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Robin J.m. Franklin - One of the best experts on this subject based on the ideXlab platform.
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pre existing mature oligodendrocytes do not contribute to Remyelination following toxin induced spinal cord demyelination
American Journal of Pathology, 2016Co-Authors: Abbe H Crawford, Richa B Tripathi, Sarah Foerster, Ian A Mckenzie, Eleni Kougioumtzidou, Matthew Grist, William D Richardson, Robin J.m. FranklinAbstract:Remyelination is the regenerative response to demyelination. Although the oligodendrocyte progenitor is established as the major source of remyelinating cells, there is no conclusive evidence on whether mature, differentiated oligodendrocytes can also contribute to Remyelination. Using two different inducible myelin-CreER mouse strains in which mature oligodendrocytes were prelabeled by the expression of membrane-bound Green fluorescent protein, we found that after focal spinal cord demyelination, the surrounding surviving labeled oligodendrocytes did not proliferate but remained at a consistent density. Furthermore, existing (prelabeled) oligodendrocytes showed no evidence of incorporation or migration into the lesioned area, or of process extension from the peripheral margins into the lesion. Thus, mature oligodendrocytes do not normally contribute to Remyelination and are therefore not a promising target for regenerative therapy.
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Identification of endothelin 2 as an inflammatory factor that promotes central nervous system Remyelination
Brain, 2013Co-Authors: Tracy J Yuen, Chao Zhao, Anna Williams, Kory R. Johnson, Veronique E. Miron, Jacqueline A. Quandt, Marie C. Harrisingh, Matthew Swire, Henry F. Mcfarland, Robin J.m. FranklinAbstract:The development of new regenerative therapies for multiple sclerosis is hindered by the lack of potential targets for enhancing Remyelination. The study of naturally regenerative processes such as the innate immune response represents a powerful approach for target discovery to solve this problem. By ‘mining’ these processes using transcriptional profiling we can identify candidate factors that can then be tested individually in clinically-relevant models of demyelination and Remyelination. Here, therefore, we have examined a previously described in vivo model of the innate immune response in which zymosan-induced macrophage activation in the retina promotes myelin sheath formation by oligodendrocytes generated from transplanted precursor cells. While this model is not itself clinically relevant, it does provide a logical starting point for this study as factors that promote myelination must be present. Microarray analysis of zymosan-treated retinae identified several cytokines (CXCL13, endothelin 2, CCL20 and CXCL2) to be significantly upregulated. When tested in a cerebellar slice culture model, CXCL13 and endothelin 2 promoted myelination and endothelin 2 also promoted Remyelination. In studies to identify the receptor responsible for this regenerative effect of endothelin 2, analysis of both Remyelination following experimental demyelination and of different stages of multiple sclerosis lesions in human post-mortem tissue revealed high levels of endothelin receptor type B in oligodendrocyte lineage cells. Confirming a role for this receptor in Remyelination, small molecule agonists and antagonists of endothelin receptor type B administered in slice cultures promoted and inhibited Remyelination, respectively. Antagonists of endothelin receptor type B also inhibited Remyelination of experimentally-generated demyelination in vivo. Our work therefore identifies endothelin 2 and the endothelin receptor type B as a regenerative pathway and suggests that endothelin receptor type B agonists represent a promising therapeutic approach to promote myelin regeneration.
