Therapeutic application of histone deacetylase inhibitors for central nervous system disorders (original) (raw)

• Hardy, J. & Orr, H. The genetics of neurodegenerative diseases. J. Neurochem. 97, 1690–1699 (2006).
  Article CAS PubMed Google Scholar
• Coppede, F., Mancuso, M., Siciliano, G., Migliore, L. & Murri, L. Genes and the environment in neurodegeneration. Biosci. Rep. 26, 341–367 (2006).
  Article CAS PubMed Google Scholar
• Dosunmu, R., Wu, J., Basha, M. R. & Zawia, N. H. Environmental and dietary risk factors in Alzheimer's disease. Expert Rev. Neurother. 7, 887–900 (2007).
  Article CAS PubMed Google Scholar
• Krichmar, J. L. & Edelman, G. M. Brain-based devices for the study of nervous systems and the development of intelligent machines. Artif. Life 11, 63–77 (2005).
  Article PubMed Google Scholar
• Broderick, D. F. Neuroimaging in neuropsychiatry. Psychiatr. Clin. North Am. 28, 549–566 (2005).
  Article PubMed Google Scholar
• Gallen, C. C. Strategic challenges in neurotherapeutic pharmaceutical development. NeuroRx 1, 165–180 (2004).
  Article PubMed PubMed Central Google Scholar
• Lipinski, C. & Hopkins, A. Navigating chemical space for biology and medicine. Nature 432, 855–861 (2004).
  Article CAS PubMed Google Scholar
• Davie, J. R. & Spencer, V. A. Control of histone modifications. J. Cell. Biochem. 75 (Suppl. 32), 141–148 (1999).
  Article Google Scholar
• Langley, B., Gensert, J. M., Beal, M. F. & Ratan, R. R. Remodeling chromatin and stress resistance in the central nervous system: histone deacetylase inhibitors as novel and broadly effective neuroprotective agents. Curr. Drug Targets CNS Neurol. Disord. 4, 41–50 (2005).
  Article CAS PubMed Google Scholar
• Bhaumik, S. R., Smith, E. & Shilatifard, A. Covalent modifications of histones during development and disease pathogenesis. Nature Struct. Mol. Biol. 14, 1008–1016 (2007).
  Article CAS Google Scholar
• Hubbert, C. et al. HDAC6 is a microtubule-associated deacetylase. Nature 417, 455–458 (2002).
  Article CAS PubMed Google Scholar
• Matsuyama, A. et al. In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation. EMBO J. 21, 6820–6831 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Michan, S. & Sinclair, D. Sirtuins in mammals: insights into their biological function. Biochem. J. 404, 1–13 (2007).
  Article CAS PubMed Google Scholar
• Kim, S. C. et al. Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol. Cell 23, 607–618 (2006).
  Article CAS PubMed Google Scholar
• Gregoire, S. et al. Histone deacetylase 3 interacts with and deacetylates myocyte enhancer factor 2. Mol. Cell. Biol. 27, 1280–1295 (2007).
  Article CAS PubMed Google Scholar
• Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).
  Article CAS PubMed Google Scholar
• Kruhlak, M. J. et al. Regulation of global acetylation in mitosis through loss of histone acetyltransferases and deacetylases from chromatin. J. Biol. Chem. 276, 38307–38319 (2001).
  Article CAS PubMed Google Scholar
• Neely, K. E. & Workman, J. L. The complexity of chromatin remodeling and its links to cancer. Biochim. Biophys. Acta 1603, 19–29 (2002).
  CAS PubMed Google Scholar
• Sun, J. M., Spencer, V. A., Chen, H. Y., Li, L. & Davie, J. R. Measurement of histone acetyltransferase and histone deacetylase activities and kinetics of histone acetylation. Methods 31, 12–23 (2003).
  Article CAS PubMed Google Scholar
• Zhang, Y. et al. HDAC-6 interacts with and deacetylates tubulin and microtubules in vivo. EMBO J. 22, 1168–1179 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Bolden, J. E., Peart, M. J. & Johnstone, R. W. Anticancer activities of histone deacetylase inhibitors. Nature Rev. Drug Discov. 5, 769–784 (2006).
  Article CAS Google Scholar
• Gregoretti, I. V., Lee, Y. M. & Goodson, H. V. Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J. Mol. Biol. 338, 17–31 (2004).
  Article CAS PubMed Google Scholar
• Xu, W. S., Parmigiani, R. B. & Marks, P. A. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26, 5541–5552 (2007).
  Article CAS PubMed Google Scholar
• Marsoni, S., Damia, G. & Camboni, G. A work in progress: the clinical development of histone deacetylase inhibitors. Epigenetics 3, 164–171 (2008).
  Article PubMed Google Scholar
• Abel, T. & Zukin, R. S. Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders. Curr. Opin. Pharmacol. 8, 57–64 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Morrison, B. E., Majdzadeh, N. & D'Mello, S. R. Histone deacetylases: focus on the nervous system. Cell. Mol. Life Sci. 64, 2258–2269 (2007).
  Article CAS PubMed Google Scholar
• Hahnen, E. et al. Histone deacetylase inhibitors: possible implications for neurodegenerative disorders. Expert Opin. Investig. Drugs 17, 169–184 (2008).
  Article CAS PubMed Google Scholar
• Butler, R. & Bates, G. P. Histone deacetylase inhibitors as therapeutics for polyglutamine disorders. Nature Rev. Neurosci. 7, 784–796 (2006).
  Article CAS Google Scholar
• Thiagalingam, S. et al. Histone deacetylases: unique players in shaping the epigenetic histone code. Ann. NY Acad. Sci. 983, 84–100 (2003).
