Demyelination and remyelination play key roles in spinal cord injury(SCI),affecting the recovery of motor and sensory functions.Research in rodent models is extensive,but the study of these processes in non-human prim...Demyelination and remyelination play key roles in spinal cord injury(SCI),affecting the recovery of motor and sensory functions.Research in rodent models is extensive,but the study of these processes in non-human primates is limited.Therefore,our goal was to thoroughly study the histological features of demyelination and remyelination after contusion injury of the cervical spinal cord in Macaca fascicularis.In a previous study,we created an SCI model in M.fascicularis by controlling the contusion displacement.We used Eriochrome Cyanine staining,immunohistochemical analysis,and toluidine blue staining to evaluate demyelination and remyelination.The results showed demyelination ipsilateral to the injury epicenter both rostrally and caudally,the former mainly impacting sensory pathways,while the latter primarily affected motor pathways.Toluidine blue staining showed myelin loss and axonal distension at the injury site.Schwann cell-derived myelin sheaths were only found at the center,while thinner myelin sheaths from oligodendrocytes were seen at the center and surrounding areas.Our study showed that long-lasting demyelination occurs in the spinal cord of M.fascicularis after SCI,with oligodendrocytes and Schwann cells playing a significant role in myelin sheath formation at the injury site.展开更多
Chronic cerebral hypoperfusion is one of the pathophysiological mechanisms contributing to cognitive decline by causing white matter injury.Microglia phagocytosing myelin debris in a timely manner can promote remyelin...Chronic cerebral hypoperfusion is one of the pathophysiological mechanisms contributing to cognitive decline by causing white matter injury.Microglia phagocytosing myelin debris in a timely manner can promote remyelination and contribute to the repair of white matter.However,milk fat globule-epidermal growth factor-factor 8(MFG-E8),a microglial phagocytosis-related protein,has not been well studied in hypoperfusion-related cognitive dysfunction.We found that the expression of MFG-E8 was significantly decreased in the brain of mice after bilateral carotid artery stenosis(BCAS).MFG-E8 knockout mice demonstrated more severe BCAS-induced cognitive impairments in the behavioral tests.In addition,we discovered that the deletion of MFG-E8 aggravated white matter damage and the destruction of myelin microstructure through fluorescent staining and electron microscopy.Meanwhile,MFG-E8 overexpression by AAV improved white matter injury and increased the number of mature oligodendrocytes after BCAS.Moreover,in vitro and in vivo experiments showed that MFG-E8 could enhance the phagocytic function of microglia via theαVβ3/αVβ5/Rac1 pathway and IGF-1 production to promote the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes.Interestingly,we found that MFG-E8 was mainly derived from astrocytes,not microglia.Our findings suggest that MFG-E8 is a potential therapeutic target for cognitive impairments following cerebral hypoperfusion.展开更多
Oligodencrocytes（OLs） are the main glial cells of the central nervous system involved in myelination of axons. In multiple sclerosis（MS）, there is an imbalance between demyelination and remyelination processes, th...Oligodencrocytes（OLs） are the main glial cells of the central nervous system involved in myelination of axons. In multiple sclerosis（MS）, there is an imbalance between demyelination and remyelination processes, the last one performed by oligodendrocyte progenitor cells（OPCs） and OLs, resulting into a permanent demyelination, axonal damage and neuronal loss. In MS lesions, astrocytes and microglias play an important part in permeabilization of blood-brain barrier and initiation of OPCs proliferation. Migration and differentiation of OPCs are influenced by various factors and the process is finalized by insufficient acummulation of OLs into the MS lesion. In relation to all these processes, the author will discuss the potential targets for remyelination strategies.展开更多
Axon regeneration and remyelination of the damaged region is the most common repair strategy for spinal cord injury.However,achieving good outcome remains difficult.Our previous study showed that porcine decellularize...Axon regeneration and remyelination of the damaged region is the most common repair strategy for spinal cord injury.However,achieving good outcome remains difficult.Our previous study showed that porcine decellularized optic nerve better mimics the extracellular matrix of the embryonic porcine optic nerve and promotes the directional growth of dorsal root ganglion neurites.However,it has not been reported whether this material promotes axonal regeneration in vivo.In the present study,a porcine decellularized optic nerve was seeded with neurotrophin-3-overexpressing Schwann cells.This functional scaffold promoted the directional growth and remyelination of regenerating axons.In vitro,the porcine decellularized optic nerve contained many straight,longitudinal channels with a uniform distribution,and microscopic pores were present in the channel wall.The spatial micro topological structure and extracellular matrix were conducive to the adhesion,survival and migration of neural stem cells.The scaffold promoted the directional growth of dorsal root ganglion neurites,and showed strong potential for myelin regeneration.Furthermore,we transplanted the porcine decellularized optic nerve containing neurotrophin-3-overexpressing Schwann cells in a rat model of T10 spinal cord defect in vivo.Four weeks later,the regenerating axons grew straight,the myelin sheath in the injured/transplanted area recovered its structure,and simultaneously,the number of inflammatory cells and the expression of chondroitin sulfate proteoglycans were reduced.Together,these findings suggest that porcine decellularized optic nerve loaded with Schwann cells overexpressing neurotrophin-3 promotes the directional growth of regenerating spinal cord axons as well as myelin regeneration.All procedures involving animals were conducted in accordance with the ethical standards of the Institutional Animal Care and Use Committee of Sun Yat-sen University(approval No.SYSU-IACUC-2019-B034)on February 28,2019.展开更多
The obstacle to successful remyelination in demyelinating diseases, such as multiple sclerosis, mainly lies in the inability of oligodendrocyte precursor cells(OPCs) to differentiate, since OPCs and oligodendrocytelin...The obstacle to successful remyelination in demyelinating diseases, such as multiple sclerosis, mainly lies in the inability of oligodendrocyte precursor cells(OPCs) to differentiate, since OPCs and oligodendrocytelineage cells that are unable to fully differentiate are found in the areas of demyelination. Thus, promoting the differentiation of OPCs is vital for the treatment of demyelinating diseases. Shikimic acid(SA) is mainly derived from star anise, and is reported to have antiinfluenza, anti-oxidation, and anti-tumor effects. In the present study, we found that SA significantly promoted the differentiation of cultured rat OPCs without affecting their proliferation and apoptosis. In mice, SA exerted therapeutic effects on experimental autoimmune encephalomyelitis(EAE), such as alleviating clinical EAE scores, inhibiting inflammation, and reducing demyelination in the CNS. SA also promoted the differentiation of OPCs as well as their remyelination after lysolecithin-induced demyelination.Furthermore, we showed that the promotion effect of SA on OPC differentiation was associated with the up-regulation of phosphorylated m TOR. Taken together, our resultsdemonstrated that SA could act as a potential drug candidate for the treatment of demyelinating diseases.展开更多
