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
Schizophrenia is a mental disease that mainly affects young individuals （15 to 35 years old） but its etiology remains largely undefined. Recently, accumulating evidence indicated that demyelination and/or dysfunctio...Schizophrenia is a mental disease that mainly affects young individuals （15 to 35 years old） but its etiology remains largely undefined. Recently, accumulating evidence indicated that demyelination and/or dysfunction of oligodendrocytes is an important feature of its pathogenesis. We hypothesized that the vulnerability of young individuals to demyelination may contribute to the onset of schizophrenia. In the present study, three different age cohorts of mice, i.e. juvenile （3 weeks）, young-adult （6 weeks） and middle-aged （8 months）, were subjected to a 6-week diet containing 0.2% cuprizone （CPZ） to create an animal model of acute demyelination. Then, age-related vulnerability to CPZ-induced demyelination, behavioral outcomes, and myelination-related molecular biological changes were assessed. We demonstrated： （1） CPZ treatment led to more severe demyelination in juvenile and young-adult mice than in middle-aged mice in the corpus callosum, a region closely associated with the pathophysiology of schizophrenia; （2） the higher levels of demyelination in juvenile and young-adult mice were correlated with a greater reduction of myelin basic protein, more loss of CC-1- positive mature oligodendrocytes, and higher levels of astrocyte activation; and （3） CPZ treatment resulted in a more prominent exploratory behavior deficit in juvenile and young-adult mice than in middle-aged mice. Together, our data demonstrate an age-relatedvulnerability to demyelination with a concurrent behavioral deficit, providing supporting evidence for better understanding the susceptibility of the young to the onset of schizophrenia.展开更多
Chronic long-term exposure to cuprizone causes severe brain demyelination in mice,which leads to changes in locomotion,working memory and anxiety.These findings suggest the importance of intact myelin for these behavi...Chronic long-term exposure to cuprizone causes severe brain demyelination in mice,which leads to changes in locomotion,working memory and anxiety.These findings suggest the importance of intact myelin for these behaviors.This study aimed to investigate the possible behavioral changes in mice with mild oligodendrocyte/myelin damage that parallels the white matter changes seen in the brains of patients with psychiatric disporders.We used the cuprizonetreated mouse model to test both tissue changes and behavioral functions（locomotor activity,anxiety status,and spatial working memory）.The results showed that mice given cuprizone in their diet for 7 days had no significant myelin breakdown as evaluated by immunohistochemical staining for myelin basic protein,while the number of mature oligodendrocytes was reduced.The number and length of Caspr protein clusters,a structural marker of the node of Ranvier,did not change.The locomotor activity of the cuprizonetreated mice increased whereas their anxiety levels were lower than in normal controls;spatial working memory,however,did not change.These results,for the first time,link emotion-related behavior with mild white matter damage in cuprizone-treated mice.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 demyelinati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
Induction of demyelination in the central nervous system （CNS） of experimental mice using cuprizone is widely used as an animal model for studying the pathogenesis and treatment of demyelination. How- ever, differen...Induction of demyelination in the central nervous system （CNS） of experimental mice using cuprizone is widely used as an animal model for studying the pathogenesis and treatment of demyelination. How- ever, different mouse strains used result in different pathological outcomes. Moreover, because current medicinal treatments are not always effective in multiple sclerosis patients, so the study of exogenous cell transplantation in an animal model is of great importance. The aims of the present study were to establish an alternative ICR outbred mouse model for studying demyelination and to evaluate the effects of intrave- nous cell transplantation in the present developed mouse model. Two sets of experiments were conducted. Firstly, ICR outbred and BALB/c inbred mice were fed with 0.2% cuprizone for 6 consecutive weeks; then demyelinating scores determined by luxol fast blue stain or immunolabeling with CNPase were evaluated. Secondly, attenuation of demyelination in ICR mice by intravenous injection of mES cells was studied. Scores for demyelination in the brains of ICR mice receiving cell injection （mES cells-injected group） and vehicle （sham-inoculated group） were assessed and compared. The results showed that cuprizone signifi- cantly induced demyelination in the cerebral cortex and corpus callosum of both ICR and BALB/c mice. Additionally, intravenous transplantation of mES cells potentially attenuated demyelination in ICR mice compared with sham-inoculated groups. The present study is among the earliest reports to describe the cuprizone-induced demyelination in ICR outbred mice. Although it remains unclear whether mES cells or trophic effects from mES cells are the cause of enhanced remyelination, the results of the present study may shed some light on exogenous cell therapy in central nervous system demyelinating diseases.展开更多
Multiple sclerosis is 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
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。
基金supported by the National Natural Science Foundation of China (81071084)the International Science &Technology Cooperation Program of China (2010DFB30820)the Natural Science Foundation of Chongqing Municipality, China(2010DBF30820)
文摘Schizophrenia is a mental disease that mainly affects young individuals （15 to 35 years old） but its etiology remains largely undefined. Recently, accumulating evidence indicated that demyelination and/or dysfunction of oligodendrocytes is an important feature of its pathogenesis. We hypothesized that the vulnerability of young individuals to demyelination may contribute to the onset of schizophrenia. In the present study, three different age cohorts of mice, i.e. juvenile （3 weeks）, young-adult （6 weeks） and middle-aged （8 months）, were subjected to a 6-week diet containing 0.2% cuprizone （CPZ） to create an animal model of acute demyelination. Then, age-related vulnerability to CPZ-induced demyelination, behavioral outcomes, and myelination-related molecular biological changes were assessed. We demonstrated： （1） CPZ treatment led to more severe demyelination in juvenile and young-adult mice than in middle-aged mice in the corpus callosum, a region closely associated with the pathophysiology of schizophrenia; （2） the higher levels of demyelination in juvenile and young-adult mice were correlated with a greater reduction of myelin basic protein, more loss of CC-1- positive mature oligodendrocytes, and higher levels of astrocyte activation; and （3） CPZ treatment resulted in a more prominent exploratory behavior deficit in juvenile and young-adult mice than in middle-aged mice. Together, our data demonstrate an age-relatedvulnerability to demyelination with a concurrent behavioral deficit, providing supporting evidence for better understanding the susceptibility of the young to the onset of schizophrenia.
基金supported by the Manitoba Health Research Council Foundationthe Canadian Institutes of Health Research Foundationthe Health Science Centre Foundation
文摘Chronic long-term exposure to cuprizone causes severe brain demyelination in mice,which leads to changes in locomotion,working memory and anxiety.These findings suggest the importance of intact myelin for these behaviors.This study aimed to investigate the possible behavioral changes in mice with mild oligodendrocyte/myelin damage that parallels the white matter changes seen in the brains of patients with psychiatric disporders.We used the cuprizonetreated mouse model to test both tissue changes and behavioral functions（locomotor activity,anxiety status,and spatial working memory）.The results showed that mice given cuprizone in their diet for 7 days had no significant myelin breakdown as evaluated by immunohistochemical staining for myelin basic protein,while the number of mature oligodendrocytes was reduced.The number and length of Caspr protein clusters,a structural marker of the node of Ranvier,did not change.The locomotor activity of the cuprizonetreated mice increased whereas their anxiety levels were lower than in normal controls;spatial working memory,however,did not change.These results,for the first time,link emotion-related behavior with mild white matter damage in cuprizone-treated mice.
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 demyelinati
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.
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.
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.
