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
BACKGROUND Hepatitis B rarely leads to demyelinating neuropathy,despite peripheral neuropathy being the first symptom of hepatitis B infection.CASE SUMMARY A 64-year-old man presented with sensorimotor symptoms in mul...BACKGROUND Hepatitis B rarely leads to demyelinating neuropathy,despite peripheral neuropathy being the first symptom of hepatitis B infection.CASE SUMMARY A 64-year-old man presented with sensorimotor symptoms in multiple peripheral nerves.Serological testing showed that these symptoms were due to hepatitis B.After undergoing treatment involving intravenous immunoglobulin and an antiviral agent,there was a notable improvement in his symptoms.CONCLUSION Although hepatitis B virus(HBV)infection is known to affect hepatocytes,it is crucial to recognize the range of additional manifestations linked to this infection.The connection between long-term HBV infection and demyelinating neuropathy has seldom been documented;hence,prompt diagnostic and treatment are essential.The patient's positive reaction to immunoglobulin seems to be associated with production of the antigen-antibody immune complex.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
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
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
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
Schwann cells,the myelinating glia of the peripheral nervous system,wrap axons multiple times to build their myelin sheath.Myelin is of paramount importance for axonal integrity and fast axon potential propagation.How...Schwann cells,the myelinating glia of the peripheral nervous system,wrap axons multiple times to build their myelin sheath.Myelin is of paramount importance for axonal integrity and fast axon potential propagation.However,myelin is lacking or dysfunctional in several neuropathies including demyelinating and dysmyelinating Charcot-M arie-To oth disease.Charcot-Marie-To oth disease represents the most prevalent inherited neuropathy in humans and is classified either as axonal,demyelinating or dysmyelinating,or as intermediate.The demyelinating or dysmyelinating forms of Charcot-Marie-Tooth disease constitute the majority of the disease cases and are most frequently due to mutations in the three following myelin genes:peripheral myelin protein 22,myelin protein ze ro and gap junction beta 1(coding for Connexin 32) causing Charcot-M arie-Tooth disease type 1A,Charcot-Marie-Tooth disease type 1B,and X-linked Charcot-M arie-Tooth disease type 1,respectively.The resulting perturbation of myelin structure and function leads to axonal demyelination or dysmyelination and causes severe disabilities in affected patients.No treatment to cure or slow down the disease progression is currently available on the market,howeve r,scientific discoveries led to a better understanding of the pathomechanisms of the disease and to potential treatment strategies.In this review,we describe the features and molecular mechanisms of the three main demyelinating or dysmyelinating forms of Charcot-Marie-Tooth disease,the rodent models used in research,and the emerging therapeutic approaches to cure or counteract the progression of the disease.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
Astrocytes are indispensable for central nervous system development and homeostasis.In response to injury and disease,astrocytes are integral to the immunological-and the,albeit limited,repair response.In this review,...Astrocytes are indispensable for central nervous system development and homeostasis.In response to injury and disease,astrocytes are integral to the immunological-and the,albeit limited,repair response.In this review,we will examine some of the functions reactive astrocytes play in the context of multiple sclerosis and related animal models.We will consider the heterogeneity or plasticity of astrocytes and the mechanisms by which they promote or mitigate demyelination.Finally,we will discuss a set of biomedical strategies that can stimulate astrocytes in their promyelinating response.展开更多
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.
文摘BACKGROUND Hepatitis B rarely leads to demyelinating neuropathy,despite peripheral neuropathy being the first symptom of hepatitis B infection.CASE SUMMARY A 64-year-old man presented with sensorimotor symptoms in multiple peripheral nerves.Serological testing showed that these symptoms were due to hepatitis B.After undergoing treatment involving intravenous immunoglobulin and an antiviral agent,there was a notable improvement in his symptoms.CONCLUSION Although hepatitis B virus(HBV)infection is known to affect hepatocytes,it is crucial to recognize the range of additional manifestations linked to this infection.The connection between long-term HBV infection and demyelinating neuropathy has seldom been documented;hence,prompt diagnostic and treatment are essential.The patient's positive reaction to immunoglobulin seems to be associated with production of the antigen-antibody immune complex.
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supported by the Deutsche Forschungsgemeinshaft (to CJ)。
文摘Schwann cells,the myelinating glia of the peripheral nervous system,wrap axons multiple times to build their myelin sheath.Myelin is of paramount importance for axonal integrity and fast axon potential propagation.However,myelin is lacking or dysfunctional in several neuropathies including demyelinating and dysmyelinating Charcot-M arie-To oth disease.Charcot-Marie-To oth disease represents the most prevalent inherited neuropathy in humans and is classified either as axonal,demyelinating or dysmyelinating,or as intermediate.The demyelinating or dysmyelinating forms of Charcot-Marie-Tooth disease constitute the majority of the disease cases and are most frequently due to mutations in the three following myelin genes:peripheral myelin protein 22,myelin protein ze ro and gap junction beta 1(coding for Connexin 32) causing Charcot-M arie-Tooth disease type 1A,Charcot-Marie-Tooth disease type 1B,and X-linked Charcot-M arie-Tooth disease type 1,respectively.The resulting perturbation of myelin structure and function leads to axonal demyelination or dysmyelination and causes severe disabilities in affected patients.No treatment to cure or slow down the disease progression is currently available on the market,howeve r,scientific discoveries led to a better understanding of the pathomechanisms of the disease and to potential treatment strategies.In this review,we describe the features and molecular mechanisms of the three main demyelinating or dysmyelinating forms of Charcot-Marie-Tooth disease,the rodent models used in research,and the emerging therapeutic approaches to cure or counteract the progression of the disease.
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supported by the Heart and Stroke Foundation and Ontario Institute of Regenerative Medicine (New Ideas Grant)Canada First Research Excellence Fund(Medicine by Design)+2 种基金the National Sciences and Engineering Research Councilthe Jurgen Manchot Foundationthe Christiane and Claudia Hempel Foundation for Clinical Stem Cell Research and the James and Elisabeth Cloppenburg,Peek and Cloppenburg Düsseldorf Stiftung (to PK)
文摘Astrocytes are indispensable for central nervous system development and homeostasis.In response to injury and disease,astrocytes are integral to the immunological-and the,albeit limited,repair response.In this review,we will examine some of the functions reactive astrocytes play in the context of multiple sclerosis and related animal models.We will consider the heterogeneity or plasticity of astrocytes and the mechanisms by which they promote or mitigate demyelination.Finally,we will discuss a set of biomedical strategies that can stimulate astrocytes in their promyelinating response.