The differentiation and maturation of oligodendrocyte precursor cells(OPCs) is essential for myelination and remyelination in the CNS. The failure of OPCs to achieve terminal differentiation in demyelinating lesions o...The differentiation and maturation of oligodendrocyte precursor cells(OPCs) is essential for myelination and remyelination in the CNS. The failure of OPCs to achieve terminal differentiation in demyelinating lesions often results in unsuccessful remyelination in a variety of human demyelinating diseases. However, the molecular mechanisms controlling OPC differentiation under pathological conditions remain largely unknown. Myt1 L(myelin transcription factor 1-like), mainly expressed in neurons,has been associated with intellectual disability, schizophrenia, and depression. In the present study, we found that Myt1 L was expressed in oligodendrocyte lineage cells during myelination and remyelination. The expression level of Myt1 L in neuron/glia antigen 2-positive(NG2+)OPCs was significantly higher than that in mature CC1+oligodendrocytes. In primary cultured OPCs,overexpression of Myt1 L promoted, while knockdown inhibited OPC differentiation. Moreover, Myt1 L was potently involved in promoting remyelination after lysolecithin-induced demyelination in vivo. Ch IP assays showed that Myt1 L bound to the promoter of Olig1 and transcriptionally regulated Olig1 expression. Taken together, our findings demonstrate that Myt1 L is an essential regulator of OPC differentiation, thereby supporting Myt1 L as a potential therapeutic target for demyelinating diseases.展开更多
Rosmarinic acid,a common ester extracted from Rosemary,Perilla frutescens,and Salvia miltiorrhiza Bunge,has been shown to have protective effects against various diseases.This is an investigation into whether rosmarin...Rosmarinic acid,a common ester extracted from Rosemary,Perilla frutescens,and Salvia miltiorrhiza Bunge,has been shown to have protective effects against various diseases.This is an investigation into whether rosmarinic acid can also affect the changes of white matter fibers and cognitive deficits caused by hypoxic injury.The right common carotid artery of 3-day-old rats was ligated for 2 hours.The rats were then prewarmed in a plastic container with holes in the lid,which was placed in 37°C water bath for 30 minutes.Afterwards,the rats were exposed to an atmosphere with 8% O2 and 92% N2 for 30 minutes to establish the perinatal hypoxia/ischemia injury models.The rat models were intraperitoneally injected with rosmarinic acid 20 mg/kg for 5 consecutive days.At 22 days after birth,rosmarinic acid was found to improve motor,anxiety,learning and spatial memory impairments induced by hypoxia/ischemia injury.Furthermore,rosmarinic acid promoted the proliferation of oligodendrocyte progenitor cells in the subventricular zone.After hypoxia/ischemia injury,rosmarinic acid reversed to some extent the downregulation of myelin basic protein and the loss of myelin sheath in the corpus callosum of white matter structure.Rosmarinic acid partially slowed down the expression of oligodendrocyte marker Olig2 and myelin basic protein and the increase of oligodendrocyte apoptosis marker inhibitors of DNA binding 2.These data indicate that rosmarinic acid ameliorated the cognitive dysfunction after perinatal hypoxia/ischemia injury by improving remyelination in corpus callosum.This study was approved by the Animal Experimental Ethics Committee of Xuzhou Medical University,China (approval No.20161636721) on September 16,2017.展开更多
The massive loss of oligodendrocytes caused by various pathological factors is a basic feature of many demyelinating diseases of the central nervous system(CNS). Based on a variety of studies, it is now well establish...The massive loss of oligodendrocytes caused by various pathological factors is a basic feature of many demyelinating diseases of the central nervous system(CNS). Based on a variety of studies, it is now well established that impairment of oligodendrocyte precursor cells(OPCs) to differentiate and remyelinate axons is a vital event in the failed treatment of demyelinating diseases. Recent evidence suggests that Foxg1 is essential for the proliferation of certain precursors and inhibits premature neurogenesis during brain development. To date, very little attention has been paid to the role of Foxg1 in the proliferation and differentiation of OPCs in demyelinating diseases of the CNS. Here, for the first time, we examined the effects of Foxg1 on demyelination and remyelination in the brain using a cuprizone(CPZ)-induced mouse model. In this work, 7-week-old Foxg1 conditional knockout and wild-type(WT) mice were fed a diet containing 0.2% CPZ w/w for 5 weeks, after which CPZ was withdrawn to enable remyelination. Our results demonstrated that, compared with WT mice, Foxg1-knockout mice exhibited not only alleviated demyelination but also accelerated remyelination of the demyelinated corpus callosum. Furthermore, we found that Foxg1 knockout decreased the proliferation of OPCs and accelerated their differentiation into mature oligodendrocytes both in vivo and in vitro. Wnt signaling plays a critical role in development and in a variety of diseases. GSK-3 b, a key regulatory kinase in the Wnt pathway, regulates the ability of b-catenin to enter nuclei, where it activates the expression of Wnt target genes. We then used SB216763,a selective inhibitor of GSK-3 b activity, to further demonstrate the regulatory mechanism by which Foxg1 affects OPCs in vitro. The results showed that SB216763 clearly inhibited the expression of GSK-3 b, which abolished the effect of the proliferation and differentiation of OPCs caused by the knockdown of Foxg1. These results suggest that Foxg1 is involved in the proliferation and differentiation of OPCs through the Wnt signaling pathway. The present experimental results are some of the first to suggest that Foxg1 is a new therapeutic target for the treatment of demyelinating diseases of the CNS.展开更多
Our previous study revealed that intragastric administration of naringin improved remyelination in rats with spinal cord injury and promoted the recovery of neurological function of the injured spinal cord.This study ...Our previous study revealed that intragastric administration of naringin improved remyelination in rats with spinal cord injury and promoted the recovery of neurological function of the injured spinal cord.This study sought to reveal the mechanisms by which naringin improves oligodendrocyte precursor cell differentiation and maturation,and promotes remyelination.Spinal cord injury was induced in rats by the weight-drop method.Naringin was intragastrically administered daily（20,40 mg/kg） for 4 weeks after spinal cord injury induction.Behavioral assessment,histopathological staining,immunofluorescence spectroscopy,ultrastructural analysis and biochemical assays were employed.Naringin treatment remarkably mitigated demyelination in the white matter,increased the quality of myelinated nerve fibers and myelin sheath thickness,promoted oligodendrocyte precursor cell differentiation by upregulating the expression of NKx2.2 and 2′3′-cyclic nucleotide 3′-phosphodiesterase,and inhibited β-catenin expression and glycogen synthase kinase-3β（GSK-3β） phosphorylation.These findings indicate that naringin treatment regulates oligodendrocyte precursor cell differentiation and promotes remyelination after spinal cord injury through the β-catenin/GSK-3β signaling pathway.展开更多
