BACKGROUND Acute disseminated encephalomyelitis(ADEM),which is rare,primarily affects children.It usually manifests as acute encephalopathy and multifocal neurological impairments after infection or vaccination.Diagno...BACKGROUND Acute disseminated encephalomyelitis(ADEM),which is rare,primarily affects children.It usually manifests as acute encephalopathy and multifocal neurological impairments after infection or vaccination.Diagnosis is still difficult due to the clinical and radiological similarity to other central nervous system disorders.Adult-onset ADEM calls for thorough reporting in order to improve diagnosis and treatment.CASE SUMMARY A 55-year-old man with hypertension had a high fever,intense headache and a steady decline in his neurological function after two weeks.Left facial paralysis was the initial symptom,which progressed to left hemiparesis,reduced consciousness level,photophobia,phonophobia,vomiting,and a focal seizure in the right leg.He had no history of autoimmune disease,vaccinations,or infections.Investigations showed negative infectious/autoimmune serology,mild cerebrospinal fluid lymphocytic pleocytosis(protein 76 mg/dL),and lymphopenia.Brain magnetic resonance imaging without contrast revealed bilateral,symmetrical T2/fluid-attenuated inversion recovery hyperintensities,primarily in the middle cerebellar peduncles,with minor involvement in the pontine and periventricular regions.Neoplastic,metabolic,vascular,and infectious conditions were not included.The patient showed spontaneous neurological improvement by Week 3 with near-complete motor recovery(limb strength 4/5)after methylprednisolone and rehabilitation,despite logistical delays in starting immunotherapy.The monophasic course and radiological/clinical remission were supported by idiopathic ADEM.CONCLUSION This case shows an uncommon,idiopathic,cerebellar-predominant ADEM variation in an adult without conventional triggers.It emphasizes the diagnostic difficulty in distinguishing ADEM from mimics(such as stroke or infection)in adults.Spontaneous improvement before treatment,although early detection is still crucial,should be highlighted,although early detection is still crucial.Increased clinician awareness,fair access to neuroimaging,and focused research on adult ADEM are crucial to fill these gaps and improve outcomes in places with limited resources.展开更多
Background:Multiple sclerosis(MS)is a chronic disease of the central nervous system(CNS),exhibiting hallmarks of both inflammation and neurodegeneration and with limited treatment options.The intricate nature of MS pa...Background:Multiple sclerosis(MS)is a chronic disease of the central nervous system(CNS),exhibiting hallmarks of both inflammation and neurodegeneration and with limited treatment options.The intricate nature of MS pathophysiology and its variable progression pose severe challenges for the development of effective therapies.The experimental autoimmune encephalomyelitis(EAE)MS model,in its most common form,is an aggressive disease,which is not representative of the MS course and offers a limited time window for drug evaluation.This study aimed to generate an attenuated EAE variant,which extends the clinical testing window while preserving the high incidence of the standard EAE model.Methods:Components of the EAE induction protocol were titrated to develop a milder disease profile.In a subsequent drug trial using the MS medication fingolimod hydrochloride(FTY,Gilenya),the new variant was validated under prophylactic and therapeutic treatment regimens.Results:The attenuated EAE variant retains the standard hallmarks of neuroinflammation and,crucially,significantly extends the time frame for clinical drug testing.Unlike the standard variant,where FTY efficacy could only be demonstrated by prophylactic treatment,the attenuated variant facilitated differentiation of drug effects by therapeutic treatment initiated early in the acute phase of disease.Conclusion:The new EAE variant is suitable for use in preclinical assessment of candidate therapeutics and the identification of targetable molecular mechanisms underpinning disease development and progression.This study illustrates the importance of optimizing and refining the experimental tool to enhance the translational success of the candidate therapeutics for MS.展开更多
Myalgic encephalomyelitis/chronic fatigue syndrome-an insidious disease:The recent COVID-19 pandemic has brought substantial attention to the overlapping symptoms between long COVID and myalgic encephalomyelitis/chron...Myalgic encephalomyelitis/chronic fatigue syndrome-an insidious disease:The recent COVID-19 pandemic has brought substantial attention to the overlapping symptoms between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS),a chronic and poorly understood neurological disorder(Shankar et al.,2024).展开更多
High mobility group box 1(HMGB1),when released extracellularly,plays a pivotal role in the development of spinal cord synapses and exacerbates autoimmune diseases within the central nervous system.In experimental auto...High mobility group box 1(HMGB1),when released extracellularly,plays a pivotal role in the development of spinal cord synapses and exacerbates autoimmune diseases within the central nervous system.In experimental autoimmune encephalomyelitis(EAE),a condition that models multiple sclerosis,the levels of extracellular HMGB1 and interleukin-33(IL-33)have been found to be inversely correlated.However,the mechanism by which IL-33 deficiency enhances HMGB1 release during EAE remains elusive.Our study elucidates a potential signaling pathway whereby the absence of IL-33 leads to increased binding of P300/CBP-associated factor with HMGB1 in the nuclei of astrocytes,upregulating HMGB1 acetylation and promoting its release from astrocyte nuclei in the spinal cord of EAE mice.Conversely,the addition of IL-33 counteracts the TNF-α-induced increase in HMGB1 and acetylated HMGB1 levels in primary astrocytes.These findings underscore the potential of IL-33-associated signaling pathways as a therapeutic target for EAE treatment.展开更多
Infiltration and activation of peripheral immune cells are critical in the progression of multiple sclerosis and its experimental animal model,experimental autoimmune encephalomyelitis(EAE).This study investigates the...Infiltration and activation of peripheral immune cells are critical in the progression of multiple sclerosis and its experimental animal model,experimental autoimmune encephalomyelitis(EAE).This study investigates the role of high mobility group box 1(HMGB1)in oligodendrocyte precursor cells(OPCs)in modulating pathogenic T cells infiltrating the central nervous system through the blood-brain barrier(BBB)by using OPC-specific HMGB1 knockout(KO)mice.We found that HMGB1 released from OPCs promotes BBB disruption,subsequently allowing increased immune cell infiltration.The migration of CD4+T cells isolated from EAE-induced mice was enhanced when co-cultured with OPCs compared to oligodendrocytes(OLs).OPC-specific HMGB1 KO mice exhibited lower BBB permeability and reduced immune cell infiltration into the CNS,leading to less damage to the myelin sheath and mitigated EAE progression.CD4+T cell migration was also reduced when co-cultured with HMGB1 knock-out OPCs.Our findings reveal that HMGB1 secretion from OPCs is crucial for regulating immune cell infiltration and provides insights into the immunomodulatory function of OPCs in autoimmune diseases.展开更多
Multiple sclerosis is characterized by demyelination and neuronal loss caused by inflammatory cell activation and infiltration into the central nervous system.Macrophage polarization plays an important role in the pat...Multiple sclerosis is characterized by demyelination and neuronal loss caused by inflammatory cell activation and infiltration into the central nervous system.Macrophage polarization plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis,a traditional experimental model of multiple sclerosis.This study investigated the effect of Fasudil on macrophages and examined the therapeutic potential of Fasudil-modified macrophages in experimental autoimmune encephalomyelitis.We found that Fasudil induced the conversion of macrophages from the pro-inflammatory M1 type to the anti-inflammatory M2 type,as shown by reduced expression of inducible nitric oxide synthase/nitric oxide,interleukin-12,and CD16/32 and increased expression of arginase-1,interleukin-10,CD14,and CD206,which was linked to inhibition of Rho kinase activity,decreased expression of toll-like receptors,nuclear factor-κB,and components of the mitogen-activated protein kinase signaling pathway,and generation of the pro-inflammatory cytokines tumor necrosis factor-α,interleukin-1β,and interleukin-6.Crucially,Fasudil-modified macrophages effectively decreased the impact of experimental autoimmune encephalomyelitis,resulting in later onset of disease,lower symptom scores,less weight loss,and reduced demyelination compared with unmodified macrophages.In addition,Fasudil-modified macrophages decreased interleukin-17 expression on CD4^(+)T cells and CD16/32,inducible nitric oxide synthase,and interleukin-12 expression on F4/80^(+)macrophages,as well as increasing interleukin-10 expression on CD4^(+)T cells and arginase-1,CD206,and interleukin-10 expression on F4/80^(+)macrophages,which improved immune regulation and reduced inflammation.These findings suggest that Fasudil-modified macrophages may help treat experimental autoimmune encephalomyelitis by inducing M2 macrophage polarization and inhibiting the inflammatory response,thereby providing new insight into cell immunotherapy for multiple sclerosis.展开更多
