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Demyelination

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Robin J.m. Franklin – One of the best experts on this subject based on the ideXlab platform.

  • Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin
    Proceedings of the National Academy of Sciences of the United States of America, 2016
    Co-Authors: Bartosz Bielecki, Sakina Mhaouty-kodja, Abdel M. Ghoumari, Claudia Mattern, Sumaira Javaid, Kaja Smietanka, Charly Abi Ghanem, M. Said Ghandour, Etienne-emile Baulieu, Robin J.m. Franklin
    Abstract:

    Lost myelin can be replaced after injury or during demyelinating diseases in a regenerative process called remyelination. In the central nervous system (CNS), the myelin sheaths, which protect axons and allow the fast propagation of electrical impulses, are produced by oligodendrocytes. The abundance and widespread distribution of oligodendrocyte progenitors (OPs) within the adult CNS account for this remarkable regenerative potential. Here, we report a key role for the male gonad, testosterone, and androgen receptor (AR) in CNS remyelination. After lysolecithin-induced Demyelination of the male mouse ventral spinal cord white matter, the recruitment of glial fibrillary acidic protein-expressing astrocytes was compromised in the absence of testes and testosterone signaling via AR. Concomitantly, the differentiation of OPs into oligodendrocytes forming myelin basic protprotein (MBP)(+) and proteolipid protein-positive myelin was impaired. Instead, in the absence of astrocytes, axons were remyelinated by protein zero (P0)(+) and peripheral myelin protprotein 22-kDa (PMP22)(+) myelin, normally only produced by Schwann cells in the peripheral nervous system. Thus, testosterone favors astrocyte recruitment and spontaneous oligodendrocyte-mediated remyelination. This finding may have important implications for demyelinating diseases, psychiatric disorders, and cognitive aging. The testosterone dependency of CNS oligodendrocyte remyelination may have roots in the evolutionary history of the AR, because the receptor has evolved from an ancestral 3-keto-steroid receptor through gene duplication at the time when myelin appeared in jawed vertebrates.

  • Demyelination causes adult cns progenitors to revert to an immature state and express immune cues that support their migration
    The Journal of Neuroscience, 2015
    Co-Authors: Sarah Moyon, Marie-stéphane Aigrot, Jeffrey K. Huang, Christophe Kerninon, Anne Laure Dubessy, Matthew Trotter, Luce Dauphinot, Marieclaude Potier, Stephane Melik Parsadaniantz, Robin J.m. Franklin
    Abstract:

    The declining efficiency of myelin regeneration in individuals with multiple sclerosis has stimulated a search for ways by which it might be therapeutically enhanced. Here we have used gene expression profiling on purified murine oligodendrocyte progenitor cells (OPCs), the remyelinating cells of the adult CNS, to obtain a comprehensive picture of how they become activated after Demyelination and how this enables them to contribute to remyelination. We find that adult OPCs have a transcriptome more similar to that of oligodendrocytes than to neonatal OPCs, but revert to a neonatal-like transcriptome when activated. Part of the activation response involves increased expression of two genes of the innate immune system, IL1β and CCL2, which enhance the mobilization of OPCs. Our results add a new dimension to the role of the innate immune system in CNS regeneration, revealing how OPCs themselves contribute to the postinjury inflammatory milieu by producing cytokines that directly enhance their repopulation of areas of Demyelination and hence their ability to contribute to remyelination.

  • Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells
    Neurotherapeutics, 2011
    Co-Authors: Jeffrey K. Huang, Stephen P.j. Fancy, Chao Zhao, David H Rowitch, Charles Ffrench-constant, Robin J.m. Franklin
    Abstract:

    Regeneration of myelin sheaths (remyelination) after central nervous system Demyelination is important to restore saltatory conduction and to prevent axonal loss. In multiple sclerosis, the insufficiency of remyelination leads to the irreversible degeneration of axons and correlated clinical decline. Therefore, a regenerative strategy to encourage remyelination may protect axons and improve symptoms in multiple sclerosis. We highlight recent studies on factors that influence endogenous remyelination and potential promising pharmacological targets that may be considered for enhancing central nervous system remyelination.

Martin Stangel – One of the best experts on this subject based on the ideXlab platform.

