophys. Res. Commun. 342 (2006) 1034-1039
75. Zhang W., Wang T., Pei Z., Miller D.S., Wu X., Block M.L., Wilson B., Zhou Y., Hong J.S., and Zhang J. Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson's disease. FASEB J. 19 (2005) 533-542
76. Reynolds A.D., Glanzer J.G., Kadiu I., Ricardo-Dukelow M., Chaudhuri A., Ciborowski P., Cerny R., Gelman B., Thomas M.P., Mosley R.L., and Gendelman H.E. Nitrated alpha-synuclein-activated microglial profiling for Parkinson's disease. J. Neurochem. 104 (2008) 1504-1525
77. Reynolds A.D., Kadiu I., Garg S.K., Glanzer J.G., Nordgren T., Ciborowski P., Banerjee R., and Gendelman H.E. Nitrated alpha-synuclein and microglial neuroregulatory activities. J. Neuroimmune. Pharmacol. 3 (2008) 59-74
78. Ghosh A., Roy A., Liu X., Kordower J.H., Mufson E.J., Hartley D.M., Ghosh S., Mosley R.L., Gendelman H.E., and Pahan K. Selective inhibition of NF-kappaB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson's disease. Proc. Natl. Acad. Sci. U. S. A. 104 (2007) 18754-18759
79. Bower J.H., Maraganore D.M., Peterson B.J., Ahlskog J.E., and Rocca W.A. Immunologic diseases, anti-inflammatory drugs, and Parkinson disease: a case-control study. Neurology 67 (2006) 494-496
80. Chen H., Jacobs E., Schwarzschild M.A., McCullough M.L., Calle E.E., Thun M.J., and Ascherio A. Nonsteroidal antiinflammatory drug use and the risk for Parkinson's disease. Ann. Neurol. 58 (2005) 963-967
81. Chen H., Zhang S.M., Hernan M.A., Schwarzschild M.A., Willett W.C., Colditz G.A., Speizer F.E., and Ascherio A. Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease. Arch. Neurol. 60 (2003) 1059-1064
82. Hernan M.A., Logroscino G., and Garcia Rodriguez L.A. Nonsteroidal anti-inflammatory drugs and the incidence of Parkinson disease. Neurology 66 (2006) 1097-1099
83. Ton T.G., Heckbert S.R., Longstreth Jr. W.T., Rossing M.A., Kukull W.A., Franklin G.M., Swanson P.D., Smith-Weller T., and Checkoway H. Nonsteroidal anti-inflammatory drugs and risk of Parkinson's disease. Mov. Disord. 21 (2006) 964-969
84. Wolozin B., Wang S.W., Li N.C., Lee A., Lee T.A., and Kazis L.E. Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease. BMC Med. 5 (2007) 20
85. Wahner A.D., Bronstein J.M., Bordelon Y.M., and Ritz B. Statin use and the risk of Parkinson disease. Neurology 70 (2008) 1418-1422
86. A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. Neurology 66 (2006) 664-671
87. Mody I., and MacDonald J.F. NMDA receptor-dependent excitotoxicity: the role of intracellular Ca2+ release. Trends Pharmacol. Sci. 16 (1995) 356-359
88. Dawson V.L., and Dawson T.M. Nitric oxide neurotoxicity. J. Chem. Neuroanat. 10 (1996) 179-190
89. Good P.F., Hsu A., Werner P., Perl D.P., and Olanow C.W. Protein nitration in Parkinson's disease. J. Neuropathol. Exp. Neurol. 57 (1998) 338-342
90. Turski L., Bressler K., Rettig K.J., Loschmann P.A., and Wachtel H. Protection of substantia nigra from MPP+ neurotoxicity by N-methyl-d-aspartate antagonists. Nature 349 (1991) 414-418
91. Brouillet E., and Beal M.F. NMDA antagonists partially protect against MPTP induced neurotoxicity in mice. Neuroreport 4 (1993) 387-390
92. Jankovic J., and Hunter C. A double-blind, placebo-controlled and longitudinal study of riluzole in early Parkinson's disease. Parkinsonism Relat. Disord. 8 (2002) 271-276
93. Kornhuber J., Weller M., Schoppmeyer K., and Riederer P. Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties. J. Neural. Transm. Suppl. 43 (1994) 91-104
94. Counihan T.J., Landwehrmeyer G.B., Standaert D.G., Kosinski C.M., Scherzer C.R., Daggett L.P., Velicelebi G., Young A.B., and Penney Jr. J.B. Expression of N-methyl-d-aspartate receptor subunit mRNA in the human brain: mesencephalic dopaminergic neurons. J. Comp. Neurol. 390 (1998) 91-101
95. Hallett P.J., and Standaert D.G. Rationale for and use of NMDA receptor antagonists in Parkinson's disease. Pharmacol. Ther. 102 (2004) 155-174
96. Surmeier D.J. Calcium, ageing, and neuronal vulnerability in Parkinson's disease. Lancet Neurol. 6 (2007) 933-938
97. Chan C.S., Guzman J.N., Ilijic E., Mercer J.N., Rick C., Tkatch T., Meredith G.E., and Surmeier D.J. 'Rejuvenation' protects neurons in mouse models of Parkinson's disease. Nature 447 (2007) 1081-1086
98. Rodnitzky R.L. Can calcium antagonists provide a neuroprotective effect in Parkinson's disease?. Drugs 57 (1999) 845-849
99. Anglade P., Vyas S., Javoy-Agid F., Herrero M.T., Michel P.P., Marquez J., Mouatt-Prigent A., Ruberg M., Hirsch E.C., and Agid Y. Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease. Histol. Histopathol. 12 (1997) 25-31