Early growth response protein 1(Egr-1)triggers the transcription of many genes involved in cell growth,differentiation,synaptic plasticity,and neurogenesis.However,its mechanism in neuronal survival and degeneration i...Early growth response protein 1(Egr-1)triggers the transcription of many genes involved in cell growth,differentiation,synaptic plasticity,and neurogenesis.However,its mechanism in neuronal survival and degeneration is still poorly understood.This study demonstrated that Egr-1 was down-regulated at mRNA and protein levels in the central nervous system(CNS)of experimental autoimmune encephalomyelitis(EAE)mice.Egr-1 knockout exacerbated EAE progression in mice,as shown by increased disease severity and incidence;it also aggravated neuronal apoptosis,which was associated with weakened activation of the BDNF/TGFβ1/MAPK/Akt signaling pathways in the CNS of EAE mice.Consistently,Egr-1 siRNA promoted apoptosis but mitigated the activation of BDNF/TGFβ1/MAPK/Akt signaling in SH-SY5Y cells.Our results revealed that Egr-1 is a crucial regulator of neuronal survival in EAE by regulating TGFβ1-mediated signaling activation,implicating the important role of Egr-1 in the pathogenesis of multiple sclerosis as a potential novel therapy target.展开更多
We investigated the effects of glucosamine(GS) on blood-brain barrier(BBB) function and matrix metalloproteinase-9 (MMP-9) expression in rats with experimental autoimmune encephalomyelitis(EAE).Animals were randomly d...We investigated the effects of glucosamine(GS) on blood-brain barrier(BBB) function and matrix metalloproteinase-9 (MMP-9) expression in rats with experimental autoimmune encephalomyelitis(EAE).Animals were randomly divided into three groups,among which the EAE and GS groups were immunized with complete antigen and pertussis toxin,and the adjuvant group was immunized with complete Freund's adjuvant and pertussis toxin.Rats were treated by peritoneal injection of GS 180 mg/(kg·d) in the GS group and peritoneal injection of phosphate-buffered saline 4.5 mL/(kg·d) in the EAE and adjuvant groups.We proposed to assess the integrity of BBB by calculating cerebrospinal fluid to serum albumin quotient(QA) on days 6,8,10,12,14,16 and 18 post-immunization.At the same time,the brains and spinal cords were removed for MMP-9 immunohistochemical staining. Experiments demonstrated that in the EAE group,QA value and MMP-9 expression were highly elevated and up-regulated and correlated to disease severity.Moreover,there was statistically significantly positive correlation between QA value and MMP-9 expression.In the GS group,we observed that the mean disease onset date was delayed,the incidence and mean score of symptom were suppressed at the peak phase of disease(P<0.05).Furthermore,QA value and MMP-9 expression in the GS group showed stronger inhibition when compared with those of the EAE group(P<0.05).Our study showed that GS would reduce the BBB breakdown and leukocyte trafficking by inhibiting the production of MMP-9 and mitigate EAE.展开更多
The transcription factor nuclear factor κB（NF-κB） plays major roles in inflammatory diseases through regulation of inflammation and cell viability.Multiple sclerosis（MS） is a chronic inflammatory demyelinating a...The transcription factor nuclear factor κB（NF-κB） plays major roles in inflammatory diseases through regulation of inflammation and cell viability.Multiple sclerosis（MS） is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system（CNS）.It has been shown that NF-κB is activated in multiple cell types in the CNS of MS patients,including T cells,microglia/macrophages,astrocytes,oligodendrocytes,and neurons.Interestingly,data from animal model studies,particularly studies of experimental autoimmune encephalomyelitis,have suggested that NF-κB activation in these individual cell types has distinct effects on the development of MS.In this review,we will cover the current literature on NF-κB and the evidence for its role in the development of MS and its animal model experimental autoimmune encephalomyelitis.展开更多
Multiple sclerosis is an autoimmune neurodegenerative disease of the central nervous system characterized by pronounced inflammatory infiltrates entering the brain,spinal cord and optic nerve leading to demyelination....Multiple sclerosis is an autoimmune neurodegenerative disease of the central nervous system characterized by pronounced inflammatory infiltrates entering the brain,spinal cord and optic nerve leading to demyelination.Focal demyelination is associated with relapsing-remitting multiple sclerosis,while progressive forms of the disease show axonal degeneration and neuronal loss.The tests currently used in the clinical diagnosis and management of multiple sclerosis have limitations due to specificity and sensitivity.MicroRNAs(miRNAs)are dysregulated in many diseases and disorders including demyelinating and neuroinflammatory diseases.A review of recent studies with the experimental autoimmune encephalomyelitis animal model(mostly female mice 6–12 weeks of age)has confirmed miRNAs as biomarkers of experimental autoimmune encephalomyelitis disease and importantly at the pre-onset(asymptomatic)stage when assessed in blood plasma and urine exosomes,and spinal cord tissue.The expression of certain miRNAs was also dysregulated at the onset and peak of disease in blood plasma and urine exosomes,brain and spinal cord tissue,and at the post-peak(chronic)stage of experimental autoimmune encephalomyelitis disease in spinal cord tissue.Therapies using miRNA mimics or inhibitors were found to delay the induction and alleviate the severity of experimental autoimmune encephalomyelitis disease.Interestingly,experimental autoimmune encephalomyelitis disease severity was reduced by overexpression of miR-146a,miR-23b,miR-497,miR-26a,and miR-20b,or by suppression of miR-182,miR-181c,miR-223,miR-155,and miR-873.Further studies are warranted on determining more fully miRNA profiles in blood plasma and urine exosomes of experimental autoimmune encephalomyelitis animals since they could serve as biomarkers of asymptomatic multiple sclerosis and disease course.Additionally,studies should be performed with male mice of a similar age,and with aged male and female mice.展开更多
Sinomenine is a bioactive alkaloid isolated from the Chinese medicinal plant Sinomenium acutum. It is widely used as an immunosuppressive drug for treating rheumatic and arthritic diseases. In our previous studies, we...Sinomenine is a bioactive alkaloid isolated from the Chinese medicinal plant Sinomenium acutum. It is widely used as an immunosuppressive drug for treating rheumatic and arthritic diseases. In our previous studies, we found that sinomenine reduced cellular infiltration within the spinal cord and alleviated experimental autoimmune encephalomyelitis （EAE） in rats. In this study, we further investigated the mechanisms of sinomenine treatment in EAE rats. In EAE rats, treatment with sinomenine exerted an anti-inducible NO synthase （anti-iNOS） effect, which is related to the reductions of Thl cytokine interferon-y （IFN-7） and its transcription factor, T-bet, in spinal cords. Moreover, sinomenine treatment of splenocytes stimulated with anti-CD3 antibody and recombinant rat in- terleukin 12 reduced the expression of T-bet and IFN-y in vitro and also reduced the capability of supernatants of splenocyte culture to induce iNOS expression by primary astrocytes. However, sinomenine had no direct inhibito- ry effect on iNOS produced by astrocytes cultured with IFN-y and tumor necrosis factor α in vitro. In conclusion, the anti-iNOS effect of sinomenine on EAE is mediated via the suppression of T-bet/IFN-y pathway.展开更多
The present study was conducted to clarify the therapeutic effect of cornuside on experimental autoimmune encephalomyelitis(EAE)and its influence on T helper 17(Th17)cell and regulatory T(Treg)cell infiltration into t...The present study was conducted to clarify the therapeutic effect of cornuside on experimental autoimmune encephalomyelitis(EAE)and its influence on T helper 17(Th17)cell and regulatory T(Treg)cell infiltration into the central nervous system.Rats were randomly placed into four treatment groups:control,EAE,EAE+cornuside,and EAE+prednisolone.The neurological function scores of rats were assessed daily.On the second day after EAE rats began to show neurological deficit symptoms,the four groups were treated with normal saline,normal saline,cornuside(150 mg/kg),and prednisolone(5 mg/kg),respectively.The treatment was discontinued after two weeks,and the spinal cord was obtained for hematoxylin and eosin(H&E)and luxol fast blue staining,as well as retinoic acid receptor-related orphan receptorγ(RORγ)and forkhead box protein P3(Foxp3)immunohistochemical staining.Blood was collected for Th17 and Treg cell flow cytometry testing,and the serum levels of interleukin(IL)-17A,IL-10,transforming growth factor-β(TGF-β),IL-6,IL-23,and IL-2 were measured via enzymelinked immunosorbent assay(ELISA).Compared with rats in the EAE group,rats in the EAE+cornuside and EAE+prednisolone groups began to recover from neurological deficits earlier,and had a greater degree of improvement of symptoms.Focal inflammation,demyelination,and RORγ-positive cell infiltration were reduced by cornuside or prednisolone treatment,whereas the Foxp3-positive cell numbers were not significantly different.Meanwhile,the number of Th17 cells and the IL-17A,IL-6,and IL-23 levels were lower in the blood after cornuside or prednisolone treatment,whereas the number of Treg cells or the levels of IL-10,TGF-β,and IL-2 were not markedly different.Cornuside can alleviate symptoms of EAE neurological deficits through its anti-inflammatory and immunosuppressive effects,and Th17 cells may be one of its therapeutic targets.展开更多