The exacerbation of progressive multiple sclerosis(MS)is closely associated with obstruction of the differentiation of oligodendrocyte progenitor cells(OPCs).To discover novel therapeutic compounds for enhancing remye...The exacerbation of progressive multiple sclerosis(MS)is closely associated with obstruction of the differentiation of oligodendrocyte progenitor cells(OPCs).To discover novel therapeutic compounds for enhancing remyelination by endogenous OPCs,we screened for myelin basic protein expression using cultured rat OPCs and a library of small-molecule compounds.One of the most effective drugs was pinocembrin,which remarkably promoted OPC differentiation and maturation without affecting cell proliferation and survival.Based on these in vitro effects,we further assessed the therapeutic effects of pinocembrin in animal models of demyelinating diseases.We demonstrated that pinocembrin significantly ameliorated the progression of experimental autoimmune encephalomyelitis(EAE)and enhanced the repair of demyelination in lysolectin-induced lesions.Further studies indicated that pinocembrin increased the phosphorylation level of mammalian target of rapamycin(mTOR).Taken together,our results demonstrated that pinocembrin promotes OPC differentiation and remyelination through the phosphorylated mTOR pathway,and suggest a novel therapeutic prospect for this natural flavonoid product in treating demyelinating diseases.展开更多
Multiple sclerosis is an autoimmune disease in which the immune system attacks the myelin sheath in the central nervous system.It is characterized by blood-brain barrier dysfunction throughout the course of multiple s...Multiple sclerosis is an autoimmune disease in which the immune system attacks the myelin sheath in the central nervous system.It is characterized by blood-brain barrier dysfunction throughout the course of multiple sclerosis, followed by the entry of immune cells and activation of local microglia and astrocytes.Glial cells(microglia, astrocytes, and oligodendrocyte lineage cells) are known as the important mediators of neuroinflammation, all of which play major roles in the pathogenesis of multiple sclerosis.Network communications between glial cells affect the activities of oligodendrocyte lineage cells and influence the demyelination-remyelination process.A finely balanced glial response may create a favorable lesion environment for efficient remyelination and neuroregeneration.This review focuses on glial response and neurodegeneration based on the findings from multiple sclerosis and major rodent demyelination models.In particular, glial interaction and molecular crosstalk are discussed to provide insights into the potential cell-and molecule-specific therapeutic targets to improve remyelination and neuroregeneration.展开更多
BACKGROUND： Acupuncture treatment on injured cerebral axons has shown to provide efficacy in clinical practice. It is unknown whether acupuncture produces therapeutic effects by protecting injured cerebral myelin in ...BACKGROUND： Acupuncture treatment on injured cerebral axons has shown to provide efficacy in clinical practice. It is unknown whether acupuncture produces therapeutic effects by protecting injured cerebral myelin in ischemic stroke. OBJECTIVE： To test whether acupuncture provides protection for injured cerebral myelin, based on quantitative data from cerebral ischemia-reperfusion rats, and to compare the effects of early and late acupuncture on serum myelin basic protein （MBP） content and remyelination of the ischemic internal capsule.DESIGN, TIME AND SETTING： A randomized, controlled experiment was performed at the Neurobiological Laboratory, Sichuan University from March 2005 to March 2006. MATERIALS： ＂Hua Tuo＂ Brand filiform needles were produced by the Medical Instrument Factory of Suzhou, China.METHODS： A total of 52 adult, healthy, male, Sprague Dawley rats were randomly assigned to four groups： control （n = 4）, model （n = 16）, early acupuncture （n = 16）, and late acupuncture （n = 16）. The focal cerebral ischemia-reperfusion model was established by middle cerebral artery occlusion in the right hemisphere using the modified thread embolism method in the latter three groups. Early and late acupuncture groups underwent acupuncture after ischemia for 30 minutes and 2 hours using the Xingnaokaiqiao needling method, respectively. Acupoints were ＂Neiguarf＇ （PC 6） and ＂Sanyinjiao＂ （SP 6） on the bilateral sides, as well as ＂Shuigou＇ （DU 26） and ＂Baihui＂ （DU 20） with stimulation for 1 minute at each acupoint. Acupuncture at all acupoints was performed two or three times while the needle was retained, once per day. No special handling was administered to the control clroup.MAIN OUTCOME MEASURES： For each group, remyelination of the internal capsule was observed by Pal-Weigert＇s myelin staining and serum MBP content was detected using enzyme-linked immunosorbent assay method on days 1,3, 5, and 7 following ischemia-reperfusion injury.RESULTS： Compared with the control group, massive demyelination of the internal capsule occurred, and serum MBP content increased in the model group （P 〈 0.05）. Compared with the model group, the extent of demyelination in the internal capsule was less distinct and serum MBP content was significantly less in the early and late acupuncture group （P 〈 0.01 ）. Compared with the late acupuncture group, serum MBP content reached a peak later and the peak value was less in the early acupuncture group. CONCLUSION： Results suggest that acupuncture exerts a protective effect on injured cerebral myelin in ischemia-reperfusion rats by reducing serum MBP content and promoting remyelination. The study also suggests that the effect of early acupuncture is superior to late acupuncture.展开更多
Remyelination plays a key role in functional recovery of axons after spinal cord injury.Glial cells are the most abundant cells in the central nervous system.When spinal cord injury occurs,many glial cells at the lesi...Remyelination plays a key role in functional recovery of axons after spinal cord injury.Glial cells are the most abundant cells in the central nervous system.When spinal cord injury occurs,many glial cells at the lesion site are immediately activated,and different cells differentially affect inflammatory reactions after injury.In this review,we aim to discuss the core role of oligodendrocyte precursor cells and crosstalk with the rest of glia and their subcategories in the remyelination process.Activated astrocytes influence proliferation,differentiation,and maturation of oligodendrocyte precursor cells,while activated microglia alter remyelination by regulating the inflammatory reaction after spinal cord injury.Understanding the interaction between oligodendrocyte precursor cells and the rest of glia is necessary when designing a therapeutic plan of remyelination after spinal cord injury.展开更多