100. Tompkins M.M., Basgall E.J., Zamrini E., and Hill W.D. Apoptotic-like changes in Lewy-body-associated disorders and normal aging in substantia nigral neurons. Am. J. Pathol. 150 (1997) 119-131
101. Hirsch E.C., Hunot S., Faucheux B., Agid Y., Mizuno Y., Mochizuki H., Tatton W.G., Tatton N., and Olanow W.C. Dopaminergic neurons degenerate by apoptosis in Parkinson's disease. Mov. Disord. 14 (1999) 383-385
102. Tatton N.A. Increased caspase 3 and Bax immunoreactivity accompany nuclear GAPDH translocation and neuronal apoptosis in Parkinson's disease. Exp. Neurol. 166 (2000) 29-43
103. Tatton W.G., Chalmers-Redman R., Brown D., and Tatton N. Apoptosis in Parkinson's disease: signals for neuronal degradation. Ann. Neurol. 53 Suppl. 3 (2003) S61-S70 discussion S70-62
104. Blum D., Torch S., Lambeng N., Nissou M., Benabid A.L., Sadoul R., and Verna J.M. Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson's disease. Prog. Neurobiol. 65 (2001) 135-172
105. Jellinger K.A. Cell death mechanisms in neurodegeneration. J. Cell Mol. Med. 5 (2001) 1-17
106. Mattson M.P. Neuronal life-and-death signaling, apoptosis, and neurodegenerative disorders. Antioxid. Redox Signal. 8 (2006) 1997-2006
107. Olanow C.W., Schapira A.H., LeWitt P.A., Kieburtz K., Sauer D., Olivieri G., Pohlmann H., and Hubble J. TCH346 as a neuroprotective drug in Parkinson's disease: a double-blind, randomised, controlled trial. Lancet Neurol. 5 (2006) 1013-1020
108. Mixed lineage kinase inhibitor CEP-1347 fails to delay disability in early Parkinson disease. Neurology 69 (2007) 1480-1490
109. Howells D.W., Porritt M.J., Wong J.Y., Batchelor P.E., Kalnins R., Hughes A.J., and Donnan G.A. Reduced BDNF mRNA expression in the Parkinson's disease substantia nigra. Exp. Neurol. 166 (2000) 127-135
110. Chauhan N.B., Siegel G.J., and Lee J.M. Depletion of glial cell line-derived neurotrophic factor in substantia nigra neurons of Parkinson's disease brain. J. Chem. Neuroanat. 21 (2001) 277-288
111. Mogi M., Togari A., Kondo T., Mizuno Y., Komure O., Kuno S., Ichinose H., and Nagatsu T. Brain-derived growth factor and nerve growth factor concentrations are decreased in the substantia nigra in Parkinson's disease. Neurosci. Lett. 270 (1999) 45-48
112. Kordower J.H., Emborg M.E., Bloch J., Ma S.Y., Chu Y., Leventhal L., McBride J., Chen E.Y., Palfi S., Roitberg B.Z., Brown W.D., Holden J.E., Pyzalski R., Taylor M.D., Carvey P., Ling Z., Trono D., Hantraye P., Deglon N., and Aebischer P. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science 290 (2000) 767-773
113. Eslamboli A., Georgievska B., Ridley R.M., Baker H.F., Muzyczka N., Burger C., Mandel R.J., Annett L., and Kirik D. Continuous low-level glial cell line-derived neurotrophic factor delivery using recombinant adeno-associated viral vectors provides neuroprotection and induces behavioral recovery in a primate model of Parkinson's disease. J. Neurosci. 25 (2005) 769-777
114. Gasmi M., Brandon E.P., Herzog C.D., Wilson A., Bishop K.M., Hofer E.K., Cunningham J.J., Printz M.A., Kordower J.H., and Bartus R.T. AAV2-mediated delivery of human neurturin to the rat nigrostriatal system: long-term efficacy and tolerability of CERE-120 for Parkinson's disease. Neurobiol. Dis. 27 (2007) 67-76
115. Gasmi M., Herzog C.D., Brandon E.P., Cunningham J.J., Ramirez G.A., Ketchum E.T., and Bartus R.T. Striatal delivery of neurturin by CERE-120, an AAV2 vector for the treatment of dopaminergic neuron degeneration in Parkinson's disease. Mol. Ther. 15 (2007) 62-68
116. Kordower J.H., Herzog C.D., Dass B., Bakay R.A., Stansell III J., Gasmi M., and Bartus R.T. Delivery of neurturin by AAV2 (CERE-120)-mediated gene transfer provides structural and functional neuroprotection and neurorestoration in MPTP-treated monkeys. Ann. Neurol. 60 (2006) 706-715
117. Gill S.S., Patel N.K., Hotton G.R., O'Sullivan K., McCarter R., Bunnage M., Brooks D.J., Svendsen C.N., and Heywood P. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat. Med. 9 (2003) 589-595
118. Lang A.E., Gill S., Patel N.K., Lozano A., Nutt J.G., Penn R., Brooks D.J., Hotton G., Moro E., Heywood P., Brodsky M.A., Burchiel K., Kelly P., Dalvi A., Scott B., Stacy M., Turner D., Wooten V.G., Elias W.J., Laws E.R., Dhawan V., Stoessl A.J., Matcham J., Coffey R.J., and Traub M. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann. Neurol. 59 (2006) 459-466
