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Neuroprotective effects of phenylbutyrate against MPTP neurotoxicity

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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.

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References

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Steffan J. S., Bodai L., Pallos J., et al. (2001) Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413, 739–743.

    Article  PubMed  CAS  Google Scholar 

  • Tissenbaum H. A. and Guarente L. (2001) Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410, 227–230.

    Article  PubMed  CAS  Google Scholar 

  • Wu H., Kanatous S. B., Thurmond F. A., et al. (2002) Regulation of mitochondrial biogenesis in skeletal muscle by CaMK. Science 296, 349–352.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

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Correspondence to M. Flint Beal.

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Gardian, G., Yang, L., Cleren, C. et al. Neuroprotective effects of phenylbutyrate against MPTP neurotoxicity. Neuromol Med 5, 235–241 (2004). https://doi.org/10.1385/NMM:5:3:235

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  • DOI: https://doi.org/10.1385/NMM:5:3:235

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