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Neurotherapeutics. 2008 Apr; 5(2): 270–280.
PMCID: PMC5084169
PMID: 18394569
Treatment of Parkinson’s disease with trophic factors
Summary
Trophic factors are proteins that support and protect subpopulations of cells. A number have been reported to act on dopaminergic neurons in vitro and in vivo, making them potential therapeutic candidates for Parkinson’s disease. All of these candidate factors protect dopaminergic neurons if given prior to, or with, selective neurotoxins. Fewer trophic factors, primarily glial-derived neurotrophic factor (GDNF) and its relative, neurturin (NRTN; also known as NTN), have been shown to restore function in damaged dopamine neurons after the acute effects of neurotoxins have subsided. A major barrier to clinical translation has been delivery. GDNF delivered by intracerebroventricular injection in patients was ineffective, probably because GDNF did not reach the target, the putamen, and intraputaminal infusion was ineffective, probably because of limited distribution within the putamen. A randomized clinical trial with gene therapy for NRTN is underway, in an attempt to overcome these problems with targeting and distribution. Other strategies are available to induce trophic effects in the CNS, but have not yet been the focus of human research. To date, clinical trials have focused on restoration of function (i.e., improvement of parkinsonism). Protection (i.e., slowing or halting disease progression and functional decline) might be a more robust effect of trophic agents. Laboratory research points to their effectiveness in protecting neurons and even restoring dopaminergic function after a monophasic neurotoxic insult. Utility for such compounds in patients with Parkinson’s disease and ongoing loss of dopaminergic neurons remains to be proven.
Key Words: Parkinson’s disease, trophic factors, clinical trials, glial-derived neurotrophic factors, neurturin
References
1. Bennett CL, Luminari S, Nissenson AR, et al. Pure red-cell aplasia and epoetin therapy. N Engl J Med. 2004;351:1403–1408. [PubMed] [Google Scholar]
2. Cohen S, Levi-Montalcini R, Hamburger V. A nerve growth-stimulating factor isolated from sarcomas 37 and 180. Proc Natl Acad Sci U S A. 1954;40:1014–1018. [PMC free article] [PubMed] [Google Scholar]
3. Marti HH, Wenger RH, Rivas LA, et al. Erythropoietin gene expression in human, monkey and murine brain. Eur J Neurosci. 1996;8:666–676. [PubMed] [Google Scholar]
4. Butte MJ. Neurotrophic factor structures reveal clues to evolution, binding, specificity, and receptor activation. Cell Mol Life Sci. 2001;58:1003–1013. [PubMed] [Google Scholar]
5. Maisonpierre PC, Belluscio L, Friedman B, et al. NT-3, BDNF, and NGF in the developing rat nervous system: parallel as well as reciprocal patterns of expression. Neuron. 1990;5:501–509. [PubMed] [Google Scholar]
6. Maisonpierre PC, Le Beau MM, Espinosa R, et al. Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations. Genomics. 1991;10:558–568. [PubMed] [Google Scholar]
7. Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F. GDNF: A glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science. 1993;260:1130–1132. [PubMed] [Google Scholar]
8. Bespalov MM, Saarma M. GDNF family receptor complexes are emerging drug targets. Trends Pharmacol Sci. 2007;28:68–74. [PubMed] [Google Scholar]
9. Petrova P, Raibekas A, Pevsner J, et al. MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons. J Mol Neurosci. 2003;20:173–188. [PubMed] [Google Scholar]
10. Lindholm P, Voutilainen MH, Lauren J, et al. Novel neurotrophic factor CDNF protects and rescues midbrain dopamine neurons in vivo. Nature. 2007;448:73–77. [PubMed] [Google Scholar]
11. Shults CW. Neurotrophic factors. In: Watts RL, Koller WC, editors. Movement disorders: neurologic principles and practice. 2nd ed. New York: McGraw-Hill; 2004. pp. 131–142. [Google Scholar]
