NeuroMolecular Medicine

, Volume 5, Issue 3, pp 235–241 | Cite as

Neuroprotective effects of phenylbutyrate against MPTP neurotoxicity

  • Gabriella Gardian
  • Lichuan Yang
  • Carine Cleren
  • Noel Y. Calingasan
  • Peter Klivenyi
  • M. Flint Beal
Original Article

Abstract

There is increasing evidence that administration of histone deacetylase (HDAC) inhibitors can exert neuroprotective effects by a variety of mechanisms. Phenylbutyrate is a well-known HDAC inhibitor, which increases gene transcription of a number of genes, and also exerts neuroprotective effects. These include several antioxidant enzymes, chaperones, and genes involved in cell survival. We examined whether administration of phenylbutyrate could exert significant neuroprotective effects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which has been used to model Parkinson’s disease. Administration of phenylbutyrate significantly attenuated MPTP-induced depletion of striatal dopamine and loss of tyrosine hydroxylase-positive neurons in the substantia nigra. These findings provide further evidence that administration of phenylbutyrate may be a useful approach for the treatment of neurodegenerative diseases.

Indiex entries

Histone acetylation gene transcription phenylbutynate Parkinson’s disease MPTP 

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References

  1. Beal M. F., Ferrante R. J., Henshaw R., et al. (1995) 3-Nitropropionic acid neurotoxicity is attenuated in copper/zinc superoxide dismutase transgenic mice. J. Neurochem. 65, 919–922.PubMedCrossRefGoogle Scholar
  2. Beal M. F., Matson W. R., Storey E., et al. (1992) Kynurenic acid concentrations are reduced in Huntington’s disease cerebral cortex. J. Neurol. Sci. 108, 80–87.PubMedCrossRefGoogle Scholar
  3. Beal M. F., Matson W. R., Swartz K. J., Gamache P. H., and Bird E. D. (1990) Kynurenine pathway measurements in Huntington’s disease striatum: evidence for reduced formation of kynurenic acid. J. Neurochem. 55, 1327–1339.PubMedCrossRefGoogle Scholar
  4. Chang J. G., Hsieh-Li H. M., Jong Y. J., Wang N. M., Tsai C. H., and Li H. (2001) Treatment of spinal muscular atrophy by sodium butyrate. Proc. Natl. Acad. Sci. USA 98, 9808–9813.PubMedCrossRefGoogle Scholar
  5. Corcoran L. J., Mitchison T. J., and Liu Q. (2004) Anovel action of histone deacetylase inhibitors in a protein aggresome disease model. Curr. Biol. 14, 488–492.PubMedCrossRefGoogle Scholar
  6. Czubryt M. P., McAnally J., Fishman G. I., and Olson E. N. (2003) Regulation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) and mitochondrial function by MEF2 and HDAC5. Proc. Natl. Acad. Sci. USA 100, 1711–1716.PubMedCrossRefGoogle Scholar
  7. Ferrante R. J., Kubilus J. K., Lee J., et al. (2003) Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington’s disease mice. J. Neurosci. 23, 9418–9427.PubMedGoogle Scholar
  8. Hockly E., Richon V. M., Woodman B., 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.PubMedCrossRefGoogle Scholar
  9. Jeong M. R., Hashimoto R., Senatorov V. V., et al. (2003) Valproic acid, a mood stabilizer and anticonvulsant, protects rat cerebral cortical neurons from spontaneous cell death: a role of histone deacetylase inhibition. FEBS Lett. 542, 74–78.PubMedCrossRefGoogle Scholar
  10. Kaeberlein M., McVey M., and Guarente L. (1999) The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Gene Dev. 13, 2570–2580.PubMedCrossRefGoogle Scholar
