Effect of 1.25(OH)2D3 on experimental autoimmune neuritis and its mechanism

Objective: To study the potential therapeutic effects of active vitamin D3 (1.25(OH)2D3) in the experimental autoimmune neuritis (EAN). Methods: The EAN model was established by actively immunizing Lewis rats with synthetic P0180–199 pepide and Freund’s complete adjuvant. 1.25(OH)2D3 treatment was given, weight change of rats and clinical score were analyzed. HE staining was used to detect the inflammatory cell infiltration of sciatic nerves and demyelination of sciatic nerves was observed by transmission electron microscope (TEM) at the same time. The expressions of inflammatory cytokines IL-17, IL-10, TGF-β, IFN-γ were detected by ELISA, and the expressions of Th17, Treg were examined by RT-PCR. Results: 1.25(OH)2D3 ameliorated body weight loss and myelin lesions. It decreased expressions of inflammatory cytokines IL-17, IFN-γ and RORrt while those of IL-10, TGF-β and FoxP3 were increased. Conclusions: 1.25(OH)2D3 can improve the clinical pathological changes of EAN rats, and the mechanism may be related to the changes of inflammatory cytokines. 1.25(OH)2D3 is expected to become a new strategy for the clinical treatment of GBS/EAN.

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CKD-506: A novel HDAC6-selective inhibitor that exerts therapeutic effects in a rodent model of multiple sclerosis

Scientific Reports ◽

10.1038/s41598-021-93232-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Daekwon Bae ◽

Ji-Young Lee ◽

Nina Ha ◽

Jinsol Park ◽

Jiyeon Baek ◽

...

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Immune Responses ◽

Therapeutic Potential ◽

Autoimmune Encephalitis ◽

Selective Inhibitor ◽

Therapeutic Effects ◽

Treatment Regimens ◽

Ifn Γ ◽

Experimental Autoimmune

AbstractDespite advances in therapeutic strategies for multiple sclerosis (MS), the therapy options remain limited with various adverse effects. Here, the therapeutic potential of CKD-506, a novel HDAC6-selective inhibitor, against MS was evaluated in mice with myelin oligodendrocyte glycoprotein35–55 (MOG35–55)-induced experimental autoimmune encephalitis (EAE) under various treatment regimens. CKD-506 exerted prophylactic and therapeutic effects by regulating peripheral immune responses and maintaining blood–brain barrier (BBB) integrity. In MOG35–55-re-stimulated splenocytes, CKD-506 decreased proliferation and downregulated the expression of IFN-γ and IL-17A. CKD-506 downregulated the levels of pro-inflammatory cytokines in the blood of EAE mice. Additionally, CKD-506 decreased the leakage of intravenously administered Evans blue into the spinal cord; CD4+ T cells and CD4−CD11b+CD45+ macrophage/microglia in the spinal cord was also decreased. Moreover, CKD-506 exhibited therapeutic efficacy against MS, even when drug administration was discontinued from day 15 post-EAE induction. Disease exacerbation was not observed when fingolimod was changed to CKD-506 from day 15 post-EAE induction. CKD-506 alleviated depression-like behavior at the pre-symptomatic stage of EAE. In conclusion, CKD-506 exerts therapeutic effects by regulating T cell- and macrophage-mediated peripheral immune responses and strengthening BBB integrity. Our results suggest that CKD-506 is a potential therapeutic agent for MS.

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Human umbilical cord mesenchymal stem cell-derived extracellular vesicles attenuate experimental autoimmune encephalomyelitis via regulating pro and anti-inflammatory cytokines

Scientific Reports ◽

10.1038/s41598-021-91291-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Samira Ahmadvand Koohsari ◽

Abdorrahim Absalan ◽

Davood Azadi

Keyword(s):