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fibronectin aggregation in multiple sclerosis lesions impairs Remyelination
Brain, 2013Co-Authors: Josephine M J Stoffels, Robin J.m. Franklin, Mirjana Stancic, Jenny C De Jonge, Anita Nomden, Miriam E Van Strien, Zuzana Siskova, Olaf Maier, Charles Ffrenchconstant, Dick HoekstraAbstract:Remyelination following central nervous system demyelination is essential to prevent axon degeneration. However, Remyelination ultimately fails in demyelinating diseases such as multiple sclerosis. This failure of Remyelination is likely mediated by many factors, including changes in the extracellular signalling environment. Here, we examined the expression of the extracellular matrix molecule fibronectin on demyelinating injury and how this affects Remyelination by oligodendrocytes progenitors. In toxin-induced lesions undergoing efficient Remyelination, fibronectin expression was transiently increased within demyelinated areas and declined as Remyelination proceeded. Fibronectin levels increased both by leakage from the blood circulation and by production from central nervous system resident cells. In chronically demyelinated multiple sclerosis lesions, fibronectin expression persisted in the form of aggregates, which may render fibronectin resistant to degradation. Aggregation of fibronectin was similarly observed at the relapse phase of chronic experimental autoimmune encephalitis, but not on toxin-induced demyelination, suggesting that fibronectin aggregation is mediated by inflammation-induced demyelination. Indeed, the inflammatory mediator lipopolysaccharide induced fibronectin aggregation by astrocytes. Most intriguingly, injection of astrocyte-derived fibronectin aggregates in toxin-induced demyelinated lesions inhibited oligodendrocyte differentiation and Remyelination, and fibronectin aggregates are barely expressed in remyelinated multiple sclerosis lesions. Therefore, these findings suggest that fibronectin aggregates within multiple sclerosis lesions contribute to Remyelination failure. Hence, the inhibitory signals induced by fibronectin aggregates or factors that affect fibronectin aggregation could be potential therapeutic targets for promoting Remyelination.
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promotion of central nervous system Remyelination by induced differentiation of oligodendrocyte precursor cells
Annals of Neurology, 2009Co-Authors: Robert H. Miller, Xinhua Lee, Wei Tang, Yi Ping Zhang, Christopher B Shields, Yongjie Zhang, Steven D Miklasz, Diana Shea, Jeff Mason, Robin J.m. FranklinAbstract:Objective Repair of demyelinated axons in diseases such as multiple sclerosis requires activation of the myelination program in existing or newly recruited oligodendrocyte precursor cells (OPCs). The control of OPC differentiation and initiation of myelination during repair is poorly understood. In this study, we test the ability of anti–LINGO-1 reagents to promote myelination in vitro and Remyelination in the rodent adult central nervous system in vivo. Methods The effects of LINGO-1 antagonists on the differentiation of OPCs and the promotion of myelination has been assayed using a combination of coculture and slice culture preparations. Using three different animal models of demyelination and Remyelination, we morphologically and functionally assessed the effects of LINGO-1 antagonists on OPC differentiation and myelin repair. Results The data indicate that in vitro treatment with antagonists of LINGO-1 promote OPC differentiation and myelination, whereas in vivo Remyelination is accelerated in lysophosphatidylcholine- or cuprizone-induced demyelination. This Remyelination is associated with enhanced OPC differentiation and functional recovery of conduction velocities in demyelinated axons. Interpretation Our studies demonstrate that LINGO-1 antagonism promotes OPC differentiation and Remyelination, and suggest LINGO-1 functions as an inhibitor of OPC differentiation to retard central nervous system Remyelination. Ann Neurol 2009;65:304–315
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Remyelination in Experimental Models of Toxin-Induced Demyelination
Current topics in microbiology and immunology, 2008Co-Authors: William F. Blakemore, Robin J.m. FranklinAbstract:Remyelination is the regenerative process by which demyelinated axons are reinvested with new myelin sheaths. It is associated with functional recovery and maintenance of axonal health. It occurs as a spontaneous regenerative response following demyelination in a range of pathologies including traumatic injury as well as primary demyelinating disease such as multiple sclerosis (MS). Experimental models of demyelination based on the use of toxins, while not attempting to accurately mimic a disease with complex etiology and pathogenesis such as MS, have nevertheless proven extremely useful for studying the biology of Remyelination. In this chapter, we review the main toxin models of demyelination, drawing attention to their differences and how they can be used to study different aspects of Remyelination. We also describe the optimal use of these models, highlighting potential pitfalls in interpretation, and how Remyelination can be unequivocally recognized. Finally, we discuss the role of toxin models alongside viral and immune-mediated models of demyelination.
Regina C. Armstrong - One of the best experts on this subject based on the ideXlab platform.