  Article CAS PubMed Google Scholar
• Wang, S., Yan-Neale, Y., Zeremski, M. & Cohen, D. Transcription regulation by histone deacetylases. Novartis Found. Symp. 259, 238–245 (2004).
  CAS PubMed Google Scholar
• Yang, W. M., Tsai, S. C., Wen, Y. D., Fejer, G. & Seto, E. Functional domains of histone deacetylase-3. J. Biol. Chem. 277, 9447–9454 (2002).
  Article CAS PubMed Google Scholar
• Laherty, C. D. et al. Histone deacetylases associated with the mSin3 corepressor mediate mad transcriptional repression. Cell 89, 349–356 (1997).
  Article CAS PubMed Google Scholar
• Zhang, Y. et al. Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev. 13, 1924–1935 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Wen, Y. D. et al. The histone deacetylase-3 complex contains nuclear receptor corepressors. Proc. Natl Acad. Sci. USA 97, 7202–7207 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Martin, M., Kettmann, R. & Dequiedt, F. Class IIa histone deacetylases: regulating the regulators. Oncogene 26, 5450–5467 (2007).
  Article CAS PubMed Google Scholar
• Majdzadeh, N., Morrison, B. E. & D'Mello, S. R. Class IIA HDACs in the regulation of neurodegeneration. Front. Biosci. 13, 1072–1082 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, C. L., McKinsey, T. A. & Olson, E. N. Association of class II histone deacetylases with heterochromatin protein 1: potential role for histone methylation in control of muscle differentiation. Mol. Cell. Biol. 22, 7302–7312 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Fischle, W. et al. Human HDAC7 histone deacetylase activity is associated with HDAC3 in vivo. J. Biol. Chem. 276, 35826–35835 (2001).
  Article CAS PubMed Google Scholar
• Lahm, A. et al. Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases. Proc. Natl Acad. Sci. USA 104, 17335–17340 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Jones, P. et al. Probing the elusive catalytic activity of vertebrate class IIa histone deacetylases. Bioorg. Med. Chem. Lett. 18, 1814–1819 (2008).
  Article CAS PubMed Google Scholar
• Wang, A. H. & Yang, X. J. Histone deacetylase 4 possesses intrinsic nuclear import and export signals. Mol. Cell. Biol. 21, 5992–6005 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Bertos, N. R., Wang, A. H. & Yang, X. J. Class II histone deacetylases: structure, function, and regulation. Biochem. Cell Biol. 79, 243–252 (2001).
  Article CAS PubMed Google Scholar
• Zhang, C. L., McKinsey, T. A. & Olson, E. N. The transcriptional corepressor MITR is a signal-responsive inhibitor of myogenesis. Proc. Natl Acad. Sci. USA 98, 7354–7359 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Petrie, K. et al. The histone deacetylase 9 gene encodes multiple protein isoforms. J. Biol. Chem. 278, 16059–16072 (2003).
  Article CAS PubMed Google Scholar
• Grozinger, C. M. & Schreiber, S. L. Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization. Proc. Natl Acad. Sci. USA 97, 7835–7840 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Kao, H. Y. et al. Mechanism for nucleocytoplasmic shuttling of histone deacetylase 7. J. Biol. Chem. 276, 47496–47507 (2001).
  Article CAS PubMed Google Scholar
• Ellis, J. J. et al. CaM kinase IIdeltaC phosphorylation of 14-3-3β in vascular smooth muscle cells: activation of class II HDAC repression. Mol. Cell Biochem. 242, 153–161 (2003).
  Article CAS PubMed Google Scholar
• Tong, J. J., Liu, J., Bertos, N. R. & Yang, X. J. Identification of HDAC10, a novel class II human histone deacetylase containing a leucine-rich domain. Nucleic Acids Res. 30, 1114–1123 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Gao, L., Cueto, M. A., Asselbergs, F. & Atadja, P. Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family. J. Biol. Chem. 277, 25748–25755 (2002).
  Article CAS PubMed Google Scholar
• Liu, H., Hu, Q., Kaufman, A., D'Ercole, A. J. & Ye, P. Developmental expression of histone deacetylase 11 in the murine brain. J. Neurosci. Res. 86, 537–543 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Gan, L. & Mucke, L. Paths of convergence: sirtuins in aging and neurodegeneration. Neuron 58, 10–14 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Sauve, A. A., Wolberger, C., Schramm, V. L. & Boeke, J. D. The biochemistry of sirtuins. Annu. Rev. Biochem. 75, 435–465 (2006).
  Article CAS PubMed Google Scholar
• North, B. J., Schwer, B., Ahuja, N., Marshall, B. & Verdin, E. Preparation of enzymatically active recombinant class III protein deacetylases. Methods 36, 338–345 (2005).
  Article CAS PubMed Google Scholar
• Denu, J. M. The Sir 2 family of protein deacetylases. Curr. Opin. Chem. Biol. 9, 431–440 (2005).
  Article CAS PubMed Google Scholar
• Vaquero, A. et al. Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol. Cell 16, 93–105 (2004).
  Article CAS PubMed Google Scholar
• Senawong, T., Peterson, V. J. & Leid, M. BCL11A-dependent recruitment of SIRT1 to a promoter template in mammalian cells results in histone deacetylation and transcriptional repression. Arch. Biochem. Biophys. 434, 316–325 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Tanno, M., Sakamoto, J., Miura, T., Shimamoto, K. & Horio, Y. Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1. J. Biol. Chem. 282, 6823–6832 (2007).
  Article CAS PubMed Google Scholar
• North, B. J., Marshall, B. L., Borra, M. T., Denu, J. M. & Verdin, E. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol. Cell 11, 437–444 (2003).