Spinal Cord ◽

Body Weight ◽

Extracellular Vesicles ◽

Inflammatory Cytokines ◽

Clinical Score ◽

Human Umbilical Cord ◽

Therapeutic Effects ◽

Leukocyte Infiltration ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

AbstractThe therapeutic effects of mesenchymal stem cells-extracellular vesicles have been proved in many inflammatory animal models. In the current study, we aimed to investigate the effect of extracellular vesicles (EVs) derived from human umbilical cord-MSC (hUCSC-EV) on the clinical score and inflammatory/anti-inflammatory cytokines on the EAE mouse model. After induction of EAE in C57Bl/6 mice, they were treated intravenously with hUCSC-EV or vehicle. The clinical score and body weight of all mice was registered every day. On day 30, mice were sacrificed and splenocytes were isolated for cytokine assay by ELISA. Cytokine expression of pro-/anti-inflammatory cytokine by real-time PCR, leukocyte infiltration by hematoxylin and eosin (H&E) staining, and the percent of glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) positive cells by immunohistochemistry were assessed in the spinal cord. Our results showed that hUCSC-EV-treated mice have lower maximum mean clinical score (MMCS), pro-inflammatory cytokines, and inflammatory score in comparison to the control mice. We also showed that hUCSC-EV administration significantly improved body weight and increased the anti-inflammatory cytokines and the frequency of Treg cells in the spleen. There was no significant difference in the percent of GFAP and MBP positive cells in the spinal cord of experimental groups. Finally, we suggest that intravenous administration of hUCSC-EV alleviate induce-EAE by reducing the pro-inflammatory cytokines, such as IL-17a, TNF-α, and IFN-γ, and increasing the anti-inflammatory cytokines, IL-4 and IL-10, and also decrease the leukocyte infiltration in a model of MS. It seems that EVs from hUC-MSCs have the same therapeutic effects similar to EVs from other sources of MSCs, such as adipose or bone marrow MSCs.

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Preventive and therapeutic effects of the selective Rho-kinase inhibitor fasudil on experimental autoimmune neuritis

Journal of the Neurological Sciences ◽

10.1016/j.jns.2011.03.031 ◽

2011 ◽

Vol 306 (1-2) ◽

pp. 115-120 ◽

Cited By ~ 12

Author(s):

Arnold Angelo M. Pineda ◽

Motozumi Minohara ◽

Nobutoshi Kawamura ◽

Takuya Matsushita ◽

Ryo Yamasaki ◽

...

Keyword(s):

Kinase Inhibitor ◽

Rho Kinase ◽

Therapeutic Effects ◽

Experimental Autoimmune Neuritis ◽

Rho Kinase Inhibitor ◽

Experimental Autoimmune

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Celastrol ameliorates experimental autoimmune neuritis by shifting the polarization of M1/M2 macrophages via the hypoxic response pathway

10.21203/rs.3.rs-25002/v1 ◽

2020 ◽

Author(s):

Yun Qian ◽

Bo Tang ◽

Minhai Jiang ◽

Shan Lu ◽

Huan Huang ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Macrophage Polarization ◽

Polarization State ◽

Immunofluorescence Staining ◽

Experimental Autoimmune Neuritis ◽

Inflammatory Infiltration ◽

Histological Changes ◽

Hypoxic Response ◽

Effective Therapeutic Strategy ◽

Experimental Autoimmune

Abstract BackgroundGBS is an autoimmune disease characterized by inflammatory infiltration and demyelination of peripheral nerves. Macrophage polarization is involved in different stages of GBS. Altering the polarization of macrophages may be an effective therapeutic strategy for GBS. Celastrol was previously shown to contribute to anti-neuroinflammation. However, the mechanism underlying the effect of celastrol in GBS animal model experimental autoimmune neuritis (EAN) is unclear. We hypothesized that celastrol may shift the polarization of macrophages through the NRF /HIF-1αpathway.MethodsClinical scores, weight and histological changes were assessed to investigate the effects of celastrol on EAN. To detect the polarization state of macrophages, flow cytometry and immunofluorescence staining were applied. Inflammation cytokines were evaluated by ELISA. The expression of NRF2 and HIF-1α were detected by western-blot and immunofluorescence staining.ResultsCelastrol treatment significantly ameliorates the severity and neuroinflammation of EAN. The polarization state of macrophages from M1 to M2 was observed upon celastrol application. Consistently, pro-inflammatory cytokines were decreased, whereas anti-inflammatory cytokines were increased upon celastrol treatment. Furthermore, we found that celastrol treatment may increase expression of Nrf2 and decrease the expression of HIF-1α. ConclusionTaken together, these data demonstrate that celastrol may ameliorate the severity and neuroinflammation of EAN via promoting the polarization state of macrophages into M2, likely by modulating the hypoxic response. Celastrol may therefore serve as a novel therapeutic agent for GBS.

