Demyelinating diseases of the central nervous system are common,yet few effective strategies for myelin repair and remyelination are available.An increasing number of studies highlight the role of microRNAs(miRNAs)as ...Demyelinating diseases of the central nervous system are common,yet few effective strategies for myelin repair and remyelination are available.An increasing number of studies highlight the role of microRNAs(miRNAs)as key regulators of demyelination.miRNA mimics and inhibitors,which are currently in preclinical development,have shown promise as novel therapeutic agents.However,the mechanisms by which they protect myelin are not fully understood.Using a mouse model of acute central nervous system demyelination induced by infection with Angiostrongylus cantonensis,we investigated alterations in miRNA expression in the mouse brain.Our findings revealed a significant early-stage increase in the levels of miR-200,particularly miR-200a and miR-200c.Subsequent analysis demonstrated that combined miR-200a and miR-200c overexpression improved neurobehavioral outcomes and attenuated demyelination in Angiostrongylus cantonensis-infected mice.Further lipid metabolomic profiling indicated that miR-200a and miR-200c synergistically inhibited the production of phosphatase and tensin homolog(PTEN)and activated the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway,as confirmed by double luciferase reporter assay and western blotting.Additionally,in vitro experiments showed that miR-200a and miR-200c protected oligodendrocyte precursor cells from lipopolysaccharide-induced damage and enhanced their survival.Our study indicates the critical role of miR-200a and miR-200c in protecting against central nervous system demyelination by targeting PTEN and modulating key survival pathways.Furthermore,our findings suggest that miR-200a and miR-200c are promising diagnostic biomarkers of and therapeutic targets for treating demyelination-related disorders.展开更多
This article discusses a study by Li et al,which investigates the role of the microglial voltage-gated proton channel 1(Hv1)in diabetes-related cognitive decline.The authors showed that Hv1 is upregulated in the corpu...This article discusses a study by Li et al,which investigates the role of the microglial voltage-gated proton channel 1(Hv1)in diabetes-related cognitive decline.The authors showed that Hv1 is upregulated in the corpus callosum of diabetic mice and that its knockout improves working memory,reduces microglial production of interleukin-1βand tumour necrosis factor alpha,and decreases apoptosis of oligodendrocyte progenitor cells.Furthermore,electron microscopy revealed that the myelin thickness and the g-ratio were preserved in Hv1 knockout mice,remaining within normal limits.In addition,Hv1 knockdown mitigated interleukin-1βsecretion and suppressed ferroptosis markers(ferritin heavy chain/ferritin light chain,CCAAT/enhancer binding protein homologous protein,glucose-regulated protein 78,etc.)in vitro,suggesting the involvement of an Hv1-reactive oxygen species-glucose-regulated protein 78 axis in diabetic demyelination.We highlight the translational implications of these findings and recommend future studies employing microglia-specific Hv1 deletion models,longitudinal cognitive assessments and preclinical evaluation of pharmacological Hv1 inhibitors.展开更多
Demyelination and remyelination play key roles in spinal cord injury(SCI),affecting the recovery of motor and sensory functions.Research in rodent models is extensive,but the study of these processes in non-human prim...Demyelination and remyelination play key roles in spinal cord injury(SCI),affecting the recovery of motor and sensory functions.Research in rodent models is extensive,but the study of these processes in non-human primates is limited.Therefore,our goal was to thoroughly study the histological features of demyelination and remyelination after contusion injury of the cervical spinal cord in Macaca fascicularis.In a previous study,we created an SCI model in M.fascicularis by controlling the contusion displacement.We used Eriochrome Cyanine staining,immunohistochemical analysis,and toluidine blue staining to evaluate demyelination and remyelination.The results showed demyelination ipsilateral to the injury epicenter both rostrally and caudally,the former mainly impacting sensory pathways,while the latter primarily affected motor pathways.Toluidine blue staining showed myelin loss and axonal distension at the injury site.Schwann cell-derived myelin sheaths were only found at the center,while thinner myelin sheaths from oligodendrocytes were seen at the center and surrounding areas.Our study showed that long-lasting demyelination occurs in the spinal cord of M.fascicularis after SCI,with oligodendrocytes and Schwann cells playing a significant role in myelin sheath formation at the injury site.展开更多
Multiple sclerosis(MS)is an autoimmune demyelinating disease of the central nervous system,and microglia and macrophages play important roles in its pathogenesis.The activation of microglia and macrophages ac-companie...Multiple sclerosis(MS)is an autoimmune demyelinating disease of the central nervous system,and microglia and macrophages play important roles in its pathogenesis.The activation of microglia and macrophages ac-companies disease development,whereas depletion of these cells significantly decreases disease severity.Microglia and macrophages usually have diverse and plastic phenotypes.Both pro-inflammatory and anti-inflammatory microglia and macrophages exist in MS and its animal model,experimental autoimmune enceph-alomyelitis.The polarization of microglia and macrophages may underlie the differing functional properties that have been reported.In this review,we discuss the responses and polarization of microglia and macrophages in MS,and their effects on its pathogenesis and repair.Harnessing their beneficial effects by modulating their polarization states holds great promise for the treatment of inflammatory demyelinating diseases.展开更多
The differentiation and maturation of oligodendrocyte precursor cells(OPCs) is essential for myelination and remyelination in the CNS. The failure of OPCs to achieve terminal differentiation in demyelinating lesions o...The differentiation and maturation of oligodendrocyte precursor cells(OPCs) is essential for myelination and remyelination in the CNS. The failure of OPCs to achieve terminal differentiation in demyelinating lesions often results in unsuccessful remyelination in a variety of human demyelinating diseases. However, the molecular mechanisms controlling OPC differentiation under pathological conditions remain largely unknown. Myt1 L(myelin transcription factor 1-like), mainly expressed in neurons,has been associated with intellectual disability, schizophrenia, and depression. In the present study, we found that Myt1 L was expressed in oligodendrocyte lineage cells during myelination and remyelination. The expression level of Myt1 L in neuron/glia antigen 2-positive(NG2+)OPCs was significantly higher than that in mature CC1+oligodendrocytes. In primary cultured OPCs,overexpression of Myt1 L promoted, while knockdown inhibited OPC differentiation. Moreover, Myt1 L was potently involved in promoting remyelination after lysolecithin-induced demyelination in vivo. Ch IP assays showed that Myt1 L bound to the promoter of Olig1 and transcriptionally regulated Olig1 expression. Taken together, our findings demonstrate that Myt1 L is an essential regulator of OPC differentiation, thereby supporting Myt1 L as a potential therapeutic target for demyelinating diseases.展开更多
The APPSwe/PSEN1 dE9（APP/PS1） transgenic mouse model is an Alzheimer＇s disease mouse model exhibiting symptoms of dementia, and is commonly used to explore pathological changes in the development of Alzheimer＇s di...The APPSwe/PSEN1 dE9（APP/PS1） transgenic mouse model is an Alzheimer＇s disease mouse model exhibiting symptoms of dementia, and is commonly used to explore pathological changes in the development of Alzheimer＇s disease. Previous clinical autopsy and imaging studies suggest that Alzheimer＇s disease patients have white matter and oligodendrocyte damage, but the underlying mechanisms of these have not been revealed. Therefore, the present study used APP/PS1 mice to assess cognitive change, myelin loss, and corresponding changes in oligodendrocytes, and to explore the underlying mechanisms. Morris water maze tests were performed to evaluate cognitive change in APP/PS1 mice and normal C57 BL/6 mice aged 3 and 6 months. Luxol fast blue staining of the corpus callosum and quantitative reverse transcription-polymerase chain reaction（q RT-PCR） for myelin basic protein（MBP） mRNA were carried out to quantify myelin damage. Immunohistochemistry staining for NG2 and qRT-PCR for monocarboxylic acid transporter 1（MCT1） mRNA were conducted to assess corresponding changes in oligodendrocytes. Our results demonstrate that compared with C57 BL/6 mice, there was a downregulation of MBP mRNA in APP/PS1 mice aged 3 months. This became more obvious in APP/PS1 mice aged 6 months accompanied by other abnormalities such as prolonged escape latency in the Morris water maze test, shrinkage of the corpus callosum, upregulation of NG2-immunoreactive cells, and downregulation of MCT1 mRNA. These findings indicate that the involvement of early demyelination at 3 months and the oligodendrocyte dysfunction at 6 months in APP/PS1 mice are in association with Alzheimer＇s disease pathogenesis.展开更多
