目的比较2种神经髓鞘染色方法在Cuprizone小鼠模型脑组织中脱髓鞘的形态学变化,为实验诊断提供病理依据。方法将Cuprizone掺入饲料中喂食小鼠4周,造成神经脱髓鞘模型。取脑后切片,分别用牢固蓝(Luxol Fast Blue)和油红O两种染色方法观...目的比较2种神经髓鞘染色方法在Cuprizone小鼠模型脑组织中脱髓鞘的形态学变化,为实验诊断提供病理依据。方法将Cuprizone掺入饲料中喂食小鼠4周,造成神经脱髓鞘模型。取脑后切片,分别用牢固蓝(Luxol Fast Blue)和油红O两种染色方法观察脑纹状体和海马两个切面胼胝体髓鞘脱失变化。结果牢固蓝和油红O两种染色方法均可显示Cuprizone模型小鼠脑内胼胝体部位有脱髓鞘发生,但在纹状体切面油红O染色法能清晰显示髓鞘脱失和炎性细胞浸润,而牢固蓝染色法显示髓鞘脱失与周围组织结构界限不明显。结论与牢固蓝染色法相比,油红O染色法能更清晰显示脱髓鞘,颜色对比明显,是一种简单易行的神经髓鞘染色方法。展开更多
This study aimed to analyze the regulatory role of Sox10 in remyelination of the hippocampus in a demyelination mouse model.Mice were fed with 0.2%cuprizone(CPZ)for six weeks to.establish the acute demyelinating model...This study aimed to analyze the regulatory role of Sox10 in remyelination of the hippocampus in a demyelination mouse model.Mice were fed with 0.2%cuprizone(CPZ)for six weeks to.establish the acute demyelinating model.Behavioral changes of these mice were assessed via open field and tail suspension tests.The ultrastructure of the myelin sheaths in the hippocampus was observed by transmission electron microscopy.The expression levels of myelin sheath-related proteins and the transcription factor Sox10 were detected with immunohistochemistry and Western blotting.Furthermore,Soxl0-overexpressing adeno-associated viras was injected into the hippocampus after esta blishing the demyelinating model to investigate effects of Sox10 on remyelination.CPZ mice showed abnormal behavioral changes,a large number of pathological changes in the myelin sheaths,and significantly reduced protein expression of the myelin sheath markers.The protein expression of(the oligodendrocyte precursor cell marker)NG2 increased,whereas Sox10 expression decreased.After Sox10 overexpression,the abnormal behavior was improved,the ultrastructure of the myelin sheaths was restored,and the expression of myelin sheath protein was reversed.展开更多
Oligodendrocytes play a critical role in neuroprotection by both remyelination-dependent and remyelination-independent mechanisms and confer protection in both inflammatory and degenerative diseases that involve the c...Oligodendrocytes play a critical role in neuroprotection by both remyelination-dependent and remyelination-independent mechanisms and confer protection in both inflammatory and degenerative diseases that involve the central nervous system,including multiple sclerosis,Alzheimer’s disease and potentially Parkinson’s disease.1,2,3,4 Although accumulating data have supported a major role for inflammation in the susceptibility of oligodendrocytes to cuprizone,the molecular pathways that regulate oligodendrocyte survival have not been well established.Here,we report that the targeted mutation of either Cd24 or Siglecg,which forms an axis that selectively regulates the innate inflammatory response to danger-associated molecular patterns(DAMPs),protects mice against cuprizone-induced oligodendrocyte loss.Moreover,the systemic administration of CD24Fc,which is known to stimulate Siglec G signaling and suppress the inflammatory response in vivo,protects oligodendrocytes against chronic exposure to cuprizone.Our data suggest that the host response to cellular injury actively participates in oligodendrocyte loss and provides a new approach to maintain oligodendrocytes under pathological conditions.展开更多
M ultiple sclerosis is a chro nic central nervous system demyelinating disease whose onset and progression are driven by a combination of immune dysregulation,genetic predisposition,and environmental fa ctors.The acti...M ultiple sclerosis is a chro nic central nervous system demyelinating disease whose onset and progression are driven by a combination of immune dysregulation,genetic predisposition,and environmental fa ctors.The activation of microglia and astrocytes is a key player in multiple sclerosis immunopathology,playing specific roles associated with anatomical location and phase of the disease and controlling demyelination and neurodegeneration.Even though reactive mic roglia can