scholarly journals Bu Shen Yi Sui Capsule Alleviates Neuroinflammation and Demyelination by Promoting Microglia toward M2 Polarization, Which Correlates with Changes in miR-124 and miR-155 in Experimental Autoimmune Encephalomyelitis

2021 ◽  
Vol 2021 ◽  
pp. 1-26
Author(s):  
Zheng Zha ◽  
Yan-Fang Gao ◽  
Jing Ji ◽  
Ya-Qin Sun ◽  
Jun-Ling Li ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Target Genes ◽  
Neuroprotective Effect ◽  
Mrna Level ◽  
The Body ◽  
Intragastric Administration ◽  
Autoimmune Encephalomyelitis ◽  
Neuroprotective Effects ◽  
M2 Polarization ◽  
Experimental Autoimmune

Background. Bu Shen Yi Sui capsule (BSYS) is a traditional Chinese medicine prescription that has shown antineuroinflammatory and neuroprotective effects in treating multiple sclerosis (MS) and its animal model of experimental autoimmune encephalomyelitis (EAE). Microglia play an important role in neuroinflammation. The M1 phenotype of microglia is involved in the proinflammatory process of the disease, while the M2 phenotype plays an anti-inflammatory role. Promoting the polarization of microglia to M2 in MS/EAE is a promising therapeutic strategy. This study is aimed at exploring the effects of BSYS on microglial polarization in mice with EAE. Methods. The EAE model was established by the intraperitoneal injection of pertussis toxin and subcutaneous injection of myelin oligodendrocyte glycoprotein (MOG)35-55 in C57BL/6J mice. The mice were treated with BSYS (3.02 g/kg), FTY720 (0.3 mg/kg), or distilled water by intragastric administration. H&E and LFB staining, transmission electron microscopy, qRT-PCR, immunofluorescence, ELISA, fluorescence in situ hybridization, and western blotting were used to detect the histological changes in myelin, microglial M1/M2 polarization markers, and the expression of key genes involved in EAE. Results and Conclusions. BSYS treatment of EAE mice increased the body weight, decreased the clinical score, and reduced demyelination induced by inflammatory infiltration. BSYS also inhibited the mRNA expression of M1 microglial markers while increasing the mRNA level of M2 markers. Additionally, BSYS led to a marked decrease in the ratio of M1 microglia (iNOS+/Iba1+) and an obvious increase in the number of M2 microglia (Arg1+/Iba1+). In the EAE mouse model, miR-124 expression was decreased, and miR-155 expression was increased, while BSYS treatment significantly reversed this effect and modulated the levels of C/EBP α, PU.1, and SOCS1 (target genes of miR-124 and miR-155). Therefore, the neuroprotective effect of BSYS against MS/EAE was related to promoting microglia toward M2 polarization, which may be correlated with changes in miR-124 and miR-155 in vivo.

scholarly journals Bu-Shen-Yi-Sui Capsule, an Herbal Medicine Formula, Promotes Remyelination by Modulating the Molecular Signals via Exosomes in Mice with Experimental Autoimmune Encephalomyelitis

2020 ◽  
Vol 2020 ◽  
pp. 1-19 ◽  
Author(s):  
Pei-Yuan Zhao ◽  
Jing Ji ◽  
Xi-Hong Liu ◽  
Hui Zhao ◽  
Bin Xue ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Neuroprotective Effect ◽  
The Body ◽  
Biological Information ◽  
Neurological Injury ◽  
Autoimmune Encephalomyelitis ◽  
Molecular Signals ◽  
Serum Exosomes ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a common inflammatory demyelinating disorder of the central nervous system. Bu-shen-yi-sui capsule (BSYSC) could significantly reduce the relapse rate, prevent the progression of MS, and enhance remyelination following neurological injury in experimental autoimmune encephalomyelitis (EAE), an established model of MS; however, the mechanism underlying the effect of BSYSC on remyelination has not been well elucidated. This study showed that exosomes carrying biological information are involved in the pathological process of MS and that modified exosomes can promote remyelination by modulating related proteins and microRNAs (miRs). Here, the mechanism by which BSYSC promoted remyelination via exosome-mediated molecular signals was investigated in EAE mice and oligodendrocyte progenitor cells (OPCs) in vitro. The results showed that BSYSC treatment significantly improved the body weight and clinical scores of EAE mice, alleviated inflammatory infiltration and nerve fiber injury, protected the ultrastructural integrity of the myelin sheath, and significantly increased the expression of myelin basic protein (MBP) in EAE mice. In an in vitro OPC study, BSYSC-containing serum, especially 20% BSYSC, promoted the proliferation and migration of OPCs and induced OPCs to differentiate into mature oligodendrocytes that expressed MBP. Furthermore, BSYSC treatment regulated the expression of neuropilin- (NRP-) 1 and GTX, downregulated the expression of miR-16, let-7, miR-15, miR-98, miR-486, and miR-182, and upregulated the level of miR-146 in serum exosomes of EAE mice. In conclusion, these results suggested that BSYSC has a neuroprotective effect and facilitates remyelination and that the mechanism underlying the effect of BSYSC on remyelination probably involves regulation of the NRP-1 and GTX proteins and miRs in serum exosomes, which drive promyelination.