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NF-κB inhibitor suppresses experimental autoimmune neuritis in mice via declining macrophages polarization to M1 type

10.22541/au.161961436.61203158/v1 ◽

2021 ◽

Author(s):

Donghui Shen ◽

Fengna Chu ◽

Yue Lang ◽

Chao Zheng ◽

Chunrong Li ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Demyelinating Disease ◽

Clinical Symptoms ◽

M2 Macrophage ◽

Experimental Autoimmune Neuritis ◽

Peak Period ◽

Duration Of Symptoms ◽

Beneficial Effects ◽

M1 Macrophage ◽

Experimental Autoimmune

Guillain–Barre’ syndrome (GBS) is an acute inflammatory and immune-mediated demyelinating disease of peripheral nervous system (PNS). Macrophages playing a central role in its animal model, experimental autoimmune neuritis (EAN) has been well-accepted. Additionally, NF-κB inhibitors has been used to treat cancers and showed beneficial effects. Here we investigated the therapeutic effect of M2 macrophage and NF-κB pathway is correlated with macrophages activation in experimental autoimmune neuritis (EAN) in C57BL/6 mice. We demonstrated that M2 macrophage transfusion can alleviate the clinical symptoms of EAN by reducing the proportion of M1 macrophage in the peak period, inhibiting the phosphorylation of NF-κB p65. The NF-κB inhibitor (BAY-11-7082) could alleviate the clinical symptoms of EAN and shorten the duration of symptoms by reducing the proportion of M1 macrophages and the expression of pro-inflammatory cytokines. Consequently, BAY-11-7082 exhibits strong potential as a therapeutic strategy for ameliorating EAN by influencing the balance of M1/M2 macrophages and inflammatory cytokines.

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Time Course of Axon and Myelin Degeneration in Peripheral Nerves in Experimental Autoimmune Neuritis Rats

Toxicologic Pathology ◽

10.1177/0192623319838993 ◽

2019 ◽

Vol 47 (4) ◽

pp. 542-552 ◽

Cited By ~ 1

Author(s):

Emi Tomikawa ◽

Mayu Mutsuga ◽

Kojiro Hara ◽

Chihiro Kaneko ◽

Yuko Togashi ◽

...

Keyword(s):

Peripheral Nerves ◽

Time Course ◽

Nerve Fibers ◽

Neurological Symptoms ◽

Experimental Autoimmune Neuritis ◽

Histopathological Changes ◽

Cell Cytoplasm ◽

Myelinated Nerve ◽

Transmission Electron ◽

Experimental Autoimmune

Experimental autoimmune neuritis (EAN) is an animal model for Guillain–Barré syndrome (GBS), which results in neurological symptoms and histopathological changes in peripheral nerves. In this model, the correlation between the progression of the disease and the histopathological changes is not clear. To further examine histopathological changes in peripheral nerves in EAN rats, sciatic nerves were sampled at onset (day 10), peak (day 16), and recovery (days 22 and 25) of neurological symptoms in P2(57-81)-peptide-administered rats. Axon and myelin degeneration was observed by light microscopy at onset, degeneration became severe at peak, and persisted at recovery. Densities of myelinated nerve fibers and myelin areas decreased from day 10 to a minimum on day 22. Slight axon and myelin degeneration, such as accumulation of vesicles in axons and focal myelin splitting and folding, was observed by transmission electron microscopy at onset; severe degeneration, such as axonal loss, myelin ovoid, and demyelination, increased at peak; and regenerative changes, such as remyelination and enlargement of Schwann cell cytoplasm, occurred at recovery. These results suggest that EAN rats have histopathological similarities to some types of GBS patients and that EAN rats are a useful model to understand the pathogenesis of GBS.

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