  • Investigation of Cuprizone Inactivation by Temperature
    Neurotoxicity Research, 2017
    Co-Authors: Sandra Heckers, Nadine Held, Jessica Kronenberg, Thomas Skripuletz, André Bleich, Viktoria Gudi, Martin Stangel
    Abstract:

    Animal models, such as cuprizone (bis-cyclohexanone oxaldihydrazone) feeding, are helpful to study experimental Demyelination and remyelination in the context of diseases like multiple sclerosis. Cuprizone is a copper chelator, which when supplemented to the normal food of C57BL/6J mice in a concentration of 0.2% leads to oligodendroglial loss, subsequent microglia and astrocyte activation, resulting in Demyelination. Termination of the cuprizone diet results in remyelination, promoted by newly formed mature oligodendrocytes. The exact mode of cuprizone’s action is not well understood, and information about its inactivation and cleavage are still not available. The knowledge of these processes could lead to a better understanding of cuprizone’s mode of action, as well as a safer handling of this toxin. We therefore performed experiments with the aim to inactivate cuprizone by thermal heating, since it was suggested in the past that cuprizone is heat sensitive. C57BL/6J mice were fed for 4 weeks with 0.2% cuprizone, either thermally pretreated (60, 80, 105, 121 °C) or not heated. In addition, primary rat oligodendrocytes, as a known selective toxic target of cuprizone, were incubated with 350 μM cuprizone solutions, which were either thermally pretreated or not. Our results demonstrate that none of the tested thermal pretreatment conditions could abrogate or restrict the toxic and demyelinating effects of cuprizone, neither in vitro nor in vivo. In conclusion, the current study rebuts the hypothesis of cuprizone as a heat-sensitive compound, as well as the assumption that heat exposure is a reason for an insufficient Demyelination of cuprizone-containing pellets.

  • astrocytes regulate myelin clearance through recruitment of microglia during cuprizone induced Demyelination
    Brain, 2013
    Co-Authors: Thomas Skripuletz, Viktoria Gudi, Refik Pul, Diane Hackstette, Katharina Bauer, Elke Voss, Katharina Berger, Markus Kipp, Wolfgang Baumgartner, Martin Stangel
    Abstract:

    Recent evidence suggests that astrocytes play an important role in regulating de- and remyelination in multiple sclerosis. The role of astrocytes is controversial, and both beneficial as well as detrimental effects are being discussed. We performed loss-of-function studies based on astrocyte depletion in a cuprizone-induced rodent model of Demyelination. This led to strong astrogliosis accompanied by microgliosis and Demyelination in C57BL/6 wild-type mice. Ablation of astrocytes in glial fibrillary acidic proteinthymidine kinase transgenic mice was associated with a failure of damaged myelin removal and a consecutive delay in remyelination. Despite oligodendrocyte death, myelin was still present, but ultrastructual investigations showed that the myelin structure was loosened and this damaged myelin did not protect axons. These alterations were associated with a decrease in microglial activation. Thus, our results show that astrocyte loss does not prevent myelin damage, but clearance of damaged myelin through recruitment of microglia is impaired. Further studies suggest that this process is regulated by the chemokine CXCL10. As a consequence of the delayed removal of myelin debris, remyelination and oligodendrocyte precursor cell proliferation were impaired. Experiments omitting the influence of myelin debris demonstrated an additional beneficial effect of astrocytes on oligodendrocyte regeneration during remyelination. In conclusion, these data demonstrate for the first time in vivo that astrocytes provide the signal environment that forms the basis for the recruitment of microglia to clear myelin debris, a process required for subsequent repair mechanisms. This is of great importance to understanding regenerative processes in demyelinating diseases such as multiple sclerosis.

  • regional differences between grey and white matter in cuprizone induced Demyelination
    Brain Research, 2009
    Co-Authors: Viktoria Gudi, Thomas Skripuletz, Corinna Trebst, Paraskevi N. Koutsoudaki, Alexandra Kotsiari, Darius Moharreghkhiabani, Jelena Skuljec, Martin Stangel
    Abstract:

