A. Symptomatic Therapy
Currently, only symptomatic therapy is available for HD.96 The major goals of symptomatic therapy are to control psychosis, treat depression and suicidal tendencies, and possibly control the severity of chorea and other motor manifestations. Dopaminergic and serotonergic receptor blockade with typical and atypical antipsychotics have been the major source symptomatic therapy for HD patients. Among the drugs that are commonly used are haloperidol, risperidol, quetiapine, olanzapine, and clozaril.97-100 Anti-dopaminergic agents appear to be ineffective in the treatment of chorea. However, long-term use of typical antipsychotics may also complicate the course of the disease by inducing either drug-induced Parkinson's disease and/or tardive dyskinesias and tardive dystonia. Severe depression is treated with SSRIs and other antidepressants.
Based on the theory that glutamate excitotoxicity plays a major role in progressive degeneration of spiny striatal neurons,101 several drugs that decrease glutamatergic transmission have been tried as symptomatic treatment as well as their potentials as neuroprotective agents.102 Among these, riluzole, a drug that inhibits glutamate release and induces neuroprotection in 3-nitroproprionic acid,103 quinolinic acid104 and in transgenic models of HD,105 has not demonstrated significant and sustained benefit in human clinical trials.106-108 Remacemide and amantadine, two noncompetitive NMDA antagonists, and lamotrigine, an antiepileptic that inhibits glutamate release, might offer transient symptomatic improvement,109,110 but do not have neuroprotective properties.
The theory that oxidative stress resulting from mito-chondrial dysfunction111 may play a role in striatal neuronal death in HD is reinforced by the observation that in HD patients complex II is deficient,112,113 and that 3-nitropropri-onic acid,114,115 a specific and an irreversible inhibitor of complex II, and malonate, another complex II inhibitor, replicate several pathogenic mechanisms observed in the spiny neurons of the striatum of HD patients. A dose of 600 mg of coenzyme Q10, a mitochondrial protector, has been shown to be marginally effective in HD.116
Glutamate toxicity and mitochondrial dysfunction together might ultimately induce the molecular cascades that are involved in apoptosis. Investigators have tried minocy-cline and doxycycline, caspase inhibitors, in transgenic models, but the results are inconclusive.117-120
The histone deacetylase (HDAC) inhibitors are a promising new avenue for the treatment of HD. The earliest step of neurodegeneration might be the accumulation of the polyQ tracts in the cytoplasm followed by the entry of fragments into the nucleus, which ultimately may interfere with several transcriptional factors necessary for normal function and survival of spiny neurons of the striatum. This may lead ultimately to cell death. The HDAC inhibitors are a new class of drugs, several of which are already in clinical trials to treat different types of cancers,121 that can reactivate the expression of suppressed genes for transcription factors and might help to prevent neurotoxicity. HDAC inhibitors have been shown to "arrest" polyQ toxicity in cell culture,122 yeast,123 Drosophila,124 and mouse models of HD,125 and improve motor function in the R6/2 HD mouse model.126
Restoration of striatal dysfunction by administering growth factors, including ciliary neurotrophic factor, nerve growth factor, BDNF, NT3, or by transplanting xenografts, human fetal cells or stem cells, has provided mixed results.127-131
This work was supported by the Grace Benson Research Fund.
1. Biglan, K., and I. Shoulson. 2002. Huntington's disease. In Parkinson s Disease and Movement Disorders. 4th Ed. Ed. J. Jankovic, and E. Tolosa. pp. 212-227. Philadelphia: Lippincott, Williams & Wilkins.
2. Wexler, N.S., J. Lorimer, J. Porter, F. Gomez, C. Moskowitz, E. Shackell, K. Marder, et al. 2004. Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset. Proc Natl Acad Sci USA 101:3498-3503.
3. Margolis, R.L., and C.A. Ross. 2003. Diagnosis of Huntington disease. Clin Chem 49:1726-1732.
4. Murgod, U.A., Q. Saleem, A. Anand, S.K. Brahmachari, S. Jain, and U.B. Muthane. 2001. Aclinical study of patients with genetically confirmed Huntington's disease from India. J Neurol Sci 190:73-78.