119. Nutt J.G., Burchiel K.J., Comella C.L., Jankovic J., Lang A.E., Laws Jr. E.R., Lozano A.M., Penn R.D., Simpson Jr. R.K., Stacy M., and Wooten G.F. Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 60 (2003) 69-73
120. Slevin J.T., Gerhardt G.A., Smith C.D., Gash D.M., Kryscio R., and Young B. Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line-derived neurotrophic factor. J. Neurosurg. 102 (2005) 216-222
121. Suchowersky O., Gronseth G., Perlmutter J., Reich S., Zesiewicz T., and Weiner W.J. Practice Parameter: neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 66 (2006) 976-982
122. Hung A.Y., and Schwarzschild M.A. Clinical trials for neuroprotection in Parkinson's disease: overcoming angst and futility?. Curr. Opin. Neurol. 20 (2007) 477-483
123. Fahn S. Is levodopa toxic?. Neurology 47 (1996) S184-S195
124. Barzilai A., Melamed E., and Shirvan A. Is there a rationale for neuroprotection against dopamine toxicity in Parkinson's disease?. Cell. Mol. Neurobiol. 21 (2001) 215-235
125. Murer M.G., Dziewczapolski G., Menalled L.B., Garcia M.C., Agid Y., Gershanik O., and Raisman-Vozari R. Chronic levodopa is not toxic for remaining dopamine neurons, but instead promotes their recovery, in rats with moderate nigrostriatal lesions. Ann. Neurol. 43 (1998) 561-575
126. Datla K.P., Blunt S.B., and Dexter D.T. Chronic L-DOPA administration is not toxic to the remaining dopaminergic nigrostriatal neurons, but instead may promote their functional recovery, in rats with partial 6-OHDA or FeCl(3) nigrostriatal lesions. Mov. Disord. 16 (2001) 424-434
127. Fahn S., Oakes D., Shoulson I., Kieburtz K., Rudolph A., Lang A., Olanow C.W., Tanner C., and Marek K. Levodopa and the progression of Parkinson's disease. N. Engl. J. Med. 351 (2004) 2498-2508
128. Ravina B., Eidelberg D., Ahlskog J.E., Albin R.L., Brooks D.J., Carbon M., Dhawan V., Feigin A., Fahn S., Guttman M., Gwinn-Hardy K., McFarland H., Innis R., Katz R.G., Kieburtz K., Kish S.J., Lange N., Langston J.W., Marek K., Morin L., Moy C., Murphy D., Oertel W.H., Oliver G., Palesch Y., Powers W., Seibyl J., Sethi K.D., Shults C.W., Sheehy P., Stoessl A.J., and Holloway R. The role of radiotracer imaging in Parkinson disease. Neurology 64 (2005) 208-215
129. Allain H., Bentue-Ferrer D., and Akwa Y. Disease-modifying drugs and Parkinson's disease. Prog. Neurobiol. 84 (2008) 25-39
130. Ogawa N., Tanaka K., Asanuma M., Kawai M., Masumizu T., Kohno M., and Mori A. Bromocriptine protects mice against 6-hydroxydopamine and scavenges hydroxyl free radicals in vitro. Brain Res. 657 (1994) 207-213
131. Carvey P.M., Pieri S., and Ling Z.D. Attenuation of levodopa-induced toxicity in mesencephalic cultures by pramipexole. J. Neural. Transm. 104 (1997) 209-228
132. Kitamura Y., Kosaka T., Kakimura J.I., Matsuoka Y., Kohno Y., Nomura Y., and Taniguchi T. 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. 54 (1998) 1046-1054
133. Iida M., Miyazaki I., Tanaka K., Kabuto H., Iwata-Ichikawa E., and Ogawa N. Dopamine D2 receptor-mediated antioxidant and neuroprotective effects of ropinirole, a dopamine agonist. Brain Res. 838 (1999) 51-59
134. Vu T.Q., Ling Z.D., Ma S.Y., Robie H.C., Tong C.W., Chen E.Y., Lipton J.W., and Carvey P.M. Pramipexole attenuates the dopaminergic cell loss induced by intraventricular 6-hydroxydopamine. J. Neural. Transm. 107 (2000) 159-176
135. Zou L., Xu J., Jankovic J., He Y., Appel S.H., and Le W. 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. 281 (2000) 167-170
136. Iravani M.M., Haddon C.O., Cooper J.M., Jenner P., and Schapira A.H. Pramipexole protects against MPTP toxicity in non-human primates. J. Neurochem. 96 (2006) 1315-1321
137. Olanow C.W., Jenner P., and Brooks D. Dopamine agonists and neuroprotection in Parkinson's disease. Ann. Neurol. 44 (1998) S167-S174
138. Cassarino D.S., Fall C.P., Smith T.S., and Bennett Jr. J.P. 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. 71 (1998) 295-301
139. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 287 (2002) 1653-1661
140. Whone A.L., Watts R.L., Stoessl A.J., Davis M., Reske S., Nahmias C., Lang A.E., Rascol O., Ribeiro M.J., Remy P., Poewe W.H., Hauser R.A., and Brooks D.J. Slower progression of Parkinson's disease with ropinirole versus levodopa: the REAL-PET study. Ann. Neurol. 54 (2003) 93-101
141. Effect of deprenyl on the progression of disability in early Parkinson's disease. The Parkinson Study Group. N. Engl. J. Med. 321 (1989) 1364-1371
142. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. The Parkinson Study Group. N. Engl. J. Med. 328 (1993) 176-183
143. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch. Neurol. 61 (2004) 561-566
144. Beal M.F., Matthews R.T., Tieleman A., and Shults C.W. Coenzyme Q10 attenuates the 1-methyl-4-phenyl-1,2,3,tetrahydropyridine (MPTP) induced loss of striatal dopamine and dopaminergic axons in aged mice. Brain Res. 783 (1998) 109-114
145. Shults C.W., Oakes D., Kieburtz K., Beal M.F., Haas R., Plumb S., Juncos J.L., Nutt J., Shoulson I., Carter J., Kompoliti K., Perlmutter J.S., Reich S., Stern M., Watts R.L., Kurlan R., Molho E., Harrison M., and Lew M. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch. Neurol. 59 (2002) 1541-1550
146. A randomized clinical trial of coenzyme Q10 and GPI-1485 in early Parkinson disease. Neurology 68 (2007) 20-28
147. Elm J.J., Goetz C.G., Ravina B., Shannon K., Wooten G.F., Tanner C.M., Palesch Y.Y., Huang P., Guimaraes P., Kamp C., Tilley B.C., and Kieburtz K. A responsive outcome for Parkinson's disease neuroprotection futility studies. Ann. Neurol. 57 (2005) 197-203
148. Schwid S.R., and Cutter G.R. Futility studies: spending a little to save a lot. Neurology 66 (2006) 626-627
149. Tilley B.C., Palesch Y.Y., Kieburtz K., Ravina B., Huang P., Elm J.J., Shannon K., Wooten G.F., Tanner C.M., and Goetz G.C. Optimizing the ongoing search for new treatments for Parkinson disease: using futility designs. Neurology 66 (2006) 628-633
150. Matthews R.T., Ferrante R.J., Klivenyi P., Yang L., Klein A.M., Mueller G., Kaddurah-Daouk R., and Beal M.F. Creatine and cyclocreatine attenuate MPTP neurotoxicity. Exp. Neurol. 157 (1999) 142-149
151. Bender A., Koch W., Elstner M., Schombacher Y., Bender J., Moeschl M., Gekeler F., Muller-Myhsok B., Gasser T., Tatsch K., and Klopstock T. Creatine supplementation in Parkinson disease: a placebo-controlled randomized pilot trial. Neurology 67 (2006) 1262-1264
152. Andringa G., Eshuis S., Perentes E., Maguire R.P., Roth D., Ibrahim M., Leenders K.L., and Cools A.R. TCH346 prevents motor symptoms and loss of striatal FDOPA uptake in bilaterally MPTP-treated primates. Neurobiol. Dis. 14 (2003) 205-217
153. Andringa G., van Oosten R.V., Unger W., Hafmans T.G., Veening J., Stoof J.C., and Cools A.R. Systemic administration of the propargylamine CGP 3466B prevents behavioural and morphological deficits in rats with 6-hydroxydopamine-induced lesions in the substantia nigra. Eur. J. Neurosci. 12 (2000) 3033-3043
154. Saporito M.S., Brown E.M., Miller M.S., and Carswell S. CEP-1347/KT-7515, an inhibitor of c-jun N-terminal kinase activation, attenuates the 1-methyl-4-phenyl tetrahydropyridine-mediated loss of nigrostriatal dopaminergic neurons In vivo. J. Pharmacol. Exp. Ther. 288 (1999) 421-427
155. Mathiasen J.R., McKenna B.A., Saporito M.S., Ghadge G.D., Roos R.P., Holskin B.P., Wu Z.L., Trusko S.P., Connors T.C., Maroney A.C., Thomas B.A., Thomas J.C., and Bozyczko-Coyne D. Inhibition of mixed lineage kinase 3 attenuates MPP+-induced neurotoxicity in SH-SY5Y cells. Brain Res. 1003 (2004) 86-97
156. Lotharius J., Falsig J., van Beek J., Payne S., Dringen R., Brundin P., and Leist M. Progressive degeneration of human mesencephalic neuron-derived cells triggered by dopamine-dependent oxidative stress is dependent on the mixed-lineage kinase pathway. J. Neurosci. 25 (2005) 6329-6342
157. Wang L.H., and Johnson Jr. E.M. Mixed lineage kinase inhibitor cep-1347 fails to delay disability in early Parkinson disease. Neurology 71 (2008) 462 author reply 462-463
158. Lin L.F., Doherty D.H., Lile J.D., Bektesh S., and Collins F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260 (1993) 1130-1132
159. Lewis T.B., and Standaert D.G. Design of clinical trials of gene therapy in Parkinson disease. Exp. Neurol. 209 (2008) 41-47
160. Akerud P., Alberch J., Eketjall S., Wagner J., and Arenas E. Differential effects of glial cell line-derived neurotrophic factor and neurturin on developing and adult substantia nigra dopaminergic neurons. J. Neurochem. 73 (1999) 70-78
161. Horger B.A., Nishimura M.C., Armanini M.P., Wang L.C., Poulsen K.T., Rosenblad C., Kirik D., Moffat B., Simmons L., Johnson Jr. E., Milbrandt J., Rosenthal A., Bjorklund A., Vandlen R.A., Hynes M.A., and Phillips H.S. Neurturin exerts potent actions on survival and function of midbrain dopaminergic neurons. J. Neurosci. 18 (1998) 4929-4937