BACKGROUND： Yishendaluo decoction reduces production of inflammatory mediators, relieves damage due to inflammatory reactions, and improves neural functions during experimental autoimmune encephalomyelitis. OBJECTIVE...BACKGROUND： Yishendaluo decoction reduces production of inflammatory mediators, relieves damage due to inflammatory reactions, and improves neural functions during experimental autoimmune encephalomyelitis. OBJECTIVE： To investigate the effects of Yishendaluo decoction on a mouse model of experimental autoimmune encephalomyelitis. DESIGN, TIME AND SETTING： The randomized, controlled, neuropathological, and molecular biological animal study was performed at the Key Laboratory of Chinese Internal Medicine, Ministry of Education, Dongzhimen Hospital of Beijing University of Chinese Medicine and Center for Neuroinformatics, General Hospital of Chinese PLA from 2005 to 2006. MATERIALS： Yishendaluo decoction pieces consisting of prepared rehmannia root, colla comus cervi, cape jasmine fruit, and grassleaf sweetflag rhizome were purchased from the Dongzhimen Hospital of Beijing University of Chinese Medicine. Rabbit anti-mouse β-amyloid precursor protein and p38 polyclonal antibody （Zhongshan Goldenbridge Biotechnology, China）, as well interferon-y and interleukin-4 ELISA kit （Boster, China）, were used in this study. METHODS： A total of 96 healthy, female, SJL/J mice, aged 8 12 weeks, were equally and randomly assigned to normal, model, hormone, and Chinese medicine groups. A total of 0.2 mL antigen preparation, supplemented with 150 μg PLP 139-151 and 400 μg H37RA, was subcutaneously injected into the upper abdomen of mice from the model, hormone, and Chinese medicine groups. Mouse models of experimental autoimmune encephalomyelitis were established by intravenous injection of 0.1 mL Bordetella pertussis solution containing 0.6 × 10^6 Bordetella pertussis at days 1 and 3. Mice from the model, Chinese medicine, and hormone groups were respectively subjected to 0.2 mL saline, 2 g/kg Yishendaluo decoction, and 0.078 mg/kg prednisone acetate, once daily for 14 consecutive days. Mice from the normal group were left intact. MAIN OUTCOME MEASURES： Pathological changes were observed using hematoxylin-eosin staining and Luxol fast blue staining. Expression of β-amyloid precursor protein and p38 protein was determined by immunohistochemistry. Levels of interferon-y and interleukin-4 were detected by ELISA. Behavioral changes were assessed in mice according to scores of neurological function. RESULTS： A few inflammatory cell infiltration, nerve fiber breakage and slight demyelination were detected in the central nervous system of mice from the Chinese medicine and hormone groups compared with the model group. Expression of β-amyloid precursor protein and p38 protein was significantly diminished in the central nervous system of mice from the Chinese medicine and hormone groups compared with the model group （P 〈 0.05 or P 〈 0.01）, and the decrease was greatest in the Chinese medicine group. The decrease in mouse weight was not significant, and neurological function scores were less in the Chinese medicine and hormone groups compared with the model group （P 〈 0.05 or P 〈 0.01）. Interferon-y levels were significantly reduced （P 〈 0.01）, and interleukin-4 levels were significantly increased （P 〈 0.01） in the brains of the Chinese medicine and hormone groups, compared with the model group. CONCLUSION： Yishendaluo decoction improved neurological function in mice with experimental autoimmune encephalomyelitis by downregulating β-amyloid precursor protein expression, resistingaxonal degeneration, and relieving inflammatory reaction. The anti-inflammatory mechanism was regulated by inhibition of the p38 mitogen-activated protein kinase signal pathway.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
Multiple sclerosis(MS)is a chronic and incurable autoimmune neurodegenerative disease of the central nervous system.Although the symptoms of MS can be managed by vitamin D3 treatment alone,this condition cannot be com...Multiple sclerosis(MS)is a chronic and incurable autoimmune neurodegenerative disease of the central nervous system.Although the symptoms of MS can be managed by vitamin D3 treatment alone,this condition cannot be completely eradicated.Thus,there might be unknown factors capable of regulating the vitamin D receptor(VDR).Genome-wide analysis showed that miRNAs were associated with VDRs.We sought to determine the role and mechanism of action of miRNA-125a-5p and VDRs in a model of MS,mice with experimental autoimmune encephalomyelitis(EAE),which was induced by myelin oligodendrocyte glycoprotein 35–55 peptides.EAE mice showed decreased mean body weight but increased mean clinical scores compared with vehicle or control mice.And inflammatory infiltration was found in the lumbosacral spinal cord of EAE mice.In addition,VDR expression was significantly lower while the expression of miR-125a-5p was markedly higher in the spinal ventral horn of EAE mice than in vehicle or control mice.Importantly,activation of VDRs by paricalcitol or inhibition of miR-125a-5p by its antagomir markedly decreased the mean clinical scores in EAE mice.Interestingly,VDR and miR-125a-5p were co-localized in the same neurons of the ventral horn.More importantly,inhibition of miR-125a-5p remarkably blocked the decrease of VDRs in EAE mice.These results support a critical role for miR-125a-5p in modulating VDR activity in EAE and suggest potential novel therapeutic interventions.展开更多
OBJECTIVE:To examine the effects of catalpol and rhein on pro-and anti-inflammatory responses in C57 BL/6 mice with experimental autoimmune encephalomyelitis(EAE),a model of multiple sclerosis.METHODS:Female C57 BL/6 ...OBJECTIVE:To examine the effects of catalpol and rhein on pro-and anti-inflammatory responses in C57 BL/6 mice with experimental autoimmune encephalomyelitis(EAE),a model of multiple sclerosis.METHODS:Female C57 BL/6 mice were randomly divided into four groups(n=30):(a)normal salinecontrol,(b)EAE control,(c)EAE+prednisone acetate(PA,6 mg/kg),and(d)EAE+catalpol(40 mg/kg)and rhein(5 mg/kg).EAE was induced by injection of myelin oligodendrocyte glycoprotein 35-55 plus pertussis toxin.Treatments were orally administered daily for 40 d.Disease progression and neurological function were assessed using a semi-quantitative scale of tail and limb paralysis.Brains and spinal cords were collected on Days 6,20,and 40 and assessed for histopathological changes by hematoxylin and eosin staining.Production of interleukin(IL)-2,IL-4,IL-10,and IL-17 A protein was measured by enzyme-linked immunosorbent assay.Expression of the T helper(Th)1-,Th2-,Th17-,and regulatory T cell(Treg)-specific transcription factors T-bet,GATA3,ROR-γt,and Foxp3,respectively,were analyzed by quantitative reverse-transcription polymerase chain reaction and western blot analysis.RESULTS:Combination treatment with catalpol and rhein significantly alleviated the clinical disability and neurological dysfunction of mice with EAE.Catalpol and rhein treatment also reduced the infiltration of pro-inflammatory T cells into pathological lesions;significantly increased the expression of the anti-inflammatory factors GATA3,Foxp3,IL-4,and IL-10;and significantly decreased the expression of the pro-inflammatory factors T-bet,ROR-γt,IL-2,and IL-17 A.CONCLUSION:Catalpol and rhein reduced the neurological disabilities of mice with EAE,at least in part by rebalancing the pro-and anti-inflammatory environment in the brains and spinal cords.展开更多
BACKGROUND： Studies have demonstrated that experimental autoimmune encephalomyelitis （EAE） onset correlates with increased interferon-v （IFN-γ） and tumor necrosis factor-α （TNF-α） expression. Oxymatrine （OM...BACKGROUND： Studies have demonstrated that experimental autoimmune encephalomyelitis （EAE） onset correlates with increased interferon-v （IFN-γ） and tumor necrosis factor-α （TNF-α） expression. Oxymatrine （OM） has been shown to inhibit autoimmune responses, but there are no reports showing that it could prevent the development of EAE. OBJECTIVE： To observe the effect of OM on serum levels of IFN-γ and TNF-α in a rat model of EAE.DESIGN, TIME AND SETTING： A randomized, controlled, animal study was performed at the Experimental Animal Center of Henan Academy of Chinese Medicine and at the Key Disciplines Laboratory Clinical Medicine of Henan Province between July and December 2008. MATERIALS： OM was purchased from Chia-tai Tianqing Pharmaceutical, China; complete Freund＇s adjuvant was purchased from Sigma, USA. METHODS： Forty female Wistar rats were randomly assigned to four groups： EAE model （M）, low-dose OM treatment （OM-L）, high-dose OM treatment （OM-H）, and normal control （N, no immunization）, with 10 rats in each group. EAE was established in the M, OM-L, and OM-H groups following immunization with Guinea pig spinal cord homogenate and complete Freund＇s adjuvant. The M and N groups were intraperitoneally injected with normal saline （6.7 mL/kg per day）, the OM-L group received an intraperitoneal injection of OM （100 mg/kg per day）, and the OM-H group received OM （150 mg/kg per day）. MAIN OUTCOME MEASURES： At 16 days after immunization, the degree of histopathological changes in the spinal cord was assessed by hematoxylin-eosin stanining. Enzyme-linked immunosorbent assay was used to detect serum levels of IFN-γ, and radioimmunoassay was utilized to determine serum TNF-α level. Neurological scores were measured on a daily basis according to a 0-5 scale. RESULTS： Daily injections of OM, both high and low doses, resulted in decreased neurological scores in EAE rats （P〈0.01）, as well as reduced cellular infiltration in the spinal cord and decreased levels of serum IFN-γ and TNF-α （P〈 0.01）. CONCLUSION： OM reduced the onset and severity of EAE, which correlated with decreased IFN-γ and TNF-α expression.展开更多