5. Byers, R.K., and J.A. Dodge. 1967. Huntington's chorea in children. Report of four cases. Neurology 17:587-596.
6. Byers, R.K., F.H. Gilles, and C. Fung. 1973. Huntington's disease in children. Neuropathologic study of four cases. Neurology 23:561569.
7. The Huntington's Disease Collaborative Research Group. 1993. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72:971-983.
8. Squitieri, F., C. Gellera, M. Cannella, C. Mariotti, G. Cislaghi, D.C. Rubinsztein, E.W. Almqvist, et al. 2003. Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course. Brain 126:946-955.
9. McInnis, M.G. 1996. Anticipation: an old idea in new genes. Am J Hum Genet 59:973-979.
10. Ranen, N.G., O.C. Stine, M.H. Abbott, M. Sherr, A.M. Codori, M.L. Franz, N.I. Chao, A.S. Chung, et al. 1995. Anticipation and instability of IT-15 (CAG)n repeats in parent-offspring pairs with Huntington disease. Am J Hum Genet 57:593-602.
11. Gusella, J.F., N.S. Wexler, P.M. Conneally, S.L. Naylor, M.A. Anderson, R.E. Tanzi, P.C. Watkins, et al. 1983. Apolymorphic DNA marker genetically linked to Huntington's disease. Nature 306:234238.
12. Takano, H., and J.F. Gusella. 2002. The predominantly HEAT-like motif structure of huntingtin and its association and coincident nuclear entry with dorsal, an NF-kB/Rel/dorsal family transcription factor. BMC Neurosci 3:15.
13. Andrade, M.A., and P. Bork. 1995. HEAT repeats in the Huntington's disease protein. Nat Genet 11:115-116.
14. Andrade, M.A., C. Perez-Iratxeta, and C.P. 2001. Protein repeats: structures, functions, and evolution. J Struct Biol 134:117131.
15. MacDonald, M.E. 2003. Huntingtin: alive and well and working in middle management. Sci STKE 2003: pe48.
16. Harjes, P., and E.E. Wanker. 2003. The hunt for huntingtin function: interaction partners tell many different stories. Trends Biochem Sci 28:425-433.
17. Landwehrmeyer, G.B., S.M. McNeil, L.St. Dure, P. Ge, H. Aizawa, Q. Huang, C.M. Ambrose, et al. 1995. Huntington's disease gene: regional and cellular expression in brain of normal and affected individuals. Ann Neurol 37:218-230.
18. Sharp, A.H., S.J. Loev, G. Schilling, S.H. Li, X.J. Li, J. Bao, M.V Wagster, et al. 1995. Widespread expression of Huntington's disease gene (IT15) protein product. Neuron 14:1065-1074.
19. Strong, T.V., D.A. Tagle, J.M. Valdes, L.W. Elmer, K. Boehm, M. Swaroop, K.W. Kaatz, et al. 1993. Widespread expression of the human and rat Huntington's disease gene in brain and nonneural tissues. Nat Genet 5:259-265.
20. Ferrante, R.J., C.A. Gutekunst, F. Persichetti, S.M. McNeil, N.W. Kowall, J.F. Gusella, M.E. MacDonald, et al. 1997. Heterogeneous topographic and cellular distribution of huntingtin expression in the normal human neostriatum. J Neurosci 17:3052-3063.
21. Hilditch-Maguire, P., F. Trettel, L.A. Passani, A. Auerbach, F. Per-sichetti, and M.E. MacDonald. 2000. Huntingtin: an iron-regulated protein essential for normal nuclear and perinuclear organelles. Hum Mol Genet 9:2789-2797.
22. Lunkes, A., K.S. Lindenberg, L. Ben-Haiem, C. Weber, D. Devys, G.B. Landwehrmeyer, J.L. Mandel, and Y. Trottier. 2002. Proteases acting on mutant huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions. Mol Cell 10: 259-269.