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Astrogliosis during acute and chronic cuprizone demyelination and implications for Remyelination
ASN neuro, 2012Co-Authors: Norah Hibbits, Jun E. Yoshino, Regina C. ArmstrongAbstract:In multiple sclerosis, microglia/macrophage activation and astrocyte reactivity are important components of the lesion environment that can impact Remyelination. The current study characterizes these glial populations relative to expression of candidate regulatory molecules in cuprizone demyelinated corpus callosum. Importantly, periods of recovery after acute or chronic cuprizone demyelination are examined to compare conditions of efficient versus limited Remyelination, respectively. Microglial activation attenuates after early demyelination. In contrast, astrocyte reactivity persists throughout demyelination and a 6-week recovery period following either acute or chronic demyelination. This astrocyte reaction is characterized by (a) early proliferation, (b) increased expression of GFAP (glial fibrillary acidic protein), Vim (vimentin), Fn1 (fibronectin) and CSPGs (chondroitin sulphate proteoglycans) and (c) elaboration of a dense network of processes. Glial processes elongated in the axonal plane persist throughout lesion areas during both the robust Remyelination that follows acute demyelination and the partial Remyelination that follows chronic demyelination. However, prolonged astrocyte reactivity with chronic cuprizone treatment does not progress to barrier formation, i.e. dense compaction of astrocyte processes to wall off the lesion area. Multiple candidate growth factors and inflammatory signals in the lesion environment show strong correlations with GFAP across the acute cuprizone demyelination and recovery time course, yet there is more divergence across the progression of chronic cuprizone demyelination and recovery. However, differential glial scar formation does not appear to be responsible for differential Remyelination during recovery in the cuprizone model. The astrocyte phenotype and lesion characteristics in this demyelination model inform studies to identify triggers of non-remyelinating sclerosis in chronic multiple sclerosis lesions.
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reduced axonopathy and enhanced Remyelination after chronic demyelination in fibroblast growth factor 2 fgf2 null mice differential detection with diffusion tensor imaging
Journal of Neuropathology and Experimental Neurology, 2011Co-Authors: Jennifer E Tobin, Mingqiang Xie, Shengkwei Song, Regina C. ArmstrongAbstract:Chronic central nervous system demyelinating diseases result in long-term disability because of limited Remyelination capacity and cumulative damage to axons. Corpus callosum demyelination in mice fed cuprizone provides a reproducible model of chronic demyelination in which the demyelinating agent can be removed to test modifications that promote recovery and to develop noninvasive neuroimaging techniques for monitoring changes in myelin and axons. We used the cuprizone model in mice with genetic deletion of fibroblast growth factor 2 ( Fgf2 ) to determine the impact of FGF2 on axon pathology and Remyelination after chronic demyelination. We also evaluated the ability of quantitative magnetic resonance diffusion tensor imaging (DTI) to distinguish the corresponding pathological changes in axons and myelin during the progression of demyelination and Remyelination. During the recovery period after chronic demyelination, Fgf2 -null mice exhibited enhanced Remyelination that was detected using DTI measures of radial diffusivity and confirmed by electron microscopic analysis of the proportion of remyelinated axons. Ultrastructural analysis also demonstrated reduced axonal atrophy in chronically demyelinated Fgf2 -null versus wild-type mice. This difference in axon atrophy was further demonstrated as reduced immunohistochemical detection of neurofilament dephosphorylation in Fgf2 -null mice. Diffusion tensor imaging axial and radial diffusivity measures did not differentiate Fgf2 -null mice from wild-type mice to correlate with changes in axonal atrophy during chronic demyelination. Overall, these findings demonstrate that attenuation of FGF2 signaling promotes neuroprotection of axons and Remyelination, suggesting that FGF2 is an important negative regulator of recovery after chronic demyelination.