damage tissue and heighten deleterious effects and neurodegeneration,activated microglia also perform neuroprotective functions such as debris phagocytosis and growth fa ctor secretion.Astrocytes can be activated into pro-inflammato ry phenotype A1 through a mechanism mediated by activated neuroinflammatory microglia,which could also mediate neurodegeneration.This A1 phenotype inhibits oligodendrocyte prolife ration and differe ntiation and is toxic to both oligodendrocytes and neurons.Howeve r,astroglial activation into phenotype A2 may also take place in response to neurodegeneration and as a protective mechanism.A variety of animal models mimicking specific multiple sclerosis features and the associated pathophysiological processes have helped establish the cascades of events that lead to the initiation,progression,and resolution of the disease.The colonystimulating facto r-1 receptor is expressed by myeloid lineage cells such as peripheral monocytes and macrophages and central nervous system microglia.Importantly,as microglia development and survival critically rely on colony-stimulating factor-1 receptor signaling,colony-stimulating factor-1 receptor inhibition can almost completely eliminate microglia from the brain.In this context,the present review discusses the impact of microglial depletion through colo ny-stimulating factor-1 receptor inhibition on demyelination,neurodegeneration,astroglial activation,and behavior in different multiple sclerosis models,highlighting the diversity of microglial effects on the progression of demyelinating diseases and the strengths and weaknesses of microglial modulation in therapy design.展开更多
Multiple sclerosis is a multifactorial chronic inflammatory disease of the central nervous system that leads to demyelination and neuronal cell death,resulting in functional disability.Remyelination is the natural rep...Multiple sclerosis is a multifactorial chronic inflammatory disease of the central nervous system that leads to demyelination and neuronal cell death,resulting in functional disability.Remyelination is the natural repair process of demyelination,but it is often incomplete or fails in multiple sclerosis.Available therapies reduce the inflammatory state and prevent clinical relapses.However,therapeutic approaches to increase myelin repair in humans are not yet available.The substance cytidine-5′-diphosphocholine,CDP-choline,is ubiquitously present in eukaryotic cells and plays a crucial role in the synthesis of cellular phospholipids.Regenerative properties have been shown in various animal models of diseases of the central nervous system.We have already shown that the compound CDPcholine improves myelin regeneration in two animal models of multiple sclerosis.However,the results from the animal models have not yet been studied in patients with multiple sclerosis.In this review,we summarise the beneficial effects of CDP-choline on biolipid metabolism and turnover with regard to inflammatory and regenerative processes.We also explain changes in phospholipid and sphingolipid homeostasis in multiple sclerosis and suggest a possible therapeutic link to CDP-choline.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. However, different mou...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. However, 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 intravenous 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 m ES cells was studied. Scores for demyelination in the brains of ICR mice receiving cell injection(m ES cells-injected group) and vehicle(sham-inoculated group) were assessed and compared. The results showed that cuprizone significantly induced demyelination in the cerebral cortex and corpus callosum of both ICR and BALB/c mice. Additionally, intravenous transplantation of m ES 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 m ES cells or trophic effects from m ES 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