23. DiFiglia, M. 2002. Huntingtin fragments that aggregate go their separate ways. Mol Cell 10:224-225.
24. Trushina, E., M.P. Heldebrant, C.M. Perez-Terzic, R. Bortolon, I.V Kovtun, J.D. Badger, 2nd, A. Terzic, et al. 2003. Microtubule desta-bilization and nuclear entry are sequential steps leading to toxicity in Huntington's disease. Proc Natl Acad Sci USA 100:12171-12176.
25. Sugars, K.L., and D.C. Rubinsztein. 2003. Transcriptional abnormalities in Huntington disease. Trends Genet 19:233-238.
26. Li, S.H., and X.J. Li. 2004. Huntingtin-protein interactions and the pathogenesis of Huntington's disease. Trends Genet 20:146-154.
27. Burke, M.G., R. Woscholski, and S.N. Yaliraki. 2003. Differential hydrophobicity drives self-assembly in Huntington's disease. Proc Natl Acad Sci USA 100:13928-13933.
28. Vonsattel, J.P., R.H. Myers, T.J. Stevens, R.J. Ferrante, E.D. Bird, and E.P. Richardson, Jr. 1985. Neuropathological classification of Huntington's disease. J Neuropathol Exp Neurol 44:559-577.
29. Cicchetti, F., L. Prensa, Y. Wu, and A. Parent. 2000. Chemical anatomy of striatal interneurons in normal individuals and in patients with Huntington's disease. Brain Res Rev 34:80-101.
30. Bugiani, O., M. Tabaton, and S. Cammarata. 1984. Huntington's disease: survival of large striatal neurons in the rigid variant. Ann Neurol 15:154-156.
32. Glass, M., M. Dragunow, and R.L. Faull. 2000. The pattern of neurodegeneration in Huntington's disease: a comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington's disease. Neuroscience 97:505-519.
33. Denovan-Wright, E.M., and H.A. Robertson. 2000. Cannabinoid receptor messenger RNA levels decrease in a subset of neurons of the lateral striatum, cortex and hippocampus of transgenic Huntington's disease mice. Neuroscience 98:705-713.
34. Rosas, H.D., A.K. Liu, S. Hersch, M. Glessner, R.J. Ferrante, D.H. Salat, A. van der Kouwe, et al. 2002. Regional and progressive thinning of the cortical ribbon in Huntington's disease. Neurology 58:695-701.
35. Selemon, L.D., G. Rajkowska, and P.S. Goldman-Rakic. 2004. Evidence for progression in frontal cortical pathology in late-stage Huntington's disease. J Comp Neurol 468:190-204.
36. Macdonald, V., G.M. Halliday, R.J. Trent, and E.A. McCusker. 1997. Significant loss of pyramidal neurons in the angular gyrus of patients with Huntington's disease. Neuropathol Appl Neurobiol 23:492495.
37. Macdonald, V., and G. Halliday. 2002. Pyramidal cell loss in motor cortices in Huntington's disease. Neurobiol Dis 10:378-386.
38. Yohrling, G.J., G.C. Jiang, M.M. DeJohn, D.W. Miller, A.B. Young, K.E. Vrana, and J.H. Cha. 2003. Analysis of cellular, transgenic and human models of Huntington's disease reveals tyrosine hydroxylase alterations and substantia nigra neuropathology. Brain Res Mol Brain Res 119:28-36.
39. Berardelli, A., J. Noth, P.D. Thompson, E.L. Bollen, A. Curra, G. Deuschl, J.G. van Dijk, et al. 1999. Pathophysiology of chorea and bradykinesia in Huntington's disease. Mov Disord 14:398-403.
40. Myers, R.H., D.S. Sax, M. Schoenfeld, E.D. Bird, P.A. Wolf, J.P. Vonsattel, R.F. White, and J.B. Martin. 1985. Late onset of Huntington's disease. J Neurol Neurosurg Psychiatry 48:530-534.
41. McCusker, E., F. Richards, D. Sillence, M. Wilson, and R.J. Trent. 2000. Huntington's disease: neurological assessment of potential gene carriers presenting for predictive DNA testing. J Clin Neurosci 7: 38-41.
