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

doi:10.1016/j.neuroscience.2010.04.074

Neuroscience

Volume 169, Issue 1, 11 August 2010, Pages 370-377

https://doi.org/10.1016/j.neuroscience.2010.04.074 Get rights and content

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.

Section snippets

Animals

Male Lewis rats (8–10 weeks, 170–200 g, Charles River, Sulzfeld, Germany) were housed under a 12-h light/dark cycle with free access to food and water. All animal procedures were in accordance with a protocol approved by the local Administration District Official Committee. All efforts were made to minimize the number of animals and their suffering.

EAN induction and MS-275 treatment

EAN was induced as described (Zhang et al., 2008a). Briefly, rats were immunized by s.c. injection at the basal part of tails with 100 μL of an

Therapeutic MS-275 treatment ameliorated EAN

EAN was induced by s.c. injection of neuritogenic synthetic P2 peptide. For therapeutic treatment, MS-275 or PBS (control group) was injected once daily from the onset of neurological signs (day 10–14 post immunization). The first neurologic sign (reduced tonus of tail) of control EAN rats was observed at day 10 (mean clinical score ± SEM: 0.3±0.2). The neurologic severity of EAN increased fast in the control group with a maximal score at day 15 (5.5±0.8). Thereafter, the severity of EAN slowly

Discussion

EAN is the prime animal model for inflammatory demyelinating polyneuropathies and useful in investigating new therapeutic approaches. We have studied the therapeutic effects of MS-275 on EAN. Our findings demonstrate that MS-275 greatly reduced paraparesis through substantial reduction of infiltration of lymphocytes and macrophages into the peripheral nerves and suppression of local level of inflammatory molecules, even when administrated after the appearance of the first neurological signs.

Conclusion

In summary, our data demonstrate that MS-275 treatment greatly reduced severity and duration of EAN, and attenuated inflammation and demyelination in the peripheral nerves. Besides attenuated accumulation of immune cells and decreased local expression of a variety of pro-inflammatory molecules in sciatic nerves of EAN rats, MS-275 treatment changed the lymph node cytokine profile and increased the proportion of anti-inflammatory Foxp3⁺ cells and M2 macrophages in sciatic nerves of EAN rats.

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¹: Present address: Institute of Immunology, Third Military Medical University of PLA, 30 Gaotanyan Street, Chongqing 400038, PR China.

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Neurodegeneration, Neuroprotection, and Disease-Oriented NeuroscienceResearch PaperMS-275, an histone deacetylase inhibitor, reduces the inflammatory reaction in rat experimental autoimmune neuritis

Abstract

Section snippets

Animals

EAN induction and MS-275 treatment

Therapeutic MS-275 treatment ameliorated EAN

Discussion

Conclusion

Best Pract Res Clin Rheumatol

Allergol Int

Drug Discov Today

Cancer Lett

Mol Med Today

Pharmacol Ther

Int J Biochem Cell Biol

Cell Immunol

Cell Immunol

Exp Neurol

Exp Neurol

J Neuroimmunol

Histone deacetylase inhibitors as novel anti-inflammatory agents

Curr Opin Investig Drugs

Macrophage phenotype as a determinant of biologic scaffold remodeling

Tissue Eng Part A

Induction and effector functions of T(H) 17 cells

Nature

TH17 cells in development: an updated view of their molecular identity and genetic programming

Nat Rev Immunol

Clinical development of histone deacetylase inhibitors as anticancer agents

Annu Rev Pharmacol Toxicol

Anti-inflammatory effect of Trichostatin-A on murine bone marrow-derived macrophages

Arch Pharm Res

Neurodegeneration, Neuroprotection, and Disease-Oriented Neuroscience
Research Paper
MS-275, an histone deacetylase inhibitor, reduces the inflammatory reaction in rat experimental autoimmune neuritis