  Article CAS PubMed Google Scholar
• Southwood, C. M., Peppi, M., Dryden, S., Tainsky, M. A. & Gow, A. Microtubule deacetylases, SirT2 and HDAC6, in the nervous system. Neurochem. Res. 32, 187–195 (2007).
  Article CAS PubMed Google Scholar
• Vaquero, A. et al. SirT2 is a histone deacetylase with preference for histone H4 Lys16 during mitosis. Genes Dev. 20, 1256–1261 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Schwer, B., North, B. J., Frye, R. A., Ott, M. & Verdin, E. The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase. J. Cell Biol. 158, 647–657 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Schwer, B., Bunkenborg, J., Verdin, R. O., Andersen, J. S. & Verdin, E. Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc. Natl Acad. Sci. USA 103, 10224–10229 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Hallows, W. C., Lee, S. & Denu, J. M. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc. Natl Acad. Sci. USA 103, 10230–10235 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Michishita, E., Park, J. Y., Burneskis, J. M., Barrett, J. C. & Horikawa, I. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol. Biol. Cell 16, 4623–4635 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Michishita, E. et al. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 452, 492–496 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Broide, R. S. et al. Distribution of histone deacetylases 1–11 in the rat brain. J. Mol. Neurosci. 31, 47–58 (2007).
  Article CAS PubMed Google Scholar
• Lu, J., McKinsey, T. A., Zhang, C. L. & Olson, E. N. Regulation of skeletal myogenesis by association of the MEF2 transcription factor with class II histone deacetylases. Mol. Cell 6, 233–244 (2000).
  Article CAS PubMed Google Scholar
• Zhang, C. L., McKinsey, T. A., Lu, J. R. & Olson, E. N. Association of COOH-terminal-binding protein (CtBP) and MEF2-interacting transcription repressor (MITR) contributes to transcriptional repression of the MEF2 transcription factor. J. Biol. Chem. 276, 35–39 (2001).
  Article CAS PubMed Google Scholar
• Mao, Z., Bonni, A., Xia, F., Nadal-Vicens, M. & Greenberg, M. E. Neuronal activity-dependent cell survival mediated by transcription factor MEF2. Science 286, 785–790 (1999).
  Article CAS PubMed Google Scholar
• Zhou, X., Richon, V. M., Rifkind, R. A. & Marks, P. A. Identification of a transcriptional repressor related to the noncatalytic domain of histone deacetylases 4 and 5. Proc. Natl Acad. Sci. USA 97, 1056–1061 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Chawla, S., Vanhoutte, P., Arnold, F. J., Huang, C. L. & Bading, H. Neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5. J. Neurochem. 85, 151–159 (2003).
  Article CAS PubMed Google Scholar
• Belfield, J. L., Whittaker, C., Cader, M. Z. & Chawla, S. Differential effects of Ca2+ and cAMP on transcription mediated by MEF2D and cAMP-response element-binding protein in hippocampal neurons. J. Biol. Chem. 281, 27724–27732 (2006).
  Article CAS PubMed Google Scholar
• Bolger, T. A. & Yao, T. P. Intracellular trafficking of histone deacetylase 4 regulates neuronal cell death. J. Neurosci. 25, 9544–9553 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Berdeaux, R. et al. SIK1 is a class II HDAC kinase that promotes survival of skeletal myocytes. Nature Med. 13, 597–603 (2007).
  Article CAS PubMed Google Scholar
• Morrison, B. E. et al. Neuroprotection by histone deacetylase-related protein. Mol. Cell. Biol. 26, 3550–3564 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Kawaguchi, Y. et al. The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115, 727–738 (2003). This provided a new role for HDAC6 that led to work by Kopito and others to show that HDAC6 and microtubules are involved in the clearance of protein aggregates in neurodegenerative disease ( J. Biol Chem. 280, 40282–40292; 2005).
  Article CAS PubMed Google Scholar
• Iwata, A., Riley, B. E., Johnston, J. A. & Kopito, R. R. HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin. J. Biol. Chem. 280, 40282–40292 (2005).
  Article CAS PubMed Google Scholar
• Pandey, U. B. et al. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447, 859–863 (2007).
  Article CAS PubMed Google Scholar
• Kovacs, J. J. et al. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol. Cell 18, 601–607 (2005).
  Article CAS PubMed Google Scholar
• Murphy, P. J., Morishima, Y., Kovacs, J. J., Yao, T. P. & Pratt, W. B. Regulation of the dynamics of hsp90 action on the glucocorticoid receptor by acetylation/deacetylation of the chaperone. J. Biol. Chem. 280, 33792–33799 (2005).
  Article CAS PubMed Google Scholar
• Li, W. et al. Sirtuin 2, a mammalian homolog of yeast silent information regulator-2 longevity regulator, is an oligodendroglial protein that decelerates cell differentiation through deacetylating α-tubulin. J. Neurosci. 27, 2606–2616 (2007).
  Article PubMed PubMed Central CAS Google Scholar
• Chen, D. & Guarente, L. SIR2: a potential target for calorie restriction mimetics. Trends Mol. Med. 13, 64–71 (2007).
  Article CAS PubMed Google Scholar
• Bishop, N. A. & Guarente, L. Genetic links between diet and lifespan: shared mechanisms from yeast to humans. Nature Rev. Genet. 8, 835–844 (2007).
  Article CAS PubMed Google Scholar
• Yeung, F. et al. Modulation of NF-κB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 23, 2369–2380 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Sakamoto, J., Miura, T., Shimamoto, K. & Horio, Y. Predominant expression of Sir2alpha, an NAD-dependent histone deacetylase, in the embryonic mouse heart and brain. FEBS Lett. 556, 281–286 (2004).