42. Starr, A. 1967. A disorder of rapid eye movements in Huntington's chorea. Brain 90:545-564.
43. Leigh, R.J., S.A. Newman, S.E. Folstein, A.G. Lasker, and B.A. Jensen. 1983. Abnormal ocular motor control in Huntington's disease. Neurology 33:1268-1275.
44. Lasker, A.G., and D.S. Zee. 1997. Ocular motor abnormalities in Huntington's disease. Vision Res 37:3639-3645.
45. Winograd-Gurvich, C.T., N. Georgiou-Karistianis, A. Evans, L. Millist, J.L. Bradshaw, A. Churchyard, E. Chiu, and O.B. White. 2003. Hypometric primary saccades and increased variability in visually-guided saccades in Huntington's disease. Neuropsychologia 41:1683-1692.
46. Jayaraman, A. 1985. Functional compartments of the cat striatum. Neurosci Abs 11:199.
47. Louis, E.D., P. Lee, L. Quinn, and K. Marder. 1999. Dystonia in Huntington's disease: prevalence and clinical characteristics. Mov Disord 14:95-101.
48. Ashizawa, T., and J. Jankovic. 1996. Cervical dystonia as the initial presentation of Huntington's disease. Mov Disord 11:457-459.
49. Jankovic, J., and T. Ashizawa. 1995. Tourettism associated with Huntington's disease. Mov Disord 10:103-105.
50. Sanchez-Pernaut, R., G. Kunig, A. del Barrio Alba, J.G. de Yebenes, P. Vontobel, and K.L. Leenders. 2000. Bradykinesia in early Huntington's disease. Neurology 54:119-125.
51. van Vugt, J.P., K.K. Piet, L.J. Vink, S. Siesling, A.H. Zwinderman, H.A. Middelkoop, and R.A. Roos. 2004. Objective assessment of motor slowness in Huntington's disease: clinical correlates and 2-year follow-up. Mov Disord 19:285-297.
52. Koller, W.C., and J. Trimble. 1985. The gait abnormality of Huntington's disease. Neurology 35:1450-1454.
53. Thaut, M.H., R. Miltner, H.W. Lange, C.P. Hurt, and V. Hoemberg. 1999. Velocity modulation and rhythmic synchronization of gait in Huntington's disease. Mov Disord 14:808-819.
54. Hausdorff, J.M., S.L. Mitchell, R. Firtion, C.K. Peng, M.E. Cudkowicz, J.Y. Wei, and A.L. Goldberger. 1997. Altered fractal dynamics of gait: reduced stride-interval correlations with aging and Huntington's disease. J Appl Physiol 82:262-269.
55. Churchyard, A.J., M.E. Morris, N. Georgiou, E. Chiu, R. Cooper, and R. Iansek. 2001. Gait dysfunction in Huntington's disease: parkin-sonism and a disorder of timing. Implications for movement rehabilitation. Adv Neurol 87:375-385.
56. Ho, A.K., B.J. Sahakian, R.G. Brown, R.A. Barker, J.R. Hodges, M.N. Ane, J. Snowden, et al. 2003. Profile of cognitive progression in early Huntington's disease. Neurology 61:1702-1706.
57. Snowden, J.S., D. Craufurd, J. Thompson, and D. Neary. 2002. Psychomotor, executive, and memory function in preclinical Huntington's disease. J Clin Exp Neuropsychol 24:133-145.
58. Mendez, M.F. 1994. Huntington's disease: update and review of neu-ropsychiatric aspects. Int J Psychiatry Med 24:189-208.
59. Rosenblatt, A., and I. Leroi. 2000. Neuropsychiatry of Huntington's disease and other basal ganglia disorders. Psychosomatics 41:24-30.
60. Paulsen, J.S., R.E. Ready, J.M. Hamilton, M.S. Mega, and J.L. Cummings. 2001. Neuropsychiatric aspects of Huntington's disease. J Neurol Neurosurg Psychiatry 71:310-314.