scholarly journals Treatment With CD52 Antibody Protects Neurons in Experimental Autoimmune Encephalomyelitis Mice During the Recovering Phase

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenlin Hao ◽  
Qinghua Luo ◽  
Michael D. Menger ◽  
Klaus Fassbender ◽  
Yang Liu
Keyword(s):  
Spinal Cord ◽  
T Lymphocytes ◽  
Experimental Autoimmune Encephalomyelitis ◽  
B Lymphocytes ◽  
Neuroprotective Effect ◽  
Recovery Phase ◽  
Conditional Knockout ◽  
Autoimmune Encephalomyelitis ◽  
Inflammatory Infiltration ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a chronic autoimmune disease driven by T and B lymphocytes. The remyelination failure and neurodegeneration results in permanent clinical disability in MS patients. A desirable therapy should not only modulate the immune system, but also promote neuroprotection and remyelination. To investigate the neuroprotective effect of CD52 antibody in MS, both C57BL/6J and SJL mice with experimental autoimmune encephalomyelitis (EAE) were treated with CD52 antibody at the peak of disease. Treatment with CD52 antibody depleted T but not B lymphocytes in the blood, reduced the infiltration of T lymphocytes and microglia/macrophages in the spinal cord. Anti-CD52 therapy attenuated EAE scores during the recovery phase. It protected neurons immediately after treatment (within 4 days) as shown by reducing the accumulation of amyloid precursor proteins. It potentially promoted remyelination as it increased the number of olig2/CC-1-positive mature oligodendrocytes and prevented myelin loss in the following days (e.g., 14 days post treatment). In further experiments, EAE mice with a conditional knockout of BDNF in neurons were administered with CD52 antibodies. Neuronal deficiency of BDNF attenuated the effect of anti-CD52 treatment on reducing EAE scores and inflammatory infiltration but did not affect anti-CD52 treatment-induced improvement of myelin coverage in the spinal cord. In summary, anti-CD52 therapy depletes CD4-positive T lymphocytes, prevents myelin loss and protects neurons in EAE mice. Neuronal BDNF regulates neuroprotective and anti-inflammatory effect of CD52 antibody in EAE mice.

scholarly journals Bixin Attenuates Experimental Autoimmune Encephalomyelitis by Suppressing TXNIP/NLRP3 Inflammasome Activity and Activating NRF2 Signaling

2020 ◽  
Vol 11 ◽  
Author(s):  
Ye Yu ◽  
Dong-Ming Wu ◽  
Jing Li ◽  
Shi-Hua Deng ◽  
Teng Liu ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Enzyme Linked Immunosorbent Assay ◽  
Intragastric Administration ◽  
Autoimmune Encephalomyelitis ◽  
Nrf2 Signaling Pathway ◽  
Anti Inflammatory ◽  
Inflammasome Activity ◽  
Experimental Autoimmune

