Neurochemical Research

, Volume 27, Issue 5, pp 403–406

The Effects of Lithium Chloride and Other Substances on Levels of Brain N-Acetyl-L-Aspartic Acid in Canavan Disease-Like Rats

  • Morris H. Baslow
  • Kazuhiro Kitada
  • Raymond F. Suckow
  • Basalingappa L. Hungund
  • Tadao Serikawa


Canavan disease (CD) is a human early-onset leukodystrophy, genetic in nature and resulting from an autosomally inherited recessive trait. CD is characterized by loss of the axon's myelin sheath, while leaving the axons intact, and spongiform degeneration, especially in white matter. It is an osmotic disease that affects both gray and white matter and is caused by the inability of oligodendrocytes to hydrolyze N-acetyl-L-aspartate (NAA) because of a lack of aspartoacylase activity. As a result, there is a build-up of NAA in brain with both cellular and extracellular edema, as well as NAA acidemia and NAA aciduria. Recent studies have indicated that several compounds have the ability to reduce brain levels of NAA in normal mice and rats. In this investigation, these compounds have been tested, using a CD-like rat model of the human disease to evaluate their potential for use in the treatment of the disease. Of seven substances tested in an acute 5-day study, only lithium chloride treatment resulted in a significant reduction of about 13% in whole-brain NAA levels in the CD-like rat model. This is the first pharmacological investigation of the effect of drugs on the level of brain NAA in an animal model of CD, and the first report of a substance that can reduce the brain NAA level in this model.

Aspartoacylase N-acetyl-L-aspartate brain Canavan disease lithium chloride spongiform leukodystrophy 


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  1. 1.
    Leone, P., Janson, C. G., McFhee, S. J., and During, M. J. 1999. Global CNS gene transfer for a childhood neurogenetic enzyme deficiency: Canavan disease. Curr. Opin. Mol. Therap. 1:487–492.Google Scholar
  2. 2.
    Matalon, R. and Michals-Matalon, K. 1999. Biochemistry and molecular biology of Canavan disease. Neurochem. Res. 24: 507–513.Google Scholar
  3. 3.
    Baslow, M. H. 2000. Canavan's spongiform leukodystrophy: a clinical anatomy of a genetic metabolic CNS disease. An analytical review. J. Mol. Neurosci. 15:61–69.Google Scholar
  4. 4.
    Kitada, K., Akimitsu, T., Shigematsu, Y., Kondo, A., Maihara, T., Yokoi, N., Kuramoto, T., Sasa, M., and Serikawa, T. 2000. Accumulation of N-acetyl-L-aspartate in the brain of the tremor rat, a mutant exhibiting absence-like seizure and spongiform degeneration in the central nervous system. J. Neurochem. 74:2512–2519.Google Scholar
  5. 5.
    Matalon, R., Rady, P. L., Platt, K. A., Skinner, H. B., Quast, M. J., Campbell, G. A., and Matalon, K., Ceci, D., Tyring, K., Nehls, M., Surendran, S., Wei, J., Ezell, E. H., and Szucs, S. 2000. Knock-out mouse for Canavan disease: a model for gene transfer to the central nervous system. J. Gene Med. 2:165–175.Google Scholar
  6. 6.
    Baslow, M. H., Suckow, R. F., and Hungund, B. L. 2000. Effects of ethanol and of alcohol dehydrogenase inhibitors on the reduction of N-acetylaspartate levels of brain in mice in vivo: a search for substances that may have therapeutic value in the treatment of Canavan disease, an autosomally inherited recessive CNS disease. J. Inher. Metab. Dis. 23:684–692.Google Scholar
  7. 7.
    O'Donnell, T., Rotzinger, S., Nakashima, T. T., Hanstock, C. C., Ulrich, M., and Silverstone, P. I. 2000. Chronic lithium and sodium valproate both decrease the concentration of myoinositol and increase the concentration of inositol monophosphates in rat brain. Brain Res. 880:84–91.Google Scholar
  8. 8.
    Guynn, R. W. and Faillace, L. A. 1979. The effect of the combination of lithium and haloperidol on brain intermediary metabolism in vivo. Psychopharmacol. 61:155–159.Google Scholar
  9. 9.
    Huang, W., Galdzicki, Z., van Gelderen, P., Balbo, A., Chikhale, E. G., Schapiro, M. B., and Rapoport, S. I. 2000. Brain myo-inositol level is elevated in Ts65Dn mouse and reduced after lithium treatment. NeuroReport 11:445–448.Google Scholar
  10. 10.
    Stoll, A. L., Renshaw, P. F., Sachs, G. S., Guimaraes, A. R., Miller, C., Cohen, B. M., Lafer, B., and Gonzales, R. G. 1992. The human brain resonance of choline-containing compounds is similar in patients receiving lithium treatment and controls: an in vivo proton magnetic resonance spectroscopy study. Biol. Psychiatry 32:944–949.Google Scholar
  11. 11.
    Davanzo, P., Thomas, M. A., Yue, K., Oshiro, T., Belin, T., Strober, M., and McCraken, J. 2001. Decreased anterior cingulated myo-inositol/creatine spectroscopy resonance with lithium treatment in children with bipolar disorder. Neuropsychopharmocology 24:359–369.Google Scholar
  12. 12.
    Moore, G. J., Bebchuk, J. M., Hasanat, K., Chen, G., Seraji-Bozorgzad, N., Wilds, I. B., Faulk, M. W., Koch, S., Glitz, D. A., Jolkovsky, L., and Manji, H. K. 2000. Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2's neurotropic effects? Biol. Psychiat. 48:1–8.Google Scholar
  13. 13.
    Sharma, R., Venkatasubramanian, P. N., Barany, M. and Davis, J. 1992. Proton magnetic resonance spectroscopy of the brain in schizophrenic and affective patients. Schizophren. Res. 8:43–49.Google Scholar

Copyright information

© Plenum Publishing Corporation 2002

Authors and Affiliations

  • Morris H. Baslow
    • 1
  • Kazuhiro Kitada
    • 2
  • Raymond F. Suckow
    • 3
  • Basalingappa L. Hungund
    • 1
    • 3
  • Tadao Serikawa
    • 2
  1. 1.Nathan S. Kline Institute for Psychiatric ResearchOrangeburg
  2. 2.Institute of Laboratory Animals, Graduate School of MedicineKyoto University Sakyo-KuKyotoJapan
  3. 3.New York State Psychiatric Institute and Columbia University College of Physicians and SurgeonsNew York

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