162. Marks Jr. W.J., Ostrem J.L., Verhagen L., Starr P.A., Larson P.S., Bakay R.A., Taylor R., Cahn-Weiner D.A., Stoessl A.J., Olanow C.W., and Bartus R.T. Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinson's disease: an open-label, phase I trial. Lancet Neurol. 7 (2008) 400-408
163. Steiner J.P., Connolly M.A., Valentine H.L., Hamilton G.S., Dawson T.M., Hester L., and Snyder S.H. Neurotrophic actions of nonimmunosuppressive analogues of immunosuppressive drugs FK506, rapamycin and cyclosporin A. Nat. Med. 3 (1997) 421-428
164. Guo X., Dawson V.L., and Dawson T.M. Neuroimmunophilin ligands exert neuroregeneration and neuroprotection in midbrain dopaminergic neurons. Eur. J. Neurosci. 13 (2001) 1683-1693
165. Khan Z., Ferrari G., Kasper M., Tonge D.A., Steiner J.P., Hamilton G.S., and Gordon-Weeks P.R. The non-immunosuppressive immunophilin ligand GPI-1046 potently stimulates regenerating axon growth from adult mouse dorsal root ganglia cultured in Matrigel. Neuroscience 114 (2002) 601-609
166. Steiner J.P., Hamilton G.S., Ross D.T., Valentine H.L., Guo H., Connolly M.A., Liang S., Ramsey C., Li J.H., Huang W., Howorth P., Soni R., Fuller M., Sauer H., Nowotnik A.C., and Suzdak P.D. Neurotrophic immunophilin ligands stimulate structural and functional recovery in neurodegenerative animal models. Proc. Natl. Acad. Sci. U. S. A. 94 (1997) 2019-2024
167. Costantini L.C., Cole D., Chaturvedi P., and Isacson O. Immunophilin ligands can prevent progressive dopaminergic degeneration in animal models of Parkinson's disease. Eur. J. Neurosci. 13 (2001) 1085-1092
168. Zhang C., Steiner J.P., Hamilton G.S., Hicks T.P., and Poulter M.O. Regeneration of dopaminergic function in 6-hydroxydopamine-lesioned rats by neuroimmunophilin ligand treatment. J. Neurosci. 21 (2001) RC156
169. Emborg M.E., Shin P., Roitberg B., Sramek J.G., Chu Y., Stebbins G.T., Hamilton J.S., Suzdak P.D., Steiner J.P., and Kordower J.H. Systemic administration of the immunophilin ligand GPI 1046 in MPTP-treated monkeys. Exp. Neurol. 168 (2001) 171-182
170. Eberling J.L., Pivirotto P., Bringas J., Steiner J.P., Kordower J.H., Chu Y., Emborg M.E., and Bankiewicz K.S. The immunophilin ligand GPI-1046 does not have neuroregenerative effects in MPTP-treated monkeys. Exp. Neurol. 178 (2002) 236-242
171. Tanaka K., Fujita N., and Ogawa N. Immunosuppressive (FK506) and non-immunosuppressive (GPI1046) immunophilin ligands activate neurotrophic factors in the mouse brain. Brain Res. 970 (2003) 250-253
172. Tanaka K., Fujita N., Yoshioka M., and Ogawa N. Immunosuppressive and non-immunosuppressive immunophilin ligands improve H(2)O(2)-induced cell damage by increasing glutathione levels in NG108-15 cells. Brain Res. 889 (2001) 225-228
173. Tanaka K., Yoshioka M., Miyazaki I., Fujita N., and Ogawa N. GPI1046 prevents dopaminergic dysfunction by activating glutathione system in the mouse striatum. Neurosci. Lett. 321 (2002) 45-48
174. Poulter M.O., Payne K.B., and Steiner J.P. Neuroimmunophilins: a novel drug therapy for the reversal of neurodegenerative disease?. Neuroscience 128 (2004) 1-6
175. Ramaker C., Marinus J., Stiggelbout A.M., and Van Hilten B.J. Systematic evaluation of rating scales for impairment and disability in Parkinson's disease. Mov. Disord. 17 (2002) 867-876
176. The Unified Parkinson's Disease Rating Scale (UPDRS): status and recommendations. Mov. Disord. 18 (2003) 738-750
177. Goetz C.G., Fahn S., Martinez-Martin P., Poewe W., Sampaio C., Stebbins G.T., Stern M.B., Tilley B.C., Dodel R., Dubois B., Holloway R., Jankovic J., Kulisevsky J., Lang A.E., Lees A., Leurgans S., LeWitt P.A., Nyenhuis D., Olanow C.W., Rascol O., Schrag A., Teresi J.A., Van Hilten J.J., and LaPelle N. Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): process, format, and clinimetric testing plan. Mov. Disord. 22 (2007) 41-47
178. Kieburtz K. Issues in neuroprotection clinical trials in Parkinson's disease. Neurology 66 (2006) S50-57
179. 18F]dopa PET. J. Neurol. Neurosurg. Psychiatry 64 (1998) 314-319
180. 123I]beta-CIT SPECT imaging assessment of the rate of Parkinson's disease progression. Neurology 57 (2001) 2089-2094
181. Betarbet R., Sherer T.B., and Greenamyre J.T. Animal models of Parkinson's disease. Bioessays 24 (2002) 308-318
182. Hashimoto M., Rockenstein E., and Masliah E. Transgenic models of alpha-synuclein pathology: past, present, and future. Ann. N. Y. Acad. Sci. 991 (2003) 171-188
183. Maries E., Dass B., Collier T.J., Kordower J.H., and Steece-Collier K. The role of alpha-synuclein in Parkinson's disease: insights from animal models. Nat. Rev. Neurosci. 4 (2003) 727-738