12. Fontan A, Rojo A, Sanchez-Pernaute R, et al. Effects of fibroblast growth factor and glial-derived neurotrophic factor on akinesia, F-DOPA uptake and dopamine cells in parkinsonian primates. Parkinsonism Relat Disord. 2002;8:311–323. [PubMed] [Google Scholar]
13. Levi-Montalcini R. The nerve growth factor 35 years later. Science. 1987;237:1154–1162. [PubMed] [Google Scholar]
14. Heerssen HM, Segal RA. Location, location, location: a spatial view of neurotrophin signal transduction. Trends Neurosci. 2002;25:160–165. [PubMed] [Google Scholar]
15. Kohara K, Kitamura A, Morishima M, Tsumoto T. Activity-dependent transfer of brain-derived neurotrophic factor to postsynaptic neurons. Science. 2001;291:2419–2423. [PubMed] [Google Scholar]
16. Conner JM, Lauterborn JC, Yan Q, Gall CM, Varon S. Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport. J Neurosci. 1997;17:2295–2313. [PMC free article] [PubMed] [Google Scholar]
17. Delgado M, Ganea D. Neuroprotective effect of vasoactive intestinal peptide (VIP) in a mouse model of Parkinson’s disease by blocking microglial activation. FASEB J. 2003;17:944–946. [PubMed] [Google Scholar]
18. Baquet ZC, Bickford PC, Jones KR. Brain-derived neurotrophic factor is required for the establishment of the proper number of dopaminergic neurons in the substantia nigra pars compacta. J Neurosci. 2005;25:6251–6259. [PMC free article] [PubMed] [Google Scholar]
19. Seroogy KB, Lundgren KH, Tran TM, Guthrie KM, Isackson PJ, Gall CM. Dopaminergic neurons in rat ventral midbrain express brain-derived neurotrophic factor and neurotrophin-3 mRNAs. J Comp Neurol. 1994;342:321–334. [PubMed] [Google Scholar]
20. Zhang HT, Li LY, Zou XL, et al. Immunohistochemical distribution of NGF, BDNF, NT-3, and NT-4 in adult rhesus monkey brains. J Histochem Cytochem. 2007;55:1–19. [PubMed] [Google Scholar]
21. Mogi M, Togari A, Kondo T, et al. Brain-derived growth factor and nerve growth factor concentrations are decreased in the substantia nigra in Parkinson’s disease. Neurosci Lett. 1999;270:45–48. [PubMed] [Google Scholar]
22. Howells DW, Porritt MJ, Wong JY, et al. Reduced BDNF mRNA expression in the Parkinson’s disease substantia nigra. Exp Neurol. 2000;166:127–135. [PubMed] [Google Scholar]
23. Hyman C, Hofer M, Barde YA, et al. BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature. 1991;350:230–232. [PubMed] [Google Scholar]
24. Spina MB, Hyman C, Squinto S, Lindsay RM. Brain-derived neurotrophic factor protects dopaminergic cells from 6-hydroxydopamine toxicity. Ann N Y Acad Sci. 1992;648:348–350. [PubMed] [Google Scholar]
25. Frim DM, Uhler TA, Galpern WR, Beal MF, Breakefield XO, Isacson O. Implanted fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevent l-methyl-4-phenylpyridinium toxicity to dopaminergic neurons in the rat. Proc Natl Acad Sci U S A. 1994;91:5104–5108. [PMC free article] [PubMed] [Google Scholar]
26. Shults CW, Kimber T, Altai- CA. BDNF attenuates the effects of intrastriatal injection of 6-hydroxydopamine. Neuroreport. 1995;6:1109–1112. [PubMed] [Google Scholar]
27. von Bohlen und Halbach O, Minichiello L, Unsicker K. Haploinsufficiency for trkB and trkC receptors induces cell loss and accumulation of accumulation of α-synuclein in the substantia nigra. FASEB J 1919;1740–1742. [PubMed]
28. Karamohamed S, Latourelle JC, Racette BA, et al. BDNF genetic variants are associated with onset age of familial Parkinson disease: GenePD Study. Neurology. 2005;65:1823–1825. [PubMed] [Google Scholar]
29. Granholm AC, Reyland M, Albeck D, et al. Glial cell line-derived neurotrophic factor is essential for postnatal survival of midbrain dopamine neurons. J Neurosci. 2000;20:3182–3190. [PMC free article] [PubMed] [Google Scholar]