Emodin,a substance extracted from herbs such as rhubarb,has a protective effect on the central nervous system.However,the potential therapeutic effect of emodin in the context of multiple sclerosis remains unknown.In ...Emodin,a substance extracted from herbs such as rhubarb,has a protective effect on the central nervous system.However,the potential therapeutic effect of emodin in the context of multiple sclerosis remains unknown.In this study,a rat model of experimental autoimmune encephalomyelitis was established by immune induction to simulate multiple sclerosis,and the rats were intraperitoneally injected with emodin(20 mg/kg/d)from the day of immune induction until they were sacrificed.In this model,the nucleotide-binding domain-like receptor family pyrin domain containing 3(NLRP3)inflammasome and the microglia exacerbated neuroinflammation,playing an important role in the development of multiple sclerosis.In addition,silent information regulator of transcription 1(SIRT1)/peroxisome proliferator-activated receptor-alpha coactivator(PGC-1α)was found to inhibit activation of the NLRP3 inflammasome,and SIRT1 activation reduced disease severity in experimental autoimmune encephalomyelitis.Furthermore,treatment with emodin decreased body weight loss and neurobehavioral deficits,alleviated inflammatory cell infiltration and demyelination,reduced the expression of inflammatory cytokines,inhibited microglial aggregation and activation,decreased the levels of NLRP3 signaling pathway molecules,and increased the expression of SIRT1 and PGC-1α.These findings suggest that emodin improves the symptoms of experimental autoimmune encephalomyelitis,possibly through regulating the SIRT1/PGC-1α/NLRP3 signaling pathway and inhibiting microglial inflammation.These findings provide experimental evidence for treatment of multiple sclerosis with emodin,enlarging the scope of clinical application for emodin.展开更多
The massive loss of oligodendrocytes caused by various pathological factors is a basic feature of many demyelinating diseases of the central nervous system(CNS). Based on a variety of studies, it is now well establish...The massive loss of oligodendrocytes caused by various pathological factors is a basic feature of many demyelinating diseases of the central nervous system(CNS). Based on a variety of studies, it is now well established that impairment of oligodendrocyte precursor cells(OPCs) to differentiate and remyelinate axons is a vital event in the failed treatment of demyelinating diseases. Recent evidence suggests that Foxg1 is essential for the proliferation of certain precursors and inhibits premature neurogenesis during brain development. To date, very little attention has been paid to the role of Foxg1 in the proliferation and differentiation of OPCs in demyelinating diseases of the CNS. Here, for the first time, we examined the effects of Foxg1 on demyelination and remyelination in the brain using a cuprizone(CPZ)-induced mouse model. In this work, 7-week-old Foxg1 conditional knockout and wild-type(WT) mice were fed a diet containing 0.2% CPZ w/w for 5 weeks, after which CPZ was withdrawn to enable remyelination. Our results demonstrated that, compared with WT mice, Foxg1-knockout mice exhibited not only alleviated demyelination but also accelerated remyelination of the demyelinated corpus callosum. Furthermore, we found that Foxg1 knockout decreased the proliferation of OPCs and accelerated their differentiation into mature oligodendrocytes both in vivo and in vitro. Wnt signaling plays a critical role in development and in a variety of diseases. GSK-3 b, a key regulatory kinase in the Wnt pathway, regulates the ability of b-catenin to enter nuclei, where it activates the expression of Wnt target genes. We then used SB216763,a selective inhibitor of GSK-3 b activity, to further demonstrate the regulatory mechanism by which Foxg1 affects OPCs in vitro. The results showed that SB216763 clearly inhibited the expression of GSK-3 b, which abolished the effect of the proliferation and differentiation of OPCs caused by the knockdown of Foxg1. These results suggest that Foxg1 is involved in the proliferation and differentiation of OPCs through the Wnt signaling pathway. The present experimental results are some of the first to suggest that Foxg1 is a new therapeutic target for the treatment of demyelinating diseases of the CNS.展开更多
Induction of demyelination in the central nervous system （CNS） of experimental mice using cuprizone is widely used as an animal model for studying the pathogenesis and treatment of demyelination. How- ever, differen...Induction of demyelination in the central nervous system （CNS） of experimental mice using cuprizone is widely used as an animal model for studying the pathogenesis and treatment of demyelination. How- ever, different mouse strains used result in different pathological outcomes. Moreover, because current medicinal treatments are not always effective in multiple sclerosis patients, so the study of exogenous cell transplantation in an animal model is of great importance. The aims of the present study were to establish an alternative ICR outbred mouse model for studying demyelination and to evaluate the effects of intrave- nous cell transplantation in the present developed mouse model. Two sets of experiments were conducted. Firstly, ICR outbred and BALB/c inbred mice were fed with 0.2% cuprizone for 6 consecutive weeks; then demyelinating scores determined by luxol fast blue stain or immunolabeling with CNPase were evaluated. Secondly, attenuation of demyelination in ICR mice by intravenous injection of mES cells was studied. Scores for demyelination in the brains of ICR mice receiving cell injection （mES cells-injected group） and vehicle （sham-inoculated group） were assessed and compared. The results showed that cuprizone signifi- cantly induced demyelination in the cerebral cortex and corpus callosum of both ICR and BALB/c mice. Additionally, intravenous transplantation of mES cells potentially attenuated demyelination in ICR mice compared with sham-inoculated groups. The present study is among the earliest reports to describe the cuprizone-induced demyelination in ICR outbred mice. Although it remains unclear whether mES cells or trophic effects from mES cells are the cause of enhanced remyelination, the results of the present study may shed some light on exogenous cell therapy in central nervous system demyelinating diseases.展开更多
Multiple sclerosis is an autoimmune disease in which the immune system attacks the myelin sheath in the central nervous system.It is characterized by blood-brain barrier dysfunction throughout the course of multiple s...Multiple sclerosis is an autoimmune disease in which the immune system attacks the myelin sheath in the central nervous system.It is characterized by blood-brain barrier dysfunction throughout the course of multiple sclerosis, followed by the entry of immune cells and activation of local microglia and astrocytes.Glial cells(microglia, astrocytes, and oligodendrocyte lineage cells) are known as the important mediators of neuroinflammation, all of which play major roles in the pathogenesis of multiple sclerosis.Network communications between glial cells affect the activities of oligodendrocyte lineage cells and influence the demyelination-remyelination process.A finely balanced glial response may create a favorable lesion environment for efficient remyelination and neuroregeneration.This review focuses on glial response and neurodegeneration based on the findings from multiple sclerosis and major rodent demyelination models.In particular, glial interaction and molecular crosstalk are discussed to provide insights into the potential cell-and molecule-specific therapeutic targets to improve remyelination and neuroregeneration.展开更多
Oligodendrocyte lineage cells(OL-lineage cells)are a cell population that are crucial for mammalian central nervous system(CNS)myelination.OL-lineage cells go through developmental stages,initially differentiating int...Oligodendrocyte lineage cells(OL-lineage cells)are a cell population that are crucial for mammalian central nervous system(CNS)myelination.OL-lineage cells go through developmental stages,initially differentiating into oligodendrocyte precursor cells(OPCs),before becoming immature oligodendrocytes,then mature oligodendrocytes(OLs).While the main function of cell lineage is in myelin formation,and increasing number of studies have turned to explore the immunological characteristics of these cells.Initially,these studies focused on discovering how OPCs and OLs are affected by the immune system,and then,how these immunological changes influence the myelination process.However,recent studies have uncovered another feature of OL-lineage cells in our immune systems.It would appear that OL-lineage cells also express immunological factors such as cytokines and chemokines in response to immune activation,and the expression of these factors changes under various pathologic conditions.Evidence suggests that OL-lineage cells actually modulate immune functions.Indeed,OL-lineage cells appear to play both"victim"and"agent"in the CNS which raises a number of questions.Here,we summarize immunologic changes in OL-lineage cells and their effects,as well as consider OL-lineage cell changes which influence immune cells under pathological conditions.We also describe some of the underlying mechanisms of these changes and their effects.Finally,we describe several studies which use OL-lineage cells as immunotherapeutic targets for demyelination diseases.展开更多