BACKGROUND： The transcription factor Oligl is required for oligodendrocyte maturation and demyelinated lesion repair, and is a key regulator of myelinogenesis following ischemia. OBJECTIVE： To examine the efficacy o...BACKGROUND： The transcription factor Oligl is required for oligodendrocyte maturation and demyelinated lesion repair, and is a key regulator of myelinogenesis following ischemia. OBJECTIVE： To examine the efficacy of intraventricular injection of a recombinant adenovirus-expressing Oligl gene （Ad5-Oligl-eGFP） on oligodendrocyte maturation and myelin repair following focal cerebral ischemia. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Department of Neurology, Beijing Friendship Hospital Affiliated to Capital Medical University from January 2007 to March 2008. MATERIALS： Adenovirus and a recombinant adenovirus containing Oiigl gene （Ad5-Oligl） were provided by Vector Gene Technology, China. METHODS： All 50 rats were induced by middle cerebral artery occlusion. A total of 46 rats were successfully induced and were subsequently randomly assigned to a adenovirus （Ad5） group and recombinant adenovirus-expression Oligl gene （Ad5-Oligl） group, with 23 rats per group. One day after middle cerebral artery occlusion, either Ad5-Oligl-eGFP or Ad5-eGFP （10 μL, 2.3 ×10^11/mL） was injected into the lateral ventricle on the ischemic hemisphere. MAIN OUTCOME MEASURES： Adenovirus-mediated Oligl gene expression in vitro and in vivo was measured by reverse transcription-polymerase chain reaction and immunofluorescence, respectively. Myelin basic protein （MBP） levels were evaluated by Western Blot, immunostaining, and electron microscopy. RESULTS： Exogenous Oligl expression was measured at the periventricular zone of the lateral ventricle 1 day after Ad5-Oligl injection. In the Ad5-Oligl-treated group, MBP protein levels and average intensity of MBP-immunoreactivity （-ir） increased 28 days after middle cerebral artery occlusion, compared with the control group （P 〈 0.01, P 〈 0.05）. Furthermore, myelinated axonal numbers markedly increased following Ad5-Oligl treatment. CONCLUSION： The present data suggested that Ad5-Oligl gene therapy increased MBP expression and the number of remyelinating axons following cerebral ischemia.展开更多
Myelin plays important roles in vertebrates,ensuring the rapid propagation of action potentials and the long-term integrity of axons,but the molecular mechanisms of myelin formation remain poorly understood.Recent stu...Myelin plays important roles in vertebrates,ensuring the rapid propagation of action potentials and the long-term integrity of axons,but the molecular mechanisms of myelin formation remain poorly understood.Recent studies have demonstrated that myelination is regulated by the TYRO3,AXL（also known as UFO）and MERTK.展开更多
Background and early studies： Endogenous tri-potential neural stem cells （NSCs） exist in the adult mammalian central nervous system （CNS）. In the spinal cord, NSCs distribute throughout the entire cord, but exist...Background and early studies： Endogenous tri-potential neural stem cells （NSCs） exist in the adult mammalian central nervous system （CNS）. In the spinal cord, NSCs distribute throughout the entire cord, but exist predominately in white matter tracts. The phenotypic fate of these cells in white matter is glial, largely oligodendrocyte, but not neuronal.展开更多
Spinal cord injuries(SCI)usually result in impairment of axonal conduction and sensorimotor function.There are no effective therapy to completely repair SCI.Axonal demyelination is very common as a pathologic change i...Spinal cord injuries(SCI)usually result in impairment of axonal conduction and sensorimotor function.There are no effective therapy to completely repair SCI.Axonal demyelination is very common as a pathologic change in SCI,and demyelination partly contributes to neural function impairment.So,it may be reasonable that remyelination of demyelinated axons become one of effective therapeutic targets for SCI treatment. Demyelination involves myelin breakdown and loss of myelin-forming cells(oligodendrocytes).The death of oligodendrocytes plays a key role in axonal demyelination in SCI.Recently a number of studies demonstrate that cell replacements could facilitate axonal remyelination and restore axonal conductive func- tion.Thus,it is expected that myelinogenetic cell transplantation(oligodendroglial lineage)will have good prospect as an effective therapy to improve axonal remyelination and restore neural function for SCI treat- ment in the near future.展开更多
Multiple sclerosis (MS) and neuromyelitis optica (NMO) are inflammatory diseases of the central nervous system (CNS) resulting in CNS inflammation, infiltration of peripheral immune cells, loss of myelin and oligodend...Multiple sclerosis (MS) and neuromyelitis optica (NMO) are inflammatory diseases of the central nervous system (CNS) resulting in CNS inflammation, infiltration of peripheral immune cells, loss of myelin and oligodendrocytes, interruption of axonal communication, and neurologic deficits. Following oligodendrocyte injury, newly generated myelinating oligodendrocytes derived from oligodendrocyte progenitors (OPCs) may produce new myelin sheaths around denuded axons (remyelination) restoring neuronal function (Verden and Macklin, 2016). While remyelination is apparent in MS lesions, the process is often inefficient;in NMO, remyelination is even more limited.展开更多
This study was aimed to assess remyelination and axon regeneration of compounds using Hunter Biotech＇ s zebrafish MS models. Zebrafish at 2 day post fertilization （2 dpf） were treated with demyelinating agent ethid...This study was aimed to assess remyelination and axon regeneration of compounds using Hunter Biotech＇ s zebrafish MS models. Zebrafish at 2 day post fertilization （2 dpf） were treated with demyelinating agent ethidium bromide （EB） for 72 hours （hrs） to induce demyelination. After removing EB, demyelinated zebrafish were treated with test compounds for another 24 hrs; Compound effect on demyelination-associated motility was as- sessed using a video-track motion detector. We found that compounds 2 and 9 recovered motility in EB-induced de- myelinated zebrafish ; whereas compounds 2 and 9 had significant effect on motility. Compounds 2 and 9 were con- firmed by whole mount anti-myelin basic protein （anti-MBP） immunostainging, further supporting that demyelina- tion-associated motility assay （primary assay） in combination with Fluoro Myelin staining （secondary assay） is a reliable array of methods for relatively high throughput in vivo remyelinating drug screening and assessment.展开更多
Multiple sclerosis is a chronic companied by demyelination inflammatory disease that is ac- and axonal damage resulting in neurological deficits. Remyelination is the natural endogenous repair mechanism of demyelinate...Multiple sclerosis is a chronic companied by demyelination inflammatory disease that is ac- and axonal damage resulting in neurological deficits. Remyelination is the natural endogenous repair mechanism of demyelinated axons and it is supposed to protect axons/neurons from degeneration and thus the patient from progressive disability （Franklin and Ffrench-Constant, 2008）. Current therapeutics for patients with multiple sclerosis are to some extent very effective in inhibiting neuroinflamma- tion and demyelination. However, to date there are no substanc- es available that can enhance remyelination. Remyelination is the result of recruitment/proliferation of new oligodendrocyte precursor cells （OPC） and differentiation into mature myelin producing oligodendrocytes （Franklin and Ffrench-Constant, 2008）. These processes are supported by many factors and signals and failure at any stage might lead to repair failure. Strategies to enhance myelin repair are either the promotion of endogenous repair mechanisms via modulation of OPC prolif- eration and oligodendrocyte differentiation or the transplantion of myelinating cells into lesions. Due to the multiloculated pro- cess in multiple sclerosis and the ethical problems with the cell source, the latter is less favoured. The endogenous promotion of remvelination could be achieved by several approaches such as：展开更多
基金supported by the National Natural Science Foundation of China(81972064)the Guangdong Basic and Applied Basic Research Foundation(2021A1515111117,2020A1515011415).
