MS-275, an histone deacetylase inhibitor, reduces the inflammatory reaction in rat experimental autoimmune neuritis

• Published in: Neuroscience Vol. 169; no. 1; pp. 370 - 377
• Main Authors: Zhang, Z.Y, Zhang, Z, Schluesener, H.J
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 11.08.2010; Elsevier
• Subjects: Animal models; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Benzamides - pharmacology; Benzamides - therapeutic use; Biological and medical sciences; Cytokines - biosynthesis; Cytokines - genetics; Demyelinating Diseases - pathology; Drug Evaluation, Preclinical; experimental autoimmune neuritis; Forkhead Transcription Factors - analysis; Foxp3 + T cell; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; HDAC inhibitor; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; Inflammation; Lymph Nodes - metabolism; Lymph Nodes - pathology; Lymphocyte Subsets - pathology; M2 macrophage; Macrophages - pathology; Male; Matrix Metalloproteinase 9 - biosynthesis; Matrix Metalloproteinase 9 - genetics; MS-275; Neuritis, Autoimmune, Experimental - drug therapy; Neuritis, Autoimmune, Experimental - enzymology; Neuritis, Autoimmune, Experimental - pathology; Neurology; Nitric Oxide Synthase Type II - biosynthesis; Nitric Oxide Synthase Type II - genetics; Pyridines - pharmacology; Pyridines - therapeutic use; Rats; Rats, Inbred Lew; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Sciatic Nerve - metabolism; Sciatic Nerve - pathology; Vertebrates: nervous system and sense organs; immunoreactivity; PEX; blood nerve barrier; luxol fast blue; transforming growth factor beta; Treg cell; VPA; LFB; peripheral nervous system; experimental autoimmune neuritis; T helper cell; inducible nitric oxide synthase; IFN-γ; experimental autoimmune encephalomyelitis; PNS; histone deacetylase inhibitor; interferon γ; iNOS; TGF-β; interleukin; plasma exchange; intravenous immunoglobulin; PBS; MS-275; IL; EAE; IR; IVIG; Foxp3 + T cell; regulatory T cell; valproic acid; fox head box protein3; histone deacetylase; MMP; M2 macrophage; EAN; T h cell; phosphate buffered saline; BNB; HDAC inhibitor; Foxp3; HDACI; matrix metallopeptidase; HDAC; Rat; T cell; Rodentia; Inflammation; Nevritis; Vertebrata; Mammalia; Animal; T-Lymphocyte; Histone; Macrophage
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2010.04.074

Abstract Experimental autoimmune neuritis (EAN) is a T cell-mediated autoimmune inflammatory demyelinating disease of the peripheral nervous system and serves as the animal model of human inflammatory demyelinating polyradiculoneuropathies. MS-275, a potent histone deacetylase inhibitor currently undergoing clinical investigations for various malignancies, has been reported to demonstrate promising anti-inflammatory activities. In our present study, MS-275 administration (3.5 mg/kg i.p.) to EAN rats once daily from the appearance of first neurological signs greatly reduced the severity and duration of EAN and attenuated local accumulation of macrophages, T cells and B cells, and demyelination of sciatic nerves. Further, significant reduction of mRNA levels of pro-inflammatory interleukin-1β, interferon-γ, interleukine-17, inducible nitric oxide synthase and matrix metalloproteinase-9 was observed in sciatic nerves of MS-275 treated EAN rats. In lymph nodes, MS-275 depressed pro-inflammatory cytokines as well, but increased expression of anti-inflammatory cytokine interleukine-10 and of foxhead box protein3 (Foxp3), a unique transcription factor of regulatory T cells. In addition, MS-275 treatment increased proportion of infiltrated Foxp3+ cells and anti-inflammatory M2 macrophages in sciatic nerves of EAN rats. In summary, our data demonstrated that MS-275 could effectively suppress inflammation in EAN, through suppressing inflammatory T cells, macrophages and cytokines, and inducing anti-inflammatory immune cells and molecules, suggesting MS-275 as a potent candidate for treatment of autoimmune neuropathies.