Increasing evidence suggests that white matter disorders based on myelin sheath impairment may underlie the neuropathological changes in schizophrenia.But it is unknown whether enhancing remyelination is a beneficial ...Increasing evidence suggests that white matter disorders based on myelin sheath impairment may underlie the neuropathological changes in schizophrenia.But it is unknown whether enhancing remyelination is a beneficial approach to schizophrenia.To investigate this hypothesis,we used clemastine,an FDA-approved drug with high potency in promoting oligodendroglial differentiation and myelination,on a cuprizone-induced mouse model of demyelination.The mice exposed to cuprizone（0.2%in chow） for 6 weeks displayed schizophrenia-like behavioral changes,including decreased exploration of the center in the open field test and increased entries into the arms of the Y-maze,as well as evident demyelination in the cortex and corpus callosum.Clemastine treatment was initiated upon cuprizone withdrawal at 10 mg/kg per day for3 weeks.As expected,myelin repair was greatly enhanced in the demyelinated regions with increased mature oligodendrocytes（APC-positive） and myelin basic protein.More importantly,the clemastine treatment rescued the schizophrenia-like behavioral changes in the open field test and the Y-maze compared to vehicle,suggesting a beneficial effect via promoting myelin repair.Our findings indicate that enhancing remyelination may be a potential therapy for schizophrenia.展开更多
Background Multiple sclerosis(MS)is an autoimmune,inflammatory demyelinating disease of the central nervous system(CNS)characterized by de-/remyelination,neuroinflammation and oligodendrocyte loss.Although a greater u...Background Multiple sclerosis(MS)is an autoimmune,inflammatory demyelinating disease of the central nervous system(CNS)characterized by de-/remyelination,neuroinflammation and oligodendrocyte loss.Although a greater understanding of MS have increased acquaintance of the pathogenesis and pathophysiology,the exploration of treatment is still challenging.Fasudil,one of the most thoroughly studied Rho kinase(ROCK)inhibitors,has been shown to have effects in neurodegenerative diseases.However,the effect of Fasudil on preventing the progression of the demyelination in MS has not been evaluated.Cuprizone(CPZ)-induced demyelination is a model used to study de-/remyelination in the CNS.Some aspects of the histological pattern induced by CPZ are similar to MS.The aim of the study is to investigate the effect of Fasudil on CPZ-induced demyelination,and to explore the mechanisms for the possible remyelination.Materials and Methods Male C57 BL/6 mice(10-12 weeks old)were assigned into normal group,fed a normal diet;CPZ group,fed CPZ and intraperitoneally(i.p.)injected with normal saline after 4 weeks for consecutive 2 weeks;Fasudil-treated CPZ group,which were i.p.injected with Fasudil(40 mg/kg/day)after 4 weeks for consecutive 2 weeks.All groups were assessed by Elevated plus-maze(EPM)test and Pole test at the end of the experiment.For examing the extent of demyelination,Luxol Fast Blue(LFB)staining,Black GoldⅡand myelin basic protein(MBP)immunohistochemistry staining were used for slides of brains.Splenic MNCs were fixed and stained with the following antibodies:Alexa Fluor B220,FITCCD4/PE-IFN-γ,FITC-CD4/PE-IL-17.At least 10,000 events were collected using flow cytometer.Results Following CPZ-exposure,mice presented a lower density of LFB,Black GoldⅡand MBP expression,loss of mature oligodendrocytes.Spleen atrophy was observed in CPZ-group compared to normal mice,and we firstly found that CPZ feeding induced the formation of MOG antibody.Fasudil treatment improved behavioral abnormality,promoted remyelination,inhibited spleen atrophy and production of MOG antibodies,prevented the infiltration of peripheral T cells,B cells,macrophages,and declined the neuroinflammation by inhibiting Iba1+iNOS+,Iba1+NF-κB+microglia.Fasudil treatment also reduced the levels of IL-1β,IL-6 and TNF-α.Discussion In this study,we demonstrated that demyelinating model was successfully established.Then we tested whether Fasudil plays a remyelinating role in this model.Spleen atrophy was observed after CPZ-feeding compared to normal mice.Previous studies have shown that splenic atrophy in experimental stroke may contribute to brain injury possibly through the release of inflammatory mediators and spleen-derived inflammatory cells to the circulation and migration into the brain,which aggravate the brain inflammatory response and led to secondary injure.At present,we lack direct evidence to elucidate the mechanisms for spleen atrophy in CPZ-induced demyelination.We firstly found that CPZ-feeding induced the formation of MOG antibody.Recent study indicated that BBB hyperpermeability precedes demyelination in CPZ-demyelinating model.Another study suggested that debris of damaged cells in the CNS may present as antigens after penetrating the BBB,giving rise to autoantibodies.Therefore,it is possible that the myelin debris produced the destruction of myelin sheath can enter the blood circulation and stimulate the immune response of T and B cells.We found that MOG antibody was elevated in the supernatant of cultured plenocytes,indicating that the MOG antibodies were derived from peripheral immune cells.Our results showed that the level of MOG antibody in the brain homogenate of CPZ-treated mice was higher than that of normal mice,suggesting that antibodies can enter brain tissue and anti a-synuclein antibody was negative,which indicate that anti MOG antibody is a specific antibody.In our study,MOG antibody was capable of being detected in the brain of CPZ-treated mice,providing a possibility for specific MOG antibody-mediated oligodendrocyte damage.CPZ induced a wide range of Iba-1+microglia,which was inhibited by Fasudil.These results suggest that the suppression of inflammatory microenvironment may contribute to the remyelination.In conclusion,the administration of Fasudil promoted remyelination by multiple mechanisms.展开更多
Background:Multiple sclerosis(MS)is a chronic demyelinating disease characterized by autoimmune attacks on myelin sheaths.Its deleterious effects may be reversed by remyelination,a process that restores the integrity ...Background:Multiple sclerosis(MS)is a chronic demyelinating disease characterized by autoimmune attacks on myelin sheaths.Its deleterious effects may be reversed by remyelination,a process that restores the integrity of myelin sheaths and,consequently,neuronal function.However,the functional implications of demyelination and remyelination in MS,as well as the potential impact of therapeutic interventions,remain incompletely understood.We used noninvasive longitudinal resting-state functional magnetic resonance imaging in a cuprizone murine model of demyelination to investigate these unsolved questions.Methods:Three groups of(n=6)animals were studied.A control group was fed with standard food for 5 weeks while two treatment groups(cuprizone and clemastine)suffered progressive demyelination by feeding them with 2%cuprizone.At Week 5(W5),all animals returned to the standard diet and studied for another 5-week period to compare controls vs spontaneous(cuprizone group)vs clemastine-aided(clemastine group)remyelination group.Group clemastine was treated with this antihistaminic(oral gavage)during the remyelination period(Weeks 5–10).Anatomical magnetic resonance imaging(T2w-MRI)and resting state functional MRI(rs-FMRI)studies were conducted on weeks W0,W2,W5(maximal demyelination)W7 and W10(remyelination).MRI images were processed with the FMRIB Software Library,involving seed-free functional imaging and seed-based correlation.This study uses the t-test and the D'Agostino–Pearson normality test to make an assessment.Results:The principal findings of our research include:(1)cuprizone-treated animals suffer an initial phase of elevated connectivity at Week 2 with respect to controls,transitioning to reduced connectivity at Week 5;(2)different temporal trajectories across brain regions,reflecting varying susceptibility to demyelination;(3)while spontaneous remyelination normalizes connectivity in most networks at Week 10(5 weeks after ceasing cuprizone intoxication),the thalamocortical axis exhibits lasting disruption even 6 months after normalization of diet;and(4)on the contrary,clemastine-aided remyelination re-establishes normal thalamocortical connectivity at 6 months after demyelination.Conclusion:This approach provides insights into the dynamic processes of demyelination and remyelination,informing the development of more effective interventions for MS.展开更多
Objective: To examine the anti-inflammatory effect of grape seed extract(GSE) in animal and cellular models and explore its mechanism of action. Methods: This study determined the inhibitory effect of GSE on macrophag...Objective: To examine the anti-inflammatory effect of grape seed extract(GSE) in animal and cellular models and explore its mechanism of action. Methods: This study determined the inhibitory effect of GSE on macrophage inflammation and Th1 and Th17 polarization in vitro. Based on the in vitro results, the effects and mechanisms of GSE on multiple sclerosis(MS)-experimental autoimmune encephalomyelitis(EAE) mice model were further explored. The C57BL/6 mice were intragastrically administered with 50 mg/kg of GSE once a day from the 3rd day to the 27th day after immunization. The activation of microglia, the polarization of Th1 and Th17and the inflammatory factors such as tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), IL-6, IL-12, IL-17and interferon-γ(IFN-γ) secreted by them were detected in vitro and in vivo by flow cytometry, enzyme linked immunosorbent assay(ELISA), immunofluorescence staining and Western blot, respectively. Results: GSE reduced the secretion of TNF-α, IL-1β and IL-6 in bone marrow-derived macrophages stimulated by lipopolysaccharide(P<0.01), inhibited the secretion of TNF-α, IL-1β, IL-6, IL-12, IL-17 and IFN-γ in spleen cells of EAE mice immunized for 9 days(P<0.05 or P<0.01), and reduced the differentiation of Th1 and Th17 mediated by CD3 and CD28 factors(P<0.01). GSE significantly improved the clinical symptoms of EAE mice, and inhibited spinal cord demyelination and inflammatory cell infiltration. Peripherally, GSE downregulated the expression of toll-like-receptor 4(TLR4) and Rho-associated kinase(ROCKⅡ, P<0.05 or P<0.01), and inhibited the secretion of inflammatory factors(P<0.01 or P<0.05). In the central nervous system, GSE inhibited the infiltration of CD45+CD11b+and CD45+CD4+cells, and weakened the differentiation of Th1 and Th17(P<0.05). Moreover, it reduced the secretion of inflammatory factors(P<0.01), and prevented the activation of microglia(P<0.05). Conclusion: GSE had a beneficial effect on the pathogenesis and progression of EAE by inhibiting inflammatory response as a potential drug and strategy for the treatment of MS.展开更多