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cuprizone demyelination of the corpus callosum in mice correlates with altered social interaction and impaired bilateral sensorimotor coordination
Asn Neuro, 2009Co-Authors: Norah Hibbits, Ravinder Pannu, Regina C. ArmstrongAbstract:For studies of Remyelination in demyelinating diseases, the cuprizone model of CC (corpus callosum) demyelination has experimental advantages that include overall size, proximity to neural stem cells of the subventricular zone, and correlation with a lesion predilection site in multiple sclerosis. In addition, cuprizone treatment can be ended to allow more direct analysis of Remyelination than with viral or autoimmune models. However, CC demyelination lacks a useful functional correlate in rodents for longitudinal analysis throughout the course of demyelination and Remyelination. In the present study, we tested two distinct behavioural measurements in mice fed 0.2% cuprizone. Running on a 'complex' wheel with varied rung intervals requires integration between cerebral hemispheres for rapid bilateral sensorimotor coordination. Maximum running velocity on the 'complex' wheel decreased during acute (6 week) and chronic (12 week) cuprizone demyelination. Running velocity on the complex wheel distinguished treated (for 6 weeks) from non-treated mice, even after a 6-week recovery period for spontaneous Remyelination. A second behavioural assessment was a resident-intruder test of social interaction. The frequency of interactive behaviours increased among resident mice after acute or chronic demyelination. Differences in both sensorimotor coordination and social interaction correlated with demonstrated CC demyelination. The wheel assay is applicable for longitudinal studies. The resident-intruder assay provides a complementary assessment of a distinct modality at a specific time point. These behavioural measurements are sufficiently robust for small cohorts as a non-invasive assessment of demyelination to facilitate analysis of subsequent Remyelination. These measurements may also identify CC involvement in other mouse models of central nervous system injuries and disorders.
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Myelin transcription factor 1 (Myt1) expression in demyelinated lesions of rodent and human CNS.
Glia, 2007Co-Authors: Adam C. Vana, Claudia F. Lucchinetti, Regina C. ArmstrongAbstract:Myelin transcription factor 1 (Myt1) is a zinc-finger DNA binding protein that influences developing oligodendrocyte progenitor (OP) cell proliferation, differentiation, and myelin gene transcription in vitro. The potential of Myt1 to play a role in OP responses leading to Remyelination was examined using murine hepatitis virus strain A59 (MHV) to induce spinal cord demyelination and potential relevance to human pathology was evaluated in multiple sclerosis (MS) lesions. In MHV-infected mice, the density of Myt1 expressing cells markedly increased in lesioned areas of spinal cord white matter. Myt1 expressing cells proliferated most extensively during active demyelination and subsequently accumulated to maximal levels during early Remyelination. Cells with nuclear Myt1 immunoreactivity were mainly OP cells, identified by co-localization with platelet-derived growth factor alpha receptor, with additional phenotypes being either oligodendrocytes or neural stem cells, identified by CC1 antigen and Musashi1, respectively. The density of OP cells expressing Myt1 was significantly increased in white matter of MHV-infected mice during demyelination and early Remyelination then as Remyelination advanced the values returned to levels comparable to PBS-injected control mice. In MHV lesions, Myt1 was not expressed in astrocytes, lymphocytes, or macrophage/microglial cells. MS lesions demonstrated increased Myt1 expression in both the periplaque white matter adjacent to lesions and within early remyelinating lesions. These results suggesta potential role for Myt1 in the regeneration of oligodendrocyte lineage cells in response to demyelination. © 2007 Wiley-Liss, Inc.
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demyelination increases radial diffusivity in corpus callosum of mouse brain
NeuroImage, 2005Co-Authors: Shengkwei Song, Regina C. Armstrong, Anne H Cross, Jun E. Yoshino, Shiowjiuan Lin, Shuwei SunAbstract:Myelin damage, as seen in multiple sclerosis (MS) and other demyelinating diseases, impairs axonal conduction and can also be associated with axonal degeneration. Accurate assessments of these conditions may be highly beneficial in evaluating and selecting therapeutic strategies for patient management. Recently, an analytical approach examining diffusion tensor imaging (DTI) derived parameters has been proposed to assess the extent of axonal damage, demyelination, or both. The current study uses the well-characterized cuprizone model of experimental demyelination and Remyelination of corpus callosum in mouse brain to evaluate the ability of DTI parameters to detect the progression of myelin degeneration and regeneration. Our results demonstrate that the extent of increased radial diffusivity reflects the severity of demyelination in corpus callosum of mouse brain affected by cuprizone treatment. Subsequently, radial diffusivity decreases with the progression of Remyelination. Furthermore, radial diffusivity changes were specific to the time course of changes in myelin integrity as distinct from axonal injury, which was detected by betaAPP immunostaining and shown to be most extensive prior to demyelination. Radial diffusivity offers a specific assessment of demyelination and Remyelination, as distinct from acute axonal damage.