  Article CAS PubMed Google Scholar
• Milne, J. C. & Denu, J. M. The Sirtuin family: therapeutic targets to treat diseases of aging. Curr. Opin. Chem. Biol. 12, 11–17 (2008).
  Article CAS PubMed Google Scholar
• Outeiro, T. F., Marques, O. & Kazantsev, A. Therapeutic role of sirtuins in neurodegenerative disease. Biochim. Biophys. Acta 1782, 363–369 (2008).
  Article CAS PubMed Google Scholar
• Petrij, F. et al. Rubinstein–Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature 376, 348–351 (1995).
  Article CAS PubMed Google Scholar
• Oike, Y. et al. Truncated CBP protein leads to classical Rubinstein–Taybi syndrome phenotypes in mice: implications for a dominant-negative mechanism. Hum. Mol. Genet. 8, 387–396 (1999).
  Article CAS PubMed Google Scholar
• Alarcon, J. M. et al. Chromatin acetylation, memory, and LTP are impaired in CBP +/− mice: a model for the cognitive deficit in Rubinstein–Taybi syndrome and its amelioration. Neuron 42, 947–959 (2004).
  Article CAS PubMed Google Scholar
• Barco, A. The Rubinstein–Taybi syndrome: modeling mental impairment in the mouse. Genes Brain Behav. 6 (Suppl. 1), 32–39 (2007).
  Article CAS PubMed Google Scholar
• Vecsey, C. G. et al. Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CBP-dependent transcriptional activation. J. Neurosci. 27, 6128–6140 (2007). This important paper demonstrates the effects of HDAC inhibitors on restoration of memory loss by enhancing transcriptional expression of specific neuronal genes and suggests benefits of HDAC treatment for Rubinstein–Taybi syndrome.
  Article CAS PubMed PubMed Central Google Scholar
• Tsankova, N., Renthal, W., Kumar, A. & Nestler, E. J. Epigenetic regulation in psychiatric disorders. Nature Rev. Neurosci. 8, 355–367 (2007).
  Article CAS Google Scholar
• Tsankova, N. M. et al. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nature Neurosci. 9, 519–525 (2006). This paper provides in vivo evidence of therapeutic application HDAC inhibitors for the treatment of depression by a chromatin remodelling mechanism.
  Article CAS PubMed Google Scholar
• Schroeder, F. A., Lin, C. L., Crusio, W. E. & Akbarian, S. Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse. Biol. Psychiatry 62, 55–64 (2007).
  Article CAS PubMed Google Scholar
• Fischer, A., Sananbenesi, F., Wang, X., Dobbin, M. & Tsai, L. H. Recovery of learning and memory is associated with chromatin remodelling. Nature 447, 178–182 (2007).
  Article CAS PubMed Google Scholar
• Amir, R. E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genet. 23, 185–188 (1999). A landmark paper linking epigenetic regulation and pathology in Rett syndrome, paving the way for the potential therapeutic application of HDAC inhibitors for treating of this human disorder.
  Article CAS PubMed Google Scholar
• Chahrour, M. & Zoghbi, H. Y. The story of Rett syndrome: from clinic to neurobiology. Neuron 56, 422–437 (2007).
  Article CAS PubMed Google Scholar
• LaSalle, J. M. The odyssey of MeCP2 and parental imprinting. Epigenetics 2, 5–10 (2007).
  Article PubMed Google Scholar
• Pandolfo, M. Friedreich's ataxia: clinical aspects and pathogenesis. Semin. Neurol. 19, 311–321 (1999).
  Article CAS PubMed Google Scholar
• Herman, D. et al. Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxia. Nature Chem. Biol. 2, 551–558 (2006). This paper shows the efficacious effect of a benzamide-based HDAC inhibitor on heterochromatin-mediated repression, resulting in transcriptional reactivation of silenced frataxin gene product in Friedreich's ataxia.
  Article CAS Google Scholar
• Rai, M. et al. HDAC inhibitors correct frataxin deficiency in a Friedreich ataxia mouse model. PLoS ONE 3, e1958 (2008).
  Article PubMed PubMed Central CAS Google Scholar
• O'Donnell, W. T. & Warren, S. T. A decade of molecular studies of fragile X syndrome. Annu. Rev. Neurosci. 25, 315–338 (2002).
  Article CAS PubMed Google Scholar
• Garber, K., Smith, K. T., Reines, D. & Warren, S. T. Transcription, translation and fragile X syndrome. Curr. Opin. Genet. Dev. 16, 270–275 (2006).
  Article CAS PubMed Google Scholar
• Chandler, S. P., Kansagra, P. & Hirst, M. C. Fragile X (CGG)n repeats induce a transcriptional repression in cis upon a linked promoter: evidence for a chromatin mediated effect. BMC Mol. Biol. 4, 3 (2003).
  Article PubMed PubMed Central Google Scholar
• Chiurazzi, P. et al. Synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of the FMR1 gene. Hum. Mol. Genet. 8, 2317–2323 (1999).
  Article CAS PubMed Google Scholar
• Pietrobono, R. et al. Quantitative analysis of DNA demethylation and transcriptional reactivation of the FMR1 gene in fragile X cells treated with 5-azadeoxycytidine. Nucleic Acids Res. 30, 3278–3285 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Tabolacci, E. et al. Differential epigenetic modifications in the FMR1 gene of the fragile X syndrome after reactivating pharmacological treatments. Eur. J. Hum. Genet. 13, 641–648 (2005).