30. Oo TF, Ries V, Cho J, Kholodilov N, Burke RE. Anatomical basis of glial cell line-derived neurotrophic factor expression in the striatum and related basal ganglia during postnatal development of the rat. J Comp Neurol. 2005;484:57–67. [PMC free article] [PubMed] [Google Scholar]
31. Mogi M, Togari A, Kondo T, et al. Glial cell line-derived neurotrophic factor in the substantia nigra from control and parkinsonian brains. Neurosci Lett. 2001;300:179–181. [PubMed] [Google Scholar]
32. Bäckman CM, Shan L, Zhang YJ, et al. Gene expression patterns for GDNF and its receptors in the human putamen affected by Parkinson’s disease: a real-time PCR study. Mol Cell Endocrinol. 2006;252:160–166. [PubMed] [Google Scholar]
33. Tomac A, Lindqvist E, Lin LF, et al. Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature. 1995;373:335–339. [PubMed] [Google Scholar]
34. Kearns CM, Gash DM. GDNF protects nigral dopamine neurons against 6-hydroxydopamine in vivo. Brain Res. 1995;672:104–111. [PubMed] [Google Scholar]
35. Kirik D, Georgievska B, Björklund A. Localized striatal delivery of GDNF as a treatment for Parkinson disease. Nat Neurosci. 2004;7:105–110. [PubMed] [Google Scholar]
36. Kirik D, Rosenblad C, Björklund A. Reservation of a functional nigrostriatal dopamine pathway by GDNF in the intrastriatal 6-OHDA lesion model depends on the site of administration of the trophic factor. Eur J Neurosci. 2000;12:3871–3882. [PubMed] [Google Scholar]
37. 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. [PubMed] [Google Scholar]
38. Georgievska B, Kirik D, Björklund A. Aberrant sprouting and downregulation of tyrosine hydroxylase in lesioned nigrostriatal dopamine neurons induced by long-lasting overexpression of glial cell line derived neurotrophic factor in the striatum by lentiviral gene transfer. Exp Neurol. 2002;177:461–474. [PubMed] [Google Scholar]
39. Eslamboli A, Georgievska B, Ridley RM, et al. 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. 2005;25:769–777. [PMC free article] [PubMed] [Google Scholar]
40. Kirik D, Georgievska B, Rosenblad C, Björklund A. Delayed infusion of GDNF promotes recovery of motor function in the partial lesion model of Parkinson’s disease. Eur J Neurosci. 2001;13:1589–1599. [PubMed] [Google Scholar]
41. Gash DM, Zhang Z, Ovadia A, et al. Functional recovery in parkinsonian monkeys treated with GDNF. Nature. 1996;380:252–255. [PubMed] [Google Scholar]
42. Zhang Z, Miyoshi Y, Lapchak PA, et al. Dose response to intraventricular glial cell line-derived neurotrophic factor administration in parkinsonian monkeys. J Pharmacol Exp Ther. 1997;282:1396–1401. [PubMed] [Google Scholar]
43. Grondin R, Zhang Z, Yi A, et al. Chronic, controlled GDNF infusion promotes structural and functional recovery in advanced parkinsonian monkeys. Brain. 2002;125:2191–2201. [PubMed] [Google Scholar]
44. Yang F, Feng L, Zheng F, et al. GDNF acutely modulates excitability and A-type K+ channels in midbrain dopaminergic neurons. Nat Neurosci. 2001;4:1071–1078. [PubMed] [Google Scholar]
45. Hebert MA, Van Horne CG, Hoffer BJ, Gerhardt GA. Functional effects of GDNF in normal rat striatum: presynaptic studies using in vivo electrochemistry and microdialysis. J Pharmacol Exp Ther. 1996;279:1181–1190. [PubMed] [Google Scholar]
46. Kotzbauer PT, Lampe PA, Heuckeroth RO, et al. Neurturin, a relative of glial-cell-line-derived neurotrophic factor. Nature. 1996;384:467–470. [PubMed] [Google Scholar]
47. Horger BA, Nishimura MC, Armanini MP, et al. Neurturin exerts potent actions on survival and function of midbrain dopaminergic neurons. J Neurosci. 1998;18:4929–4937. [PMC free article] [PubMed] [Google Scholar]
48. Hoane MR, Gulwadi AG, Morrison S, Hovanesian G, Lindner MD, Tao W. Differential in vivo effects of neurturin and glial cell-line-derived neurotrophic factor. Exp Neurol. 1999;160:235–243. [PubMed] [Google Scholar]
