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Antiglutamate therapies in Huntington’s disease

  • K. Kieburtz
Conference paper
Part of the 6th International Winter Conference on N eurodegeneration book series (NEURAL SUPPL, volume 55)

Summary

Huntington’s disease is an autosomal dominant neurodegenerative disorder caused by an unstable trinucleotide CAG repeat. The mechanism by which the genetic defect leads to neuronal injury and death is unknown, but is thought to include glutamate-mediated excitotoxicity and abnormalities of mitochondrial energy production. Both of these mechanisms may lead to a final common pathway of increased production of free radical species. Prior clinical trials in patients with Huntington’s disease that have addressed these hypotheses have been limited by size. A current, NIH-funded trial of remacemide hydrochloride and Coenzyme Q10 in 340 patients with Huntington’s disease is described. This is the largest and longest multi-center trial in Huntington’s disease to address the glutamate- and mitochondrialmediated hypotheses of neurodegeneration.

Keywords

Quinolinic Acid Striatal Projection Neuron Total Functional Capacity Prior Clinical Trial Hopkins Verbal Learning Test 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Albin RL, Young AB, Penney JB (1989) The functional anatomy of basal ganglia disorders. Trends Neurosci 12: 366–375.PubMedCrossRefGoogle Scholar
  2. Albin RL, Young AB, Penney JB, Handelin B, Balfour R, Anderson KD, Markel DS, Tourtellotte WW, Reiner A (1990) Abnormalities of striatal projection neurons and N-methyl-D-aspartate receptors in presymptornatic Huntington’s disease. N Engl J Med 332: 1293–1298.CrossRefGoogle Scholar
  3. Bamford KA, Caine ED, Kido DR, Plassche WM, Shoulson I (1989) Clinical-pathologic correlation in Huntington’s disease: A neuropsychological and computed tomography study. Neurology 39: 796–801.PubMedGoogle Scholar
  4. Beal MF, Kowall NW, Ellison DW, Mazurek MF, Swartz KJ, Martin JB (1986) Replication of the neurochemical characteristics of Huntington’s disease by quinolinic acid. Nature 321: 168–171.PubMedCrossRefGoogle Scholar
  5. Beal MF, Ferrante RJ, Swartz KJ, Kowall NW (1991) Chronic quinolinic acid lesions in rats closely resemble Huntington’s disease. J Neurosci 11: 1649–1659.PubMedGoogle Scholar
  6. Beal W, Brouillet E, Jenkins BG, Ferrante RJ, Kowall NW, Miller JM, Storey E, Srivastava R, Rosen BR, Hyman BT (1993a) Neurochemical and histological characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid. J Neurosci 13: 4181–4192.PubMedGoogle Scholar
  7. Beal MF, Brouillet E, Jenkins BG, Henshaw R, Rosen B, Hyman BT (1993b) Agedependent striatal excitotoxic lesions produced by the endogenous mitochondrial inhibitor malonate. J Neurochem 61: 1147–1150.PubMedCrossRefGoogle Scholar
  8. Beal MF, Henshaw DR, Jenkins BG, Rosen BR, Schulz JB (1994) Coenzyme Q10 and nicotinamide block striatal lesions produced by the mitochondrial toxin malonate. Ann Neurol 36: 882–888.PubMedCrossRefGoogle Scholar
  9. Brandt J (1991) The Hopkins verbal learning test: development of a new memory test with six equivalent forms. Clin Neuropsychol 5: 125–142.CrossRefGoogle Scholar
  10. Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1: 623–634.PubMedCrossRefGoogle Scholar
  11. Coyle JT, Schwarcz R (1976) Lesion of striatal neurons with kainic acid provides a model for Huntington’s chorea. Nature 263: 244–246.PubMedCrossRefGoogle Scholar
  12. Feigin A, Kieburtz K, Bordwell K, Como P, Steinberg K, Sotack J, Zimmerman C, Hickey C, Orme C, Shoulson I (1995) Functional decline in Huntington’s disease. Mov Disord 10: 211–214.PubMedCrossRefGoogle Scholar
  13. Graveland GA, Williams RS, DiFiglia M (1985) Evidence of degenerative and regenerative changes in neostriatal spiny neurons in Huntington’s disease. Science 227: 770–773.PubMedCrossRefGoogle Scholar
  14. Greenamyre JT, Shoulson I (1994) Huntington’s Disease. In: Calne DB (ed) Neurodegenerative disease. Saunders, Philadelphia, pp 685–704.Google Scholar
  15. Greene JG, Porter MP, Eller RV, Greenamyre JT (1993) Inhibition of succinate dehydrogenase by malonic acid produces an “excitotoc” lesion in rat striatum. J Neurochem 61: 1151–1154.PubMedCrossRefGoogle Scholar