  Article CAS PubMed Google Scholar
• Biacsi, R., Kumari, D. & Usdin, K. SIRT1 inhibition alleviates gene silencing in fragile X mental retardation syndrome. PLoS Genet. 4, e1000017 (2008).
  Article PubMed PubMed Central CAS Google Scholar
• Vaquero, A. et al. SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation. Nature 450, 440–444 (2007).
  Article CAS PubMed Google Scholar
• Avila, A. M. et al. Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy. J. Clin. Invest. 117, 659–671 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Riessland, M., Brichta, L., Hahnen, E. & Wirth, B. The benzamide M344, a novel histone deacetylase inhibitor, significantly increases SMN2 RNA/protein levels in spinal muscular atrophy cells. Hum. Genet. 120, 101–110 (2006).
  Article CAS PubMed Google Scholar
• Hirtz, D. et al. Challenges and opportunities in clinical trials for spinal muscular atrophy. Neurology 65, 1352–1357 (2005).
  Article CAS PubMed Google Scholar
• Kernochan, L. E. et al. The role of histone acetylation in SMN gene expression. Hum. Mol. Genet. 14, 1171–1182 (2005).
  Article CAS PubMed Google Scholar
• Hahnen, E. et al. In vitro and ex vivo evaluation of second-generation histone deacetylase inhibitors for the treatment of spinal muscular atrophy. J. Neurochem. 98, 193–202 (2006).
  Article CAS PubMed Google Scholar
• Ryu, H. et al. Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice. J. Neurochem. 93, 1087–1098 (2005).
  Article CAS PubMed Google Scholar
• Rouaux, C. et al. Sodium valproate exerts neuroprotective effects in vivo through CREB-binding protein-dependent mechanisms but does not improve survival in an amyotrophic lateral sclerosis mouse model. J. Neurosci. 27, 5535–5545 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Minamiyama, M. et al. Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Hum. Mol. Genet. 13, 1183–1192 (2004).
  Article CAS PubMed Google Scholar
• Orr, H. T. & Zoghbi, H. Y. Trinucleotide repeat disorders. Annu. Rev. Neurosci. 30, 575–621 (2007).
  Article CAS PubMed Google Scholar
• Steffan, J. S. et al. The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc. Natl Acad. Sci. USA 97, 6763–6768 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Luthi-Carter, R. et al. Polyglutamine and transcription: gene expression changes shared by DRPLA and Huntington's disease mouse models reveal context-independent effects. Hum. Mol. Genet. 11, 1927–1937 (2002).
  Article CAS PubMed Google Scholar
• Zuccato, C. et al. Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nature Genet. 35, 76–83 (2003).
  Article CAS PubMed Google Scholar
• Serra, H. G. et al. Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice. Hum. Mol. Genet. 13, 2535–2543 (2004).
  Article CAS PubMed Google Scholar
• Tsai, C. C. et al. Ataxin 1, a SCA1 neurodegenerative disorder protein, is functionally linked to the silencing mediator of retinoid and thyroid hormone receptors. Proc. Natl Acad. Sci. USA 101, 4047–4052 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Helmlinger, D., Tora, L. & Devys, D. Transcriptional alterations and chromatin remodeling in polyglutamine diseases. Trends Genet. 22, 562–570 (2006).
  Article CAS PubMed Google Scholar
• Nakamura, K. et al. SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum. Mol. Genet. 10, 1441–1448 (2001).
  Article CAS PubMed Google Scholar
• La Spada, A. R., Wilson, E. M., Lubahn, D.B., Harding, A. E. & Fischbeck, K. H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352, 77–79 (1991).
  Article CAS PubMed Google Scholar
• Helmlinger, D. et al. Ataxin-7 is a subunit of GCN5 histone acetyltransferase-containing complexes. Hum. Mol. Genet. 13, 1257–1265 (2004).
  Article CAS PubMed Google Scholar
• Evert, B. O. et al. Ataxin-3 represses transcription via chromatin binding, interaction with histone deacetylase 3, and histone deacetylation. J. Neurosci. 26, 11474–11486 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Steffan, J. S. et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413, 739–743 (2001). This demonstrated for the first time efficacy of HDAC inhibitors in neurodegeneration models.
  Article CAS PubMed Google Scholar
• Hockly, E. et al. 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 (2003). This paper showed the benefits of a HDAC inhibitor (voronistat) in a mouse model of neurodegeneration.
  Article CAS PubMed PubMed Central Google Scholar
• Ferrante, R. J. et al. Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice. J. Neurosci. 23, 9418–9427 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Thomas, E. A. et al. The histone deacetylase inhibitor, HDACi 4b, ameliorates the disease phenotype and transcriptional abnormalities in Huntington's disease transgenic mice. Proc. Natl Acad. Sci. USA (in the press).
• Sadri-Vakili, G. & Cha, J. H. Histone deacetylase inhibitors: a novel therapeutic approach to Huntington's disease (complex mechanism of neuronal death). Curr. Alzheimer Res. 3, 403–408 (2006).
  Article CAS PubMed Google Scholar
• Bates, E. A., Victor, M., Jones, A. K., Shi, Y. & Hart, A. C. Differential contributions of Caenorhabditis elegans histone deacetylases to huntingtin polyglutamine toxicity. J. Neurosci. 26, 2830–2838 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Pallos, J. et al. Inhibition of specific HDACs and sirtuins suppresses pathogenesis in a Drosophila model of Huntington's disease. Hum. Mol. Genet. 1 Sep 2008 (doi:10.1093/hmg/ddn273).
  Article CAS PubMed PubMed Central Google Scholar
• Fernandez-Funez, P. et al. Identification of genes that modify ataxin-1-induced neurodegeneration. Nature 408, 101–106 (2000).