49. Li H, He Z, Su T, et al. Protective action of recombinant neurturin on dopaminergic neurons in substantia nigra in a rhesus monkey model of Parkinson’s disease. Neurol Res. 2003;25:263–267. [PubMed] [Google Scholar]
50. Kordower JH, Herzog CD, Dass B, et al. Delivery of neurturin by AAV2 (CERE-120)-mediated gene transfer provides structural and functional neuroprotection and neurorestoration in MPTP-treated monkeys. Ann Neurol. 2006;60:706–715. [PubMed] [Google Scholar]
51. Rosenblad C, Kirik D, Devaux B, Moffat B, Phillips HS, Björklund A. Protection and regeneration of nigral dopaminergic neurons by neurturin or GDNF in a partial lesion model of Parkinson’s disease after administration into the striatum or the lateral ventricle. Eur J Neurosci. 1999;11:1554–1566. [PubMed] [Google Scholar]
52. Oiwa Y, Yoshimura R, Nakai K, Itakura T. Dopaminergic neuroprotection and regeneration by neurturin assessed by using behavioral, biochemical and histochemical measurements in a model of progressive Parkinson’s disease. Brain Res. 2002;947:271–283. [PubMed] [Google Scholar]
53. Tseng JL, Bruhn SL, Zurn AD, Aebischer P. Neurturin protects dopaminergic neurons following medial forebrain bundle axotomy. Neuroreport. 1998;9:1817–1822. [PubMed] [Google Scholar]
54. Herzog CD, Dass B, Holden JE, et al. Striatal delivery of CERE-120, an AAV2 vector encoding human neurturin, enhances activity of the dopaminergic nigrostriatal system in aged monkeys. Mov Disord. 2007;22:1124–1132. [PubMed] [Google Scholar]
55. Langsten JW. The Parkinson’s complex: parkinsonism is just the tip of the iceberg. Ann Neurol. 2006;59:591–596. [PubMed] [Google Scholar]
56. Beck M, Flachenecker P, Magnus T, et al. Autonomic dysfunction in ALS: a preliminary study on the effects of intrathecal BDNF. Amyotroph Lateral Scler Other Motor Neuron Disord. 2005;6:100–103. [PubMed] [Google Scholar]
57. Fischer W, Wictorin K, Björklund A, Williams LR, Varon S, Gage FH. Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor. Nature. 1987;329:65–68. [PubMed] [Google Scholar]
58. Gash DM, Zhang Z, Cass WA, et al. Morphological and functional effects of intranigrally administered GDNF in normal rhesus monkeys. J Comp Neurol. 1995;363:345–358. [PubMed] [Google Scholar]
59. Oiwa Y, Nakai K, Itakura T. Histological effects of intraputaminal infusion of glial cell line-derived neurotrophic factor in Parkinson disease model macaque monkeys. Neurol Med Chir (Tokyo) 2006;46:267–275. [PubMed] [Google Scholar]
60. Ai Y, Markesbery W, Zhang Z, et al. Intraputamenal infusion of GDNF in aged rhesus monkeys: distribution and dopaminergic effects. J Comp Neurol. 2003;461:250–261. [PubMed] [Google Scholar]
61. Laske DW, Morrison PF, Lieberman DM, et al. Chronic interstitial infusion of protein to primate brain: determination of drug distribution and clearance with single-photon emission computerized tomography imaging. J Neurosurg. 1997;87:586–594. [PubMed] [Google Scholar]
62. Slevin JT, Gash DM, Smith CD, et al. Unilateral intraputamenal glial cell line-derived neurotrophic factor in patients with Parkinson disease: response to 1 year of treatment and 1 year of withdrawal. J Neurosurg. 2007;106:614–620. [PubMed] [Google Scholar]
63. Hadaczek P, Kohutnicka M, Krauze MT, et al. Convection-enhanced delivery of adeno-associated virus type 2 (AAV2) into the striatum and transport of AAV2 within monkey brain. Hum Gene Ther. 2006;17:291–302. [PubMed] [Google Scholar]
64. Doolittle ND, Miner ME, Hall WA, et al. Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood—brain barrier for the treatment of patients with malignant brain tumors. Cancer. 2000;88:637–647. [PubMed] [Google Scholar]
65. Muldoon LL, Nilaver G, Kroll RA, et al. Comparison of intracerebral inoculation and osmotic blood—brain barrier disruption for delivery of adenovirus, herpesvirus, and iron oxide particles to normal rat brain. Am J Pathol. 1995;147:1840–1851. [PMC free article] [PubMed] [Google Scholar]