Multiple sclerosis (MS), an autoimmune and degenerative disease, is characterized by demyelination and chronic neuroinflammation. Bixin is a carotenoid isolated from the seeds of Bixa orellana that exhibits various potent pharmacological activities, including antioxidant, anti-inflammatory, and anti-tumor properties. However, the effects of bixin on MS have not yet been examined. To evaluate the effects and underlying molecular mechanisms of bixin on MS, experimental autoimmune encephalomyelitis (EAE) was established in C57BL/6 mice, which were treated via intragastric administration of bixin solutions. To evaluate the molecular mechanisms of bixin, quantitative reverse-transcription PCR, western blot, immunohistochemistry, flow cytometry, and enzyme-linked immunosorbent assay analyses were performed. We found that bixin significantly improved the symptoms and pathology in EAE mice, reduced the release of inflammatory cytokines TNF-α, IL-6, IL-8, IL-17, and IFN-γ, and increased the expression of the anti-inflammatory cytokine IL-10. And bixin reduced the proportion of Th1 and Th17 cells in the spleen and CNS, and suppressed microglia aggregation, and TXNIP/NLRP3 inflammasome activity by scavenging excessive reactive oxygen species (ROS) in EAE mice. Furthermore, bixin inhibited inflammation and oxidative stress via activating nuclear factor erythroid 2-related factor 2 (NRF2), and its downstream genes in EAE mice, meanwhile, these effects were suppressed upon treatment with an NRF2 inhibitor, ML385. Bixin prevented neuroinflammation and demyelination in EAE mice primarily by scavenging ROS through activation of the NRF2 signaling pathway. Taken together, our results indicate that bixin is a promising therapeutic candidate for treatment of MS.

Neuroprotective effects of a polyphenolic white grape juice extract in a mouse model of experimental autoimmune encephalomyelitis

Fitoterapia ◽  
2015 ◽  
Vol 103 ◽  
pp. 171-186 ◽  
Author(s):  
Sabrina Giacoppo ◽  
Maria Galuppo ◽  
Giovanni Enrico Lombardo ◽  
Maria Malgorzata Ulaszewska ◽  
Fulvio Mattivi ◽  
...  
Keyword(s):  
Mouse Model ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Grape Juice ◽  
Autoimmune Encephalomyelitis ◽  
Neuroprotective Effects ◽  
Experimental Autoimmune

scholarly journals Arctigenin Exerts Neuroprotective Effect By Ameliorating Cortical Activities in Experimental Autoimmune Encephalomyelitis in Vivo

2021 ◽  
Author(s):  
Liangpeng Wei ◽  
Zhenyi Xue ◽  
Baihui Lan ◽  
Shiyang Yuan ◽  
Yuanyuan Li ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Ampa Receptor ◽  
Calcium Influx ◽  
Neuroprotective Effect ◽  
Network Activity ◽  
Autoimmune Encephalomyelitis ◽  
Preclinical Stage ◽  
Eae Model ◽  
Experimental Autoimmune

Abstract Background Multiple sclerosis (MS) is a chronic disease in the central nervous system (CNS), characterized by inflammatory cells invade into the brain and the spinal cord. Among a bulk of different MS models, the rodent model of experimental autoimmune encephalomyelitis (EAE) is the most widely used and best understood. Arctigenin, a botanical extract from Arctium lappa, is reported to exhibit pharmacological properties including anti-inflammation and neuroprotection. However, the effects of Arctigenin on neural activity attacked by inflammation in MS are still unclear.Methods Female C57BL/6 mice were expressed by an ultra-sensitive protein calcium sensor GCamp6f in somatosensory cortex neurons through stereotaxic virus injection. Then we induced EAE model in mice with myelin oligodendrocyte glycoprotein (MOG) peptide (35-55) and used two-photon calcium imaging to chronically observe cortical activity in vivo throughout the disease progression. Besides, we performed whole-cell electrophysiological recording to determine the frequency of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated spontaneous excitatory postsynaptic current (sEPSC) in cortical brain slices of preclinical EAE mice.ResultsHere we found added hyperactive cells, calcium influx, network connectivity and synchronization, mainly at preclinical stage of EAE model. Besides, more silent cells and decreased calcium influx and reduced network synchronization accompanied by a compensatory rise in functional connectivity were found at the remission stage. Arctigenin treatment not only restricted inordinate individually neural spiking, calcium influx and network activity at preclinical stage, but also restored neuronal activity and communication at remission stage. In addition, we confirmed that the frequency of AMPA receptor-sEPSC was also increased at preclinical stage and can be blunted by Arctigenin. Conclusions Our findings suggest that excitotoxicity resulted from calcium influx is involved in EAE at preclinical stage. Moreover, Arctigenin exerts neuroprotective effect by limiting hyperactivity at preclinical stage and ameliorates EAE symptoms, indicating Arctigenin could be a potential therapeutic drug for neuroprotection in MS-related neuropsychological disorders.