  Article CAS PubMed Google Scholar
• Parker, J. A. et al. Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Nature Genet. 37, 349–350 (2005). This paper provides genetic and pharmacological evidence relating to possible the protective effects of SIRT1 activation in in vivo neurodegeneration models.
  Article CAS PubMed Google Scholar
• Shao, J. & Diamond, M. I. Polyglutamine diseases: emerging concepts in pathogenesis and therapy. Hum. Mol. Genet. 16 (Spec. No. 2), R115–R123 (2007).
  Article CAS PubMed Google Scholar
• Imarisio, S. et al. Huntington's disease: from pathology and genetics to potential therapies. Biochem. J. 412, 191–209 (2008).
  Article CAS PubMed Google Scholar
• Ross, C. A. & Thompson, L. M. Transcription meets metabolism in neurodegeneration. Nature Med. 12, 1239–1241 (2006).
  Article CAS PubMed Google Scholar
• Kazantsev, A. G. & Hersch, S. M. Drug targeting of dysregulated transcription in Huntington's disease. Prog. Neurobiol. 83, 249–259 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Oliveira, J. M. et al. Mitochondrial-dependent Ca2+ handling in Huntington's disease striatal cells: effect of histone deacetylase inhibitors. J. Neurosci. 26, 11174–11186 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Dompierre, J. P. et al. Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation. J. Neurosci. 27, 3571–3583 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Berke, S. J. & Paulson, H. L. Protein aggregation and the ubiquitin proteasome pathway: gaining the UPPer hand on neurodegeneration. Curr. Opin. Genet. Dev. 13, 253–261 (2003).
  Article CAS PubMed Google Scholar
• Caughey, B. & Lansbury, P. T. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu. Rev. Neurosci. 26, 267–298 (2003).
  Article CAS PubMed Google Scholar
• Rubinsztein, D. C. et al. Autophagy and its possible roles in nervous system diseases, damage and repair. Autophagy 1, 11–22 (2005).
  Article CAS PubMed Google Scholar
• Zhang, Y. et al. Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally. Mol. Cell. Biol. 28, 1688–1701 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Outeiro, T. F. et al. Sirtuin 2 inhibitors rescue α-synuclein-mediated toxicity in models of Parkinson's disease. Science 317, 516–519 (2007). Provides evidence regarding the feasibility of a novel treatment approach for neurodegeneration using selective inhibitors of SIRT2.
  Article CAS PubMed Google Scholar
• Raine, C. S. Multiple sclerosis: immune system molecule expression in the central nervous system. J. Neuropathol. Exp. Neurol. 53, 328–337 (1994).
  Article CAS PubMed Google Scholar
• McFarland, H. F. & Martin, R. Multiple sclerosis: a complicated picture of autoimmunity. Nature Immunol. 8, 913–919 (2007).
  Article CAS Google Scholar
• Dheen, S. T., Kaur, C. & Ling, E. A. Microglial activation and its implications in the brain diseases. Curr. Med. Chem. 14, 1189–1197 (2007).
  Article CAS PubMed Google Scholar
• Camelo, S. et al. Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis. J. Neuroimmunol. 164, 10–21 (2005).
  Article CAS PubMed Google Scholar
• Gray, S. G. & Dangond, F. Rationale for the use of histone deacetylase inhibitors as a dual therapeutic modality in multiple sclerosis. Epigenetics 1, 67–75 (2006).
  Article PubMed Google Scholar
• Ren, M., Leng, Y., Jeong, M., Leeds, P. R. & Chuang, D. M. Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats: potential roles of histone deacetylase inhibition and heat shock protein induction. J. Neurochem. 89, 1358–1367 (2004).
  Article CAS PubMed Google Scholar
• Faraco, G. et al. Pharmacological inhibition of histone deacetylases by suberoylanilide hydroxamic acid specifically alters gene expression and reduces ischemic injury in the mouse brain. Mol. Pharmacol. 70, 1876–1884 (2006).
  Article CAS PubMed Google Scholar
• Kim, H. J. et al. Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. J. Pharmacol. Exp. Ther. 321, 892–901 (2007).
  Article CAS PubMed Google Scholar
• Langley, B. et al. Pulse inhibition of histone deacetylases induces complete resistance to oxidative death in cortical neurons without toxicity and reveals a role for cytoplasmic p21waf1/cip1 in cell cycle-independent neuroprotection. J. Neurosci. 28, 163–176 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Chuang, D. M. The antiapoptotic actions of mood stabilizers: molecular mechanisms and therapeutic potentials. Ann. NY Acad. Sci. 1053, 195–204 (2005).
  Article CAS PubMed Google Scholar
• Giorgini, F. et al. Histone deacetylase inhibition modulates kynurenine pathway activation in yeast, microglia, and mice expressing a mutant huntingtin fragment. J. Biol. Chem. 283, 7390–7400 (2008).
  Article CAS PubMed Google Scholar
• Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921–923 (1993).
  Article CAS PubMed Google Scholar
• Nixon, R. A. Niemann–Pick type C disease and Alzheimer's disease: the APP-endosome connection fattens up. Am. J. Pathol. 164, 757–761 (2004).
  Article PubMed PubMed Central Google Scholar
• Hooper, N. M. Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prion protein. Biochem. Soc. Trans. 33, 335–338 (2005).
  Article CAS PubMed Google Scholar
• Roff, C. F. et al. Type C Niemann–Pick disease: use of hydrophobic amines to study defective cholesterol transport. Dev. Neurosci. 13, 315–319 (1991).