Background:Multifocal motor neuropathy(MMN),Lewis-Sumner syndrome(LSS),and many chronic inflammatory demyelinating polyradiculoneuropathies(CIDPs)are representative of acquired multifocal polyneuropathy and are charac...Background:Multifocal motor neuropathy(MMN),Lewis-Sumner syndrome(LSS),and many chronic inflammatory demyelinating polyradiculoneuropathies(CIDPs)are representative of acquired multifocal polyneuropathy and are characterized by conduction block(CB).This retrospective study aimed to investigate the demyelinating distribution and the selective vulnerability of MMN,LSS,and CIDP with CB(CIDP-CB)in nerves.Methods:Fifteen LSS subjects(107 nerves),24 MMN subjects(176 nerves),and 17 CIDP-CB subjects(110 nerves)were included.Their clinical information was recorded,blood and cerebrospinal fluid tests were conducted,and nerve conductions of the median,ulnar,radial,peroneal,and tibial nerves were evaluated.CB,temporal dispersion,distal motor latency(DML),and F-wave latency were recorded,and nerve conduction velocity,terminal latency index,and modified F-wave ratio were calculated.Results:CB was more likely to occur around the elbow in CIDP-CB than in MMN(78.6%vs.6.8%,P<0.01)but less likely to occur between the wrist and the elbow than in LSS(10.7%vs.39.3%,P<0.05).Tibial nerve CB was most frequently observed in MMN(47.4%,P<0.05).CIDP-CB was characterized by a prolonged DML in all nerves,and slow motor nerve velocity of the upper limb was significant when CB nerves were excluded(P<0.05).Conclusions:We report the different distributions of segmental and diffuse demyelination of the ulnar and tibial nerves in LSS,MMN,and CIDP-CB.These distinct distributions could help in differentiating among these conditions.展开更多
Regulatory T cells,a subset of CD4^(+)T cells,play a critical role in maintaining immune tolerance and tissue homeostasis due to their potent immunosuppressive properties.Recent advances in research have highlighted t...Regulatory T cells,a subset of CD4^(+)T cells,play a critical role in maintaining immune tolerance and tissue homeostasis due to their potent immunosuppressive properties.Recent advances in research have highlighted the important therapeutic potential of Tregs in neurological diseases and tissue repair,emphasizing their multifaceted roles in immune regulation.This review aims to summarize and analyze the mechanisms of action and therapeutic potential of Tregs in relation to neurological diseases and neural regeneration.Beyond their classical immune-regulatory functions,emerging evidence points to non-immune mechanisms of regulatory T cells,particularly their interactions with stem cells and other non-immune cells.These interactions contribute to optimizing the repair microenvironment and promoting tissue repair and nerve regeneration,positioning non-immune pathways as a promising direction for future research.By modulating immune and non-immune cells,including neurons and glia within neural tissues,Tregs have demonstrated remarkable efficacy in enhancing regeneration in the central and peripheral nervous systems.Preclinical studies have revealed that Treg cells interact with neurons,glial cells,and other neural components to mitigate inflammatory damage and support functional recovery.Current mechanistic studies show that Tregs can significantly promote neural repair and functional recovery by regulating inflammatory responses and the local immune microenvironment.However,research on the mechanistic roles of regulatory T cells in other diseases remains limited,highlighting substantial gaps and opportunities for exploration in this field.Laboratory and clinical studies have further advanced the application of regulatory T cells.Technical advances have enabled efficient isolation,ex vivo expansion and functionalization,and adoptive transfer of regulatory T cells,with efficacy validated in animal models.Innovative strategies,including gene editing,cell-free technologies,biomaterial-based recruitment,and in situ delivery have expanded the therapeutic potential of regulatory T cells.Gene editing enables precise functional optimization,while biomaterial and in situ delivery technologies enhance their accumulation and efficacy at target sites.These advancements not only improve the immune-regulatory capacity of regulatory T cells but also significantly enhance their role in tissue repair.By leveraging the pivotal and diverse functions of Tregs in immune modulation and tissue repair,regulatory T cells–based therapies may lead to transformative breakthroughs in the treatment of neurological diseases.展开更多
Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neu...Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neurodegenerative and demyelinating diseases(Borst et al.,2021).Together with infiltrating monocyte-derived macrophages,microglia also play a critical role for brain tumor development,since immunosuppressive interactions between tumor cells and tumor-associated microglia and macrophages(TAM)are linked to malignant progression.This mechanism is of particular relevance in glioblastoma(GB),the deadliest form of brain cancer with a median overall survival of less than 15 months(Khan et al.,2023).Therefore,targeting microglia and macrophage activation is a promising strategy for therapeutic interference in brain disease.展开更多
Decades of research asserted that the oligodendroglial lineage comprises two cell types:oligodendrocyte precursor cells and oligodendrocytes.However,recent studies employing single-cell RNA sequencing techniques have ...Decades of research asserted that the oligodendroglial lineage comprises two cell types:oligodendrocyte precursor cells and oligodendrocytes.However,recent studies employing single-cell RNA sequencing techniques have uncovered novel cell states,prompting a revision of the existing terminology.Going forward,the oligodendroglial lineage should be delineated into five distinct cell states:oligodendrocyte precursor cells,committed oligodendrocyte precursor cells,newly formed oligodendrocytes,myelin-forming oligodendrocytes,and mature oligodendrocytes.This new classification system enables a deeper understanding of the oligodendroglia in both physiological and pathological contexts.Adopting this uniform terminology will facilitate comparison and integration of data across studies.This,including the consolidation of findings from various demyelinating models,is essential to better understand the pathogenesis of demyelinating diseases.Additionally,comparing injury models across species with varying regenerative capacities can provide insights that may lead to new therapeutic strategies to overcome remyelination failure.Thus,by standardizing terminology and synthesizing data from diverse studies across different animal models,we can enhance our understanding of myelin pathology in central nervous system disorders such as multiple sclerosis,Alzheimer's disease,and amyotrophic lateral sclerosis,all of which involve oligodendroglial and myelin dysfunction.展开更多
Demyelination and remyelination have been major focal points in the study of peripheral nerve regeneration following peripheral nerve injury.Notably,the gene regulatory network of regenerated myelin differs from that ...Demyelination and remyelination have been major focal points in the study of peripheral nerve regeneration following peripheral nerve injury.Notably,the gene regulatory network of regenerated myelin differs from that of native myelin.Silencing of enhancer of zeste homolog 2(EZH2)hinders the differentiation,maturation,and myelination of Schwann cells in vitro.To further determine the role of EZH2 in myelination and recovery post-peripheral nerve injury,conditional knockout mice lacking Ezh2 in Schwann cells(Ezh2^(fl/fl);Dhh-Cre and Ezh2^(fl/fl);Mpz-Cre)were generated.Our results show that a significant proportion of axons in the sciatic nerve of Ezh2-depleted mice remain unmyelinated.This highlights the crucial role of Ezh2 in initiating Schwann cell myelination.Furthermore,we observed that 21 days after inducing a sciatic nerve crush injury in these mice,most axons had remyelinated at the injury site in the control nerve,while Ezh2^(fl/fl);Mpz-Cre mice had significantly fewer remyelinated axons compared with their wild-type littermates.This suggests that the absence of Ezh2 in Schwann cells impairs myelin formation and remyelination.In conclusion,EZH2 has emerged as a pivotal regulatory factor in the process of demyelination and myelin regeneration following peripheral nerve injury.Modulating EZH2 activity during these processes may offer a promising therapeutic target for the treatment of peripheral nerve injuries.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82372277(to ZW),82272361(to XS),82271395(to GL)Guangdong Province Basic and Applied Basic Research Fund Project,No.2024A1515010615(to XS)+1 种基金Guangdong Province Natural Youth Promotion Project,No.2314070000241(to GL)Guangzhou Science and Technology Project,No.2025A04J4740(to GL).