文摘Demyelination and remyelination play key roles in spinal cord injury(SCI),affecting the recovery of motor and sensory functions.Research in rodent models is extensive,but the study of these processes in non-human primates is limited.Therefore,our goal was to thoroughly study the histological features of demyelination and remyelination after contusion injury of the cervical spinal cord in Macaca fascicularis.In a previous study,we created an SCI model in M.fascicularis by controlling the contusion displacement.We used Eriochrome Cyanine staining,immunohistochemical analysis,and toluidine blue staining to evaluate demyelination and remyelination.The results showed demyelination ipsilateral to the injury epicenter both rostrally and caudally,the former mainly impacting sensory pathways,while the latter primarily affected motor pathways.Toluidine blue staining showed myelin loss and axonal distension at the injury site.Schwann cell-derived myelin sheaths were only found at the center,while thinner myelin sheaths from oligodendrocytes were seen at the center and surrounding areas.Our study showed that long-lasting demyelination occurs in the spinal cord of M.fascicularis after SCI,with oligodendrocytes and Schwann cells playing a significant role in myelin sheath formation at the injury site.
基金supported by the National Natural Science Foundation of China(81801147 and 81971112).
文摘Chronic cerebral hypoperfusion is one of the pathophysiological mechanisms contributing to cognitive decline by causing white matter injury.Microglia phagocytosing myelin debris in a timely manner can promote remyelination and contribute to the repair of white matter.However,milk fat globule-epidermal growth factor-factor 8(MFG-E8),a microglial phagocytosis-related protein,has not been well studied in hypoperfusion-related cognitive dysfunction.We found that the expression of MFG-E8 was significantly decreased in the brain of mice after bilateral carotid artery stenosis(BCAS).MFG-E8 knockout mice demonstrated more severe BCAS-induced cognitive impairments in the behavioral tests.In addition,we discovered that the deletion of MFG-E8 aggravated white matter damage and the destruction of myelin microstructure through fluorescent staining and electron microscopy.Meanwhile,MFG-E8 overexpression by AAV improved white matter injury and increased the number of mature oligodendrocytes after BCAS.Moreover,in vitro and in vivo experiments showed that MFG-E8 could enhance the phagocytic function of microglia via theαVβ3/αVβ5/Rac1 pathway and IGF-1 production to promote the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes.Interestingly,we found that MFG-E8 was mainly derived from astrocytes,not microglia.Our findings suggest that MFG-E8 is a potential therapeutic target for cognitive impairments following cerebral hypoperfusion.
文摘Oligodencrocytes（OLs） are the main glial cells of the central nervous system involved in myelination of axons. In multiple sclerosis（MS）, there is an imbalance between demyelination and remyelination processes, the last one performed by oligodendrocyte progenitor cells（OPCs） and OLs, resulting into a permanent demyelination, axonal damage and neuronal loss. In MS lesions, astrocytes and microglias play an important part in permeabilization of blood-brain barrier and initiation of OPCs proliferation. Migration and differentiation of OPCs are influenced by various factors and the process is finalized by insufficient acummulation of OLs into the MS lesion. In relation to all these processes, the author will discuss the potential targets for remyelination strategies.
基金supported by grants from the National Key R&D Program of China,No.2017YFA0104704(to BQL)the Young Elite Scientist Sponsorship Program(YESS)by China Association for Science and Technology(CAST),No.2018QNRC001(to BQL)+1 种基金the Fundamental Research Funds for the Central Universities,China,No.18ykpy38(to BQL)the National Natural Science Foundation of China,Nos.81971157(to BQL),81891003(to YSZ).
文摘Axon regeneration and remyelination of the damaged region is the most common repair strategy for spinal cord injury.However,achieving good outcome remains difficult.Our previous study showed that porcine decellularized optic nerve better mimics the extracellular matrix of the embryonic porcine optic nerve and promotes the directional growth of dorsal root ganglion neurites.However,it has not been reported whether this material promotes axonal regeneration in vivo.In the present study,a porcine decellularized optic nerve was seeded with neurotrophin-3-overexpressing Schwann cells.This functional scaffold promoted the directional growth and remyelination of regenerating axons.In vitro,the porcine decellularized optic nerve contained many straight,longitudinal channels with a uniform distribution,and microscopic pores were present in the channel wall.The spatial micro topological structure and extracellular matrix were conducive to the adhesion,survival and migration of neural stem cells.The scaffold promoted the directional growth of dorsal root ganglion neurites,and showed strong potential for myelin regeneration.Furthermore,we transplanted the porcine decellularized optic nerve containing neurotrophin-3-overexpressing Schwann cells in a rat model of T10 spinal cord defect in vivo.Four weeks later,the regenerating axons grew straight,the myelin sheath in the injured/transplanted area recovered its structure,and simultaneously,the number of inflammatory cells and the expression of chondroitin sulfate proteoglycans were reduced.Together,these findings suggest that porcine decellularized optic nerve loaded with Schwann cells overexpressing neurotrophin-3 promotes the directional growth of regenerating spinal cord axons as well as myelin regeneration.All procedures involving animals were conducted in accordance with the ethical standards of the Institutional Animal Care and Use Committee of Sun Yat-sen University(approval No.SYSU-IACUC-2019-B034)on February 28,2019.
