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1
Schmitz, Thomas, and Li-Jin Chew. "Cytokines and Myelination in the Central Nervous System." Scientific World JOURNAL 8 (2008): 1119–47. http://dx.doi.org/10.1100/tsw.2008.140.
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Myelin abnormalities that reflect damage to developing and mature brains are often found in neurological diseases with evidence of inflammatory infiltration and microglial activation. Many cytokines are virtually undetectable in the uninflamed central nervous system (CNS), so that their rapid induction and sustained elevation in immune and glial cells contributes to dysregulation of the inflammatory response and neural cell homeostasis. This results in aberrant neural cell development, cytotoxicity, and loss of the primary myelin-producing cells of the CNS, the oligodendrocytes. This article provides an overview of cytokine and chemokine activity in the CNS with relevance to clinical conditions of neonatal and adult demyelinating disease, brain trauma, and mental disorders with observed white matter defects. Experimental models that mimic human disease have been developed in order to study pathogenic and therapeutic mechanisms, but have shown mixed success in clinical application. However, genetically altered animals, and models of CNS inflammation and demyelination, have offered great insight into the complexities of neuroimmune interactions that impact oligodendrocyte function. The intracellular signaling pathways of selected cytokines have also been highlighted to illustrate current knowledge of receptor-mediated events. By learning to interpret the actions of cytokines and by improving methods to target appropriate predictors of disease risk selectively, a more comprehensive understanding of altered immunoregulation will aid in the development of advanced treatment options for patients with inflammatory white matter disorders.
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Compston, Alastair. "Remyelination of the central nervous system." Multiple Sclerosis Journal 1, no. 6 (1996): 388–92. http://dx.doi.org/10.1177/135245859600100622.
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The three typical stages in the clinical course of multiple sclerosis (relapse, persistent disability and progression) can be explained on the basis of inflammation, demyelination and failure of repair leading to axon degeneration and astrocytosis. Strategies ore being evaluated for limiting the inflammatory process using immunological treatments and these may have unexpected dividends in promoting endogenous remyelination. Increasing knowledge on glial lineages and axon-glial interactions needed for stable myelination also offer the prospect for enhancing remyelination through growth factor therapy and cell implantation.
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Caillava, Céline, Renaud Vandenbosch, Beata Jablonska, et al. "Cdk2 loss accelerates precursor differentiation and remyelination in the adult central nervous system." Journal of Cell Biology 193, no. 2 (2011): 397–407. http://dx.doi.org/10.1083/jcb.201004146.
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The specific functions of intrinsic regulators of oligodendrocyte progenitor cell (OPC) division are poorly understood. Type 2 cyclin-dependent kinase (Cdk2) controls cell cycle progression of OPCs, but whether it acts during myelination and repair of demyelinating lesions remains unexplored. Here, we took advantage of a viable Cdk2−/− mutant mouse to investigate the function of this cell cycle regulator in OPC proliferation and differentiation in normal and pathological conditions. During central nervous system (CNS) development, Cdk2 loss does not affect OPC cell cycle, oligodendrocyte cell numbers, or myelination. However, in response to CNS demyelination, it clearly alters adult OPC renewal, cell cycle exit, and differentiation. Importantly, Cdk2 loss accelerates CNS remyelination of demyelinated axons. Thus, Cdk2 is dispensable for myelination but is important for adult OPC renewal, and could be one of the underlying mechanisms that drive adult progenitors to differentiate and thus regenerate myelin.
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López-Guerrero, José Antonio, Inés Ripa, Sabina Andreu, and Raquel Bello-Morales. "The Role of Extracellular Vesicles in Demyelination of the Central Nervous System." International Journal of Molecular Sciences 21, no. 23 (2020): 9111. http://dx.doi.org/10.3390/ijms21239111.
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It is being increasingly demonstrated that extracellular vesicles (EVs) are deeply involved in the physiology of the central nervous system (CNS). Processes such as synaptic activity, neuron-glia communication, myelination and immune response are modulated by EVs. Likewise, these vesicles may participate in many pathological processes, both as triggers of disease or, on the contrary, as mechanisms of repair. EVs play relevant roles in neurodegenerative disorders such as Alzheimer’s or Parkinson’s diseases, in viral infections of the CNS and in demyelinating pathologies such as multiple sclerosis (MS). This review describes the involvement of these membrane vesicles in major demyelinating diseases, including MS, neuromyelitis optica, progressive multifocal leukoencephalopathy and demyelination associated to herpesviruses.
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Coman, Irène, Gilles Barbin, Perrine Charles, Bernard Zalc, and Catherine Lubetzki. "Axonal signals in central nervous system myelination, demyelination and remyelination." Journal of the Neurological Sciences 233, no. 1-2 (2005): 67–71. http://dx.doi.org/10.1016/j.jns.2005.03.029.
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Tanaka, Tatsuhide, and Shigetaka Yoshida. "Mechanisms of remyelination: recent insight from experimental models." Biomolecular Concepts 5, no. 4 (2014): 289–98. http://dx.doi.org/10.1515/bmc-2014-0015.
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AbstractOligodendrocytes and myelin play essential roles in the vertebrate central nervous system. Demyelination disrupts saltatory nerve conduction, leading to axonal degeneration and neurological disabilities. Remyelination is a regenerative process that replaces lost myelin. However, remyelination is disrupted in demyelinating diseases such as multiple sclerosis, at least partially, due to the failure of oligodendrocyte precursor cells to differentiate into myelinating oligodendrocytes. Understanding the molecular and cellular mechanisms that impact the differentiation of oligodendrocytes and myelination may help in the development of novel therapeutic strategies for demyelinating diseases. In this review, we focus on the molecular mechanisms controlling the differentiation of oligodendrocytes during remyelination, and we discuss the function of astrocytes and microglia in animal models of demyelinating diseases.
