MS-275, an histone deacetylase inhibitor, reduces the inflammatory reaction in rat experimental autoimmune neuritis.
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-1beta, interferon-gamma, 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.
Zhang
Z Y
ZY
Institute of Brain Research, University of Tuebingen, Calwer Street 3, D-72076 Tuebingen, Baden-Württemberg, Germany. zhangzhiren@yahoo.com
Zhang
Z
Z
Schluesener
H J
HJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003711:Demyelinating Diseases / Q000473:pathology; D004353:Drug Evaluation, Preclinical; D051858:Forkhead Transcription Factors / Q000032:analysis; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D016131:Lymphocyte Subsets / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D009444:Neuritis, Autoimmune, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; D016207:Cytokines; D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D056572:Histone Deacetylase Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; C118739:entinostat; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D020780:Matrix Metalloproteinase 9