  Article CAS PubMed Google Scholar
• Vance, J. E. Lipid imbalance in the neurological disorder, Niemann–Pick C disease. FEBS Lett. 580, 5518–5524 (2006).
  Article CAS PubMed Google Scholar
• Garver, W. S. & Heidenreich, R. A. The Niemann–Pick C proteins and trafficking of cholesterol through the late endosomal/lysosomal system. Curr. Mol. Med. 2, 485–505 (2002).
  Article CAS PubMed Google Scholar
• Mukherjee, S. & Maxfield, F. R. Lipid and cholesterol trafficking in NPC. Biochim. Biophys. Acta 1685, 28–37 (2004).
  Article CAS PubMed Google Scholar
• Karten, B., Vance, D. E., Campenot, R. B. & Vance, J. E. Cholesterol accumulates in cell bodies, but is decreased in distal axons, of Niemann–Pick C1-deficient neurons. J. Neurochem. 83, 1154–1163 (2002).
  Article CAS PubMed Google Scholar
• Karten, B., Vance, D. E., Campenot, R. B. & Vance, J. E. Trafficking of cholesterol from cell bodies to distal axons in Niemann Pick C1-deficient neurons. J. Biol. Chem. 278, 4168–4175 (2003).
  Article CAS PubMed Google Scholar
• Kim, S. J., Lee, B. H., Lee, Y. S. & Kang, K. S. Defective cholesterol traffic and neuronal differentiation in neural stem cells of Niemann–Pick type C disease improved by valproic acid, a histone deacetylase inhibitor. Biochem. Biophys. Res. Commun. 360, 593–599 (2007).
  Article CAS PubMed Google Scholar
• Li, X. et al. SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Mol. Cell 28, 91–106 (2007).
  Article PubMed CAS Google Scholar
• Valenza, M. et al. Cholesterol biosynthesis pathway is disturbed in YAC128 mice and is modulated by huntingtin mutation. Hum. Mol. Genet. 16, 2187–2198 (2007).
  Article CAS PubMed Google Scholar
• Valenza, M. et al. Progressive dysfunction of the cholesterol biosynthesis pathway in the R6/2 mouse model of Huntington's disease. Neurobiol. Dis. 28, 133–142 (2007).
  Article CAS PubMed Google Scholar
• Trushina, E. et al. Mutant huntingtin inhibits clathrin-independent endocytosis and causes accumulation of cholesterol in vitro and in vivo. Hum. Mol. Genet. 15, 3578–3591 (2006).
  Article CAS PubMed Google Scholar
• Guarente, L. & Picard, F. Calorie restriction — the SIR2 connection. Cell 120, 473–482 (2005).
  Article CAS PubMed Google Scholar
• Bordone, L. & Guarente, L. Calorie restriction, SIRT1 and metabolism: understanding longevity. Nature Rev. Mol. Cell Biol. 6, 298–305 (2005).
  Article CAS Google Scholar
• Sinclair, D. A. Toward a unified theory of caloric restriction and longevity regulation. Mech. Ageing Dev. 126, 987–1002 (2005).
  Article CAS PubMed Google Scholar
• Bordone, L. et al. SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell 6, 759–767 (2007).
  Article CAS PubMed Google Scholar
• Guarente, L. Sirtuins in aging and disease. Cold Spring Harb. Symp. Quant. Biol. 72, 483–488 (2007).
  Article CAS PubMed Google Scholar
• Baur, J. A. & Sinclair, D. A. Therapeutic potential of resveratrol: the in vivo evidence. Nature Rev. Drug Discov. 5, 493–506 (2006).
  Article CAS Google Scholar
• Kim, D. et al. 2007. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J. 26, 3169–3179 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, J. et al. SIRT1 protects against microglia-dependent amyloid-β toxicity through inhibiting NF-κB signaling. J. Biol. Chem. 280, 40364–40374 (2005).
  Article CAS PubMed Google Scholar
• Catoire, H. et al. Sirtuin inhibition protects from the polyalanine muscular dystrophy protein PABPN1. Hum. Mol. Genet. 17, 2108–2117 (2008).
  Article CAS PubMed Google Scholar
• Li, Y., Xu, W., McBurney, M. W. & Longo, V. D. SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons. Cell. Metab. 8, 38–48 (2008).
  Article PubMed PubMed Central CAS Google Scholar
• Green, K. et al. Nicotinamide restores cognition in AD transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. J. Neurosci. (in the press).
• Jung, M. Inhibitors of histone deacetylase as new anticancer agents. Curr. Med. Chem. 8, 1505–1511 (2001).
  Article CAS PubMed Google Scholar
• Vigushin, D. M. et al. Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo. Clin. Cancer Res. 7, 971–976 (2001).
  CAS PubMed Google Scholar
• Wang, C. et al. Histone acetylation and the cell-cycle in cancer. Front. Biosci. 6, D610–D629 (2001).
  Article CAS PubMed Google Scholar
• Secrist, J. P., Zhou, X. & Richon, V. M. HDAC inhibitors for the treatment of cancer. Curr. Opin. Investig. Drugs 4, 1422–1427 (2003).
  CAS PubMed Google Scholar
• Vannini, A. et al. Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proc. Natl Acad. Sci. USA 101, 15064–15069 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Mai, A. et al. Synthesis and biological evaluation of 2-, 3-, and 4-acylaminocinnamyl-_N_-hydroxyamides as novel synthetic HDAC inhibitors. Med. Chem. 1, 245–254 (2005).
  Article CAS PubMed Google Scholar
• Yoshida, M. et al. Histone deacetylase as a new target for cancer chemotherapy. Cancer Chemother. Pharmacol. 48 (Suppl. 1), S20–S26 (2001).