基金supported by the National Natural Science Foundation of China(31571066 and 31771129)the National Basic Research Development Program of China(2016YFA0100802)
文摘The obstacle to successful remyelination in demyelinating diseases, such as multiple sclerosis, mainly lies in the inability of oligodendrocyte precursor cells(OPCs) to differentiate, since OPCs and oligodendrocytelineage cells that are unable to fully differentiate are found in the areas of demyelination. Thus, promoting the differentiation of OPCs is vital for the treatment of demyelinating diseases. Shikimic acid(SA) is mainly derived from star anise, and is reported to have antiinfluenza, anti-oxidation, and anti-tumor effects. In the present study, we found that SA significantly promoted the differentiation of cultured rat OPCs without affecting their proliferation and apoptosis. In mice, SA exerted therapeutic effects on experimental autoimmune encephalomyelitis(EAE), such as alleviating clinical EAE scores, inhibiting inflammation, and reducing demyelination in the CNS. SA also promoted the differentiation of OPCs as well as their remyelination after lysolecithin-induced demyelination.Furthermore, we showed that the promotion effect of SA on OPC differentiation was associated with the up-regulation of phosphorylated m TOR. Taken together, our resultsdemonstrated that SA could act as a potential drug candidate for the treatment of demyelinating diseases.
基金supported by the International Cooperation and Exchange Program of the National Natural Science Foundation of China(81461138035)the National Natural Science Foundation of China(81371326,31571066,and 31371068)+2 种基金the National Basic Research Development Program of China(2016YFA0100802)the UK Medical Research Council(MR/M010503/1)the UK Multiple Sclerosis Society(33)
文摘The differentiation and maturation of oligodendrocyte precursor cells(OPCs) is essential for myelination and remyelination in the CNS. The failure of OPCs to achieve terminal differentiation in demyelinating lesions often results in unsuccessful remyelination in a variety of human demyelinating diseases. However, the molecular mechanisms controlling OPC differentiation under pathological conditions remain largely unknown. Myt1 L(myelin transcription factor 1-like), mainly expressed in neurons,has been associated with intellectual disability, schizophrenia, and depression. In the present study, we found that Myt1 L was expressed in oligodendrocyte lineage cells during myelination and remyelination. The expression level of Myt1 L in neuron/glia antigen 2-positive(NG2+)OPCs was significantly higher than that in mature CC1+oligodendrocytes. In primary cultured OPCs,overexpression of Myt1 L promoted, while knockdown inhibited OPC differentiation. Moreover, Myt1 L was potently involved in promoting remyelination after lysolecithin-induced demyelination in vivo. Ch IP assays showed that Myt1 L bound to the promoter of Olig1 and transcriptionally regulated Olig1 expression. Taken together, our findings demonstrate that Myt1 L is an essential regulator of OPC differentiation, thereby supporting Myt1 L as a potential therapeutic target for demyelinating diseases.
基金supported by the Natural Science Foundation of Jiangsu Province of China,No.BK20171180(to XRW)
文摘Rosmarinic acid,a common ester extracted from Rosemary,Perilla frutescens,and Salvia miltiorrhiza Bunge,has been shown to have protective effects against various diseases.This is an investigation into whether rosmarinic acid can also affect the changes of white matter fibers and cognitive deficits caused by hypoxic injury.The right common carotid artery of 3-day-old rats was ligated for 2 hours.The rats were then prewarmed in a plastic container with holes in the lid,which was placed in 37°C water bath for 30 minutes.Afterwards,the rats were exposed to an atmosphere with 8% O2 and 92% N2 for 30 minutes to establish the perinatal hypoxia/ischemia injury models.The rat models were intraperitoneally injected with rosmarinic acid 20 mg/kg for 5 consecutive days.At 22 days after birth,rosmarinic acid was found to improve motor,anxiety,learning and spatial memory impairments induced by hypoxia/ischemia injury.Furthermore,rosmarinic acid promoted the proliferation of oligodendrocyte progenitor cells in the subventricular zone.After hypoxia/ischemia injury,rosmarinic acid reversed to some extent the downregulation of myelin basic protein and the loss of myelin sheath in the corpus callosum of white matter structure.Rosmarinic acid partially slowed down the expression of oligodendrocyte marker Olig2 and myelin basic protein and the increase of oligodendrocyte apoptosis marker inhibitors of DNA binding 2.These data indicate that rosmarinic acid ameliorated the cognitive dysfunction after perinatal hypoxia/ischemia injury by improving remyelination in corpus callosum.This study was approved by the Animal Experimental Ethics Committee of Xuzhou Medical University,China (approval No.20161636721) on September 16,2017.
基金supported by the National Natural Science Foundation of China(81771337 and 81271345)the National Key R&D Program of China(2017YFA0104202)+2 种基金the Natural Science Foundation of Jiangsu Province(BK20161174)the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(18KJB180028)the Six Talent Peaks Project in Jiangsu Province(2015 to RY)。
文摘The massive loss of oligodendrocytes caused by various pathological factors is a basic feature of many demyelinating diseases of the central nervous system(CNS). Based on a variety of studies, it is now well established that impairment of oligodendrocyte precursor cells(OPCs) to differentiate and remyelinate axons is a vital event in the failed treatment of demyelinating diseases. Recent evidence suggests that Foxg1 is essential for the proliferation of certain precursors and inhibits premature neurogenesis during brain development. To date, very little attention has been paid to the role of Foxg1 in the proliferation and differentiation of OPCs in demyelinating diseases of the CNS. Here, for the first time, we examined the effects of Foxg1 on demyelination and remyelination in the brain using a cuprizone(CPZ)-induced mouse model. In this work, 7-week-old Foxg1 conditional knockout and wild-type(WT) mice were fed a diet containing 0.2% CPZ w/w for 5 weeks, after which CPZ was withdrawn to enable remyelination. Our results demonstrated that, compared with WT mice, Foxg1-knockout mice exhibited not only alleviated demyelination but also accelerated remyelination of the demyelinated corpus callosum. Furthermore, we found that Foxg1 knockout decreased the proliferation of OPCs and accelerated their differentiation into mature oligodendrocytes both in vivo and in vitro. Wnt signaling plays a critical role in development and in a variety of diseases. GSK-3 b, a key regulatory kinase in the Wnt pathway, regulates the ability of b-catenin to enter nuclei, where it activates the expression of Wnt target genes. We then used SB216763,a selective inhibitor of GSK-3 b activity, to further demonstrate the regulatory mechanism by which Foxg1 affects OPCs in vitro. The results showed that SB216763 clearly inhibited the expression of GSK-3 b, which abolished the effect of the proliferation and differentiation of OPCs caused by the knockdown of Foxg1. These results suggest that Foxg1 is involved in the proliferation and differentiation of OPCs through the Wnt signaling pathway. The present experimental results are some of the first to suggest that Foxg1 is a new therapeutic target for the treatment of demyelinating diseases of the CNS.