    Cuprizone feeding is a commonly used model to study experimental de- and remyelination, with the corpus callosum being the most frequently investigated white matter tract. We have previously shown that Demyelination is also extensive in the cerebral cortex in the cuprizone model. In the current study, we have performed a detailed analysis of the dynamics of Demyelination in the cortex in comparison to the corpus callosum. Prominent and almost complete Demyelination in the corpus callosum was observed after 4.5-5 weeks of 0.2% cuprizone feeding, whereas complete cortical Demyelination was only observed after 6 weeks of cuprizone feeding. Interestingly, remyelination in the corpus callosum occurred even before the termination of cuprizone administration. Accumulation of microglia in the corpus callosum started as early as week 3 reaching its maximum at week 4.5 and was still significantly elevated at week 6 of cuprizone treatment. Within the cortex only a few scattered activated microglial cells were found. Furthermore, the intensity of astrogliosis, accumulation of oligodendrocyte progenitor cells and nestin positive cells differed between the two areas investigated. The time course and dynamics of Demyelination differ in the corpus callosum and in the cortex, suggesting different underlying pathomechanisms.

Hans S. Keirstead – One of the best experts on this subject based on the ideXlab platform.

  • Spinal cord injury is accompanied by chronic progressive Demyelination.
    The Journal of comparative neurology, 2005
    Co-Authors: Minodora O. Totoiu, Hans S. Keirstead
    Abstract:

    Preceding the development of therapeutic strategies for spinal cord injury is an identification of those pathological processes that might serve as therapeutic targets. Although Demyelination has been documented as a secondary degenerative component of spinal cord injury in several species including humans, the extent of Demyelination and its functional consequence remain unknown. In this report, we document the extent of Demyelination and remyelination up to 450 days following contusive spinal cord injury in adult rats. The overall number of demyelinated axons peaked at 1 day post injury, declined by 7-14 days post injury, and then progressively increased up to 450 days post injury. Oligodendrocyte and Schwann cell remyelinated axons appeared by 14 days post injury. Although remyelinated axons were present from 14 to 450 days post injury, remyelination was incomplete, as indicated by the presence of demyelinated axons at every time point examined. These studies demonstrate for the first time that spinal cord injury is accompanied by chronic progressive Demyelination, and they substantiate Demyelination as a target for therapeutic intervention.

  • spinal cord injury is accompanied by chronic progressive Demyelination
    The Journal of Comparative Neurology, 2005
    Co-Authors: Minodora O. Totoiu, Hans S. Keirstead
    Abstract:

    Preceding the development of therapeutic strategies for spinal cord injury is an identification of those pathological processes that might serve as therapeutic targets. Although Demyelination has been documented as a secondary degenerative component of spinal cord injury in several species including humans, the extent of Demyelination and its functional consequence remain unknown. In this report, we document the extent of Demyelination and remyelination up to 450 days following contusive spinal cord injury in adult rats. The overall number of demyelinated axons peaked at 1 day post injury, declined by 7–14 days post injury, and then progressively increased up to 450 days post injury. Oligodendrocyte and Schwann cell remyelinated axons appeared by 14 days post injury. Although remyelinated axons were present from 14 to 450 days post injury, remyelination was incomplete, as indicated by the presence of demyelinated axons at every time point examined. These studies demonstrate for the first time that spinal cord injury is accompanied by chronic progressive Demyelination, and they substantiate Demyelination as a target for therapeutic intervention. J. Comp. Neurol. 486:373–383, 2005. © 2005 Wiley-Liss, Inc.

  • neutralization of the chemokine cxcl10 reduces inflammatory cell invasion and Demyelination and improves neurological function in a viral model of multiple sclerosis
    Journal of Immunology, 2001
    Co-Authors: Michael T Liu, Hans S. Keirstead, Thomas E. Lane
    Abstract:

    Intracerebral infection of mice with mouse hepatitis virus (MHV) results in an acute encephalomyelitis followed by a chronic demyelinating disease with clinical and histological similarities with the human demyelinating disease multiple sclerosis (MS). Following MHV infection, chemokines including CXC chemokine ligand (CXCL)10 (IFN inducible protein 10 kDa), CXCL9 (monokine induced by IFN-γ), and CC chemokine ligand 5 (RANTES) are expressed during both acute and chronic stages of disease suggesting a role for these molecules in disease exacexacerbation. Previous studies have shown that during the acute phase of infection, T lymphocytes are recruited into the CNS by the chemokines CXCL10 and CXCL9. In the present study, MHV-infected mice with established Demyelination were treated with antisera against these two chemokines, and disease severity was assessed. Treatment with anti-CXCL10 reduced CD4 + T lymplymphocyte and macrophage invasion, diminished expression of IFN-γ and CC chemokine ligand 5, inhibited progression of Demyelination, and increased remyelination. Anti-CXCL10 treatment also resulted in an impediment of clinical disease progression that was characterized by a dramatic improvement in neurological function. Treatment with antisera against CXCL9 was without effect, demonstrating a critical role for CXCL10 in inflammatory Demyelination in this model. These findings document a novel therapeutic strategy using Ab-mediated neutralization of a key chemokine as a possible treatment for chronic human inflammatory demyelinating diseases such as MS.