scholarly journals Sildenafil Alleviates Murine Experimental Autoimmune Encephalomyelitis by Triggering Autophagy in the Spinal Cord

2021 ◽  
Vol 12 ◽  
Author(s):  
Eduardo Duarte-Silva ◽  
Shyrlene Meiry da Rocha Araújo ◽  
Wilma Helena Oliveira ◽  
Deniele Bezerra Lós ◽  
Amanda Pires Bonfanti ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Signaling Pathways ◽  
Nitrosative Stress ◽  
Clinical Score ◽  
Beclin 1 ◽  
Autoimmune Encephalomyelitis ◽  
Neuroprotective Effects ◽  
Phosphodiesterase Type 5 Inhibitor ◽  
Experimental Autoimmune

Multiple Sclerosis (MS) is a neuroinflammatory and chronic Central Nervous System (CNS) disease that affects millions of people worldwide. The search for more promising drugs for the treatment of MS has led to studies on Sildenafil, a phosphodiesterase type 5 Inhibitor (PDE5I) that has been shown to possess neuroprotective effects in the Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS. We have previously shown that Sildenafil improves the clinical score of EAE mice via modulation of apoptotic pathways, but other signaling pathways were not previously covered. Therefore, the aim of the present study was to further investigate the effects of Sildenafil treatment on autophagy and nitrosative stress signaling pathways in EAE. 24 female C57BL/6 mice were divided into the following groups: (A) Control - received only water; (B) EAE - EAE untreated mice; (C) SILD - EAE mice treated with 25mg/kg of Sildenafil s.c. The results showed that EAE mice presented a pro-nitrosative profile characterized by high tissue nitrite levels, lowered levels of p-eNOS and high levels of iNOS. Furthermore, decreased levels of LC3, beclin-1 and ATG5, suggests impaired autophagy, and decreased levels of AMPK in the spinal cord were also detected in EAE mice. Surprisingly, treatment with Sildenafil inhibited nitrosative stress and augmented the levels of LC3, beclin-1, ATG5, p-CREB and BDNF and decreased mTOR levels, as well as augmented p-AMPK. In conclusion, we propose that Sildenafil alleviates EAE by activating autophagy via the eNOS-NO-AMPK-mTOR-LC3-beclin1-ATG5 and eNOS-NO-AMPK-mTOR-CREB-BDNF pathways in the spinal cord.

scholarly journals Oligodendrocyte-specific Argonaute profiling identifies microRNAs associated with experimental autoimmune encephalomyelitis

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Qin Ma ◽  
Atsuko Matsunaga ◽  
Brenda Ho ◽  
Jorge R. Oksenberg ◽  
Alessandro Didonna
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Target Genes ◽  
Affinity Purification ◽  
Transcriptome Profiling ◽  
Rna Degradation ◽  
Autoimmune Encephalomyelitis ◽  
Active Involvement ◽  
Purification Technique ◽  
Experimental Autoimmune

Abstract Background MicroRNAs (miRNAs) belong to a class of evolutionary conserved, non-coding small RNAs with regulatory functions on gene expression. They negatively affect the expression of target genes by promoting either RNA degradation or translational inhibition. In recent years, converging studies have identified miRNAs as key regulators of oligodendrocyte (OL) functions. OLs are the cells responsible for the formation and maintenance of myelin in the central nervous system (CNS) and represent a principal target of the autoimmune injury in multiple sclerosis (MS). Methods MiRAP is a novel cell-specific miRNA affinity-purification technique which relies on genetically tagging Argonaut 2 (AGO2), an enzyme involved in miRNA processing. Here, we exploited miRAP potentiality to characterize OL-specific miRNA dynamics in the MS model experimental autoimmune encephalomyelitis (EAE). Results We show that 20 miRNAs are differentially regulated in OLs upon transition from pre-symptomatic EAE stages to disease peak. Subsequent in vitro differentiation experiments demonstrated that a sub-group of them affects the OL maturation process, mediating either protective or detrimental signals. Lastly, transcriptome profiling highlighted the endocytosis, ferroptosis, and FoxO cascades as the pathways associated with miRNAs mediating or inhibiting OL maturation. Conclusions Altogether, our work supports a dual role for miRNAs in autoimmune demyelination. In particular, the enrichment in miRNAs mediating pro-myelinating signals suggests an active involvement of these non-coding RNAs in the homeostatic response toward neuroinflammatory injury.

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