基金supported by the Natural Science Foundation of Beijing of China,No.7164317the Beijing Tsinghua Changgung Hospital Fund,No.12015C1028the National Natural Science Foundation of China,No.31400717
文摘Our previous study revealed that intragastric administration of naringin improved remyelination in rats with spinal cord injury and promoted the recovery of neurological function of the injured spinal cord.This study sought to reveal the mechanisms by which naringin improves oligodendrocyte precursor cell differentiation and maturation,and promotes remyelination.Spinal cord injury was induced in rats by the weight-drop method.Naringin was intragastrically administered daily（20,40 mg/kg） for 4 weeks after spinal cord injury induction.Behavioral assessment,histopathological staining,immunofluorescence spectroscopy,ultrastructural analysis and biochemical assays were employed.Naringin treatment remarkably mitigated demyelination in the white matter,increased the quality of myelinated nerve fibers and myelin sheath thickness,promoted oligodendrocyte precursor cell differentiation by upregulating the expression of NKx2.2 and 2′3′-cyclic nucleotide 3′-phosphodiesterase,and inhibited β-catenin expression and glycogen synthase kinase-3β（GSK-3β） phosphorylation.These findings indicate that naringin treatment regulates oligodendrocyte precursor cell differentiation and promotes remyelination after spinal cord injury through the β-catenin/GSK-3β signaling pathway.
基金This work was supported by the National Natural Science Foundation of China(31771129).
文摘The exacerbation of progressive multiple sclerosis(MS)is closely associated with obstruction of the differentiation of oligodendrocyte progenitor cells(OPCs).To discover novel therapeutic compounds for enhancing remyelination by endogenous OPCs,we screened for myelin basic protein expression using cultured rat OPCs and a library of small-molecule compounds.One of the most effective drugs was pinocembrin,which remarkably promoted OPC differentiation and maturation without affecting cell proliferation and survival.Based on these in vitro effects,we further assessed the therapeutic effects of pinocembrin in animal models of demyelinating diseases.We demonstrated that pinocembrin significantly ameliorated the progression of experimental autoimmune encephalomyelitis(EAE)and enhanced the repair of demyelination in lysolectin-induced lesions.Further studies indicated that pinocembrin increased the phosphorylation level of mammalian target of rapamycin(mTOR).Taken together,our results demonstrated that pinocembrin promotes OPC differentiation and remyelination through the phosphorylated mTOR pathway,and suggest a novel therapeutic prospect for this natural flavonoid product in treating demyelinating diseases.
基金partially supported by grants from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health(R21 NS098170, to JC and CBS)Kentucky Spinal Cord and Head Injury Research Trust(16-3 A, to JC and CBS)the National Natural Science Foundation of China(81601957, to YW)。
文摘Multiple sclerosis is an autoimmune disease in which the immune system attacks the myelin sheath in the central nervous system.It is characterized by blood-brain barrier dysfunction throughout the course of multiple sclerosis, followed by the entry of immune cells and activation of local microglia and astrocytes.Glial cells(microglia, astrocytes, and oligodendrocyte lineage cells) are known as the important mediators of neuroinflammation, all of which play major roles in the pathogenesis of multiple sclerosis.Network communications between glial cells affect the activities of oligodendrocyte lineage cells and influence the demyelination-remyelination process.A finely balanced glial response may create a favorable lesion environment for efficient remyelination and neuroregeneration.This review focuses on glial response and neurodegeneration based on the findings from multiple sclerosis and major rodent demyelination models.In particular, glial interaction and molecular crosstalk are discussed to provide insights into the potential cell-and molecule-specific therapeutic targets to improve remyelination and neuroregeneration.
文摘BACKGROUND： Acupuncture treatment on injured cerebral axons has shown to provide efficacy in clinical practice. It is unknown whether acupuncture produces therapeutic effects by protecting injured cerebral myelin in ischemic stroke. OBJECTIVE： To test whether acupuncture provides protection for injured cerebral myelin, based on quantitative data from cerebral ischemia-reperfusion rats, and to compare the effects of early and late acupuncture on serum myelin basic protein （MBP） content and remyelination of the ischemic internal capsule.DESIGN, TIME AND SETTING： A randomized, controlled experiment was performed at the Neurobiological Laboratory, Sichuan University from March 2005 to March 2006. MATERIALS： ＂Hua Tuo＂ Brand filiform needles were produced by the Medical Instrument Factory of Suzhou, China.METHODS： A total of 52 adult, healthy, male, Sprague Dawley rats were randomly assigned to four groups： control （n = 4）, model （n = 16）, early acupuncture （n = 16）, and late acupuncture （n = 16）. The focal cerebral ischemia-reperfusion model was established by middle cerebral artery occlusion in the right hemisphere using the modified thread embolism method in the latter three groups. Early and late acupuncture groups underwent acupuncture after ischemia for 30 minutes and 2 hours using the Xingnaokaiqiao needling method, respectively. Acupoints were ＂Neiguarf＇ （PC 6） and ＂Sanyinjiao＂ （SP 6） on the bilateral sides, as well as ＂Shuigou＇ （DU 26） and ＂Baihui＂ （DU 20） with stimulation for 1 minute at each acupoint. Acupuncture at all acupoints was performed two or three times while the needle was retained, once per day. No special handling was administered to the control clroup.MAIN OUTCOME MEASURES： For each group, remyelination of the internal capsule was observed by Pal-Weigert＇s myelin staining and serum MBP content was detected using enzyme-linked immunosorbent assay method on days 1,3, 5, and 7 following ischemia-reperfusion injury.RESULTS： Compared with the control group, massive demyelination of the internal capsule occurred, and serum MBP content increased in the model group （P 〈 0.05）. Compared with the model group, the extent of demyelination in the internal capsule was less distinct and serum MBP content was significantly less in the early and late acupuncture group （P 〈 0.01 ）. Compared with the late acupuncture group, serum MBP content reached a peak later and the peak value was less in the early acupuncture group. CONCLUSION： Results suggest that acupuncture exerts a protective effect on injured cerebral myelin in ischemia-reperfusion rats by reducing serum MBP content and promoting remyelination. The study also suggests that the effect of early acupuncture is superior to late acupuncture.
基金supported by the National Natural Science Foundation of China,No.81601957
文摘Remyelination plays a key role in functional recovery of axons after spinal cord injury.Glial cells are the most abundant cells in the central nervous system.When spinal cord injury occurs,many glial cells at the lesion site are immediately activated,and different cells differentially affect inflammatory reactions after injury.In this review,we aim to discuss the core role of oligodendrocyte precursor cells and crosstalk with the rest of glia and their subcategories in the remyelination process.Activated astrocytes influence proliferation,differentiation,and maturation of oligodendrocyte precursor cells,while activated microglia alter remyelination by regulating the inflammatory reaction after spinal cord injury.Understanding the interaction between oligodendrocyte precursor cells and the rest of glia is necessary when designing a therapeutic plan of remyelination after spinal cord injury.