Copper is a transition metal and an essential element for the organism,as alterations in its homeostasis leading to metal accumulation or deficiency have pathological effects in several organs,including the central ne...Copper is a transition metal and an essential element for the organism,as alterations in its homeostasis leading to metal accumulation or deficiency have pathological effects in several organs,including the central nervous system.Central copper dysregulations have been evidenced in two genetic disorders characterized by mutations in the copper-ATPases ATP7A and ATP7B,Menkes disease and Wilson’s disease,respectively,and also in multifactorial neurological disorders such as Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,and multiple sclerosis.This review summarizes current knowledge about the role of copper in central nervous system physiology and pathology,reports about unbalances in copper levels and/or distribution under disease,describes relevant animal models for human disorders where copper metabolism genes are dysregulated,and discusses relevant therapeutic approaches modulating copper availability.Overall,alterations in copper metabolism may contribute to the etiology of central nervous system disorders and represent relevant therapeutic targets to restore tissue homeostasis.展开更多
文摘目的比较2种神经髓鞘染色方法在Cuprizone小鼠模型脑组织中脱髓鞘的形态学变化,为实验诊断提供病理依据。方法将Cuprizone掺入饲料中喂食小鼠4周,造成神经脱髓鞘模型。取脑后切片,分别用牢固蓝(Luxol Fast Blue)和油红O两种染色方法观察脑纹状体和海马两个切面胼胝体髓鞘脱失变化。结果牢固蓝和油红O两种染色方法均可显示Cuprizone模型小鼠脑内胼胝体部位有脱髓鞘发生,但在纹状体切面油红O染色法能清晰显示髓鞘脱失和炎性细胞浸润,而牢固蓝染色法显示髓鞘脱失与周围组织结构界限不明显。结论与牢固蓝染色法相比,油红O染色法能更清晰显示脱髓鞘,颜色对比明显,是一种简单易行的神经髓鞘染色方法。
文摘This study aimed to analyze the regulatory role of Sox10 in remyelination of the hippocampus in a demyelination mouse model.Mice were fed with 0.2%cuprizone(CPZ)for six weeks to.establish the acute demyelinating model.Behavioral changes of these mice were assessed via open field and tail suspension tests.The ultrastructure of the myelin sheaths in the hippocampus was observed by transmission electron microscopy.The expression levels of myelin sheath-related proteins and the transcription factor Sox10 were detected with immunohistochemistry and Western blotting.Furthermore,Soxl0-overexpressing adeno-associated viras was injected into the hippocampus after esta blishing the demyelinating model to investigate effects of Sox10 on remyelination.CPZ mice showed abnormal behavioral changes,a large number of pathological changes in the myelin sheaths,and significantly reduced protein expression of the myelin sheath markers.The protein expression of(the oligodendrocyte precursor cell marker)NG2 increased,whereas Sox10 expression decreased.After Sox10 overexpression,the abnormal behavior was improved,the ultrastructure of the myelin sheaths was restored,and the expression of myelin sheath protein was reversed.
文摘Oligodendrocytes play a critical role in neuroprotection by both remyelination-dependent and remyelination-independent mechanisms and confer protection in both inflammatory and degenerative diseases that involve the central nervous system,including multiple sclerosis,Alzheimer’s disease and potentially Parkinson’s disease.1,2,3,4 Although accumulating data have supported a major role for inflammation in the susceptibility of oligodendrocytes to cuprizone,the molecular pathways that regulate oligodendrocyte survival have not been well established.Here,we report that the targeted mutation of either Cd24 or Siglecg,which forms an axis that selectively regulates the innate inflammatory response to danger-associated molecular patterns(DAMPs),protects mice against cuprizone-induced oligodendrocyte loss.Moreover,the systemic administration of CD24Fc,which is known to stimulate Siglec G signaling and suppress the inflammatory response in vivo,protects oligodendrocytes against chronic exposure to cuprizone.Our data suggest that the host response to cellular injury actively participates in oligodendrocyte loss and provides a new approach to maintain oligodendrocytes under pathological conditions.