BACKGROUND： It demonstrates that erhuangfang can improve clinical symptoms of multiple sclerosis and relieve side effects of hormone. However, whether erhuangfang can improve experimental allergic encephalomyelitis ...BACKGROUND： It demonstrates that erhuangfang can improve clinical symptoms of multiple sclerosis and relieve side effects of hormone. However, whether erhuangfang can improve experimental allergic encephalomyelitis （EAE） or not needs a further study. OBJECTIVE： To observe the effect of erhuangfang on neuro-pathology and astrocyte in EAE rats and compare with the effect of hormone. DESIGN： Randomized controlled animal study. SETTINGS： Department of Traditional Chinese Medicine, Beijing Tiantan Hospital, Capital Medical University; College of Traditional Chinese Medicine, Capital Medical University. MATERIALS： The experiment was carded out in the Laboratory Center of Capital Medical University from August to October 2005. Ten adult guinea pigs （SPF grade, weighing 400 - 450 g） and 70 adult Lewis rats （SPF grade, weighing 200- 220 g） were selected in this study. Erhuangfang consisted of fiudahuang, shengdi, shuizhi, dabeimu, etc. METHODS： ①Experimental intervention： Rats were randomly divided into normal group （n=10）, model group （n=20）, western medicine group （n=20） and Chinese herb group （n=20）. Mixed emulsion, which was consisted of Freund＇s adjuvant and spinal cord homogenate of guinea pigs, was subcutaneously injected into palms of the two hindfeet of rats in the latter three groups to establish EAE models. Foot pads were injected with saline and then rats were perfused with saline in the normal group.in the model group, models were established as the same as those mentioned above, and rats were also perfused with saline. Rats in the western medicine group were perfused with saline and then 5 mg/kg prednisone acetate suspension. Rats in the Chinese herb group were perfused with erhuangfang decoction （15 g raw materials per kilogram） at 5 days before model establishment. The dosage in the four groups was 3 mL/day per rat. ②Experimental evaluation： At 28 days after model establishment, rats were randomly selected for cerebral （mainly surrounding cerebral ventricle） and spinal cord （cervical enlargement and lumbar enlargement） collections, and then haematine-eosin （HE） staining and SLG myelin staining were used to observe demyelination and regeneration; meanwhile, immunohistochemical staining was used to observe the expression of glial fibriliary acidic protein （GFAP）. MAIN OUTCOME MEASURES： Cerebral and spinal demyelination and regeneration as well as expression of GFAP in EAE rats. RESULTS： All 70 Lewis rats were involved in the final analysis. ①Demyelination and regeneration： Infiltration of inflammatory cells surrounding cerebrum and small venous vessels of spinal cord white matter, demyelination surrounding vessels and plentiful foam cells at myelinolysis sites were observed in the model group. Symptoms were relieved in the western medicine group and the Chinese herb group as compared with those in the model group. While, numbers of inflammatory infiltrated cells and vascular cuffs were decreased in focal region as compared with those in the model group; in addition, areas of softening focus and demyelination were decreased. ②Expression of GFAP： Volumes and numbers of positive cells of GFAP in white matter region were respectively bigger and higher than those of normal cells in the model group. Plentiful positive cells of GFAP were disorderly aggregated in hippocampus and surrounding small vessel cuffs. While, expression of GFAP was mildly increased surrounding focus in the Chinese herb group; however, GFAP did not express surrounding focus in the western medicine group. In addition, expressions of GFAP were not increased in non-focal region in both Chinese herb group and western medicine group. CONCLUSION： Both erhuangfang and hormone can relieve inflammatory reaction of central nervoussystem and demyelination of EAE rats. On one hand, erhuangfang can regulate reaction of astrocyte in two ways, relieve reaction and proliferation of astrocyte in non-focal region and maintain the protective effect of astrocyte on brain tissue in focal region; on the other hand, hormone can overall inhibit reaction of astrocyte.展开更多
Studies have demonstrated that amyloid precursor protein （APP） expression increases in multiple sclerosis tissues during acutely and chronically active stages. To determine the relationship between axonal injury and...Studies have demonstrated that amyloid precursor protein （APP） expression increases in multiple sclerosis tissues during acutely and chronically active stages. To determine the relationship between axonal injury and regeneration in multiple sclerosis, an animal model of experimental autoimmune encephalomyelitis was induced using different doses of myelin basic protein peptide. APP and growth-associated protein 43 （GAP-43）, which is considered a specific marker of neural regeneration, were assessed by western blot analysis. Expression of APP and GAP-43, as well as the correlation between these two proteins, in brain white matter and spinal cord tissues of experimental autoimmune encephalomyelitis rats at different pathological stages was analyzed. Results showed that APP and GAP-43 expression increased during the acute stage and decreased during remission, with a positive correlation between APP and GAP-43 expression in brain white matter and spinal cord tissues. These results suggest that APP and GAP-43 could provide nutritional and protective effects on damaged neurons.展开更多
Myelin-associated inhibitory factors within the central nervous system（CNS） are considered to be one of the main obstacles for axonal regeneration following disease or injury. The nogo receptor 1（NgR1） has been we...Myelin-associated inhibitory factors within the central nervous system（CNS） are considered to be one of the main obstacles for axonal regeneration following disease or injury. The nogo receptor 1（NgR1） has been well documented to play a key role in limiting axonal regrowth in the injured and diseased mammalian CNS. However, the role of nogo receptor in immune cell activation during CNS inflammation is yet to be mechanistically elucidated. Microglia/macrophages are immune cells that are regarded as pathogenic contributors to inflammatory demyelinating lesions in multiple sclerosis（MS）. In this study, the animal model of MS, experimental autoimmune encephalomyelitis（EAE） was induced in ngr1^＋/＋ and ngr1^–/– female mice following injection with the myelin oligodendrocyte glycoprotein（MOG_（35–55）） peptide. A fatemap analysis of microglia/macrophages was performed throughout spinal cord sections of EAE-induced mice at clinical scores of 0, 1, 2 and 3, respectively（increasing locomotor disability） from both genotypes, using the CD11 b and Iba1 cell markers. Western immunoblotting using lysates from isolated spinal cord microglia/macrophages, along with immunohistochemistry and flow cytometric analysis, was performed to demonstrate the expression of nogo receptor and its two homologs during EAE progression. Myelin protein engulfment during EAE progression in ngr1^＋/＋ and ngr1^–/– mice was demonstrated by western immunblotting of lysates from isolated spinal cord microglia/macrophages, detecting levels of Nogo-A and MOG. The numbers of M1 and M2 microglia/macrophage phenotypes present in the spinal cords of EAE-induced ngr1^＋/＋ and ngr1^–/– mice, were assessed by flow cytometric analysis using CD38 and Erg-2 markers. A significant difference in microglia/macrophage numbers between ngr1^＋/＋ and ngr1^–/– mice was identified during the progression of the clinical symptoms of EAE, in the white versus gray matter regions of the spinal cord. This difference was unrelated to the expression of Ng R on these macrophage/microglial cells. We have identified that as EAE progresses, the phagocytic activity of microglia/macrophages with myelin debris, in ngr1^–/– mice, was enhanced. Moreover, we show a modulation from a predominant M1-pathogenic to the M2-neurotrophic cell phenotype in the ngr1^–/– mice during EAE progression. These findings suggest that CNS-specific macrophages and microglia of ngr1^–/– mice may exhibit an enhanced capacity to clear inhibitory molecules that are sequestered in inflammatory lesions.展开更多
文摘BACKGROUND Acute disseminated encephalomyelitis(ADEM),which is rare,primarily affects children.It usually manifests as acute encephalopathy and multifocal neurological impairments after infection or vaccination.Diagnosis is still difficult due to the clinical and radiological similarity to other central nervous system disorders.Adult-onset ADEM calls for thorough reporting in order to improve diagnosis and treatment.CASE SUMMARY A 55-year-old man with hypertension had a high fever,intense headache and a steady decline in his neurological function after two weeks.Left facial paralysis was the initial symptom,which progressed to left hemiparesis,reduced consciousness level,photophobia,phonophobia,vomiting,and a focal seizure in the right leg.He had no history of autoimmune disease,vaccinations,or infections.Investigations showed negative infectious/autoimmune serology,mild cerebrospinal fluid lymphocytic pleocytosis(protein 76 mg/dL),and lymphopenia.Brain magnetic resonance imaging without contrast revealed bilateral,symmetrical T2/fluid-attenuated inversion recovery hyperintensities,primarily in the middle cerebellar peduncles,with minor involvement in the pontine and periventricular regions.Neoplastic,metabolic,vascular,and infectious conditions were not included.The patient showed spontaneous neurological improvement by Week 3 with near-complete motor recovery(limb strength 4/5)after methylprednisolone and rehabilitation,despite logistical delays in starting immunotherapy.The monophasic course and radiological/clinical remission were supported by idiopathic ADEM.CONCLUSION This case shows an uncommon,idiopathic,cerebellar-predominant ADEM variation in an adult without conventional triggers.It emphasizes the diagnostic difficulty in distinguishing ADEM from mimics(such as stroke or infection)in adults.Spontaneous improvement before treatment,although early detection is still crucial,should be highlighted,although early detection is still crucial.Increased clinician awareness,fair access to neuroimaging,and focused research on adult ADEM are crucial to fill these gaps and improve outcomes in places with limited resources.