Chao Zhao – One of the best experts on this subject based on the ideXlab platform.

  • the microbiota regulates murine inflammatory responses to toxin induced cns Demyelination but has minimal impact on remyelination
    Proceedings of the National Academy of Sciences of the United States of America, 2019
    Co-Authors: Christopher E Mcmurran, Alerie Guzman De La Fuente, Rosana Penalva, Ofra Ben Menachemzidon, Yvonne Dombrowski, John Falconer, Ginez A Gonzalez, Chao Zhao
    Abstract:

    The microbiota is now recognized as a key influence on the host immune response in the central nervous system (CNS). As such, there has been some progress toward therapies that modulate the microbiota with the aim of limiting immune-mediated Demyelination, as occurs in multiple sclerosis. However, remyelination—the regeneration of myelin sheaths—also depends upon an immune response, and the effects that such interventions might have on remyelination have not yet been explored. Here, we show that the inflammatory response during CNS remyelination in mice is modulated by antibiotic or probiotic treatment, as well as in germ-free mice. We also explore the effect of these changes on oligodendrocyte progenitor cell differentiation, which is inhibited by antibiotics but unaffected by our other interventions. These results reveal that high combined doses of oral antibiotics impair oligodendrocyte progenitor cell responses during remyelination and further our understanding of how mammalian regeneration relates to the microbiota.

  • Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells
    Neurotherapeutics, 2011
    Co-Authors: Jeffrey K. Huang, Stephen P.j. Fancy, Chao Zhao, David H Rowitch, Charles Ffrench-constant, Robin J.m. Franklin
    Abstract:

    Regeneration of myelin sheaths (remyelination) after central nervous system Demyelination is important to restore saltatory conduction and to prevent axonal loss. In multiple sclerosis, the insufficiency of remyelination leads to the irreversible degeneration of axons and correlated clinical decline. Therefore, a regenerative strategy to encourage remyelination may protect axons and improve symptoms in multiple sclerosis. We highlight recent studies on factors that influence endogenous remyelination and potential promising pharmacological targets that may be considered for enhancing central nervous system remyelination.

  • Retinoid X receptor gamma signaling accelerates CNS remyelination
    Nature Neuroscience, 2010
    Co-Authors: Jeffrey K. Huang, Andrew A. Jarjour, Chao Zhao, Brahim Nait Oumesmar, Christophe Kerninon, Anna Williams, Wojciech Krezel, Hiroyuki Kagechika, Julien Bauer, Anne Baron-van Evercooren
    Abstract:

    The molecular basis of CNS myelin regeneration (remyelination) is poorly understood. Here we generate a comprehensive transcriptional profile of the separate stages of spontaneous remyelination following focal Demyelination in the rat CNS and show transcripts encoding retinoid acid receptor RXR-gamma is highly differentially expressed during remyelination. We find that oligodendrocyte lineage cells express RXR-gamma in rat tissues undergoing remyelination and in active and remyelinated MS lesions. RXR-gamma knockdown by RNA interference or RXR-specific antagonists severely inhibit oligodendrocyte differentiation in culture. In RXR-gamma deficient mice, adult oligodendrocyte precursor cells efficiently repopulate lesions following Demyelination, but display delayed differentiation into mature oligodendrocytes. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures and to aged rats following Demyelination results in more remyelinated axons. RXR-gamma is therefore a positive regulator of endogenous oligodendrocyte precursor cell differentiation and remyelination, and may be a pharmacological target for CNS regenerative therapy.

Hans Lassmann – One of the best experts on this subject based on the ideXlab platform.