184. Lohmann E., Periquet M., Bonifati V., Wood N.W., De Michele G., Bonnet A.M., Fraix V., Broussolle E., Horstink M.W., Vidailhet M., Verpillat P., Gasser T., Nicholl D., Teive H., Raskin S., Rascol O., Destee A., Ruberg M., Gasparini F., Meco G., Agid Y., Durr A., and Brice A. How much phenotypic variation can be attributed to parkin genotype?. Ann. Neurol. 54 (2003) 176-185
185. Lucking C.B., Durr A., Bonifati V., Vaughan J., De Michele G., Gasser T., Harhangi B.S., Meco G., Denefle P., Wood N.W., Agid Y., and Brice A. Association between early-onset Parkinson's disease and mutations in the parkin gene. N. Engl. J. Med. 342 (2000) 1560-1567
186. Deng H., Le W., Guo Y., Hunter C.B., Xie W., and Jankovic J. Genetic and clinical identification of Parkinson's disease patients with LRRK2 G2019S mutation. Ann. Neurol. 57 (2005) 933-934
187. Gilks W.P., Abou-Sleiman P.M., Gandhi S., Jain S., Singleton A., Lees A.J., Shaw K., Bhatia K.P., Bonifati V., Quinn N.P., Lynch J., Healy D.G., Holton J.L., Revesz T., and Wood N.W. A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 365 (2005) 415-416
188. Kachergus J., Mata I.F., Hulihan M., Taylor J.P., Lincoln S., Aasly J., Gibson J.M., Ross O.A., Lynch T., Wiley J., Payami H., Nutt J., Maraganore D.M., Czyzewski K., Styczynska M., Wszolek Z.K., Farrer M.J., and Toft M. Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am. J. Hum. Genet. 76 (2005) 672-680
189. Healy D.G., Falchi M., O'Sullivan S.S., Bonifati V., Durr A., Bressman S., Brice A., Aasly J., Zabetian C.P., Goldwurm S., Ferreira J.J., Tolosa E., Kay D.M., Klein C., Williams D.R., Marras C., Lang A.E., Wszolek Z.K., Berciano J., Schapira A.H., Lynch T., Bhatia K.P., Gasser T., Lees A.J., and Wood N.W. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol. 7 (2008) 583-590
190. Riederer P., and Wuketich S. Time course of nigrostriatal degeneration in Parkinson's disease. A detailed study of influential factors in human brain amine analysis. J. Neural. Transm. 38 (1976) 277-301
191. 123I]beta-CIT SPECT. J. Neurol. 245 (1998) 14-20
192. Tissingh G., Booij J., Bergmans P., Winogrodzka A., Janssen A.G., van Royen E.A., Stoof J.C., and Wolters E.C. Iodine-123-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iod ophenyl)tropane SPECT in healthy controls and early-stage, drug-naive Parkinson's disease. J. Nucl. Med. 39 (1998) 1143-1148
193. Tolosa E., Compta Y., and Gaig C. The premotor phase of Parkinson's disease. Parkinsonism Relat. Disord. Suppl. 13 (2007) S2-S7
194. Ravina B.M., Fagan S.C., Hart R.G., Hovinga C.A., Murphy D.D., Dawson T.M., and Marler J.R. Neuroprotective agents for clinical trials in Parkinson's disease: a systematic assessment. Neurology 60 (2003) 1234-1240
195. Ross G.W., Abbott R.D., Petrovitch H., Morens D.M., Grandinetti A., Tung K.H., Tanner C.M., Masaki K.H., Blanchette P.L., Curb J.D., Popper J.S., and White L.R. Association of coffee and caffeine intake with the risk of Parkinson disease. JAMA 283 (2000) 2674-2679
196. Ascherio A., Zhang S.M., Hernan M.A., Kawachi I., Colditz G.A., Speizer F.E., and Willett W.C. Prospective study of caffeine consumption and risk of Parkinson's disease in men and women. Ann. Neurol. 50 (2001) 56-63
197. Schwarzschild M.A., Agnati L., Fuxe K., Chen J.F., and Morelli M. Targeting adenosine A2A receptors in Parkinson's disease. Trends Neurosci. 29 (2006) 647-654
198. Ferre S., and Fuxe K. Dopamine denervation leads to an increase in the intramembrane interaction between adenosine A2 and dopamine D2 receptors in the neostriatum. Brain Res. 594 (1992) 124-130
199. Ferre S., O'Connor W.T., Fuxe K., and Ungerstedt U. The striopallidal neuron: a main locus for adenosine-dopamine interactions in the brain. J. Neurosci. 13 (1993) 5402-5406
200. Bara-Jimenez W., Sherzai A., Dimitrova T., Favit A., Bibbiani F., Gillespie M., Morris M.J., Mouradian M.M., and Chase T.N. Adenosine A(2A) receptor antagonist treatment of Parkinson's disease. Neurology 61 (2003) 293-296
201. Hauser R.A., Hubble J.P., and Truong D.D. Randomized trial of the adenosine A(2A) receptor antagonist istradefylline in advanced PD. Neurology 61 (2003) 297-303
202. Chen J.F., Xu K., Petzer J.P., Staal R., Xu Y.H., Beilstein M., Sonsalla P.K., Castagnoli K., Castagnoli Jr. N., and Schwarzschild M.A. Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson's disease. J. Neurosci. 21 (2001) RC143
