Camelo, S. et al. Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis. J. Neuroimmunol. 164, 10-21

Laboratory of Transcriptional and Immune Regulation, Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, Boston, MA 02139, USA.
Journal of Neuroimmunology (Impact Factor: 2.47). 08/2005; 164(1-2):10-21. DOI: 10.1016/j.jneuroim.2005.02.022
Source: PubMed


We demonstrate that the histone deacetylase (HDAC) inhibitor drug trichostatin A (TSA) reduces spinal cord inflammation, demyelination, neuronal and axonal loss and ameliorates disability in the relapsing phase of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). TSA up-regulates antioxidant, anti-excitotoxicity and pro-neuronal growth and differentiation mRNAs. TSA also inhibits caspase activation and down-regulates gene targets of the pro-apoptotic E2F transcription factor pathway. In splenocytes, TSA reduces chemotactic, pro-Th1 and pro-proliferative mRNAs. A transcriptional imbalance in MS may contribute to immune dysregulation and neurodegeneration, and we identify HDAC inhibition as a transcriptional intervention to ameliorate this imbalance.

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    • "Experimental autoimmune encephalomyelitis (EAE) has been widely used to study pathogenic mechanisms shared with MS and to develop therapies and biomarkers (Steinman and Zamvil, 2006). Chronic HDACi treatment has been reported to prevent clinical signs of EAE in rats (Zhang et al., 2012) and mice (Camelo et al., 2005; Ge et al., 2013; Lv et al., 2012). HDAC inhibition targets the immune system resulting in the reduction of IFN-γ-producing Th1 and IL-17-producing Th17 CD4+ T helper lymphocytes in the periphery (Ge et al., 2013; Lv et al., 2012) and CNS (Lv et al., 2012) in murine EAE. "
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    ABSTRACT: Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the central nervous system (CNS) in young adults. Chronic treatments with histone deacetylase inhibitors (HDACis) have been reported to ameliorate experimental autoimmune encephalomyelitis (EAE), a rodent model of MS, by targeting immune responses. We have recently shown that the HDAC inhibition/knockdown in the presence of thyroid hormone (T3) can also promote oligodendrocyte (OL) differentiation and expression of myelin genes in neural stem cells (NSCs) and oligodendrocyte precursors (OPCs). In this study, we found that treatment with an HDACi, valproic acid (VPA), and T3, alone or in combination, directly affects encephalitogenic CD4 + T cells. VPA, but not T3, compromised their proliferation, while both molecules reduced the frequency of IL-17-producing cells. Transfer of T3, VPA and VPA/T3 treated encephalitogenic CD4 + T cells into naïve rats induced less severe EAE, indicating that the effects of these molecules are persistent and do not require their maintenance after the initial stimuli. Thus, we investigated the effect of acute treatment with VPA and L-thyroxine (T4), a precursor of T3, on myelin oligodendrocyte glycoprotein-induced EAE in Dark Agouti rats, a close mimic of MS. We found that a brief treatment after disease onset led to sustained amelioration of EAE and prevention of inflammatory demyelination in the CNS accompanied with a higher expression of myelin-related genes in the brain. Furthermore, the treatment modulated immune responses, reduced the number of CD4 + T cells and affected the Th1 differentation programme in the brain. Our data indicate that an acute treatment with VPA and T4 after the onset of EAE can produce persistent clinically relevant therapeutic effects by limiting the pathogenic immune reactions while promoting myelin gene expression.
    Neurobiology of Disease 11/2014; 71(1). DOI:10.1016/j.nbd.2014.08.019 · 5.08 Impact Factor
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    • "MS, has been shown to ameliorate disease, presumably by inhibiting dendritic cell (DC) function and DC dependent polarization of the T-cell population towards Th1 or Th17 cells (Camelo et al. 2005; Ge et al. 2013). HDAC inhibition in non-inflammatory demyelinating conditions on the other hand has been shown to inhibit remyelination (Shen et al. 2008), most likely because histone acetylation and specifically the function of various HDACs is a key player in the regulation of oligodendrocyte differentiation and function (Swiss et al. 2011; Conway et al. 2012). "
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    ABSTRACT: Epigenetic regulation shapes the differentiation and response to stimuli of all tissues and cells beyond what genetics would dictate. Epigenetic regulation acts through covalent modifications of DNA and histones while leaving the nucleotide code intact. However, these chromatin modifications are known to be vital components of the regulation of cell fate and response. With regards to the central nervous system (CNS), little is known about how epigenetic regulation shapes the function of neural cell types. The focus of research so far has been on epigenetic regulation of neuronal function and the role of epigenetics in tumorigenesis. However, the glial cell compartment, which makes up 90 % of all CNS cells, has so far received scant attention as to how epigenetics shape their differentiation and function. Here, we highlight current knowledge about epigenetic changes in glial cells occurring during CNS injury, neuroinflammatory conditions and neurodegenerative disease. This review offers an overview of the current understanding of epigenetic regulation in glial cells in CNS disease.
    Cell and Tissue Research 03/2014; 356(3). DOI:10.1007/s00441-014-1815-y · 3.57 Impact Factor
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    • "HDAC inhibitors can promote transcription activation or suppression by relaxing 20 Neuromol Med (2014) 16:16–24 DNA conformations in a gene-context-dependent manner. HDAC inhibitors have been tested preclinically in various neurodegenerative conditions with perturbations of histone homeostasis such as animal models of HD (Huntington's Disease), ALS (Amyotrophic Lateral Sclerosis), and Parkinson's Disease (Alarcon et al. 2004; Camelo et al. 2005; Ferrante et al. 2004; Gardian et al. 2005; Kazantsev and Thompson 2008; Ryu et al. 2005, 2006; Sugai et al. 2004). As mentioned previously, mice with genetic alterations of CBP/CREBBP (single null mutation with truncated form of CBP or dominant negative form of CBP) have deficits in LTM (long-term memory). "
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    ABSTRACT: Rubinstein-Taybi syndrome (RTS) is an incurable genetic disorder with combination of mental retardation and physical features including broad thumbs and toes, craniofacial abnormalities, and growth deficiency. While the autosomal dominant mode of transmission is limitedly known, the majority of cases are attributable to de novo mutations in RTS. The first identified gene associated with RTS is CREB-binding protein (CREBBP/CBP). Alterations of the epigenetic 'histone code' due to dysfunction of the CBP histone acetyltransferase activity deregulate gene transcriptions that are prominently linked to RTS pathogenesis. In this review, we discuss how CBP mutation contributes to modifications of histone and how histone deacetylase inhibitors are therapeutically applicable to epigenetic conditioning in RTS. Since most genetic mutations are irreversible and therapeutic approaches are limited, therapeutic targeting of reversible epigenetic components altered in RTS may be an ideal strategy. Expeditious further study on the role of the epigenetic mechanisms in RTS is encouraged to identify novel epigenetic markers and therapeutic targets to treat RTS.
    Neuromolecular medicine 03/2014; 16(1). DOI:10.1007/s12017-013-8285-3 · 3.68 Impact Factor
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