  • Demyelination versus remyelination in progressive multiple sclerosis
    Brain, 2010
    Co-Authors: Stephan Bramow, Josa M Frischer, Hans Lassmann, Nils Kochhenriksen, Claudia F Lucchinetti, Per Soelberg Sorensen, Henning Laursen
    Abstract:

    The causes of incomplete remyelination in progressive multiple sclerosis are unknown, as are the pathological correlates of the different clinical characteristics of patients with primary and secondary progressive disease. We analysed brains and spinal cords from 51 patients with progressive multiple sclerosis by planimetry. Thirteen patients with primary progressive disease were compared with 34 with secondary progressive disease. In patients with secondary progressive multiple sclerosis, we found larger brain plaques, more Demyelination in total and higher brain loads of active Demyelination compared with patients with primary progressive disease. In addition, the brain density of plaques with high-grade inflammation and active Demyelination was highest in secondary progressive multiple sclerosis and remained ∼18% higher than in primary progressive multiple sclerosis after adjustments for other plaque types and plaque number ( P  < 0.05). Conversely, the proportion of remyelinated shadow plaques ( P  < 0.05) and the overall remyelination capacity ( P  < 0.01) per brain were higher in primary, compared with secondary, progressive multiple sclerosis. By contrast, there were no group differences in the brain load or frequency of low-grade inflammatory plaques with slowly expanding Demyelination. Spinal cord lesilesion loads and remyelination capacity were also comparable in the two patient groups. Remyelinated areas were more vulnerable than the normal-appearing white matter to new Demyelination, including active Demyelination in secondary progressive multiple sclerosis. ‘Recurrent’ slowly expanding Demyelination, affecting remyelinated areas, and the load of slowly expanding Demyelination correlated with incomplete remyelination in both groups. In turn, incomplete remyelination in the spinal cord correlated with higher disease-related disability (determined retrospectively; r  = −0.53; P  < 0.05 for remyelination capacity versus disease severity). By contrast, such a correlation was not observed in the brain. We propose that regulatory and reparative properties could protect the white matter of the brain in patients with primary progressive multiple sclerosis. These patients may, thereby, be spared symptoms until the spinal cord is affected. By contrast, recurrent active Demyelination of repaired myelin could explain why similar symptoms often develop in consecutive relapses in relapsing-remitting/secondary progressive multiple sclerosis. Our data also indicate that slowly expanding Demyelination may irreparably destroy normal and repaired myelin, supporting the concept of slowly expanding Demyelination as an important pathological correlate of clinical progression.

  • Demyelination versus remyelination in progressive multiple sclerosis
    Brain : a journal of neurology, 2010
    Co-Authors: Stephan Bramow, Josa M Frischer, Hans Lassmann, Claudia F Lucchinetti, Per Soelberg Sorensen, Nils Koch-henriksen, Henning Laursen
    Abstract:

    The causes of incomplete remyelination in progressive multiple sclerosis are unknown, as are the pathological correlates of the different clinical characteristics of patients with primary and secondary progressive disease. We analysed brains and spinal cords from 51 patients with progressive multiple sclerosis by planimetry. Thirteen patients with primary progressive disease were compared with 34 with secondary progressive disease. In patients with secondary progressive multiple sclerosis, we found larger brain plaques, more Demyelination in total and higher brain loads of active Demyelination compared with patients with primary progressive disease. In addition, the brain density of plaques with high-grade inflammation and active Demyelination was highest in secondary progressive multiple sclerosis and remained ∼18% higher than in primary progressive multiple sclerosis after adjustments for other plaque types and plaque number ( P  

  • multiple sclerosis in situ evidence for antibody and complement mediated Demyelination
    Annals of Neurology, 1998
    Co-Authors: Maria K Storch, Sara J Piddlesden, Matti Haltia, Matti Iivanainen, Paul Morgan, Hans Lassmann
    Abstract:

    We describe a case of multiple sclerosis characterized by deposition of immunoglobulin and complement in the areas of active Demyelination. This was particularly evident for the C9neo antigen, which is a marker for the activated lytic complement complex and was exclusively deposited in the areas of active myelin destruction. In addition, macrophages in the lesions contained degradation products that were immunoreactive for myelin antigens, immunoglobulins, and C9neo antigen. Destruction of myelin sheaths was associated with incomplete loss of oligodendrocytes in the active areas and reappearance of oligodendrocytes with remyelination in the inactive plaque center.