基金Private DonationLa Trobe Research Focus AreasMultiple Sclerosis Australia,Grant/Award Number:20-032。
文摘Background:Multiple sclerosis(MS)is a chronic disease of the central nervous system(CNS),exhibiting hallmarks of both inflammation and neurodegeneration and with limited treatment options.The intricate nature of MS pathophysiology and its variable progression pose severe challenges for the development of effective therapies.The experimental autoimmune encephalomyelitis(EAE)MS model,in its most common form,is an aggressive disease,which is not representative of the MS course and offers a limited time window for drug evaluation.This study aimed to generate an attenuated EAE variant,which extends the clinical testing window while preserving the high incidence of the standard EAE model.Methods:Components of the EAE induction protocol were titrated to develop a milder disease profile.In a subsequent drug trial using the MS medication fingolimod hydrochloride(FTY,Gilenya),the new variant was validated under prophylactic and therapeutic treatment regimens.Results:The attenuated EAE variant retains the standard hallmarks of neuroinflammation and,crucially,significantly extends the time frame for clinical drug testing.Unlike the standard variant,where FTY efficacy could only be demonstrated by prophylactic treatment,the attenuated variant facilitated differentiation of drug effects by therapeutic treatment initiated early in the acute phase of disease.Conclusion:The new EAE variant is suitable for use in preclinical assessment of candidate therapeutics and the identification of targetable molecular mechanisms underpinning disease development and progression.This study illustrates the importance of optimizing and refining the experimental tool to enhance the translational success of the candidate therapeutics for MS.
基金supported by the Judith Jane Mason and Harold Stannett Williams Memorial Foundation National Medical Program(#Mason2210)to JX。
文摘Myalgic encephalomyelitis/chronic fatigue syndrome-an insidious disease:The recent COVID-19 pandemic has brought substantial attention to the overlapping symptoms between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS),a chronic and poorly understood neurological disorder(Shankar et al.,2024).
基金supported by the National Natural Science Foundation of China(82001281 and 82371195)Hubei Provincial Natural Science Foundation of China for Distinguished Young Scholars(2022CFA104)the Research Fund of Jianghan University(2022XKZX28).
文摘High mobility group box 1(HMGB1),when released extracellularly,plays a pivotal role in the development of spinal cord synapses and exacerbates autoimmune diseases within the central nervous system.In experimental autoimmune encephalomyelitis(EAE),a condition that models multiple sclerosis,the levels of extracellular HMGB1 and interleukin-33(IL-33)have been found to be inversely correlated.However,the mechanism by which IL-33 deficiency enhances HMGB1 release during EAE remains elusive.Our study elucidates a potential signaling pathway whereby the absence of IL-33 leads to increased binding of P300/CBP-associated factor with HMGB1 in the nuclei of astrocytes,upregulating HMGB1 acetylation and promoting its release from astrocyte nuclei in the spinal cord of EAE mice.Conversely,the addition of IL-33 counteracts the TNF-α-induced increase in HMGB1 and acetylated HMGB1 levels in primary astrocytes.These findings underscore the potential of IL-33-associated signaling pathways as a therapeutic target for EAE treatment.
基金supported by the National Research Foundation of Korea(NRF)funded by the government of the Republic of Korea[2023R1A2C1004955]the Technology Innovation Program funded by the Ministry of Trade,Industry&Energy(Korea)(20009707)+1 种基金the Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education(2020R1A6A3A01099056)the Korea Institute for Advancement of Technology funded by the Ministry of Trade,Industry and Energy(P0025489).
文摘Infiltration and activation of peripheral immune cells are critical in the progression of multiple sclerosis and its experimental animal model,experimental autoimmune encephalomyelitis(EAE).This study investigates the role of high mobility group box 1(HMGB1)in oligodendrocyte precursor cells(OPCs)in modulating pathogenic T cells infiltrating the central nervous system through the blood-brain barrier(BBB)by using OPC-specific HMGB1 knockout(KO)mice.We found that HMGB1 released from OPCs promotes BBB disruption,subsequently allowing increased immune cell infiltration.The migration of CD4+T cells isolated from EAE-induced mice was enhanced when co-cultured with OPCs compared to oligodendrocytes(OLs).OPC-specific HMGB1 KO mice exhibited lower BBB permeability and reduced immune cell infiltration into the CNS,leading to less damage to the myelin sheath and mitigated EAE progression.CD4+T cell migration was also reduced when co-cultured with HMGB1 knock-out OPCs.Our findings reveal that HMGB1 secretion from OPCs is crucial for regulating immune cell infiltration and provides insights into the immunomodulatory function of OPCs in autoimmune diseases.
基金supported by a grant from the Department of Science and Technology of Shanxi Province,China,No.20210302123477(to CL)Datong Bureau of Science and Technology of China,No.2020152(to CL)the Opening Foundation of Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine,No.2022-KF-03(to CL).
文摘Multiple sclerosis is characterized by demyelination and neuronal loss caused by inflammatory cell activation and infiltration into the central nervous system.Macrophage polarization plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis,a traditional experimental model of multiple sclerosis.This study investigated the effect of Fasudil on macrophages and examined the therapeutic potential of Fasudil-modified macrophages in experimental autoimmune encephalomyelitis.We found that Fasudil induced the conversion of macrophages from the pro-inflammatory M1 type to the anti-inflammatory M2 type,as shown by reduced expression of inducible nitric oxide synthase/nitric oxide,interleukin-12,and CD16/32 and increased expression of arginase-1,interleukin-10,CD14,and CD206,which was linked to inhibition of Rho kinase activity,decreased expression of toll-like receptors,nuclear factor-κB,and components of the mitogen-activated protein kinase signaling pathway,and generation of the pro-inflammatory cytokines tumor necrosis factor-α,interleukin-1β,and interleukin-6.Crucially,Fasudil-modified macrophages effectively decreased the impact of experimental autoimmune encephalomyelitis,resulting in later onset of disease,lower symptom scores,less weight loss,and reduced demyelination compared with unmodified macrophages.In addition,Fasudil-modified macrophages decreased interleukin-17 expression on CD4^(+)T cells and CD16/32,inducible nitric oxide synthase,and interleukin-12 expression on F4/80^(+)macrophages,as well as increasing interleukin-10 expression on CD4^(+)T cells and arginase-1,CD206,and interleukin-10 expression on F4/80^(+)macrophages,which improved immune regulation and reduced inflammation.These findings suggest that Fasudil-modified macrophages may help treat experimental autoimmune encephalomyelitis by inducing M2 macrophage polarization and inhibiting the inflammatory response,thereby providing new insight into cell immunotherapy for multiple sclerosis.
基金supported by the National Natural Science Foundation of China(82074043,82104425,82374065,and 81673626)the China Postdoctoral Science Foundation(2021M702217).