66. Behrstock S, Ebert A, McHugh J, et al. Human neural progenitors deliver glial cell line-derived neurotrophic factor to parkinsonian rodents and aged primates. Gene Ther. 2006;13:379–388. [PubMed] [Google Scholar]
67. Pardridge WM. Targeting neurotherapeutic agents through the blood—brain barrier. Arch Neurol. 2002;59:35–40. [PubMed] [Google Scholar]
68. Wu D, Pardridge WM. Neuroprotection with noninvasive neurotrophin delivery to the brain. Proc Natl Acad Sci U S A. 1999;96:254–259. [PMC free article] [PubMed] [Google Scholar]
69. Juillerat-Jeanneret L, Schmitt F. Chemical modification of therapeutic drugs or drug vector systems to achieve targeted therapy: looking for the grail. Med Res Rev. 2007;27:574–590. [PubMed] [Google Scholar]
70. Guan J, Krishnamurthi R, Waldvogel HJ, Faull RL, Clark R, Gluckman P. N-terminal tripeptide of IGF-1 (GPE) prevents the loss of TH positive neurons after 6-OHDA induced nigral lesion in rats. Brain Res. 2000;859:286–292. [PubMed] [Google Scholar]
71. Peleshok J, Saragovi HU. Functional mimetics of neurotrophins and their receptors. Biochem Soc Trans. 2006;34:612–617. [PubMed] [Google Scholar]
72. Tokugawa K, Yamamoto K, Nishiguchi M, et al. XIB4035, a novel nonpeptidyl small molecule agonist for GFRα-1. Neurochem Int. 2003;42:81–86. [PubMed] [Google Scholar]
73. Ries V, Henchcliffe C, Kareva T, et al. Oncoprotein Akt/PKB induces trophic effects in murine models of Parkinson’s disease. Proc Natl Acad Sci U S A. 2006;103:18757–18762. [PMC free article] [PubMed] [Google Scholar]
74. He DY, Ron D. Autoregulation of glial cell line-derived neurotrophic factor expression: implications for the long-lasting actions of the anti-addiction drug, ibogaine. FASEB J. 2006;20:2420–2422. [PubMed] [Google Scholar]
75. Malberg JE, Blendy JA. Antidepressant action: to the nucleus and beyond. Trends Pharmacol Sci. 2005;26:631–638. [PubMed] [Google Scholar]
76. Adlard PA, Perreau VM, Engesser-Cesar C, Cotman CW. The timecourse of induction of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus following voluntary exercise. Neurosci Lett. 2004;363:43–48. [PubMed] [Google Scholar]
77. Cohen AD, Tillerson JL, Smith AD, Schallert T, Zigmond MJ. Neuroprotective effects of prior limb use in 6-hydroxydopamine-treated rats: possible role of GDNF. J Neurochem. 2003;85:299–305. [PubMed] [Google Scholar]
78. Smith AD, Zigmond MJ. Can the brain be protected through exercise? Lessons from an animal model of parkinsonism. Exp Neurol. 2003;184:31–39. [PubMed] [Google Scholar]
79. Nutt JG, Burchiel KJ, Cornelia CL, et al. Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology. 2003;60:69–73. [PubMed] [Google Scholar]
80. Kordower JH, Palfi S, Chen E-Y, et al. Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson’s disease. Ann Neurol. 1999;46:419–424. [PubMed] [Google Scholar]
81. Gill SS, Patel NK, Hotton GR, et al. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med. 2003;9:589–595. [PubMed] [Google Scholar]
82. Gill SS, Patel NK, Hotton GR, et al. Addendum: Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med. 2006;12:479–479. [PubMed] [Google Scholar]
83. Patel NK, Bunnage M, Plaha P, Svendsen CN, Heywood P, Gill SS. Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: a two-year outcome study. Ann Neurol. 2005;57:298–302. [PubMed] [Google Scholar]
84. Lang AE, Gill S, Patel NK, et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol. 2006;59:459–466. [PubMed] [Google Scholar]
85. Tatarewicz SM, Wei X, Gupta S, Masterman D, Swanson SJ, Moxness MS. Development of a maturing T-cell-mediated immune response in patients with idiopathic Parkinson’s disease receiving r-metHuGDNF via continuous intraputaminal infusion. J Clin Immunol. 2007;27:620–627. [PubMed] [Google Scholar]
86. Slevin JT, Gerhardt GA, Smith CD, Gash DM, Kryscio R, 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. 2005;102:216–222. [PubMed] [Google Scholar]