Simon S Murray - One of the best experts on this subject based on the ideXlab platform.
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gas6 increases myelination by oligodendrocytes and its deficiency delays recovery following cuprizone induced demyelination
PLOS ONE, 2011Co-Authors: Michele D Binder, Dennis Kemper, Simon S Murray, Junhua Xiao, Gerry Z M, Trevor J KilpatrickAbstract:Multiple sclerosis (MS) is a complex demyelinating disease of the central nervous system. Current research has shown that at least in some cases, the primary insult in MS could be directed at the oligodendrocyte, and that the earliest immune responses are primarily via innate immune cells. We have identified a family of receptor protein tyrosine kinases, known as the TAM receptors (Tyro3, Axl and Mertk), as potentially important in regulating both the oligodendrocyte and immune responses. We have previously shown that Gas6, a ligand for the TAM receptors, can affect the severity of demyelination in mice, with a loss of signalling via Gas6 leading to decreased oligodendrocyte survival and increased microglial activation during cuprizone-induced demyelination. We hypothesised TAM receptor signalling would also influence the extent of recovery in mice following demyelination. A significant effect of the absence of Gas6 was detected upon Remyelination, with a lower level of myelination after 4 weeks of recovery in comparison with wild-type mice. The delay in Remyelination was accompanied by a reduction in oligodendrocyte numbers. To understand the molecular mechanisms that drive the observed effects, we also examined the effect of exogenous Gas6 in in vitro myelination assays. We found that Gas6 significantly increased myelination in a dose-dependent manner, suggesting that TAM receptor signalling could be directly involved in myelination by oligodendrocytes. The reduced rate of Remyelination in the absence of Gas6 could thus result from a lack of Gas6 at a critical time during myelin production after injury. These findings establish Gas6 as an important regulator of both CNS demyelination and Remyelination.
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leukemia inhibitory factor signaling modulates both central nervous system demyelination and myelin repair
Glia, 2008Co-Authors: Mark Marriott, Ben Emery, Holly S. Cate, Michele D Binder, Dennis Kemper, Scott C Kolbe, Ian Gordon, Hong Wang, Gary F Egan, Simon S MurrayAbstract:Leukemia inhibitory factor (LIF) receptor signaling limits the severity of inflammatory demyelination in experimental autoimmune encephalomyelitis, a T-cell dependent animal model of multiple sclerosis (MS) [Butzkueven et al. (2002) Nat Med 8:613–619]. To identify whether LIF exerts direct effects within the central nervous system to limit demyelination, we have studied the influence of LIF upon the phenotype of mice challenged with cuprizone, a copper chelator, which produces a toxic oligodendrocytopathy. We find that exogenously administered LIF limits cuprizone-induced demyelination. Knockout mice deficient in LIF exhibit both potentiated demyelination and oligodendrocyte loss after cuprizone challenge, an effect that is ameliorated by exogenous LIF, arguing for a direct beneficial effect of endogenous LIF receptor signaling. Numbers of oligodendrocyte progenitor cells in cuprizone-challenged mice are not influenced by either exogenous LIF or LIF deficiency, arguing for effects directed to the differentiated oligodendrocyte. Studies on the influence of LIF upon Remyelination after cuprizone challenge fail to reveal any significant effect of exogenous LIF. The LIF-knockout mice do, however, display impaired Remyelination, although oligodendrocyte replenishment, previously identified to occur from the progenitor pool, is not significantly compromised. Thus endogenous LIF receptor signaling is not only protective of oligodendrocytes but can also enhance Remyelination, and exogenous LIF has therapeutic potential in limiting the consequences of oligodendrocyte damage. © 2008 Wiley-Liss, Inc.