文摘Early growth response protein 1(Egr-1)triggers the transcription of many genes involved in cell growth,differentiation,synaptic plasticity,and neurogenesis.However,its mechanism in neuronal survival and degeneration is still poorly understood.This study demonstrated that Egr-1 was down-regulated at mRNA and protein levels in the central nervous system(CNS)of experimental autoimmune encephalomyelitis(EAE)mice.Egr-1 knockout exacerbated EAE progression in mice,as shown by increased disease severity and incidence;it also aggravated neuronal apoptosis,which was associated with weakened activation of the BDNF/TGFβ1/MAPK/Akt signaling pathways in the CNS of EAE mice.Consistently,Egr-1 siRNA promoted apoptosis but mitigated the activation of BDNF/TGFβ1/MAPK/Akt signaling in SH-SY5Y cells.Our results revealed that Egr-1 is a crucial regulator of neuronal survival in EAE by regulating TGFβ1-mediated signaling activation,implicating the important role of Egr-1 in the pathogenesis of multiple sclerosis as a potential novel therapy target.
基金Natural Science Foundation of Shanxi,China (Grant No.2008011082-1)Shanxi Scholarship Council of China (Grant No.2008-86)Natural Science Foundation of Shanxi Datong University(Grant No.2009Q6).
文摘We investigated the effects of glucosamine(GS) on blood-brain barrier(BBB) function and matrix metalloproteinase-9 (MMP-9) expression in rats with experimental autoimmune encephalomyelitis(EAE).Animals were randomly divided into three groups,among which the EAE and GS groups were immunized with complete antigen and pertussis toxin,and the adjuvant group was immunized with complete Freund's adjuvant and pertussis toxin.Rats were treated by peritoneal injection of GS 180 mg/(kg·d) in the GS group and peritoneal injection of phosphate-buffered saline 4.5 mL/(kg·d) in the EAE and adjuvant groups.We proposed to assess the integrity of BBB by calculating cerebrospinal fluid to serum albumin quotient(QA) on days 6,8,10,12,14,16 and 18 post-immunization.At the same time,the brains and spinal cords were removed for MMP-9 immunohistochemical staining. Experiments demonstrated that in the EAE group,QA value and MMP-9 expression were highly elevated and up-regulated and correlated to disease severity.Moreover,there was statistically significantly positive correlation between QA value and MMP-9 expression.In the GS group,we observed that the mean disease onset date was delayed,the incidence and mean score of symptom were suppressed at the peak phase of disease(P<0.05).Furthermore,QA value and MMP-9 expression in the GS group showed stronger inhibition when compared with those of the EAE group(P<0.05).Our study showed that GS would reduce the BBB breakdown and leukocyte trafficking by inhibiting the production of MMP-9 and mitigate EAE.
基金supported by grants from the National Institutes of Health(NS094151 and NS105689)the National Multiple Sclerosis Society(RG5239-A-3)(to WL)
文摘The transcription factor nuclear factor κB（NF-κB） plays major roles in inflammatory diseases through regulation of inflammation and cell viability.Multiple sclerosis（MS） is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system（CNS）.It has been shown that NF-κB is activated in multiple cell types in the CNS of MS patients,including T cells,microglia/macrophages,astrocytes,oligodendrocytes,and neurons.Interestingly,data from animal model studies,particularly studies of experimental autoimmune encephalomyelitis,have suggested that NF-κB activation in these individual cell types has distinct effects on the development of MS.In this review,we will cover the current literature on NF-κB and the evidence for its role in the development of MS and its animal model experimental autoimmune encephalomyelitis.
文摘Multiple sclerosis is an autoimmune neurodegenerative disease of the central nervous system characterized by pronounced inflammatory infiltrates entering the brain,spinal cord and optic nerve leading to demyelination.Focal demyelination is associated with relapsing-remitting multiple sclerosis,while progressive forms of the disease show axonal degeneration and neuronal loss.The tests currently used in the clinical diagnosis and management of multiple sclerosis have limitations due to specificity and sensitivity.MicroRNAs(miRNAs)are dysregulated in many diseases and disorders including demyelinating and neuroinflammatory diseases.A review of recent studies with the experimental autoimmune encephalomyelitis animal model(mostly female mice 6–12 weeks of age)has confirmed miRNAs as biomarkers of experimental autoimmune encephalomyelitis disease and importantly at the pre-onset(asymptomatic)stage when assessed in blood plasma and urine exosomes,and spinal cord tissue.The expression of certain miRNAs was also dysregulated at the onset and peak of disease in blood plasma and urine exosomes,brain and spinal cord tissue,and at the post-peak(chronic)stage of experimental autoimmune encephalomyelitis disease in spinal cord tissue.Therapies using miRNA mimics or inhibitors were found to delay the induction and alleviate the severity of experimental autoimmune encephalomyelitis disease.Interestingly,experimental autoimmune encephalomyelitis disease severity was reduced by overexpression of miR-146a,miR-23b,miR-497,miR-26a,and miR-20b,or by suppression of miR-182,miR-181c,miR-223,miR-155,and miR-873.Further studies are warranted on determining more fully miRNA profiles in blood plasma and urine exosomes of experimental autoimmune encephalomyelitis animals since they could serve as biomarkers of asymptomatic multiple sclerosis and disease course.Additionally,studies should be performed with male mice of a similar age,and with aged male and female mice.
基金supported by Science Fund of the Health Department of Jiangsu Province (No. H200504)
文摘Sinomenine is a bioactive alkaloid isolated from the Chinese medicinal plant Sinomenium acutum. It is widely used as an immunosuppressive drug for treating rheumatic and arthritic diseases. In our previous studies, we found that sinomenine reduced cellular infiltration within the spinal cord and alleviated experimental autoimmune encephalomyelitis （EAE） in rats. In this study, we further investigated the mechanisms of sinomenine treatment in EAE rats. In EAE rats, treatment with sinomenine exerted an anti-inducible NO synthase （anti-iNOS） effect, which is related to the reductions of Thl cytokine interferon-y （IFN-7） and its transcription factor, T-bet, in spinal cords. Moreover, sinomenine treatment of splenocytes stimulated with anti-CD3 antibody and recombinant rat in- terleukin 12 reduced the expression of T-bet and IFN-y in vitro and also reduced the capability of supernatants of splenocyte culture to induce iNOS expression by primary astrocytes. However, sinomenine had no direct inhibito- ry effect on iNOS produced by astrocytes cultured with IFN-y and tumor necrosis factor α in vitro. In conclusion, the anti-iNOS effect of sinomenine on EAE is mediated via the suppression of T-bet/IFN-y pathway.
基金This work was supported by the Traditional Chinese Medical Science and Technology Project of Zhejiang Province(No.2019ZA063)the Scientific Research Fund of Zhejiang Chinese Medical University(No.2019ZY09),China.
文摘The present study was conducted to clarify the therapeutic effect of cornuside on experimental autoimmune encephalomyelitis(EAE)and its influence on T helper 17(Th17)cell and regulatory T(Treg)cell infiltration into the central nervous system.Rats were randomly placed into four treatment groups:control,EAE,EAE+cornuside,and EAE+prednisolone.The neurological function scores of rats were assessed daily.On the second day after EAE rats began to show neurological deficit symptoms,the four groups were treated with normal saline,normal saline,cornuside(150 mg/kg),and prednisolone(5 mg/kg),respectively.The treatment was discontinued after two weeks,and the spinal cord was obtained for hematoxylin and eosin(H&E)and luxol fast blue staining,as well as retinoic acid receptor-related orphan receptorγ(RORγ)and forkhead box protein P3(Foxp3)immunohistochemical staining.Blood was collected for Th17 and Treg cell flow cytometry testing,and the serum levels of interleukin(IL)-17A,IL-10,transforming growth factor-β(TGF-β),IL-6,IL-23,and IL-2 were measured via enzymelinked immunosorbent assay(ELISA).Compared with rats in the EAE group,rats in the EAE+cornuside and EAE+prednisolone groups began to recover from neurological deficits earlier,and had a greater degree of improvement of symptoms.Focal inflammation,demyelination,and RORγ-positive cell infiltration were reduced by cornuside or prednisolone treatment,whereas the Foxp3-positive cell numbers were not significantly different.Meanwhile,the number of Th17 cells and the IL-17A,IL-6,and IL-23 levels were lower in the blood after cornuside or prednisolone treatment,whereas the number of Treg cells or the levels of IL-10,TGF-β,and IL-2 were not markedly different.Cornuside can alleviate symptoms of EAE neurological deficits through its anti-inflammatory and immunosuppressive effects,and Th17 cells may be one of its therapeutic targets.