基金the National Natural Science Foundation of China,No.30570626the Natural Science Foundation of Beijing,No.7082028
文摘BACKGROUND： The transcription factor Oligl is required for oligodendrocyte maturation and demyelinated lesion repair, and is a key regulator of myelinogenesis following ischemia. OBJECTIVE： To examine the efficacy of intraventricular injection of a recombinant adenovirus-expressing Oligl gene （Ad5-Oligl-eGFP） on oligodendrocyte maturation and myelin repair following focal cerebral ischemia. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Department of Neurology, Beijing Friendship Hospital Affiliated to Capital Medical University from January 2007 to March 2008. MATERIALS： Adenovirus and a recombinant adenovirus containing Oiigl gene （Ad5-Oligl） were provided by Vector Gene Technology, China. METHODS： All 50 rats were induced by middle cerebral artery occlusion. A total of 46 rats were successfully induced and were subsequently randomly assigned to a adenovirus （Ad5） group and recombinant adenovirus-expression Oligl gene （Ad5-Oligl） group, with 23 rats per group. One day after middle cerebral artery occlusion, either Ad5-Oligl-eGFP or Ad5-eGFP （10 μL, 2.3 ×10^11/mL） was injected into the lateral ventricle on the ischemic hemisphere. MAIN OUTCOME MEASURES： Adenovirus-mediated Oligl gene expression in vitro and in vivo was measured by reverse transcription-polymerase chain reaction and immunofluorescence, respectively. Myelin basic protein （MBP） levels were evaluated by Western Blot, immunostaining, and electron microscopy. RESULTS： Exogenous Oligl expression was measured at the periventricular zone of the lateral ventricle 1 day after Ad5-Oligl injection. In the Ad5-Oligl-treated group, MBP protein levels and average intensity of MBP-immunoreactivity （-ir） increased 28 days after middle cerebral artery occlusion, compared with the control group （P 〈 0.01, P 〈 0.05）. Furthermore, myelinated axonal numbers markedly increased following Ad5-Oligl treatment. CONCLUSION： The present data suggested that Ad5-Oligl gene therapy increased MBP expression and the number of remyelinating axons following cerebral ischemia.
基金supported by Grants-in-Aid from the Japanese MEXT and MHLWsupported by the Innovative Areas’ Scientific Research(Glial Assembly)the Takeda Science Foundation
文摘Myelin plays important roles in vertebrates,ensuring the rapid propagation of action potentials and the long-term integrity of axons,but the molecular mechanisms of myelin formation remain poorly understood.Recent studies have demonstrated that myelination is regulated by the TYRO3,AXL（also known as UFO）and MERTK.
文摘Background and early studies： Endogenous tri-potential neural stem cells （NSCs） exist in the adult mammalian central nervous system （CNS）. In the spinal cord, NSCs distribute throughout the entire cord, but exist predominately in white matter tracts. The phenotypic fate of these cells in white matter is glial, largely oligodendrocyte, but not neuronal.
文摘Spinal cord injuries(SCI)usually result in impairment of axonal conduction and sensorimotor function.There are no effective therapy to completely repair SCI.Axonal demyelination is very common as a pathologic change in SCI,and demyelination partly contributes to neural function impairment.So,it may be reasonable that remyelination of demyelinated axons become one of effective therapeutic targets for SCI treatment. Demyelination involves myelin breakdown and loss of myelin-forming cells(oligodendrocytes).The death of oligodendrocytes plays a key role in axonal demyelination in SCI.Recently a number of studies demonstrate that cell replacements could facilitate axonal remyelination and restore axonal conductive func- tion.Thus,it is expected that myelinogenetic cell transplantation(oligodendroglial lineage)will have good prospect as an effective therapy to improve axonal remyelination and restore neural function for SCI treat- ment in the near future.
基金supported by National Multiple Sclerosis Society,NIH and the Guthy-Jackson Charitable Foundation
文摘Multiple sclerosis (MS) and neuromyelitis optica (NMO) are inflammatory diseases of the central nervous system (CNS) resulting in CNS inflammation, infiltration of peripheral immune cells, loss of myelin and oligodendrocytes, interruption of axonal communication, and neurologic deficits. Following oligodendrocyte injury, newly generated myelinating oligodendrocytes derived from oligodendrocyte progenitors (OPCs) may produce new myelin sheaths around denuded axons (remyelination) restoring neuronal function (Verden and Macklin, 2016). While remyelination is apparent in MS lesions, the process is often inefficient;in NMO, remyelination is even more limited.
文摘This study was aimed to assess remyelination and axon regeneration of compounds using Hunter Biotech＇ s zebrafish MS models. Zebrafish at 2 day post fertilization （2 dpf） were treated with demyelinating agent ethidium bromide （EB） for 72 hours （hrs） to induce demyelination. After removing EB, demyelinated zebrafish were treated with test compounds for another 24 hrs; Compound effect on demyelination-associated motility was as- sessed using a video-track motion detector. We found that compounds 2 and 9 recovered motility in EB-induced de- myelinated zebrafish ; whereas compounds 2 and 9 had significant effect on motility. Compounds 2 and 9 were con- firmed by whole mount anti-myelin basic protein （anti-MBP） immunostainging, further supporting that demyelina- tion-associated motility assay （primary assay） in combination with Fluoro Myelin staining （secondary assay） is a reliable array of methods for relatively high throughput in vivo remyelinating drug screening and assessment.
文摘Multiple sclerosis is a chronic companied by demyelination inflammatory disease that is ac- and axonal damage resulting in neurological deficits. Remyelination is the natural endogenous repair mechanism of demyelinated axons and it is supposed to protect axons/neurons from degeneration and thus the patient from progressive disability （Franklin and Ffrench-Constant, 2008）. Current therapeutics for patients with multiple sclerosis are to some extent very effective in inhibiting neuroinflamma- tion and demyelination. However, to date there are no substanc- es available that can enhance remyelination. Remyelination is the result of recruitment/proliferation of new oligodendrocyte precursor cells （OPC） and differentiation into mature myelin producing oligodendrocytes （Franklin and Ffrench-Constant, 2008）. These processes are supported by many factors and signals and failure at any stage might lead to repair failure. Strategies to enhance myelin repair are either the promotion of endogenous repair mechanisms via modulation of OPC prolif- eration and oligodendrocyte differentiation or the transplantion of myelinating cells into lesions. Due to the multiloculated pro- cess in multiple sclerosis and the ethical problems with the cell source, the latter is less favoured. The endogenous promotion of remvelination could be achieved by several approaches such as：