  16. 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.CrossRefGoogle Scholar
  17. The Huntington Study Group (1996) Unified Huntington’s Disease Rating Scale: Reiliability and Consistency. Mov Disord 11: 136–142.CrossRefGoogle Scholar
  18. Kieburtz K, Feigin A, McDermott M, Como P, Abwender D, Zimmerman C, Hickey C, Orme C, Claude K, Sotack J, Greenamyre JT, Dunn C, Shoulson I (1996) A controlled trial of the glutamate antagonist remacemide hydrochloride in Huntington’s disease. Mov Disord 11: 273–277.PubMedCrossRefGoogle Scholar
  19. Kremer B, Clark CM, Hardy M, Almqvist E, Raymond L, Hayden MR (1997) Lamotrigine does not retard the progression of Huntington’s disease. 17th International Meeting of the World Federation of Neurology Research Group on Huntington’s Disease 8/30-9/2/97 (abstract).Google Scholar
  20. Landwehrmeyer GB, Standaert DG, Testa CM, Penney JB, Young AB (1994) NMDA receptor subunit expression by rat striatal projection neurons and intemeurons. J Neurosci 14: 5297–5308.Google Scholar
  21. Myers RH, Sax DS, Koroshetz WJ, Mastromauro C, Cupples LA, Kiely DK, Pettengill FK, Bird ED (1991) Factors associated with slow progression in Huntington’s disease. Arch Neurol 48: 800–804.PubMedCrossRefGoogle Scholar
  22. Penney JB Jr, Young AB, Shoulson I, Starosta-Rubenstein S, Snodgrass SR, Sanchez Ramos J, Ramos-Arroyo M, Gomez F, Penchaszadeh G, Alvir J, Esteves J, DeQuiroz I, Marsol N, Moreno H, Conneally PM, Bonilla E, Wexler NS (1990) Huntington’s disease in Venezuela: 7 years of follow-up on symptomatic and asymptomatic individuals. Mov Disord 5: 93–99.PubMedCrossRefGoogle Scholar
  23. Petrides M (1990) Nonspatial conditional learning impaired in patients with unilateral frontal but not unilateral temporal lobe excisions. Neuropsychologia 28: 137–149.PubMedCrossRefGoogle Scholar
  24. Porter RHP, Greenamyre JT (1995) Regional variations in the pharmacology of NMDA receptor channel blockers: implications for therapeutic potential. J Neurochem 64: 614–623.PubMedCrossRefGoogle Scholar
  25. Reitan RM, Wolfson D (1958) The Halstead-Reitan Neuropsychological Test Batttery. Neuropsychology Press, Tucson.Google Scholar
  26. Schretlen D, Bobholz JH, Brandt J (1996) Development and psychometric properties of the Brief Test of Attention. Clin Neuropsychol 10: 80–89.CrossRefGoogle Scholar
  27. Schwarcz R, Whetsell WO, Mangano RM (1982) Quinolinic acid: An endogenous metabolite that produces axon-sparing lesions in rat brain. Science 219: 316–318.CrossRefGoogle Scholar
  28. Shoulson I, Kurlan R, Rubin AJ, Goldblatt D, Behr J, Miller C, Kennedy J, Bamford KA, Caine ED, Kido DK, Plumb S, Odoroff C (1989a) Assessment of functional capacity in neurodegenerative movement disorders: Huntington’s disease as a prototype. In: Munsat TL (ed) Quantification of neurological deficit. Butterworths, Boston, pp 271–283.Google Scholar
  29. Shoulson I, Odoroff C, Oakes D, Behr J, Goldblatt D, Caine E, Kennedy J, Miller C, Bamford K, Rubin A, Plumb S, Kurlan R (1989b) A controlled clinical trial of baclofen as protective therapy in early Huntington’s disease. Ann Neurol 25: 252–259.PubMedCrossRefGoogle Scholar
  30. Young AB, Penney JB, Starosta-Rubinstein S, Markel DS, Berent S, Giordani B, Ehrenkaufer R, Jewett D, Hichwa R (1986a) PET scan investigations of Huntington’s disease: cerebral metabolic correlates of neurological features and functional decline. Ann Neurol 20: 296–303.PubMedCrossRefGoogle Scholar
  31. Young AB, Shoulson I, Penney JB, Starosta-Rubinstein S, Gomez F, Travers H, Ramos M, Snodgrass SR, Bonilla A, Moreno H, Wexler N (1986b) Huntington’s disease in Venezuela: neurological features and functional decline. Neurology 36: 244–249.PubMedGoogle Scholar
  32. Young AB, Greenamyre JT, Hollingsworth Z, Albin R, D’Amato C, Shoulson I, Penney JB (1988) NMDA receptor losses in putamen from patients with Huntington’s disease. Science 241: 981–983.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag/Wien 1999

Authors and Affiliations

  • K. Kieburtz
    • 1
  1. 1.University of RochesterRochesterUSA

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