基金the National Natural Science Foundation of China,No.30672692
文摘BACKGROUND： Yishendaluo decoction reduces production of inflammatory mediators, relieves damage due to inflammatory reactions, and improves neural functions during experimental autoimmune encephalomyelitis. OBJECTIVE： To investigate the effects of Yishendaluo decoction on a mouse model of experimental autoimmune encephalomyelitis. DESIGN, TIME AND SETTING： The randomized, controlled, neuropathological, and molecular biological animal study was performed at the Key Laboratory of Chinese Internal Medicine, Ministry of Education, Dongzhimen Hospital of Beijing University of Chinese Medicine and Center for Neuroinformatics, General Hospital of Chinese PLA from 2005 to 2006. MATERIALS： Yishendaluo decoction pieces consisting of prepared rehmannia root, colla comus cervi, cape jasmine fruit, and grassleaf sweetflag rhizome were purchased from the Dongzhimen Hospital of Beijing University of Chinese Medicine. Rabbit anti-mouse β-amyloid precursor protein and p38 polyclonal antibody （Zhongshan Goldenbridge Biotechnology, China）, as well interferon-y and interleukin-4 ELISA kit （Boster, China）, were used in this study. METHODS： A total of 96 healthy, female, SJL/J mice, aged 8 12 weeks, were equally and randomly assigned to normal, model, hormone, and Chinese medicine groups. A total of 0.2 mL antigen preparation, supplemented with 150 μg PLP 139-151 and 400 μg H37RA, was subcutaneously injected into the upper abdomen of mice from the model, hormone, and Chinese medicine groups. Mouse models of experimental autoimmune encephalomyelitis were established by intravenous injection of 0.1 mL Bordetella pertussis solution containing 0.6 × 10^6 Bordetella pertussis at days 1 and 3. Mice from the model, Chinese medicine, and hormone groups were respectively subjected to 0.2 mL saline, 2 g/kg Yishendaluo decoction, and 0.078 mg/kg prednisone acetate, once daily for 14 consecutive days. Mice from the normal group were left intact. MAIN OUTCOME MEASURES： Pathological changes were observed using hematoxylin-eosin staining and Luxol fast blue staining. Expression of β-amyloid precursor protein and p38 protein was determined by immunohistochemistry. Levels of interferon-y and interleukin-4 were detected by ELISA. Behavioral changes were assessed in mice according to scores of neurological function. RESULTS： A few inflammatory cell infiltration, nerve fiber breakage and slight demyelination were detected in the central nervous system of mice from the Chinese medicine and hormone groups compared with the model group. Expression of β-amyloid precursor protein and p38 protein was significantly diminished in the central nervous system of mice from the Chinese medicine and hormone groups compared with the model group （P 〈 0.05 or P 〈 0.01）, and the decrease was greatest in the Chinese medicine group. The decrease in mouse weight was not significant, and neurological function scores were less in the Chinese medicine and hormone groups compared with the model group （P 〈 0.05 or P 〈 0.01）. Interferon-y levels were significantly reduced （P 〈 0.01）, and interleukin-4 levels were significantly increased （P 〈 0.01） in the brains of the Chinese medicine and hormone groups, compared with the model group. CONCLUSION： Yishendaluo decoction improved neurological function in mice with experimental autoimmune encephalomyelitis by downregulating β-amyloid precursor protein expression, resistingaxonal degeneration, and relieving inflammatory reaction. The anti-inflammatory mechanism was regulated by inhibition of the p38 mitogen-activated protein kinase signal pathway.
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 International Science and Technology Cooperation Plan of Guizhou Province,China[(2013)7027]the National Natural Science Foundation of China(81471137 and 31730040).
文摘Multiple sclerosis(MS)is a chronic and incurable autoimmune neurodegenerative disease of the central nervous system.Although the symptoms of MS can be managed by vitamin D3 treatment alone,this condition cannot be completely eradicated.Thus,there might be unknown factors capable of regulating the vitamin D receptor(VDR).Genome-wide analysis showed that miRNAs were associated with VDRs.We sought to determine the role and mechanism of action of miRNA-125a-5p and VDRs in a model of MS,mice with experimental autoimmune encephalomyelitis(EAE),which was induced by myelin oligodendrocyte glycoprotein 35–55 peptides.EAE mice showed decreased mean body weight but increased mean clinical scores compared with vehicle or control mice.And inflammatory infiltration was found in the lumbosacral spinal cord of EAE mice.In addition,VDR expression was significantly lower while the expression of miR-125a-5p was markedly higher in the spinal ventral horn of EAE mice than in vehicle or control mice.Importantly,activation of VDRs by paricalcitol or inhibition of miR-125a-5p by its antagomir markedly decreased the mean clinical scores in EAE mice.Interestingly,VDR and miR-125a-5p were co-localized in the same neurons of the ventral horn.More importantly,inhibition of miR-125a-5p remarkably blocked the decrease of VDRs in EAE mice.These results support a critical role for miR-125a-5p in modulating VDR activity in EAE and suggest potential novel therapeutic interventions.
基金Supported by the National Natural Science Foundation(No.81973599)Beijing Natural Science Foundation-Key Project of Science and Technology Plan of Beijing Education Commission(KZ/KM/SZ/SM201910025035)The Fund for Beijing Science&Technology Development of Traditional Chinese Medicine(No.QN2018-30)
文摘OBJECTIVE:To examine the effects of catalpol and rhein on pro-and anti-inflammatory responses in C57 BL/6 mice with experimental autoimmune encephalomyelitis(EAE),a model of multiple sclerosis.METHODS:Female C57 BL/6 mice were randomly divided into four groups(n=30):(a)normal salinecontrol,(b)EAE control,(c)EAE+prednisone acetate(PA,6 mg/kg),and(d)EAE+catalpol(40 mg/kg)and rhein(5 mg/kg).EAE was induced by injection of myelin oligodendrocyte glycoprotein 35-55 plus pertussis toxin.Treatments were orally administered daily for 40 d.Disease progression and neurological function were assessed using a semi-quantitative scale of tail and limb paralysis.Brains and spinal cords were collected on Days 6,20,and 40 and assessed for histopathological changes by hematoxylin and eosin staining.Production of interleukin(IL)-2,IL-4,IL-10,and IL-17 A protein was measured by enzyme-linked immunosorbent assay.Expression of the T helper(Th)1-,Th2-,Th17-,and regulatory T cell(Treg)-specific transcription factors T-bet,GATA3,ROR-γt,and Foxp3,respectively,were analyzed by quantitative reverse-transcription polymerase chain reaction and western blot analysis.RESULTS:Combination treatment with catalpol and rhein significantly alleviated the clinical disability and neurological dysfunction of mice with EAE.Catalpol and rhein treatment also reduced the infiltration of pro-inflammatory T cells into pathological lesions;significantly increased the expression of the anti-inflammatory factors GATA3,Foxp3,IL-4,and IL-10;and significantly decreased the expression of the pro-inflammatory factors T-bet,ROR-γt,IL-2,and IL-17 A.CONCLUSION:Catalpol and rhein reduced the neurological disabilities of mice with EAE,at least in part by rebalancing the pro-and anti-inflammatory environment in the brains and spinal cords.
基金a Grant from the Natural Scientific Research Project of the Education Department of Henan Province,No. 2009A350009
文摘BACKGROUND： Studies have demonstrated that experimental autoimmune encephalomyelitis （EAE） onset correlates with increased interferon-v （IFN-γ） and tumor necrosis factor-α （TNF-α） expression. Oxymatrine （OM） has been shown to inhibit autoimmune responses, but there are no reports showing that it could prevent the development of EAE. OBJECTIVE： To observe the effect of OM on serum levels of IFN-γ and TNF-α in a rat model of EAE.DESIGN, TIME AND SETTING： A randomized, controlled, animal study was performed at the Experimental Animal Center of Henan Academy of Chinese Medicine and at the Key Disciplines Laboratory Clinical Medicine of Henan Province between July and December 2008. MATERIALS： OM was purchased from Chia-tai Tianqing Pharmaceutical, China; complete Freund＇s adjuvant was purchased from Sigma, USA. METHODS： Forty female Wistar rats were randomly assigned to four groups： EAE model （M）, low-dose OM treatment （OM-L）, high-dose OM treatment （OM-H）, and normal control （N, no immunization）, with 10 rats in each group. EAE was established in the M, OM-L, and OM-H groups following immunization with Guinea pig spinal cord homogenate and complete Freund＇s adjuvant. The M and N groups were intraperitoneally injected with normal saline （6.7 mL/kg per day）, the OM-L group received an intraperitoneal injection of OM （100 mg/kg per day）, and the OM-H group received OM （150 mg/kg per day）. MAIN OUTCOME MEASURES： At 16 days after immunization, the degree of histopathological changes in the spinal cord was assessed by hematoxylin-eosin stanining. Enzyme-linked immunosorbent assay was used to detect serum levels of IFN-γ, and radioimmunoassay was utilized to determine serum TNF-α level. Neurological scores were measured on a daily basis according to a 0-5 scale. RESULTS： Daily injections of OM, both high and low doses, resulted in decreased neurological scores in EAE rats （P〈0.01）, as well as reduced cellular infiltration in the spinal cord and decreased levels of serum IFN-γ and TNF-α （P〈 0.01）. CONCLUSION： OM reduced the onset and severity of EAE, which correlated with decreased IFN-γ and TNF-α expression.