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leukemia inhibitory factor signaling modulates both central nervous system demyelination and myelin repair
Glia, 2008Co-Authors: Mark Marriott, Ben Emery, Holly S. Cate, Michele D Binder, Dennis Kemper, Scott C Kolbe, Ian Gordon, Hong Wang, Gary F Egan, Simon S MurrayAbstract:Leukemia inhibitory factor (LIF) receptor signaling limits the severity of inflammatory demyelination in experimental autoimmune encephalomyelitis, a T-cell dependent animal model of multiple sclerosis (MS) [Butzkueven et al. (2002) Nat Med 8:613-619]. To identify whether LIF exerts direct effects within the central nervous system to limit demyelination, we have studied the influence of LIF upon the phenotype of mice challenged with cuprizone, a copper chelator, which produces a toxic oligodendrocytopathy. We find that exogenously administered LIF limits cuprizone-induced demyelination. Knockout mice deficient in LIF exhibit both potentiated demyelination and oligodendrocyte loss after cuprizone challenge, an effect that is ameliorated by exogenous LIF, arguing for a direct beneficial effect of endogenous LIF receptor signaling. Numbers of oligodendrocyte progenitor cells in cuprizone-challenged mice are not influenced by either exogenous LIF or LIF deficiency, arguing for effects directed to the differentiated oligodendrocyte. Studies on the influence of LIF upon Remyelination after cuprizone challenge fail to reveal any significant effect of exogenous LIF. The LIF-knockout mice do, however, display impaired Remyelination, although oligodendrocyte replenishment, previously identified to occur from the progenitor pool, is not significantly compromised. Thus endogenous LIF receptor signaling is not only protective of oligodendrocytes but can also enhance Remyelination, and exogenous LIF has therapeutic potential in limiting the consequences of oligodendrocyte damage.
Jun E. Yoshino - One of the best experts on this subject based on the ideXlab platform.
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Astrogliosis during acute and chronic cuprizone demyelination and implications for Remyelination
ASN neuro, 2012Co-Authors: Norah Hibbits, Jun E. Yoshino, Regina C. ArmstrongAbstract:In multiple sclerosis, microglia/macrophage activation and astrocyte reactivity are important components of the lesion environment that can impact Remyelination. The current study characterizes these glial populations relative to expression of candidate regulatory molecules in cuprizone demyelinated corpus callosum. Importantly, periods of recovery after acute or chronic cuprizone demyelination are examined to compare conditions of efficient versus limited Remyelination, respectively. Microglial activation attenuates after early demyelination. In contrast, astrocyte reactivity persists throughout demyelination and a 6-week recovery period following either acute or chronic demyelination. This astrocyte reaction is characterized by (a) early proliferation, (b) increased expression of GFAP (glial fibrillary acidic protein), Vim (vimentin), Fn1 (fibronectin) and CSPGs (chondroitin sulphate proteoglycans) and (c) elaboration of a dense network of processes. Glial processes elongated in the axonal plane persist throughout lesion areas during both the robust Remyelination that follows acute demyelination and the partial Remyelination that follows chronic demyelination. However, prolonged astrocyte reactivity with chronic cuprizone treatment does not progress to barrier formation, i.e. dense compaction of astrocyte processes to wall off the lesion area. Multiple candidate growth factors and inflammatory signals in the lesion environment show strong correlations with GFAP across the acute cuprizone demyelination and recovery time course, yet there is more divergence across the progression of chronic cuprizone demyelination and recovery. However, differential glial scar formation does not appear to be responsible for differential Remyelination during recovery in the cuprizone model. The astrocyte phenotype and lesion characteristics in this demyelination model inform studies to identify triggers of non-remyelinating sclerosis in chronic multiple sclerosis lesions.