203. Ikeda K., Kurokawa M., Aoyama S., and Kuwana Y. Neuroprotection by adenosine A2A receptor blockade in experimental models of Parkinson's disease. J. Neurochem. 80 (2002) 262-270
204. Phillis J.W. The effects of selective A1 and A2a adenosine receptor antagonists on cerebral ischemic injury in the gerbil. Brain Res. 705 (1995) 79-84
205. Jones P.A., Smith R.A., and Stone T.W. Protection against hippocampal kainate excitotoxicity by intracerebral administration of an adenosine A2A receptor antagonist. Brain Res. 800 (1998) 328-335
206. Monopoli A., Lozza G., Forlani A., Mattavelli A., and Ongini E. Blockade of adenosine A2A receptors by SCH 58261 results in neuroprotective effects in cerebral ischaemia in rats. Neuroreport 9 (1998) 3955-3959
207. Selley M.L. Simvastatin prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced striatal dopamine depletion and protein tyrosine nitration in mice. Brain Res. 1037 (2005) 1-6
208. Di Napoli P., Taccardi A.A., Oliver M., and De Caterina R. Statins and stroke: evidence for cholesterol-independent effects. Eur. Heart J. 23 (2002) 1908-1921
209. de Lau L.M., Koudstaal P.J., Hofman A., and Breteler M.M. Serum cholesterol levels and the risk of Parkinson's disease. Am. J. Epidemiol. 164 (2006) 998-1002
210. Huang X., Chen H., Miller W.C., Mailman R.B., Woodard J.L., Chen P.C., Xiang D., Murrow R.W., Wang Y.Z., and Poole C. Lower low-density lipoprotein cholesterol levels are associated with Parkinson's disease. Mov. Disord. 22 (2007) 377-381
211. Tikka T., Fiebich B.L., Goldsteins G., Keinanen R., and Koistinaho J. Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J. Neurosci. 21 (2001) 2580-2588
212. Tikka T.M., and Koistinaho J.E. Minocycline provides neuroprotection against N-methyl-d-aspartate neurotoxicity by inhibiting microglia. J. Immunol. 166 (2001) 7527-7533
213. Du Y., Ma Z., Lin S., Dodel R.C., Gao F., Bales K.R., Triarhou L.C., Chernet E., Perry K.W., Nelson D.L., Luecke S., Phebus L.A., Bymaster F.P., and Paul S.M. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. Proc. Natl. Acad. Sci. U. S. A. 98 (2001) 14669-14674
214. Wu D.C., Jackson-Lewis V., Vila M., Tieu K., Teismann P., Vadseth C., Choi D.K., Ischiropoulos H., and Przedborski S. 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 (2002) 1763-1771
215. He Y., Appel S., and Le W. Minocycline inhibits microglial activation and protects nigral cells after 6-hydroxydopamine injection into mouse striatum. Brain Res. 909 (2001) 187-193
216. Ames B.N., Cathcart R., Schwiers E., and Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc. Natl. Acad. Sci. U. S. A. 78 (1981) 6858-6862
217. Davis J.W., Grandinetti A., Waslien C.I., Ross G.W., White L.R., and Morens D.M. Observations on serum uric acid levels and the risk of idiopathic Parkinson's disease. Am. J. Epidemiol. 144 (1996) 480-484
218. de Lau L.M., Koudstaal P.J., Hofman A., and Breteler M.M. Serum uric acid levels and the risk of Parkinson disease. Ann. Neurol. 58 (2005) 797-800
219. Weisskopf M.G., O'Reilly E., Chen H., Schwarzschild M.A., and Ascherio A. Plasma urate and risk of Parkinson's disease. Am. J. Epidemiol. 166 (2007) 561-567
220. Alonso A., Rodriguez L.A., Logroscino G., and Hernan M.A. Gout and risk of Parkinson disease: a prospective study. Neurology 69 (2007) 1696-1700
221. Schwarzschild M.A., Schwid S.R., Marek K., Watts A., Lang A.E., Oakes D., Shoulson I., Ascherio A., Hyson C., Gorbold E., Rudolph A., Kieburtz K., Fahn S., Gauger L., Goetz C., Seibyl J., Forrest M., and Ondrasik J. Serum urate as a predictor of clinical and radiographic progression in Parkinson disease. Arch. Neurol. 65 (2008) 716-723
222. Duan W., Ladenheim B., Cutler R.G., Kruman I.I., Cadet J.L., and Mattson M.P. Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson's disease. J. Neurochem. 80 (2002) 101-110
223. Gao X., Chen H., Choi H.K., Curhan G., Schwarzschild M.A., and Ascherio A. Diet, urate, and Parkinson's disease risk in men. Am. J. Epidemiol. 167 (2008) 831-838
224. Haywood A.F., and Staveley B.E. Parkin counteracts symptoms in a Drosophila model of Parkinson's disease. BMC Neurosci. 5 (2004) 14
225. Lo Bianco C., Schneider B.L., Bauer M., Sajadi A., Brice A., Iwatsubo T., and Aebischer P. Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson's disease. Proc. Natl. Acad. Sci. U. S. A. 101 (2004) 17510-17515
226. Yamada M., Mizuno Y., and Mochizuki H. Parkin gene therapy for alpha-synucleinopathy: a rat model of Parkinson's disease. Hum. Gene Ther. 16 (2005) 262-270