基金Beijing Technology Development Foundation of Traditional Chinese Medicine, No. 2003Ⅲ-21Beijing Key Program of Traditional Chinese Medicine, No. 2004 Ⅳ -14+1 种基金the Natural Science Foundation of Beijing, No.7062022the National Natural Science Foundation of China, No. 30640069
文摘BACKGROUND： It demonstrates that erhuangfang can improve clinical symptoms of multiple sclerosis and relieve side effects of hormone. However, whether erhuangfang can improve experimental allergic encephalomyelitis （EAE） or not needs a further study. OBJECTIVE： To observe the effect of erhuangfang on neuro-pathology and astrocyte in EAE rats and compare with the effect of hormone. DESIGN： Randomized controlled animal study. SETTINGS： Department of Traditional Chinese Medicine, Beijing Tiantan Hospital, Capital Medical University; College of Traditional Chinese Medicine, Capital Medical University. MATERIALS： The experiment was carded out in the Laboratory Center of Capital Medical University from August to October 2005. Ten adult guinea pigs （SPF grade, weighing 400 - 450 g） and 70 adult Lewis rats （SPF grade, weighing 200- 220 g） were selected in this study. Erhuangfang consisted of fiudahuang, shengdi, shuizhi, dabeimu, etc. METHODS： ①Experimental intervention： Rats were randomly divided into normal group （n=10）, model group （n=20）, western medicine group （n=20） and Chinese herb group （n=20）. Mixed emulsion, which was consisted of Freund＇s adjuvant and spinal cord homogenate of guinea pigs, was subcutaneously injected into palms of the two hindfeet of rats in the latter three groups to establish EAE models. Foot pads were injected with saline and then rats were perfused with saline in the normal group.in the model group, models were established as the same as those mentioned above, and rats were also perfused with saline. Rats in the western medicine group were perfused with saline and then 5 mg/kg prednisone acetate suspension. Rats in the Chinese herb group were perfused with erhuangfang decoction （15 g raw materials per kilogram） at 5 days before model establishment. The dosage in the four groups was 3 mL/day per rat. ②Experimental evaluation： At 28 days after model establishment, rats were randomly selected for cerebral （mainly surrounding cerebral ventricle） and spinal cord （cervical enlargement and lumbar enlargement） collections, and then haematine-eosin （HE） staining and SLG myelin staining were used to observe demyelination and regeneration; meanwhile, immunohistochemical staining was used to observe the expression of glial fibriliary acidic protein （GFAP）. MAIN OUTCOME MEASURES： Cerebral and spinal demyelination and regeneration as well as expression of GFAP in EAE rats. RESULTS： All 70 Lewis rats were involved in the final analysis. ①Demyelination and regeneration： Infiltration of inflammatory cells surrounding cerebrum and small venous vessels of spinal cord white matter, demyelination surrounding vessels and plentiful foam cells at myelinolysis sites were observed in the model group. Symptoms were relieved in the western medicine group and the Chinese herb group as compared with those in the model group. While, numbers of inflammatory infiltrated cells and vascular cuffs were decreased in focal region as compared with those in the model group; in addition, areas of softening focus and demyelination were decreased. ②Expression of GFAP： Volumes and numbers of positive cells of GFAP in white matter region were respectively bigger and higher than those of normal cells in the model group. Plentiful positive cells of GFAP were disorderly aggregated in hippocampus and surrounding small vessel cuffs. While, expression of GFAP was mildly increased surrounding focus in the Chinese herb group; however, GFAP did not express surrounding focus in the western medicine group. In addition, expressions of GFAP were not increased in non-focal region in both Chinese herb group and western medicine group. CONCLUSION： Both erhuangfang and hormone can relieve inflammatory reaction of central nervoussystem and demyelination of EAE rats. On one hand, erhuangfang can regulate reaction of astrocyte in two ways, relieve reaction and proliferation of astrocyte in non-focal region and maintain the protective effect of astrocyte on brain tissue in focal region; on the other hand, hormone can overall inhibit reaction of astrocyte.
基金the National Natural Science Foundation of China,No. 30873230Beijing Natural Science Foundation,No. 7092014+1 种基金Scientific Research Common Program of Beijing Municipal Education Commission,No. KM2007100025015Fund-ing Project for Academic Human Resources Devel-opment in Institutions of Higher Learning Under the Jurisdiction of Beijing Mu-nicipality,No. PHR201008401
文摘Studies have demonstrated that amyloid precursor protein （APP） expression increases in multiple sclerosis tissues during acutely and chronically active stages. To determine the relationship between axonal injury and regeneration in multiple sclerosis, an animal model of experimental autoimmune encephalomyelitis was induced using different doses of myelin basic protein peptide. APP and growth-associated protein 43 （GAP-43）, which is considered a specific marker of neural regeneration, were assessed by western blot analysis. Expression of APP and GAP-43, as well as the correlation between these two proteins, in brain white matter and spinal cord tissues of experimental autoimmune encephalomyelitis rats at different pathological stages was analyzed. Results showed that APP and GAP-43 expression increased during the acute stage and decreased during remission, with a positive correlation between APP and GAP-43 expression in brain white matter and spinal cord tissues. These results suggest that APP and GAP-43 could provide nutritional and protective effects on damaged neurons.
基金supported by Multiple Sclerosis Research Australia and Trish Multiple Sclerosis Research Foundation Postgraduate Scholarship(to JYL)the National Multiple Sclerosis Society Project Grant#RG4398A1/1+2 种基金International Progressive Multiple Sclerosis Alliance Challenge Award#PA0065Multiple Sclerosis Research Australia and Trish Multiple Sclerosis Research Foundation#15-022Bethlehem Griffiths Research Foundation#BGRF1706(to SP)
文摘Myelin-associated inhibitory factors within the central nervous system（CNS） are considered to be one of the main obstacles for axonal regeneration following disease or injury. The nogo receptor 1（NgR1） has been well documented to play a key role in limiting axonal regrowth in the injured and diseased mammalian CNS. However, the role of nogo receptor in immune cell activation during CNS inflammation is yet to be mechanistically elucidated. Microglia/macrophages are immune cells that are regarded as pathogenic contributors to inflammatory demyelinating lesions in multiple sclerosis（MS）. In this study, the animal model of MS, experimental autoimmune encephalomyelitis（EAE） was induced in ngr1^＋/＋ and ngr1^–/– female mice following injection with the myelin oligodendrocyte glycoprotein（MOG_（35–55）） peptide. A fatemap analysis of microglia/macrophages was performed throughout spinal cord sections of EAE-induced mice at clinical scores of 0, 1, 2 and 3, respectively（increasing locomotor disability） from both genotypes, using the CD11 b and Iba1 cell markers. Western immunoblotting using lysates from isolated spinal cord microglia/macrophages, along with immunohistochemistry and flow cytometric analysis, was performed to demonstrate the expression of nogo receptor and its two homologs during EAE progression. Myelin protein engulfment during EAE progression in ngr1^＋/＋ and ngr1^–/– mice was demonstrated by western immunblotting of lysates from isolated spinal cord microglia/macrophages, detecting levels of Nogo-A and MOG. The numbers of M1 and M2 microglia/macrophage phenotypes present in the spinal cords of EAE-induced ngr1^＋/＋ and ngr1^–/– mice, were assessed by flow cytometric analysis using CD38 and Erg-2 markers. A significant difference in microglia/macrophage numbers between ngr1^＋/＋ and ngr1^–/– mice was identified during the progression of the clinical symptoms of EAE, in the white versus gray matter regions of the spinal cord. This difference was unrelated to the expression of Ng R on these macrophage/microglial cells. We have identified that as EAE progresses, the phagocytic activity of microglia/macrophages with myelin debris, in ngr1^–/– mice, was enhanced. Moreover, we show a modulation from a predominant M1-pathogenic to the M2-neurotrophic cell phenotype in the ngr1^–/– mice during EAE progression. These findings suggest that CNS-specific macrophages and microglia of ngr1^–/– mice may exhibit an enhanced capacity to clear inhibitory molecules that are sequestered in inflammatory lesions.