61. Schoenfeld, M., R.H. Myers, L.A. Cupples, B. Berkman, D.S. Sax, and E. Clark. 1984. Increased rate of suicide among patients with Huntington's disease. J Neurol Neurosurg Psychiatry 47:1283-1287.
62. Arciniegas, D.B., and C.A. Anderson. 2002. Suicide in neurologic illness. Curr Treat Options Neurol 4:457-468.
63. Di Maio, L., F. Squitieri, G. Napolitano, G. Campanella, J.A. Trofatter, and P.M. Conneally. 1993. Suicide risk in Huntington's disease. J Med Genet 30:293-295.
64. Sorensen, S.A., and K. Fenger. 1992. Causes of death in patients with Huntington's disease and in unaffected first degree relatives. J Med Genet 29:911-914.
65. Robins Wahlin, T.B., L. Backman, A. Lundin, A. Haegermark, B. Winblad, and M. Anvret. 2000. High suicidal ideation in persons testing for Huntington's disease. Acta Neurol Scand 102:150-161.
66. Cummings, J.L. 1995. Behavioral and psychiatric symptoms associated with Huntington's disease. AdvNeurol 65:179-186.
67. Anderson, K.E., E.D. Louis, Y. Stern, and K.S. Marder. 2001. Cognitive correlates of obsessive and compulsive symptoms in Hunting-ton's disease. Am J Psychiatry 158:799-801.
68. Kremer, H.P., and R.A. Roos. 1992. Weight loss in Huntington's disease. Arch Neurol 49:349.
69. Djousse, L., B. Knowlton, L.A. Cupples, K. Marder, I. Shoulson, and R.H. Myers. 2002. Weight loss in early stage of Huntington's disease. Neurology 59:1325-1330.
70. Hamilton, J.M., T. Wolfson, G.M. Peavy, M.W. Jacobson, and J. Corey-Bloom. 2004. Rate and correlates of weight change in Huntington's disease. J Neurol Neurosurg Psychiatry 75:209-212.
71. Braak, H., and E. Braak. 1992. Anatomy of the human hypothalamus (chiasmatic and tuberal region). Prog Brain Res 93:3-14; discussion 14-16.
72. Kremer, H.P. 1992. The hypothalamic lateral tuberal nucleus: normal anatomy and changes in neurological diseases. Prog Brain Res 93: 249-261.
73. Kremer, B., S.J. Tallaksen-Greene, and R.L. Albin. 1993. AMPAand NMDA binding sites in the hypothalamic lateral tuberal nucleus: implications for Huntington's disease. Neurology 43:1593-1595.
74. Keogh, H.J., R.H. Johnson, R.N. Nanda, and W.R. Sulaiman. 1976. Altered growth hormone release in Huntington's chorea. J Neurol Neurosurg Psychiatry 39:244-248.
75. Kremer, H.P., R.A. Roos, M. Frolich, J.K. Radder, A.C. Nieuwenhuijzen Kruseman, A. Van der Velde, and O.J. Buruma. 1989. Endocrine functions in Huntington's disease. A two-and-a-half years follow-up study. J Neurol Sci 90:335-344.
76. Podolsky, S., N.A. Leopold, and D.S. Sax. 1972. Increased frequency of diabetes mellitus in patients with Huntington's chorea. Lancet 1:1356-1358.
77. Hurlbert, M.S., W. Zhou, C. Wasmeier, F.G. Kaddis, J.C. Hutton, and C.R. Freed. 1999. Mice transgenic for an expanded CAG repeat in the Huntington's disease gene develop diabetes. Diabetes 48:649-651.
78. Andreassen, O.A., A. Dedeoglu, V. Stanojevic, D.B. Hughes, S.E. Browne, C.A. Leech, R.J. Ferrante, et al. 2002. Huntington's disease of the endocrine pancreas: insulin deficiency and diabetes mellitus due to impaired insulin gene expression. Neurobiol Dis 11:410-424.
79. Nance, M.A., and R.H. Myers. 2001. Juvenile onset Huntington's disease-clinical and research perspectives. Ment Retard Dev Disabil Res Rev 7:153-157.