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demyelination increases radial diffusivity in corpus callosum of mouse brain
NeuroImage, 2005Co-Authors: Shengkwei Song, Regina C. Armstrong, Anne H Cross, Jun E. Yoshino, Shiowjiuan Lin, Shuwei SunAbstract:Myelin damage, as seen in multiple sclerosis (MS) and other demyelinating diseases, impairs axonal conduction and can also be associated with axonal degeneration. Accurate assessments of these conditions may be highly beneficial in evaluating and selecting therapeutic strategies for patient management. Recently, an analytical approach examining diffusion tensor imaging (DTI) derived parameters has been proposed to assess the extent of axonal damage, demyelination, or both. The current study uses the well-characterized cuprizone model of experimental demyelination and Remyelination of corpus callosum in mouse brain to evaluate the ability of DTI parameters to detect the progression of myelin degeneration and regeneration. Our results demonstrate that the extent of increased radial diffusivity reflects the severity of demyelination in corpus callosum of mouse brain affected by cuprizone treatment. Subsequently, radial diffusivity decreases with the progression of Remyelination. Furthermore, radial diffusivity changes were specific to the time course of changes in myelin integrity as distinct from axonal injury, which was detected by betaAPP immunostaining and shown to be most extensive prior to demyelination. Radial diffusivity offers a specific assessment of demyelination and Remyelination, as distinct from acute axonal damage.
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demyelination increases radial diffusivity in corpus callosum of mouse brain
NeuroImage, 2005Co-Authors: Shengkwei Song, Regina C. Armstrong, Anne H Cross, Jun E. Yoshino, Tuan Q LeAbstract:Abstract Myelin damage, as seen in multiple sclerosis (MS) and other demyelinating diseases, impairs axonal conduction and can also be associated with axonal degeneration. Accurate assessments of these conditions may be highly beneficial in evaluating and selecting therapeutic strategies for patient management. Recently, an analytical approach examining diffusion tensor imaging (DTI) derived parameters has been proposed to assess the extent of axonal damage, demyelination, or both. The current study uses the well-characterized cuprizone model of experimental demyelination and Remyelination of corpus callosum in mouse brain to evaluate the ability of DTI parameters to detect the progression of myelin degeneration and regeneration. Our results demonstrate that the extent of increased radial diffusivity reflects the severity of demyelination in corpus callosum of mouse brain affected by cuprizone treatment. Subsequently, radial diffusivity decreases with the progression of Remyelination. Furthermore, radial diffusivity changes were specific to the time course of changes in myelin integrity as distinct from axonal injury, which was detected by βAPP immunostaining and shown to be most extensive prior to demyelination. Radial diffusivity offers a specific assessment of demyelination and Remyelination, as distinct from acute axonal damage.
Michele D Binder - One of the best experts on this subject based on the ideXlab platform.
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gas6 increases myelination by oligodendrocytes and its deficiency delays recovery following cuprizone induced demyelination
PLOS ONE, 2011Co-Authors: Michele D Binder, Dennis Kemper, Simon S Murray, Junhua Xiao, Gerry Z M, Trevor J KilpatrickAbstract:Multiple sclerosis (MS) is a complex demyelinating disease of the central nervous system. Current research has shown that at least in some cases, the primary insult in MS could be directed at the oligodendrocyte, and that the earliest immune responses are primarily via innate immune cells. We have identified a family of receptor protein tyrosine kinases, known as the TAM receptors (Tyro3, Axl and Mertk), as potentially important in regulating both the oligodendrocyte and immune responses. We have previously shown that Gas6, a ligand for the TAM receptors, can affect the severity of demyelination in mice, with a loss of signalling via Gas6 leading to decreased oligodendrocyte survival and increased microglial activation during cuprizone-induced demyelination. We hypothesised TAM receptor signalling would also influence the extent of recovery in mice following demyelination. A significant effect of the absence of Gas6 was detected upon Remyelination, with a lower level of myelination after 4 weeks of recovery in comparison with wild-type mice. The delay in Remyelination was accompanied by a reduction in oligodendrocyte numbers. To understand the molecular mechanisms that drive the observed effects, we also examined the effect of exogenous Gas6 in in vitro myelination assays. We found that Gas6 significantly increased myelination in a dose-dependent manner, suggesting that TAM receptor signalling could be directly involved in myelination by oligodendrocytes. The reduced rate of Remyelination in the absence of Gas6 could thus result from a lack of Gas6 at a critical time during myelin production after injury. These findings establish Gas6 as an important regulator of both CNS demyelination and Remyelination.