  11. Kang H. L., Benzer S., and Min K. T. (2002) Life extension in Drosophila by feeding a drug. Proc. Natl. Acad. Sci. USA 99, 838–843.PubMedCrossRefGoogle Scholar
  12. Leoni F., Zaliani A., Bertolini G., et al. (2002) The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines. Proc. Natl. Acad. Sci. USA 99, 2995–3000.PubMedCrossRefGoogle Scholar
  13. Maehara K., Uekawa N., and Isobe K. (2002) Effects of histone acetylation on transcriptional regulation of manganese superoxide dismutase gene. Biochem. Biophys. Res. Comm. 295, 187–192.CrossRefGoogle Scholar
  14. McCampbell A., Taye A. A., Whitty L., Penney E., Steffan J. S., and Fischbeck K. H. (2001) Histone deacetylase inhibitors reduce polyglutamine toxicity. Proc. Natl. Acad. Sci. USA 98, 15,179–15,184.CrossRefGoogle Scholar
  15. McGuinness M. C., Lu J. F., Zhang H. P., et al. (2003) Role of ALDP (ABCD1) and mitochondria in X-linked adrenoleukodystrophy. Mol. Cell Biol. 23, 744–753.PubMedCrossRefGoogle Scholar
  16. McKinsey T. A., Zhang C. L., and Olson E. N. (2000) Activation of myocyte enhancer factor-2 transcription factor by calcium/calmodulin-dependent protein kinase-stimulated binding of 14-3-3 to histone deactylase 5. Proc. Natl. Acad. Sci. USA 97, 14400–14405.PubMedCrossRefGoogle Scholar
  17. Minamiyama M., Katsuno M., Adachi H., et al. (2004) Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Hum. Mol. Genet. 13, 1183–1192.PubMedCrossRefGoogle Scholar
  18. Naya F. J., Black B. L., Wu H., et al. (2002) Mitochondrial deficiency and cardiac sudden death in mice lacking the MEF2A transcription factor. Nat. Med. 8, 1303–1309.PubMedCrossRefGoogle Scholar
  19. Onyango P., Celic I., McCaffery M., et al. (2002) SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria. Proc. Natl. Acad. Sci. USA 99, 13653–13658.PubMedCrossRefGoogle Scholar
  20. Puigserver P. and Spiegelman B. M. (2003) Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr. Rev. 24, 78–90.PubMedCrossRefGoogle Scholar
  21. Ryu H., Lee J., Olofsson B. A., et al. (2003) Histone deacetylase inhibitors prevent oxidative neuronal death independent of expanded polyglutamine repeats via an Sp1-dependent pathway. Proc. Natl. Acad. Sci. USA 100, 4281–4286.PubMedCrossRefGoogle Scholar
  22. Schulz J. B., Henshaw D. R., MacGarvey U., and Beal, M. F. (1996) Involvement of oxidative stress in 3-nitropropionic acid neurotoxicity. Neurochem. Int. 29, 167–171.PubMedCrossRefGoogle Scholar
  23. Steffan J. S., Bodai L., Pallos J., et al. (2001) Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413, 739–743.PubMedCrossRefGoogle Scholar
  24. Tissenbaum H. A. and Guarente L. (2001) Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410, 227–230.PubMedCrossRefGoogle Scholar
  25. Wu H., Kanatous S. B., Thurmond F. A., et al. (2002) Regulation of mitochondrial biogenesis in skeletal muscle by CaMK. Science 296, 349–352.PubMedCrossRefGoogle Scholar
  26. Youn H. D., Grozinger C. M., and Liu J. O. (2000) Calcium regulates transcriptional repression of myocyte enhancer factor 2 by histone deacetylase 4. J. Biol. Chem. 275, 22,563–22,567.CrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2004

Authors and Affiliations

  • Gabriella Gardian
    • 1
  • Lichuan Yang
    • 1
  • Carine Cleren
    • 1
  • Noel Y. Calingasan
    • 1
  • Peter Klivenyi
    • 1
  • M. Flint Beal
    • 1
  1. 1.Department of Neurology and NeuroscienceWeill Medical College of Cornell University, New York-Presbyterian HospitalNew York

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