80. Louis, A.G.E.D., K.E. Anderson, C. Moskowitz, D.Z. Thorne, and K. Marder. 2000. Dystonia-predominant adult-onset Huntington disease: association between motor phenotype and age of onset in adults. Arch Neurol 57:1326-1330.
81. Reuter, I., M.T. Hu, T.C. Andrews, D.J. Brooks, C. Clough, and K.R. Chaudhuri. 2000. Late onset levodopa responsive Huntington's disease with minimal chorea masquerading as Parkinson plus syndrome. J Neurol Neurosurg Psychiatry 68:238-241.
82. James, C.M., G.D. Houlihan, R.G. Snell, J.P. Cheadle, and P.S. Harper. 1994. Late-onset Huntington's disease: a clinical and molecular study. Age Ageing 23:445-448.
83. James, R.C. James, F. Xiang, J. Monaghan, D. Han, Z. Zhang, L. Edstrom, M. Anvret, and S.B. Prusiner. 2001. Huntington disease phe-nocopy is a familial prion disease. Am J Hum Genet 69:1385-1388.
84. Margolis, R.L., E. O'Hearn, A. Rosenblatt, V. Willour, S.E. Holmes, M.L. Franz, C. Callahan, H.S. Hwang, J.C. Troncoso, and C.A. Ross. 2001. A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion. Ann Neurol 50:373-380.
85. Holmes, S.E., E. O'Hearn, A. Rosenblatt, C. Callahan, H.S. Hwang, R.G. Ingersoll-Ashworth, A. Fleisher, et al. 2001. Arepeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease-like 2. Nat Genet 29:377-378.
86. Walker, R.H., A. Rasmussen, D. Rudnicki, S.E. Holmes, E. Alonso, T. Matsuura, T. Ashizawa, et al. 2003. Huntington's disease-like 2 can present as chorea-acanthocytosis. Neurology 61:1002-1004.
87. Walker, R.H., J. Jankovic, E. O'Hearn, and R.L. Margolis. 2003. Phenotypic features of Huntington's disease-like 2. Mov Disord 18: 1527-1530.
88. Singer, C. 1992. "Haw River syndrome" or dentato-rubro-pallido-luysian atrophy? Arch Neurol 49:13-14.
89. Burke, J.R., T. Ikeuchi, R. Koide, S. Tsuji, M. Yamada, M.A. Pericak-Vance, and J.M. Vance. 1994. Dentatorubral-pallidoluysian atrophy and Haw River syndrome. Lancet 344:1711-1712.
90. Burke, J.R., M.S. Wingfield, K.E. Lewis, A.D. Roses, J.E. Lee, C. Hulette, M.A. Pericak-Vance, and J.M. Vance. 1994. The Haw River syndrome: dentatorubropallidoluysian atrophy (DRPLA) in an African-American family. Nat Genet 7:521-524.
91. Potter, N.T., H. Yanagisawa, and M. Yamada. 1996. Different origins of expanded repeats for Haw River syndrome and dentatorubral-pallidoluysian atrophy. Lancet 347:1271.
92. Stevanin, G., H. Fujigasaki, A.S. Lebre, A. Camuzat, C. Jeannequin, C. Dode, J. Takahashi, C. San, et al. 2003. Huntington's disease-like phenotype due to trinucleotide repeat expansions in the TBP and JPH3 genes. Brain 126:1599-1603.
93. Bauer, P., F. Laccone, A. Rolfs, U. Wullner, S. Bosch, H. Peters, S. Liebscher, et al. 2004. Trinucleotide repeat expansion in SCA17/TBP in white patients with Huntington's disease-like phenotype. J Med Genet 41:230-232.
94. Breedveld, G.J., J.W. van Dongen, C. Danesino, A. Guala, A.K. Percy, L.S. Dure, P. Harper, et al. 2002. Mutations in TITF-1 are associated with benign hereditary chorea. Hum Mol Genet 11:971-979.