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leukemia inhibitory factor signaling modulates both central nervous system demyelination and myelin repair
Glia, 2008Co-Authors: Mark Marriott, Ben Emery, Holly S. Cate, Michele D Binder, Dennis Kemper, Scott C Kolbe, Ian Gordon, Hong Wang, Gary F Egan, Simon S MurrayAbstract:Leukemia inhibitory factor (LIF) receptor signaling limits the severity of inflammatory demyelination in experimental autoimmune encephalomyelitis, a T-cell dependent animal model of multiple sclerosis (MS) [Butzkueven et al. (2002) Nat Med 8:613–619]. To identify whether LIF exerts direct effects within the central nervous system to limit demyelination, we have studied the influence of LIF upon the phenotype of mice challenged with cuprizone, a copper chelator, which produces a toxic oligodendrocytopathy. We find that exogenously administered LIF limits cuprizone-induced demyelination. Knockout mice deficient in LIF exhibit both potentiated demyelination and oligodendrocyte loss after cuprizone challenge, an effect that is ameliorated by exogenous LIF, arguing for a direct beneficial effect of endogenous LIF receptor signaling. Numbers of oligodendrocyte progenitor cells in cuprizone-challenged mice are not influenced by either exogenous LIF or LIF deficiency, arguing for effects directed to the differentiated oligodendrocyte. Studies on the influence of LIF upon Remyelination after cuprizone challenge fail to reveal any significant effect of exogenous LIF. The LIF-knockout mice do, however, display impaired Remyelination, although oligodendrocyte replenishment, previously identified to occur from the progenitor pool, is not significantly compromised. Thus endogenous LIF receptor signaling is not only protective of oligodendrocytes but can also enhance Remyelination, and exogenous LIF has therapeutic potential in limiting the consequences of oligodendrocyte damage. © 2008 Wiley-Liss, Inc.
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leukemia inhibitory factor signaling modulates both central nervous system demyelination and myelin repair
Glia, 2008Co-Authors: Mark Marriott, Ben Emery, Holly S. Cate, Michele D Binder, Dennis Kemper, Scott C Kolbe, Ian Gordon, Hong Wang, Gary F Egan, Simon S MurrayAbstract:Leukemia inhibitory factor (LIF) receptor signaling limits the severity of inflammatory demyelination in experimental autoimmune encephalomyelitis, a T-cell dependent animal model of multiple sclerosis (MS) [Butzkueven et al. (2002) Nat Med 8:613-619]. To identify whether LIF exerts direct effects within the central nervous system to limit demyelination, we have studied the influence of LIF upon the phenotype of mice challenged with cuprizone, a copper chelator, which produces a toxic oligodendrocytopathy. We find that exogenously administered LIF limits cuprizone-induced demyelination. Knockout mice deficient in LIF exhibit both potentiated demyelination and oligodendrocyte loss after cuprizone challenge, an effect that is ameliorated by exogenous LIF, arguing for a direct beneficial effect of endogenous LIF receptor signaling. Numbers of oligodendrocyte progenitor cells in cuprizone-challenged mice are not influenced by either exogenous LIF or LIF deficiency, arguing for effects directed to the differentiated oligodendrocyte. Studies on the influence of LIF upon Remyelination after cuprizone challenge fail to reveal any significant effect of exogenous LIF. The LIF-knockout mice do, however, display impaired Remyelination, although oligodendrocyte replenishment, previously identified to occur from the progenitor pool, is not significantly compromised. Thus endogenous LIF receptor signaling is not only protective of oligodendrocytes but can also enhance Remyelination, and exogenous LIF has therapeutic potential in limiting the consequences of oligodendrocyte damage.