文摘Demyelinating diseases of the central nervous system are common,yet few effective strategies for myelin repair and remyelination are available.An increasing number of studies highlight the role of microRNAs(miRNAs)as key regulators of demyelination.miRNA mimics and inhibitors,which are currently in preclinical development,have shown promise as novel therapeutic agents.However,the mechanisms by which they protect myelin are not fully understood.Using a mouse model of acute central nervous system demyelination induced by infection with Angiostrongylus cantonensis,we investigated alterations in miRNA expression in the mouse brain.Our findings revealed a significant early-stage increase in the levels of miR-200,particularly miR-200a and miR-200c.Subsequent analysis demonstrated that combined miR-200a and miR-200c overexpression improved neurobehavioral outcomes and attenuated demyelination in Angiostrongylus cantonensis-infected mice.Further lipid metabolomic profiling indicated that miR-200a and miR-200c synergistically inhibited the production of phosphatase and tensin homolog(PTEN)and activated the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway,as confirmed by double luciferase reporter assay and western blotting.Additionally,in vitro experiments showed that miR-200a and miR-200c protected oligodendrocyte precursor cells from lipopolysaccharide-induced damage and enhanced their survival.Our study indicates the critical role of miR-200a and miR-200c in protecting against central nervous system demyelination by targeting PTEN and modulating key survival pathways.Furthermore,our findings suggest that miR-200a and miR-200c are promising diagnostic biomarkers of and therapeutic targets for treating demyelination-related disorders.
基金Supported by the Top-Level Talents Support Program of Yangzhou University“Lv Yang Jin Feng”Outstanding Doctor of Yangzhou,No.YZLYJFJH2023YXBS169and Natural Science Foundation of Jiangsu Province,No.BK20240907。
文摘This article discusses a study by Li et al,which investigates the role of the microglial voltage-gated proton channel 1(Hv1)in diabetes-related cognitive decline.The authors showed that Hv1 is upregulated in the corpus callosum of diabetic mice and that its knockout improves working memory,reduces microglial production of interleukin-1βand tumour necrosis factor alpha,and decreases apoptosis of oligodendrocyte progenitor cells.Furthermore,electron microscopy revealed that the myelin thickness and the g-ratio were preserved in Hv1 knockout mice,remaining within normal limits.In addition,Hv1 knockdown mitigated interleukin-1βsecretion and suppressed ferroptosis markers(ferritin heavy chain/ferritin light chain,CCAAT/enhancer binding protein homologous protein,glucose-regulated protein 78,etc.)in vitro,suggesting the involvement of an Hv1-reactive oxygen species-glucose-regulated protein 78 axis in diabetic demyelination.We highlight the translational implications of these findings and recommend future studies employing microglia-specific Hv1 deletion models,longitudinal cognitive assessments and preclinical evaluation of pharmacological Hv1 inhibitors.
基金supported by the National Natural Science Foundation of China(81972064)the Guangdong Basic and Applied Basic Research Foundation(2021A1515111117,2020A1515011415).
文摘Demyelination and remyelination play key roles in spinal cord injury(SCI),affecting the recovery of motor and sensory functions.Research in rodent models is extensive,but the study of these processes in non-human primates is limited.Therefore,our goal was to thoroughly study the histological features of demyelination and remyelination after contusion injury of the cervical spinal cord in Macaca fascicularis.In a previous study,we created an SCI model in M.fascicularis by controlling the contusion displacement.We used Eriochrome Cyanine staining,immunohistochemical analysis,and toluidine blue staining to evaluate demyelination and remyelination.The results showed demyelination ipsilateral to the injury epicenter both rostrally and caudally,the former mainly impacting sensory pathways,while the latter primarily affected motor pathways.Toluidine blue staining showed myelin loss and axonal distension at the injury site.Schwann cell-derived myelin sheaths were only found at the center,while thinner myelin sheaths from oligodendrocytes were seen at the center and surrounding areas.Our study showed that long-lasting demyelination occurs in the spinal cord of M.fascicularis after SCI,with oligodendrocytes and Schwann cells playing a significant role in myelin sheath formation at the injury site.
基金supported by the National Basic Research Development Program(2011CB504401)the National Natural Science Foundation of China(31171030,31130024)+1 种基金the Shanghai Pujiang Project(11PJ1412300)the Shanghai Shuguang Project(07SG43)
文摘Multiple sclerosis(MS)is an autoimmune demyelinating disease of the central nervous system,and microglia and macrophages play important roles in its pathogenesis.The activation of microglia and macrophages ac-companies disease development,whereas depletion of these cells significantly decreases disease severity.Microglia and macrophages usually have diverse and plastic phenotypes.Both pro-inflammatory and anti-inflammatory microglia and macrophages exist in MS and its animal model,experimental autoimmune enceph-alomyelitis.The polarization of microglia and macrophages may underlie the differing functional properties that have been reported.In this review,we discuss the responses and polarization of microglia and macrophages in MS,and their effects on its pathogenesis and repair.Harnessing their beneficial effects by modulating their polarization states holds great promise for the treatment of inflammatory demyelinating diseases.
基金supported by the International Cooperation and Exchange Program of the National Natural Science Foundation of China(81461138035)the National Natural Science Foundation of China(81371326,31571066,and 31371068)+2 种基金the National Basic Research Development Program of China(2016YFA0100802)the UK Medical Research Council(MR/M010503/1)the UK Multiple Sclerosis Society(33)
文摘The differentiation and maturation of oligodendrocyte precursor cells(OPCs) is essential for myelination and remyelination in the CNS. The failure of OPCs to achieve terminal differentiation in demyelinating lesions often results in unsuccessful remyelination in a variety of human demyelinating diseases. However, the molecular mechanisms controlling OPC differentiation under pathological conditions remain largely unknown. Myt1 L(myelin transcription factor 1-like), mainly expressed in neurons,has been associated with intellectual disability, schizophrenia, and depression. In the present study, we found that Myt1 L was expressed in oligodendrocyte lineage cells during myelination and remyelination. The expression level of Myt1 L in neuron/glia antigen 2-positive(NG2+)OPCs was significantly higher than that in mature CC1+oligodendrocytes. In primary cultured OPCs,overexpression of Myt1 L promoted, while knockdown inhibited OPC differentiation. Moreover, Myt1 L was potently involved in promoting remyelination after lysolecithin-induced demyelination in vivo. Ch IP assays showed that Myt1 L bound to the promoter of Olig1 and transcriptionally regulated Olig1 expression. Taken together, our findings demonstrate that Myt1 L is an essential regulator of OPC differentiation, thereby supporting Myt1 L as a potential therapeutic target for demyelinating diseases.
基金supported by the National Natural Science Foundation of China,No.81371395the Liaoning Scientific and Technological Preferential Finance for Returned Overseas 2015 of China,No.[2015]125+2 种基金the Natural Science Foundation of Liaoning Province of China,No.20170541021,2015020547a grant from the Shenyang Science Technology Project,No.F16-206-9-12the China Post-doctoral Science Foundation,No.2015M581375
文摘The APPSwe/PSEN1 dE9（APP/PS1） transgenic mouse model is an Alzheimer＇s disease mouse model exhibiting symptoms of dementia, and is commonly used to explore pathological changes in the development of Alzheimer＇s disease. Previous clinical autopsy and imaging studies suggest that Alzheimer＇s disease patients have white matter and oligodendrocyte damage, but the underlying mechanisms of these have not been revealed. Therefore, the present study used APP/PS1 mice to assess cognitive change, myelin loss, and corresponding changes in oligodendrocytes, and to explore the underlying mechanisms. Morris water maze tests were performed to evaluate cognitive change in APP/PS1 mice and normal C57 BL/6 mice aged 3 and 6 months. Luxol fast blue staining of the corpus callosum and quantitative reverse transcription-polymerase chain reaction（q RT-PCR） for myelin basic protein（MBP） mRNA were carried out to quantify myelin damage. Immunohistochemistry staining for NG2 and qRT-PCR for monocarboxylic acid transporter 1（MCT1） mRNA were conducted to assess corresponding changes in oligodendrocytes. Our results demonstrate that compared with C57 BL/6 mice, there was a downregulation of MBP mRNA in APP/PS1 mice aged 3 months. This became more obvious in APP/PS1 mice aged 6 months accompanied by other abnormalities such as prolonged escape latency in the Morris water maze test, shrinkage of the corpus callosum, upregulation of NG2-immunoreactive cells, and downregulation of MCT1 mRNA. These findings indicate that the involvement of early demyelination at 3 months and the oligodendrocyte dysfunction at 6 months in APP/PS1 mice are in association with Alzheimer＇s disease pathogenesis.
基金supported by the National Natural Science Foundation of China,No.81771271Key Research and Development Program of Liaoning Province,No.2020JH2/10300047Outstanding Scientific Fund of Shengjing Hospital(all to JF).