87. Slevin JT, Gash DM, Smith CD, et al. Unilateral intraputamenal glial cell line-derived neurotrophic factor in patients with Parkinson disease: response to 1 year of treatment and 1 year of withdrawal. J Neurosurg. 2007;106:614–620. [PubMed] [Google Scholar]
88. Morrison PF, Lonser RR, Oldfield EH. Convective delivery of glial cell line-derived neurotrophic factor in the human putamen. J Neurosurg. 2007;107:74–83. [PubMed] [Google Scholar]
89. Salvatore MF, Ai Y, Fischer B, et al. Point source concentration of GDNF may explain failure of phase II clinical trial. Exp Neurol. 2006;202:497–505. [PubMed] [Google Scholar]
90. Hovland DN, Boyd RB, Butt MT, et al. Six-month continuous intraputamenal infusion toxicity study of recombinant methionyl human glial cell line-derived neurotrophic factor (r-metHuGDNF) in rhesus monkeys. Toxicol Pathol. 2007;35:1013–1029. [PubMed] [Google Scholar]
91. Chebrolu H, Slevin JT, Gash DA, et al. MRI volumetric and intensity analysis of the cerebellum in Parkinson’s disease patients infused with glial-derived neurotrophic factor (GDNF) Exp Neurol. 2006;198:450–456. [PubMed] [Google Scholar]
92. Love S, Plaha P, Patel NK, Hotton GR, Brooks DJ, Gill SS. Glial cell line-derived neurotrophic factor induces neuronal sprouting in human brain. Nat Med. 2005;11:703–704. [PubMed] [Google Scholar]
93. Hutchinson M, Gumey S, Newson R. GDNF in Parkinson disease: an object lesson in the tyranny of type II. J Neurosci Methods. 2007;163:190–192. [PubMed] [Google Scholar]
94. Matcham J, McDermott MP, Lang AE. GDNF in Parkinson’s disease: the perils of post-hoc power. J Neurosci Methods. 2007;163:193–196. [PubMed] [Google Scholar]
95. McRae C, Cherin E, Yamazaki TG, et al. Effects of perceived treatment on quality of life and medical outcomes in a double-blind placebo surgery trial. Arch Gen Psychiatry. 2004;61:412–420. [PubMed] [Google Scholar]
96. Sherer TB, Fiske BK, Svendsen CN, Lang AE, Langsten JW. Crossroads in GDNF therapy for Parkinson’s disease. Mov Disord. 2006;21:136–141. [PubMed] [Google Scholar]
97. Zaiss AK, Muruve DA. Immune responses to adeno-associated virus vectors. Curr Gene Ther. 2005;5:323–331. [PubMed] [Google Scholar]
98. Kwon I, Schaffer DV. Designer gene delivery vectors: molecular engineering and evolution of adeno-associated viral vectors for enhanced gene transfer. Pharm Res 2007 Sep 1 [Epub ahead of print]. [PMC free article] [PubMed]
99. Puskovic V, Wolfe D, Wechuck J, et al. HSV-mediated delivery of erythropoietin restores dopaminergic function in MPTP-treated mice. Mol Ther. 2006;14:710–715. [PubMed] [Google Scholar]
100. Xue YQ, Zhao LR, Guo WP, Duan WM. Intrastriatal administration of erythropoietin protects dopaminergic neurons and improves neurobehavioral outcome in a rat model of Parkinson’s disease. Neuroscience. 2007;146:1245–1258. [PubMed] [Google Scholar]
101. Reglodi D, Tamás A, Lubics A, Szalontay L, Lengvári I. Morphological and functional effects of PACAP in 6-hydroxydopamine-induced lesion of the substantia nigra in rats. Regul Pept. 2004;123:85–94. [PubMed] [Google Scholar]
102. Akerud P, Holm PC, Castelo-Branco G, Sousa K, Rodriguez FJ, Arenas E. Persephin-overexpressing neural stem cells regulate the function of nigral dopaminergic neurons and prevent their degeneration in a model of Parkinson’s disease. Mol Cell Neurosci. 2002;21:205–222. [PubMed] [Google Scholar]
103. Krishnamurthi R, Stott S, Maingay M, et al. N-terminal tripeptide of IGF-1 improves functional deficits after 6-OHDA lesion in rats. Neuroreport. 2004;15:1601–1604. [PubMed] [Google Scholar]
104. Shults CW, Ray J, Tsuboi K, Gage FH. Fibroblast growth factor-2-producing fibroblasts protect the nigrostriatal dopaminergic system from 6-hydroxydopamine. Brain Res. 2000;883:192–204. [PubMed] [Google Scholar]