  Article CAS PubMed Google Scholar
• Lu, Q. et al. Zn2+-chelating motif-tethered short-chain fatty acids as a novel class of histone deacetylase inhibitors. J. Med. Chem. 47, 467–474 (2004).
  Article CAS PubMed Google Scholar
• Liu, T., Kapustin, G. & Etzkorn, F. A. Design and synthesis of a potent histone deacetylase inhibitor. J. Med. Chem. 50, 2003–2006 (2007).
  Article CAS PubMed Google Scholar
• Curtin, M. & Glaser, K. Histone deacetylase inhibitors: the Abbott experience. Curr. Med. Chem. 10, 2373–2392 (2003).
  Article CAS PubMed Google Scholar
• Khan, N. et al. Determination of the class and isoform selectivity of small molecule HDAC inhibitors. Biochem. J. 409, 581–589 (2008).
  Article CAS PubMed Google Scholar
• Khan, N. et al. Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors. Biochem. J. 409, 581–589 (2008).
  Article CAS PubMed Google Scholar
• Glaser, K. B. et al. Differential protein acetylation induced by novel histone deacetylase inhibitors. Biochem. Biophys. Res. Commun. 325, 683–690 (2004).
  Article CAS PubMed Google Scholar
• Mai, A. et al. Exploring the connection unit in the HDAC inhibitor pharmacophore model: novel uracil-based hydroxamates. Bioorg Med. Chem. Lett. 15, 4656–4661 (2005).
  Article CAS PubMed Google Scholar
• Perez-Balado, C. et al. Bispyridinium dienes: histone deacetylase inhibitors with selective activities. J. Med. Chem. 50, 2497–2505 (2007).
  Article CAS PubMed Google Scholar
• Arts, J. et al. R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies. Br. J. Cancer 97, 1344–1353 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Haggarty, S. J., Koeller, K. M., Wong, J. C., Butcher, R. A. & Schreiber, S. L. Multidimensional chemical genetic analysis of diversity-oriented synthesis-derived deacetylase inhibitors using cell-based assays. Chem. Biol. 10, 383–396 (2003).
  Article CAS PubMed Google Scholar
• Mai, A. et al. Discovery of (aryloxopropenyl)pyrrolyl hydroxyamides as selective inhibitors of class IIa histone deacetylase homologue HD1-A. J. Med. Chem. 46, 4826–4829 (2003).
  Article CAS PubMed Google Scholar
• Haggarty, S. J., Koeller, K. M., Wong, J. C., Grozinger, C. M. & Schreiber, S. L. Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc. Natl Acad. Sci. USA 100, 4389–4394 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Glaser, K. B. HDAC inhibitors: clinical update and mechanism-based potential. Biochem. Pharmacol. 74, 659–671 (2007).
  Article CAS PubMed Google Scholar
• Beckers, T. et al. Distinct pharmacological properties of second generation HDAC inhibitors with the benzamide or hydroxamate head group. Int. J. Cancer 121, 1138–1148 (2007).
  Article CAS PubMed Google Scholar
• Hess-Stumpp, H., Bracker, T. U., Henderson, D. & Politz, O. MS-275, a potent orally available inhibitor of histone deacetylases — the development of an anticancer agent. Int. J. Biochem. Cell Biol. 39, 1388–1405 (2007).
  Article CAS PubMed Google Scholar
• Hu, E. et al. Identification of novel isoform-selective inhibitors within class I histone deacetylases. J. Pharmacol. Exp. Ther. 307, 720–728 (2003).
  Article CAS PubMed Google Scholar
• Simonini, M. V. et al. The benzamide MS-275 is a potent, long-lasting brain region-selective inhibitor of histone deacetylases. Proc. Natl Acad. Sci. USA 103, 1587–1592 (2006). This important paper describes the application of HDAC inhibitors for the treatment of CNS disorders, using one of the first benzamide-based brain-permeable HDAC inhibitors developed.
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, B. et al. HDAC inhibitor increases histone H3 acetylation and reduces microglia inflammatory response following traumatic brain injury in rats. Brain Res. 1226, 181–191 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Howitz, K. T. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191–196 (2003).
  Article CAS PubMed Google Scholar
• Marcotte, P. A. et al. Fluorescence assay of SIRT protein deacetylases using an acetylated peptide substrate and a secondary trypsin reaction. Anal. Biochem. 332, 90–99 (2004).
  Article CAS PubMed Google Scholar
• Galletti, P. et al. Diverse effects of natural antioxidants on cyclosporin cytotoxicity in rat renal tubular cells. Nephrol. Dial. Transplant. 20, 1551–1558 (2005).
  Article CAS PubMed Google Scholar
• Milne, J. C. et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450, 712–716 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Grozinger, C. M., Chao, E. D., Blackwell, H. E., Moazed, D. & Schreiber, S. L. Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. J. Biol. Chem. 276, 38837–38843 (2001).
  Article CAS PubMed Google Scholar
• Mai, A. et al. Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (Sirtuin) inhibitors. J. Med. Chem. 48, 7789–7795 (2005).
  Article CAS PubMed Google Scholar
• Napper, A. D. et al. Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1. J. Med. Chem. 48, 8045–8054 (2005).
  Article CAS PubMed Google Scholar
• Trapp, J. et al. Structure–activity studies on suramin analogues as inhibitors of NAD+-dependent histone deacetylases (Sirtuins). ChemMedChem 2, 1419–1431 (2007).
  Article CAS PubMed Google Scholar
• Pardridge, W. M. Brain drug development and brain drug targeting. Pharm. Res. 24, 1729–1732 (2007).
  Article CAS PubMed Google Scholar