95. Kambouris, M., S. Bohlega, A. Al-Tahan, and B.F. Meyer. 2000. Localization of the gene for a novel autosomal recessive neurodegenerative Huntington-like disorder to 4p15.3. Am J Hum Genet 66:445-452.
96. Grimbergen, Y.A., and R.A. Roos. 2003. Therapeutic options for Huntington's disease. Curr Opin Investig Drugs 4:51-54.
97. Parsa, M.A., E. Szigethy, J.M. Voci, and H.Y. Meltzer. 1997. Risperi-done in treatment of choreoathetosis of Huntington's disease. J Clin Psychopharmacol 17:134-135.
98. Erdemoglu, A.K., and C. Boratav. 2002. Risperidone in chorea and psychosis of Huntington's disease. Eur J Neurol 9:182-183.
99. Bonelli, R.M., F.A. Mahnert, and G. Niederwieser. 2002. Olanzapine for Huntington's disease: an open label study. Clin Neuropharmacol 25:263-265.
100. Paleacu, D., M. Anca, and N. Giladi. 2002. Olanzapine in Huntington's disease. Acta Neurol Scand 105:441-444.
101. DiFiglia, M. 1990. Excitotoxic injury of the neostriatum: a model for Huntington's disease. Trends Neurosci 13:286-289.
102. Kieburtz, K. 1999. Antiglutamate therapies in Huntington's disease. J Neural Transm Suppl 55:97-102.
103. Palfi, S., R.J. Ferrante, E. Brouillet, M.F. Beal, R. Dolan, M.C. Guyot, M. Peschanski, and P. Hantraye. 1996. Chronic 3-nitropropionic acid treatment in baboons replicates the cognitive and motor deficits of Huntington's disease. J Neurosci 16:3019-3025.
104. Mary, V., F. Wahl, and J.M. Stutzmann. 1995. Effect of riluzole on quinolinate-induced neuronal damage in rats: comparison with blockers of glutamatergic neurotransmission. Neurosci Lett 201:92-96.
105. Schiefer, J., G.B. Landwehrmeyer, H.G. Luesse, A. Sprunken, C. Puls, A. Milkereit, E. Milkereit, and C.M. Kosinski. 2002. Riluzole prolongs survival time and alters nuclear inclusion formation in a trans-genic mouse model of Huntington's disease. Mov Disord 17:748-757.
106. Rosas, H.D., W.J. Koroshetz, B.G. Jenkins, Y.I. Chen, D.L. Hayden, M.F. Beal, and M.E. Cudkowicz. 1999. Riluzole therapy in Huntington's disease (HD). Mov Disord 14:326-330.
107. Seppi, K., J. Mueller, T. Bodner, E. Brandauer, T. Benke, H. Weirich-Schwaiger, W. Poewe, and G.K. Wenning. 2001. Riluzole in Huntington's disease (HD): an open label study with one year follow up. J Neurol 248:866-869.
108. Huntington Study Group. 2003. Dosage effects of riluzole in Hun-tington's disease: a multicenter placebo-controlled study. Neurology 61:1551-1556.
109. Lucetti, C., G. Gambaccini, S. Bernardini, G. Dell'Agnello, L. Petrozzi, G. Rossi, and U. Bonuccelli. 2002. Amantadine in Hun-tington's disease: open-label video-blinded study. Neurol Sci 23 Suppl 2:S83-84.
110. Verhagen Metman, L., M.J. Morris, C. Farmer, M. Gillespie, K. Mosby, J. Wuu, and T.N. Chase. 2002. Huntington's disease: a randomized, controlled trial using the NMDA-antagonist amantadine. Neurology 59:694-699.
111. Panov, A.V., C.A. Gutekunst, B.R. Leavitt, M.R. Hayden, J.R. Burke, W.J. Strittmatter, and J.T. Greenamyre. 2002. Early mitochondrial calcium defects in Huntington's disease are a direct effect of poly-glutamines. Nat Neurosci 5:731-736.
112. Gu, M., M.T. Gash, V.M. Mann, F. Javoy-Agid, J.M. Cooper, and A.H. Schapira. 1996. Mitochondrial defect in Huntington's disease caudate nucleus. Ann Neurol 39:385-389.