227. McLean P.J., Klucken J., Shin Y., and Hyman B.T. Geldanamycin induces Hsp70 and prevents alpha-synuclein aggregation and toxicity in vitro. Biochem. Biophys. Res. Commun. 321 (2004) 665-669
228. Qiao L., Hamamichi S., Caldwell K.A., Caldwell G.A., Wilson S., Yacoubian T., Xie Z.-L., Speake L., Parks R., Crabtree D., Crimmins S., Uchiyama Y., Zhou Y., Peng L., Lu Y., Standaert D.G., Walls K.C., Shacka J.J., Roth K., and Zhang J. A neuroprotective role of lysosomal enzyme cathepsin D against a-synuclein pathogenesis. Mov. Disord. 23 (2008) S8
229. Masliah E., Rockenstein E., Adame A., Alford M., Crews L., Hashimoto M., Seubert P., Lee M., Goldstein J., Chilcote T., Games D., and Schenk D. Effects of alpha-synuclein immunization in a mouse model of Parkinson's disease. Neuron 46 (2005) 857-868
230. Chen L., and Feany M.B. Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat. Neurosci. 8 (2005) 657-663
231. Smith W.W., Margolis R.L., Li X., Troncoso J.C., Lee M.K., Dawson V.L., Dawson T.M., Iwatsubo T., and Ross C.A. Alpha-synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion formation in SH-SY5Y cells. J. Neurosci. 25 (2005) 5544-5552
232. Bodles A.M., El-Agnaf O.M., Greer B., Guthrie D.J., and Irvine G.B. Inhibition of fibril formation and toxicity of a fragment of alpha-synuclein by an N-methylated peptide analogue. Neurosci. Lett. 359 (2004) 89-93
233. El-Agnaf O.M., Paleologou K.E., Greer B., Abogrein A.M., King J.E., Salem S.A., Fullwood N.J., Benson F.E., Hewitt R., Ford K.J., Martin F.L., Harriott P., Cookson M.R., and Allsop D. A strategy for designing inhibitors of alpha-synuclein aggregation and toxicity as a novel treatment for Parkinson's disease and related disorders. FASEB J. 18 (2004) 1315-1317
234. Amer D.A., Irvine G.B., and El-Agnaf O.M. Inhibitors of alpha-synuclein oligomerization and toxicity: a future therapeutic strategy for Parkinson's disease and related disorders. Exp. Brain Res. 173 (2006) 223-233
235. Hashimoto M., Rockenstein E., Mante M., Mallory M., and Masliah E. beta-Synuclein inhibits alpha-synuclein aggregation: a possible role as an anti-parkinsonian factor. Neuron 32 (2001) 213-223
236. Windisch M., Hutter-Paier B., Rockenstein E., Hashimoto M., Mallory M., and Masliah E. Development of a new treatment for Alzheimer's disease and Parkinson's disease using anti-aggregatory beta-synuclein-derived peptides. J. Mol. Neurosci. 19 (2002) 63-69
237. T.A. Yacoubian, D.G. Standaert, Role of 14-3-3 proteins in alpha-synuclein-induced neurotoxicity, Soc Neurosci Abstract Viewer/Itinerary Planner Program #882.8/J1 (2007).
238. Lesage S., Durr A., Tazir M., Lohmann E., Leutenegger A.L., Janin S., Pollak P., and Brice A. LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs. N. Engl. J. Med. 354 (2006) 422-423
239. Lesage S., Ibanez P., Lohmann E., Pollak P., Tison F., Tazir M., Leutenegger A.L., Guimaraes J., Bonnet A.M., Agid Y., Durr A., and Brice A. G2019S LRRK2 mutation in French and North African families with Parkinson's disease. Ann. Neurol. 58 (2005) 784-787
240. Ozelius L.J., Senthil G., Saunders-Pullman R., Ohmann E., Deligtisch A., Tagliati M., Hunt A.L., Klein C., Henick B., Hailpern S.M., Lipton R.B., Soto-Valencia J., Risch N., and Bressman S.B. LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. N. Engl. J. Med. 354 (2006) 424-425
241. Hulihan M.M., Ishihara-Paul L., Kachergus J., Warren L., Amouri R., Elango R., Prinjha R.K., Upmanyu R., Kefi M., Zouari M., Sassi S.B., Yahmed S.B., El Euch-Fayeche G., Matthews P.M., Middleton L.T., Gibson R.A., Hentati F., and Farrer M.J. LRRK2 Gly2019Ser penetrance in Arab-Berber patients from Tunisia: a case-control genetic study. Lancet Neurol. 7 (2008) 591-594
242. West A.B., Moore D.J., Biskup S., Bugayenko A., Smith W.W., Ross C.A., Dawson V.L., and Dawson T.M. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc. Natl. Acad. Sci. U. S. A. 102 (2005) 16842-16847
243. Greggio E., Jain S., Kingsbury A., Bandopadhyay R., Lewis P., Kaganovich A., van der Brug M.P., Beilina A., Blackinton J., Thomas K.J., Ahmad R., Miller D.W., Kesavapany S., Singleton A., Lees A., Harvey R.J., Harvey K., and Cookson M.R. Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol. Dis. 23 (2006) 329-341
244. West A.B., Moore D.J., Choi C., Andrabi S.A., Li X., Dikeman D., Biskup S., Zhang Z., Lim K.L., Dawson V.L., and Dawson T.M. Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum. Mol. Genet. 16 (2007) 223-232