文摘M ultiple sclerosis is a chro nic central nervous system demyelinating disease whose onset and progression are driven by a combination of immune dysregulation,genetic predisposition,and environmental fa ctors.The activation of microglia and astrocytes is a key player in multiple sclerosis immunopathology,playing specific roles associated with anatomical location and phase of the disease and controlling demyelination and neurodegeneration.Even though reactive mic roglia can damage tissue and heighten deleterious effects and neurodegeneration,activated microglia also perform neuroprotective functions such as debris phagocytosis and growth fa ctor secretion.Astrocytes can be activated into pro-inflammato ry phenotype A1 through a mechanism mediated by activated neuroinflammatory microglia,which could also mediate neurodegeneration.This A1 phenotype inhibits oligodendrocyte prolife ration and differe ntiation and is toxic to both oligodendrocytes and neurons.Howeve r,astroglial activation into phenotype A2 may also take place in response to neurodegeneration and as a protective mechanism.A variety of animal models mimicking specific multiple sclerosis features and the associated pathophysiological processes have helped establish the cascades of events that lead to the initiation,progression,and resolution of the disease.The colonystimulating facto r-1 receptor is expressed by myeloid lineage cells such as peripheral monocytes and macrophages and central nervous system microglia.Importantly,as microglia development and survival critically rely on colony-stimulating factor-1 receptor signaling,colony-stimulating factor-1 receptor inhibition can almost completely eliminate microglia from the brain.In this context,the present review discusses the impact of microglial depletion through colo ny-stimulating factor-1 receptor inhibition on demyelination,neurodegeneration,astroglial activation,and behavior in different multiple sclerosis models,highlighting the diversity of microglial effects on the progression of demyelinating diseases and the strengths and weaknesses of microglial modulation in therapy design.
文摘Multiple sclerosis is a multifactorial chronic inflammatory disease of the central nervous system that leads to demyelination and neuronal cell death,resulting in functional disability.Remyelination is the natural repair process of demyelination,but it is often incomplete or fails in multiple sclerosis.Available therapies reduce the inflammatory state and prevent clinical relapses.However,therapeutic approaches to increase myelin repair in humans are not yet available.The substance cytidine-5′-diphosphocholine,CDP-choline,is ubiquitously present in eukaryotic cells and plays a crucial role in the synthesis of cellular phospholipids.Regenerative properties have been shown in various animal models of diseases of the central nervous system.We have already shown that the compound CDPcholine improves myelin regeneration in two animal models of multiple sclerosis.However,the results from the animal models have not yet been studied in patients with multiple sclerosis.In this review,we summarise the beneficial effects of CDP-choline on biolipid metabolism and turnover with regard to inflammatory and regenerative processes.We also explain changes in phospholipid and sphingolipid homeostasis in multiple sclerosis and suggest a possible therapeutic link to CDP-choline.
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. However, 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 intravenous 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 m ES cells was studied. Scores for demyelination in the brains of ICR mice receiving cell injection(m ES cells-injected group) and vehicle(sham-inoculated group) were assessed and compared. The results showed that cuprizone significantly induced demyelination in the cerebral cortex and corpus callosum of both ICR and BALB/c mice. Additionally, intravenous transplantation of m ES 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 m ES cells or trophic effects from m ES 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.
文摘Copper is a transition metal and an essential element for the organism,as alterations in its homeostasis leading to metal accumulation or deficiency have pathological effects in several organs,including the central nervous system.Central copper dysregulations have been evidenced in two genetic disorders characterized by mutations in the copper-ATPases ATP7A and ATP7B,Menkes disease and Wilson’s disease,respectively,and also in multifactorial neurological disorders such as Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,and multiple sclerosis.This review summarizes current knowledge about the role of copper in central nervous system physiology and pathology,reports about unbalances in copper levels and/or distribution under disease,describes relevant animal models for human disorders where copper metabolism genes are dysregulated,and discusses relevant therapeutic approaches modulating copper availability.Overall,alterations in copper metabolism may contribute to the etiology of central nervous system disorders and represent relevant therapeutic targets to restore tissue homeostasis.