113. Schapira, A.H. 1998. Mitochondrial dysfunction in neurodegenerative disorders. Biochim Biophys Acta 1366:225-233.
114. Vis, J.C., M.M. Verbeek, R.M. De Waal, H.J. Ten Donkelaar, and H.P. Kremer. 1999. 3-Nitropropionic acid induces a spectrum of Hunting-ton's disease-like neuropathology in rat striatum. Neuropathol Appl Neurobiol 25:513-521.
115. Napolitano, M., D. Centonze, P. Gubellini, S. Rossi, S. Spiezia, G. Bernardi, A. Gulino, and P. Calabresi. 2004. Inhibition of mitochon-
drial complex II alters striatal expression of genes involved in gluta-matergic and dopaminergic signaling: possible implications for Huntington's disease. Neurobiol Dis 15:407-414.
116. Huntington Study Group. 2001. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington's disease. Neurology 57:397-404.
117. Diguet, E., R. Rouland, and F. Tison. 2003. Minocycline is not beneficial in a phenotypic mouse model of Huntington's disease. Ann Neurol 54:841-842.
118. Hersch, S., K. Fink, J.P. Vonsattel, and R.M. Friedlander. 2003. Minocycline is protective in a mouse model of Huntington's disease. Ann Neurol 54:841; author reply 842-843.
119. Bonelli, R.M., C. Heuberger, and F. Reisecker. 2003. Minocycline for Huntington's disease: an open label study. Neurology 60:883884.
120. Smith, D.L., B. Woodman, A. Mahal, K. Sathasivam, S. Ghazi-Noori, P.A. Lowden, G.P. Bates, and E. Hockly. 2003. Minocycline and doxycycline are not beneficial in a model of Huntington's disease. Ann Neurol 54:186-196.
121. Johnstone, R.W. 2002. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov 1:287-299.
122. McCampbell, A., A.A. Taye, L. Whitty, E. Penney, J.S. Steffan, and K.H. Fischbeck. 2001. Histone deacetylase inhibitors reduce poly-glutamine toxicity. Proc Natl Acad Sci USA 98:15179-15184.
123. Hughes, R.E., R.S. Lo, C. Davis, A.D. Strand, C.L. Neal, J.M. Olson, and S. Fields. 2001. Altered transcription in yeast expressing expanded polyglutamine. Proc Natl Acad Sci USA 98:1320113206.
124. Steffan, J.S., L. Bodai, J. Pallos, M. Poelman, A. McCampbell, B.L. Apostol, A. Kazantsev, et al. 2001. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413:739-743.
125. Ferrante, R.J., J.K. Kubilus, J. Lee, H. Ryu, A. Beesen, B. Zucker, K. Smith, et al. 2003. Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice. J Neurosci 23:9418-9427.
126. Hockly, E., V.M. Richon, B. Woodman, D.L. Smith, X. Zhou, E. Rosa, K. Sathasivam, et al. 2003. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc Natl Acad Sci USA 100: 2041-2046.
127. Alberch, J., E. Perez-Navarro, and J.M. Canals. 2004. Neurotrophic factors in Huntington's disease. Prog Brain Res 146:195-229.
128. Horellou, P., and J. Mallet. 1998. Neuronal grafts for Huntington's disease. Nat Med 4:669-670.
129. Gaura, V., A.C. Bachoud-Levi, M.J. Ribeiro, J.P. Nguyen, V. Frouin, S. Baudic, P. Brugieres, et al. 2004. Striatal neural grafting improves cortical metabolism in Huntington's disease patients. Brain 127: 65-72.
130. Hauser, R.A., S. Furtado, C.R. Cimino, H. Delgado, S. Eichler, S. Schwartz, D. Scott, et al. 2002. Bilateral human fetal striatal transplantation in Huntington's disease. Neurology 58:687-695.
131. Albin, R.L. 2002. Fetal striatal transplantation in Huntington's disease: time for a pause. J Neurol Neurosurg Psychiatry 73:612.
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