文摘Emodin,a substance extracted from herbs such as rhubarb,has a protective effect on the central nervous system.However,the potential therapeutic effect of emodin in the context of multiple sclerosis remains unknown.In this study,a rat model of experimental autoimmune encephalomyelitis was established by immune induction to simulate multiple sclerosis,and the rats were intraperitoneally injected with emodin(20 mg/kg/d)from the day of immune induction until they were sacrificed.In this model,the nucleotide-binding domain-like receptor family pyrin domain containing 3(NLRP3)inflammasome and the microglia exacerbated neuroinflammation,playing an important role in the development of multiple sclerosis.In addition,silent information regulator of transcription 1(SIRT1)/peroxisome proliferator-activated receptor-alpha coactivator(PGC-1α)was found to inhibit activation of the NLRP3 inflammasome,and SIRT1 activation reduced disease severity in experimental autoimmune encephalomyelitis.Furthermore,treatment with emodin decreased body weight loss and neurobehavioral deficits,alleviated inflammatory cell infiltration and demyelination,reduced the expression of inflammatory cytokines,inhibited microglial aggregation and activation,decreased the levels of NLRP3 signaling pathway molecules,and increased the expression of SIRT1 and PGC-1α.These findings suggest that emodin improves the symptoms of experimental autoimmune encephalomyelitis,possibly through regulating the SIRT1/PGC-1α/NLRP3 signaling pathway and inhibiting microglial inflammation.These findings provide experimental evidence for treatment of multiple sclerosis with emodin,enlarging the scope of clinical application for emodin.
基金supported by the National Natural Science Foundation of China(81771337 and 81271345)the National Key R&D Program of China(2017YFA0104202)+2 种基金the Natural Science Foundation of Jiangsu Province(BK20161174)the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(18KJB180028)the Six Talent Peaks Project in Jiangsu Province(2015 to RY)。
文摘The massive loss of oligodendrocytes caused by various pathological factors is a basic feature of many demyelinating diseases of the central nervous system(CNS). Based on a variety of studies, it is now well established that impairment of oligodendrocyte precursor cells(OPCs) to differentiate and remyelinate axons is a vital event in the failed treatment of demyelinating diseases. Recent evidence suggests that Foxg1 is essential for the proliferation of certain precursors and inhibits premature neurogenesis during brain development. To date, very little attention has been paid to the role of Foxg1 in the proliferation and differentiation of OPCs in demyelinating diseases of the CNS. Here, for the first time, we examined the effects of Foxg1 on demyelination and remyelination in the brain using a cuprizone(CPZ)-induced mouse model. In this work, 7-week-old Foxg1 conditional knockout and wild-type(WT) mice were fed a diet containing 0.2% CPZ w/w for 5 weeks, after which CPZ was withdrawn to enable remyelination. Our results demonstrated that, compared with WT mice, Foxg1-knockout mice exhibited not only alleviated demyelination but also accelerated remyelination of the demyelinated corpus callosum. Furthermore, we found that Foxg1 knockout decreased the proliferation of OPCs and accelerated their differentiation into mature oligodendrocytes both in vivo and in vitro. Wnt signaling plays a critical role in development and in a variety of diseases. GSK-3 b, a key regulatory kinase in the Wnt pathway, regulates the ability of b-catenin to enter nuclei, where it activates the expression of Wnt target genes. We then used SB216763,a selective inhibitor of GSK-3 b activity, to further demonstrate the regulatory mechanism by which Foxg1 affects OPCs in vitro. The results showed that SB216763 clearly inhibited the expression of GSK-3 b, which abolished the effect of the proliferation and differentiation of OPCs caused by the knockdown of Foxg1. These results suggest that Foxg1 is involved in the proliferation and differentiation of OPCs through the Wnt signaling pathway. The present experimental results are some of the first to suggest that Foxg1 is a new therapeutic target for the treatment of demyelinating diseases of the CNS.
基金supported by the Faculty Research Fund,Faculty of Veterinary Medicine,Chiang Mai University,Thailand
文摘Induction of demyelination in the central nervous system （CNS） of experimental mice using cuprizone is widely used as an animal model for studying the pathogenesis and treatment of demyelination. How- ever, different mouse strains used result in different pathological outcomes. Moreover, because current medicinal treatments are not always effective in multiple sclerosis patients, so the study of exogenous cell transplantation in an animal model is of great importance. The aims of the present study were to establish an alternative ICR outbred mouse model for studying demyelination and to evaluate the effects of intrave- nous cell transplantation in the present developed mouse model. Two sets of experiments were conducted. Firstly, ICR outbred and BALB/c inbred mice were fed with 0.2% cuprizone for 6 consecutive weeks; then demyelinating scores determined by luxol fast blue stain or immunolabeling with CNPase were evaluated. Secondly, attenuation of demyelination in ICR mice by intravenous injection of mES cells was studied. Scores for demyelination in the brains of ICR mice receiving cell injection （mES cells-injected group） and vehicle （sham-inoculated group） were assessed and compared. The results showed that cuprizone signifi- cantly induced demyelination in the cerebral cortex and corpus callosum of both ICR and BALB/c mice. Additionally, intravenous transplantation of mES cells potentially attenuated demyelination in ICR mice compared with sham-inoculated groups. The present study is among the earliest reports to describe the cuprizone-induced demyelination in ICR outbred mice. Although it remains unclear whether mES cells or trophic effects from mES cells are the cause of enhanced remyelination, the results of the present study may shed some light on exogenous cell therapy in central nervous system demyelinating diseases.
基金partially supported by grants from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health(R21 NS098170, to JC and CBS)Kentucky Spinal Cord and Head Injury Research Trust(16-3 A, to JC and CBS)the National Natural Science Foundation of China(81601957, to YW)。
文摘Multiple sclerosis is an autoimmune disease in which the immune system attacks the myelin sheath in the central nervous system.It is characterized by blood-brain barrier dysfunction throughout the course of multiple sclerosis, followed by the entry of immune cells and activation of local microglia and astrocytes.Glial cells(microglia, astrocytes, and oligodendrocyte lineage cells) are known as the important mediators of neuroinflammation, all of which play major roles in the pathogenesis of multiple sclerosis.Network communications between glial cells affect the activities of oligodendrocyte lineage cells and influence the demyelination-remyelination process.A finely balanced glial response may create a favorable lesion environment for efficient remyelination and neuroregeneration.This review focuses on glial response and neurodegeneration based on the findings from multiple sclerosis and major rodent demyelination models.In particular, glial interaction and molecular crosstalk are discussed to provide insights into the potential cell-and molecule-specific therapeutic targets to improve remyelination and neuroregeneration.
基金This work was supported by research grants from Shenzhen Fundamental Research Program(Grants No.RCYX20200714114644167,JCYJ20190809161405495,and JCYJ20210324123212035)National Natural Science Foundation of China(Grants No.81971309,32170980,and 32070964)Guangdong Basic and Applied Basic Research Foundation(Grants No.2019A1515011333 and 2022B1515020012).
文摘Oligodendrocyte lineage cells(OL-lineage cells)are a cell population that are crucial for mammalian central nervous system(CNS)myelination.OL-lineage cells go through developmental stages,initially differentiating into oligodendrocyte precursor cells(OPCs),before becoming immature oligodendrocytes,then mature oligodendrocytes(OLs).While the main function of cell lineage is in myelin formation,and increasing number of studies have turned to explore the immunological characteristics of these cells.Initially,these studies focused on discovering how OPCs and OLs are affected by the immune system,and then,how these immunological changes influence the myelination process.However,recent studies have uncovered another feature of OL-lineage cells in our immune systems.It would appear that OL-lineage cells also express immunological factors such as cytokines and chemokines in response to immune activation,and the expression of these factors changes under various pathologic conditions.Evidence suggests that OL-lineage cells actually modulate immune functions.Indeed,OL-lineage cells appear to play both"victim"and"agent"in the CNS which raises a number of questions.Here,we summarize immunologic changes in OL-lineage cells and their effects,as well as consider OL-lineage cell changes which influence immune cells under pathological conditions.We also describe some of the underlying mechanisms of these changes and their effects.Finally,we describe several studies which use OL-lineage cells as immunotherapeutic targets for demyelination diseases.
基金supported by the National Natural Science Foundation of China ( 81100897 and 81100926 )the Natural Science Foundation of Chongqing Municipality, China (cstc2011jj A0856)
文摘Increasing evidence suggests that white matter disorders based on myelin sheath impairment may underlie the neuropathological changes in schizophrenia.But it is unknown whether enhancing remyelination is a beneficial approach to schizophrenia.To investigate this hypothesis,we used clemastine,an FDA-approved drug with high potency in promoting oligodendroglial differentiation and myelination,on a cuprizone-induced mouse model of demyelination.The mice exposed to cuprizone（0.2%in chow） for 6 weeks displayed schizophrenia-like behavioral changes,including decreased exploration of the center in the open field test and increased entries into the arms of the Y-maze,as well as evident demyelination in the cortex and corpus callosum.Clemastine treatment was initiated upon cuprizone withdrawal at 10 mg/kg per day for3 weeks.As expected,myelin repair was greatly enhanced in the demyelinated regions with increased mature oligodendrocytes（APC-positive） and myelin basic protein.More importantly,the clemastine treatment rescued the schizophrenia-like behavioral changes in the open field test and the Y-maze compared to vehicle,suggesting a beneficial effect via promoting myelin repair.Our findings indicate that enhancing remyelination may be a potential therapy for schizophrenia.
