The Therapeutic Potential of HDAC Inhibitors in the Treatment of Multiple Sclerosis

Overview

Journal Mol Med

Publisher Biomed Central

Specialties General Medicine
Molecular Biology

Date 2011 Mar 5

PMID 21373721

Citations 32

Authors

Giuseppe Faraco

Leonardo Cavone

Alberto Chiarugi

Affiliations

Soon will be listed here.

Abstract

Multiple sclerosis (MS) is a devastating autoimmune disorder of the central nervous system (CNS) for which there is no efficacious cure. Thanks to numerous preclinical and clinical studies, drugs able to mitigate the inexorable course of the disease have been made available recently. Still, there is a terrible need for compounds capable of reducing the severity of the autoimmune attack and of blocking progression of the disorder. Also, besides the classic immunosuppressive strategies, it is now appreciated that compounds directly targeting neuronal death can be of relevance to the treatment of MS patients. Acetylation homeostasis is a key regulator of both immune cell activation and neuronal survival. Of note, potent histone deacetylase inhibitors (HDACi) endowed with antiinflammatory and neuroprotective properties have been identified. Efficacy of HDACi in experimental models of MS has been reported consistently. In this review, we provide an appraisal of the literature on HDACi and MS, also discussing the mechanisms by which HDACi can suppress the autoimmune attack to the CNS.

Citing Articles

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References

Minucci S, Pelicci P . Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 2006; 6(1):38-51. DOI: 10.1038/nrc1779. View

Rivieccio M, Brochier C, Willis D, Walker B, DAnnibale M, McLaughlin K . HDAC6 is a target for protection and regeneration following injury in the nervous system. Proc Natl Acad Sci U S A. 2009; 106(46):19599-604. PMC: 2780768. DOI: 10.1073/pnas.0907935106. View

Miller S, McMahon E, Schreiner B, Bailey S . Antigen presentation in the CNS by myeloid dendritic cells drives progression of relapsing experimental autoimmune encephalomyelitis. Ann N Y Acad Sci. 2007; 1103:179-91. DOI: 10.1196/annals.1394.023. View

McMahon E, Bailey S, Castenada C, Waldner H, Miller S . Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis. Nat Med. 2005; 11(3):335-9. DOI: 10.1038/nm1202. View

Venken K, Hellings N, Liblau R, Stinissen P . Disturbed regulatory T cell homeostasis in multiple sclerosis. Trends Mol Med. 2010; 16(2):58-68. DOI: 10.1016/j.molmed.2009.12.003. View

Blanchard F, Chipoy C . Histone deacetylase inhibitors: new drugs for the treatment of inflammatory diseases?. Drug Discov Today. 2005; 10(3):197-204. DOI: 10.1016/S1359-6446(04)03309-4. View

Taveggia C, Feltri M, Wrabetz L . Signals to promote myelin formation and repair. Nat Rev Neurol. 2010; 6(5):276-87. PMC: 3062363. DOI: 10.1038/nrneurol.2010.37. View

Broide R, Redwine J, Aftahi N, Young W, Bloom F, Winrow C . Distribution of histone deacetylases 1-11 in the rat brain. J Mol Neurosci. 2007; 31(1):47-58. DOI: 10.1007/BF02686117. View

Huang L, Baban B, Johnson 3rd B, Mellor A . Dendritic cells, indoleamine 2,3 dioxygenase and acquired immune privilege. Int Rev Immunol. 2010; 29(2):133-55. PMC: 3671384. DOI: 10.3109/08830180903349669. View

10.

Suuronen T, Huuskonen J, Pihlaja R, Kyrylenko S, Salminen A . Regulation of microglial inflammatory response by histone deacetylase inhibitors. J Neurochem. 2003; 87(2):407-16. DOI: 10.1046/j.1471-4159.2003.02004.x. View

11.

Bosisio D, Vulcano M, Del Prete A, Sironi M, Salvi V, Salogni L . Blocking TH17-polarizing cytokines by histone deacetylase inhibitors in vitro and in vivo. J Leukoc Biol. 2008; 84(6):1540-8. PMC: 2614600. DOI: 10.1189/jlb.0708401. View

12.

Koyama Y, Adachi M, Sekiya M, Takekawa M, Imai K . Histone deacetylase inhibitors suppress IL-2-mediated gene expression prior to induction of apoptosis. Blood. 2000; 96(4):1490-5. View

13.

Conlon P, Oksenberg J, Zhang J, Steinman L . The immunobiology of multiple sclerosis: an autoimmune disease of the central nervous system. Neurobiol Dis. 1999; 6(3):149-66. DOI: 10.1006/nbdi.1999.0239. View

14.

Polman C, Killestein J . Anti-myelin antibodies in multiple sclerosis: clinically useful?. J Neurol Neurosurg Psychiatry. 2006; 77(6):712. PMC: 2077472. DOI: 10.1136/jnnp.2006.089839. View

15.

Zhang B, West E, Van K, Gurkoff G, Zhou J, Zhang X . HDAC inhibitor increases histone H3 acetylation and reduces microglia inflammatory response following traumatic brain injury in rats. Brain Res. 2008; 1226:181-91. PMC: 2652585. DOI: 10.1016/j.brainres.2008.05.085. View

16.

Gray S, Dangond F . Rationale for the use of histone deacetylase inhibitors as a dual therapeutic modality in multiple sclerosis. Epigenetics. 2007; 1(2):67-75. DOI: 10.4161/epi.1.2.2678. View

17.

Vanderlugt C, Miller S . Epitope spreading in immune-mediated diseases: implications for immunotherapy. Nat Rev Immunol. 2002; 2(2):85-95. DOI: 10.1038/nri724. View

18.

Kohm A, Carpentier P, Anger H, Miller S . Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J Immunol. 2002; 169(9):4712-6. DOI: 10.4049/jimmunol.169.9.4712. View

19.

Parmigiani R, Xu W, Venta-Perez G, Erdjument-Bromage H, Yaneva M, Tempst P . HDAC6 is a specific deacetylase of peroxiredoxins and is involved in redox regulation. Proc Natl Acad Sci U S A. 2008; 105(28):9633-8. PMC: 2443817. DOI: 10.1073/pnas.0803749105. View

20.

Kim H, Rowe M, Ren M, Hong J, Chen P, Chuang D . 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. 2007; 321(3):892-901. DOI: 10.1124/jpet.107.120188. View