文摘Background Multiple sclerosis(MS)is an autoimmune,inflammatory demyelinating disease of the central nervous system(CNS)characterized by de-/remyelination,neuroinflammation and oligodendrocyte loss.Although a greater understanding of MS have increased acquaintance of the pathogenesis and pathophysiology,the exploration of treatment is still challenging.Fasudil,one of the most thoroughly studied Rho kinase(ROCK)inhibitors,has been shown to have effects in neurodegenerative diseases.However,the effect of Fasudil on preventing the progression of the demyelination in MS has not been evaluated.Cuprizone(CPZ)-induced demyelination is a model used to study de-/remyelination in the CNS.Some aspects of the histological pattern induced by CPZ are similar to MS.The aim of the study is to investigate the effect of Fasudil on CPZ-induced demyelination,and to explore the mechanisms for the possible remyelination.Materials and Methods Male C57 BL/6 mice(10-12 weeks old)were assigned into normal group,fed a normal diet;CPZ group,fed CPZ and intraperitoneally(i.p.)injected with normal saline after 4 weeks for consecutive 2 weeks;Fasudil-treated CPZ group,which were i.p.injected with Fasudil(40 mg/kg/day)after 4 weeks for consecutive 2 weeks.All groups were assessed by Elevated plus-maze(EPM)test and Pole test at the end of the experiment.For examing the extent of demyelination,Luxol Fast Blue(LFB)staining,Black GoldⅡand myelin basic protein(MBP)immunohistochemistry staining were used for slides of brains.Splenic MNCs were fixed and stained with the following antibodies:Alexa Fluor B220,FITCCD4/PE-IFN-γ,FITC-CD4/PE-IL-17.At least 10,000 events were collected using flow cytometer.Results Following CPZ-exposure,mice presented a lower density of LFB,Black GoldⅡand MBP expression,loss of mature oligodendrocytes.Spleen atrophy was observed in CPZ-group compared to normal mice,and we firstly found that CPZ feeding induced the formation of MOG antibody.Fasudil treatment improved behavioral abnormality,promoted remyelination,inhibited spleen atrophy and production of MOG antibodies,prevented the infiltration of peripheral T cells,B cells,macrophages,and declined the neuroinflammation by inhibiting Iba1+iNOS+,Iba1+NF-κB+microglia.Fasudil treatment also reduced the levels of IL-1β,IL-6 and TNF-α.Discussion In this study,we demonstrated that demyelinating model was successfully established.Then we tested whether Fasudil plays a remyelinating role in this model.Spleen atrophy was observed after CPZ-feeding compared to normal mice.Previous studies have shown that splenic atrophy in experimental stroke may contribute to brain injury possibly through the release of inflammatory mediators and spleen-derived inflammatory cells to the circulation and migration into the brain,which aggravate the brain inflammatory response and led to secondary injure.At present,we lack direct evidence to elucidate the mechanisms for spleen atrophy in CPZ-induced demyelination.We firstly found that CPZ-feeding induced the formation of MOG antibody.Recent study indicated that BBB hyperpermeability precedes demyelination in CPZ-demyelinating model.Another study suggested that debris of damaged cells in the CNS may present as antigens after penetrating the BBB,giving rise to autoantibodies.Therefore,it is possible that the myelin debris produced the destruction of myelin sheath can enter the blood circulation and stimulate the immune response of T and B cells.We found that MOG antibody was elevated in the supernatant of cultured plenocytes,indicating that the MOG antibodies were derived from peripheral immune cells.Our results showed that the level of MOG antibody in the brain homogenate of CPZ-treated mice was higher than that of normal mice,suggesting that antibodies can enter brain tissue and anti a-synuclein antibody was negative,which indicate that anti MOG antibody is a specific antibody.In our study,MOG antibody was capable of being detected in the brain of CPZ-treated mice,providing a possibility for specific MOG antibody-mediated oligodendrocyte damage.CPZ induced a wide range of Iba-1+microglia,which was inhibited by Fasudil.These results suggest that the suppression of inflammatory microenvironment may contribute to the remyelination.In conclusion,the administration of Fasudil promoted remyelination by multiple mechanisms.
基金Diputación Foral de Gipuzkoa,Grant/Award Number:2022-CIEN-000090-01NextGenerationEU,Grant/Award Number:2022-CIEN-000090-01+2 种基金Instituto de Salud Carlos III,Grant/Award Number:RD21/0006/0016Agencia Estatal de Investigación,Grant/Award Numbers:PID2020-118546RBI00a,PID2023-152005OB-I00Ikerbasque,Basque Foundation for Science,Grant/Award Number:Ikerbasque Professors Program。
文摘Background:Multiple sclerosis(MS)is a chronic demyelinating disease characterized by autoimmune attacks on myelin sheaths.Its deleterious effects may be reversed by remyelination,a process that restores the integrity of myelin sheaths and,consequently,neuronal function.However,the functional implications of demyelination and remyelination in MS,as well as the potential impact of therapeutic interventions,remain incompletely understood.We used noninvasive longitudinal resting-state functional magnetic resonance imaging in a cuprizone murine model of demyelination to investigate these unsolved questions.Methods:Three groups of(n=6)animals were studied.A control group was fed with standard food for 5 weeks while two treatment groups(cuprizone and clemastine)suffered progressive demyelination by feeding them with 2%cuprizone.At Week 5(W5),all animals returned to the standard diet and studied for another 5-week period to compare controls vs spontaneous(cuprizone group)vs clemastine-aided(clemastine group)remyelination group.Group clemastine was treated with this antihistaminic(oral gavage)during the remyelination period(Weeks 5–10).Anatomical magnetic resonance imaging(T2w-MRI)and resting state functional MRI(rs-FMRI)studies were conducted on weeks W0,W2,W5(maximal demyelination)W7 and W10(remyelination).MRI images were processed with the FMRIB Software Library,involving seed-free functional imaging and seed-based correlation.This study uses the t-test and the D'Agostino–Pearson normality test to make an assessment.Results:The principal findings of our research include:(1)cuprizone-treated animals suffer an initial phase of elevated connectivity at Week 2 with respect to controls,transitioning to reduced connectivity at Week 5;(2)different temporal trajectories across brain regions,reflecting varying susceptibility to demyelination;(3)while spontaneous remyelination normalizes connectivity in most networks at Week 10(5 weeks after ceasing cuprizone intoxication),the thalamocortical axis exhibits lasting disruption even 6 months after normalization of diet;and(4)on the contrary,clemastine-aided remyelination re-establishes normal thalamocortical connectivity at 6 months after demyelination.Conclusion:This approach provides insights into the dynamic processes of demyelination and remyelination,informing the development of more effective interventions for MS.
基金Supported by the National Natural Science Foundation of China (No.81903596)Science and Technology Innovation Project of Shanxi Colleges (No.2019L0728)+2 种基金Leading Team of Medical Science and Technology of Shanxi Province (No.2020TD05)Funds for Construction of Key Disciplines from Shanxi University of Chinese Medicine (No.030200117)Cultivation Project of Shanxi University of Chinese Medicine (Nos.2019PY130 and 2020PY-JC-14)。
文摘Objective: To examine the anti-inflammatory effect of grape seed extract(GSE) in animal and cellular models and explore its mechanism of action. Methods: This study determined the inhibitory effect of GSE on macrophage inflammation and Th1 and Th17 polarization in vitro. Based on the in vitro results, the effects and mechanisms of GSE on multiple sclerosis(MS)-experimental autoimmune encephalomyelitis(EAE) mice model were further explored. The C57BL/6 mice were intragastrically administered with 50 mg/kg of GSE once a day from the 3rd day to the 27th day after immunization. The activation of microglia, the polarization of Th1 and Th17and the inflammatory factors such as tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), IL-6, IL-12, IL-17and interferon-γ(IFN-γ) secreted by them were detected in vitro and in vivo by flow cytometry, enzyme linked immunosorbent assay(ELISA), immunofluorescence staining and Western blot, respectively. Results: GSE reduced the secretion of TNF-α, IL-1β and IL-6 in bone marrow-derived macrophages stimulated by lipopolysaccharide(P<0.01), inhibited the secretion of TNF-α, IL-1β, IL-6, IL-12, IL-17 and IFN-γ in spleen cells of EAE mice immunized for 9 days(P<0.05 or P<0.01), and reduced the differentiation of Th1 and Th17 mediated by CD3 and CD28 factors(P<0.01). GSE significantly improved the clinical symptoms of EAE mice, and inhibited spinal cord demyelination and inflammatory cell infiltration. Peripherally, GSE downregulated the expression of toll-like-receptor 4(TLR4) and Rho-associated kinase(ROCKⅡ, P<0.05 or P<0.01), and inhibited the secretion of inflammatory factors(P<0.01 or P<0.05). In the central nervous system, GSE inhibited the infiltration of CD45+CD11b+and CD45+CD4+cells, and weakened the differentiation of Th1 and Th17(P<0.05). Moreover, it reduced the secretion of inflammatory factors(P<0.01), and prevented the activation of microglia(P<0.05). Conclusion: GSE had a beneficial effect on the pathogenesis and progression of EAE by inhibiting inflammatory response as a potential drug and strategy for the treatment of MS.
基金the Specific Clinical Program of Integrated Traditional Chinese and Western Medicine(Shanghai Municipal Health Commission,China,2017,ID:ZHYY-ZXJHZX-1-201701)。
文摘Background:Multifocal motor neuropathy(MMN),Lewis-Sumner syndrome(LSS),and many chronic inflammatory demyelinating polyradiculoneuropathies(CIDPs)are representative of acquired multifocal polyneuropathy and are characterized by conduction block(CB).This retrospective study aimed to investigate the demyelinating distribution and the selective vulnerability of MMN,LSS,and CIDP with CB(CIDP-CB)in nerves.Methods:Fifteen LSS subjects(107 nerves),24 MMN subjects(176 nerves),and 17 CIDP-CB subjects(110 nerves)were included.Their clinical information was recorded,blood and cerebrospinal fluid tests were conducted,and nerve conductions of the median,ulnar,radial,peroneal,and tibial nerves were evaluated.CB,temporal dispersion,distal motor latency(DML),and F-wave latency were recorded,and nerve conduction velocity,terminal latency index,and modified F-wave ratio were calculated.Results:CB was more likely to occur around the elbow in CIDP-CB than in MMN(78.6%vs.6.8%,P<0.01)but less likely to occur between the wrist and the elbow than in LSS(10.7%vs.39.3%,P<0.05).Tibial nerve CB was most frequently observed in MMN(47.4%,P<0.05).CIDP-CB was characterized by a prolonged DML in all nerves,and slow motor nerve velocity of the upper limb was significant when CB nerves were excluded(P<0.05).Conclusions:We report the different distributions of segmental and diffuse demyelination of the ulnar and tibial nerves in LSS,MMN,and CIDP-CB.These distinct distributions could help in differentiating among these conditions.
基金supported by the National Natural Science Foundation of China,Nos.32271389,31900987(both to PY)the Natural Science Foundation of Jiangsu Province,No.BK20230608(to JJ)。
文摘Regulatory T cells,a subset of CD4^(+)T cells,play a critical role in maintaining immune tolerance and tissue homeostasis due to their potent immunosuppressive properties.Recent advances in research have highlighted the important therapeutic potential of Tregs in neurological diseases and tissue repair,emphasizing their multifaceted roles in immune regulation.This review aims to summarize and analyze the mechanisms of action and therapeutic potential of Tregs in relation to neurological diseases and neural regeneration.Beyond their classical immune-regulatory functions,emerging evidence points to non-immune mechanisms of regulatory T cells,particularly their interactions with stem cells and other non-immune cells.These interactions contribute to optimizing the repair microenvironment and promoting tissue repair and nerve regeneration,positioning non-immune pathways as a promising direction for future research.By modulating immune and non-immune cells,including neurons and glia within neural tissues,Tregs have demonstrated remarkable efficacy in enhancing regeneration in the central and peripheral nervous systems.Preclinical studies have revealed that Treg cells interact with neurons,glial cells,and other neural components to mitigate inflammatory damage and support functional recovery.Current mechanistic studies show that Tregs can significantly promote neural repair and functional recovery by regulating inflammatory responses and the local immune microenvironment.However,research on the mechanistic roles of regulatory T cells in other diseases remains limited,highlighting substantial gaps and opportunities for exploration in this field.Laboratory and clinical studies have further advanced the application of regulatory T cells.Technical advances have enabled efficient isolation,ex vivo expansion and functionalization,and adoptive transfer of regulatory T cells,with efficacy validated in animal models.Innovative strategies,including gene editing,cell-free technologies,biomaterial-based recruitment,and in situ delivery have expanded the therapeutic potential of regulatory T cells.Gene editing enables precise functional optimization,while biomaterial and in situ delivery technologies enhance their accumulation and efficacy at target sites.These advancements not only improve the immune-regulatory capacity of regulatory T cells but also significantly enhance their role in tissue repair.By leveraging the pivotal and diverse functions of Tregs in immune modulation and tissue repair,regulatory T cells–based therapies may lead to transformative breakthroughs in the treatment of neurological diseases.
基金Deutsche Forschungsgemeinschaft(DFG,German Research Foundation),project numbers 324633948 and 409784463(DFG grants Hi 678/9-3 and Hi 678/10-2,FOR2953)to HHBundesministerium für Bildung und Forschung-BMBF,project number 16LW0463K to HT.
文摘Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neurodegenerative and demyelinating diseases(Borst et al.,2021).Together with infiltrating monocyte-derived macrophages,microglia also play a critical role for brain tumor development,since immunosuppressive interactions between tumor cells and tumor-associated microglia and macrophages(TAM)are linked to malignant progression.This mechanism is of particular relevance in glioblastoma(GB),the deadliest form of brain cancer with a median overall survival of less than 15 months(Khan et al.,2023).Therefore,targeting microglia and macrophage activation is a promising strategy for therapeutic interference in brain disease.
基金supported by KU Leuven Internal Funding(C3/21/012)the Research Foundation Flanders(FWO G092222N)(to LM)。
文摘Decades of research asserted that the oligodendroglial lineage comprises two cell types:oligodendrocyte precursor cells and oligodendrocytes.However,recent studies employing single-cell RNA sequencing techniques have uncovered novel cell states,prompting a revision of the existing terminology.Going forward,the oligodendroglial lineage should be delineated into five distinct cell states:oligodendrocyte precursor cells,committed oligodendrocyte precursor cells,newly formed oligodendrocytes,myelin-forming oligodendrocytes,and mature oligodendrocytes.This new classification system enables a deeper understanding of the oligodendroglia in both physiological and pathological contexts.Adopting this uniform terminology will facilitate comparison and integration of data across studies.This,including the consolidation of findings from various demyelinating models,is essential to better understand the pathogenesis of demyelinating diseases.Additionally,comparing injury models across species with varying regenerative capacities can provide insights that may lead to new therapeutic strategies to overcome remyelination failure.Thus,by standardizing terminology and synthesizing data from diverse studies across different animal models,we can enhance our understanding of myelin pathology in central nervous system disorders such as multiple sclerosis,Alzheimer's disease,and amyotrophic lateral sclerosis,all of which involve oligodendroglial and myelin dysfunction.
基金financially supported by the National Natural Science Foundation of China,Nos.82172104(to CX),81873767(to HZ)a grant from Jiangsu Provincial Research Hospital,Nos.YJXYY202204(to HZ),YJXYY202204-ZD04(to HZ)+5 种基金a grant from Jiangsu Provincial Key Medical CenterJiangsu Provincial Medical Innovation Center,No.CXZX202212Jiangsu Provincial Medical Key Discipline,No.ZDXK202240the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)Technology Project of Nantong,No.MS22022008(to HZ)Postgraduate Research&Practice Innovation Program of Jiangsu Province,No.SJCX21_1457(to WW)。
文摘Demyelination and remyelination have been major focal points in the study of peripheral nerve regeneration following peripheral nerve injury.Notably,the gene regulatory network of regenerated myelin differs from that of native myelin.Silencing of enhancer of zeste homolog 2(EZH2)hinders the differentiation,maturation,and myelination of Schwann cells in vitro.To further determine the role of EZH2 in myelination and recovery post-peripheral nerve injury,conditional knockout mice lacking Ezh2 in Schwann cells(Ezh2^(fl/fl);Dhh-Cre and Ezh2^(fl/fl);Mpz-Cre)were generated.Our results show that a significant proportion of axons in the sciatic nerve of Ezh2-depleted mice remain unmyelinated.This highlights the crucial role of Ezh2 in initiating Schwann cell myelination.Furthermore,we observed that 21 days after inducing a sciatic nerve crush injury in these mice,most axons had remyelinated at the injury site in the control nerve,while Ezh2^(fl/fl);Mpz-Cre mice had significantly fewer remyelinated axons compared with their wild-type littermates.This suggests that the absence of Ezh2 in Schwann cells impairs myelin formation and remyelination.In conclusion,EZH2 has emerged as a pivotal regulatory factor in the process of demyelination and myelin regeneration following peripheral nerve injury.Modulating EZH2 activity during these processes may offer a promising therapeutic target for the treatment of peripheral nerve injuries.