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Gacem, Nadjet, and Brahim Nait-Oumesmar. "Oligodendrocyte Development and Regenerative Therapeutics in Multiple Sclerosis." Life 11, no. 4 (2021): 327. http://dx.doi.org/10.3390/life11040327.
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Myelination by oligodendrocytes (OLs) is an important biological process essential for central nervous system (CNS) development and functions. Oligodendroglial lineage cells undergo several morphological and molecular changes at different stages of their lineage progression into myelinating OLs. The transition steps of the oligodendrocyte progenitor cells (OPCs) to myelinating oligodendrocytes are defined by a specific pattern of regulated gene expression, which is under the control of coordinated signaling pathways. Any abnormal development, loss or failure of oligodendrocytes to myelinate axons can lead to several neurodegenerative diseases like multiple sclerosis (MS). MS is characterized by inflammation and demyelination, and current treatments target only the immune component of the disease, but have little impact on remyelination. Recently, several pharmacological compounds enhancing remyelination have been identified and some of them are in clinical trials. Here, we will review the current knowledge on oligodendrocyte differentiation, myelination and remyelination. We will focus on MS as a pathological condition, the most common chronic inflammatory demyelinating disease of the CNS in young adults.
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Ghoumari, Abdel Mouman, Charly Abi Ghanem, Narimène Asbelaoui, Michael Schumacher, and Rashad Hussain. "Roles of Progesterone, Testosterone and Their Nuclear Receptors in Central Nervous System Myelination and Remyelination." International Journal of Molecular Sciences 21, no. 9 (2020): 3163. http://dx.doi.org/10.3390/ijms21093163.
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Progesterone and testosterone, beyond their roles as sex hormones, are neuroactive steroids, playing crucial regulatory functions within the nervous system. Among these, neuroprotection and myelin regeneration are important ones. The present review aims to discuss the stimulatory effects of progesterone and testosterone on the process of myelination and remyelination. These effects have been demonstrated in vitro (i.e., organotypic cultures) and in vivo (cuprizone- or lysolecithin-induced demyelination and experimental autoimmune encephalomyelitis (EAE)). Both steroids stimulate myelin formation and regeneration by acting through their respective intracellular receptors: progesterone receptors (PR) and androgen receptors (AR). Activation of these receptors results in multiple events involving direct transcription and translation, regulating general homeostasis, cell proliferation, differentiation, growth and myelination. It also ameliorates immune response as seen in the EAE model, resulting in a significant decrease in inflammation leading to a fast recovery. Although natural progesterone and testosterone have a therapeutic potential, their synthetic derivatives—the 19-norprogesterone (nestorone) and 7α-methyl-nortestosterone (MENT), already used as hormonal contraception or in postmenopausal hormone replacement therapies, may offer enhanced benefits for myelin repair. We summarize here a recent advancement in the field of myelin biology, to treat demyelinating disorders using the natural as well as synthetic analogs of progesterone and testosterone.
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Blakemore, William F., and Robin J. M. Franklin. "Transplantation Options for Therapeutic Central Nervous System Remyelination." Cell Transplantation 9, no. 2 (2000): 289–94. http://dx.doi.org/10.1177/096368970000900214.
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Persistent demyelination, in addition to being the major pathology of multiple sclerosis and the leucodystrophies, is also a feature of spinal cord trauma where there is evidence that it contributes to the functional deficit. In experimental animals it is possible to remyelinate demyelinated CNS axons by transplanting cultures containing central or peripheral myelinogenic cells. Using functional testing we have been able to show that transplant-mediated remyelination results in restoration of function lost as a consequence of demyelination. Glial cell transplantation may therefore provide a therapeutic strategy for remyelinating areas of chronic demyelination. This article reviews issues that have to be addressed before glial transplantation can be undertaken in humans. These include: what cells to use, where would the cells come from, and can we predict how much remyelination will be achieved? It concludes that the most promising approach will be to use neural multipotential stem cells isolated from embryonic CNS, expanded in vitro as neurospheres and then committed to oligodendrocyte lineage differentiation prior to implantation. However, even with such preparations, which have considerable myelinating potential, the extent of remyelination that will be achieved cannot currently be predicted with any degree of certainty.
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Maheshwari, Anurag, Kris Janssens, Jeroen Bogie, et al. "Local Overexpression of Interleukin-11 in the Central Nervous System Limits Demyelination and Enhances Remyelination." Mediators of Inflammation 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/685317.
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Demyelination is one of the pathological hallmarks of multiple sclerosis (MS). To date, no therapy is available which directly potentiates endogenous remyelination. Interleukin-11 (IL-11), a member of the gp130 family of cytokines, is upregulated in MS lesions. Systemic IL-11 treatment was shown to ameliorate clinical symptoms in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. IL-11 modulates immune cells and protects oligodendrocytesin vitro. In this study, the cuprizone-induced demyelination mouse model was used to elucidate effects of IL-11 on de- and remyelination, independent of the immune response. Prophylactic-lentiviral- (LV-) mediated overexpression of IL-11 in mouse brain significantly limited acute demyelination, which was accompanied with the preservation of CC1+mature oligodendrocytes (OLs) and a decrease in microglial activation (Mac-2+). We further demonstrated that IL-11 directly reduces myelin phagocytosisin vitro. When IL-11 expressing LV was therapeutically applied in animals with extensive demyelination, a significant enhancement of remyelination was observed as demonstrated by Luxol Fast Blue staining and electron microscopy imaging. Our results indicate that IL-11 promotes maturation of NG2+OPCs into myelinating CC1+OLs and may thus explain the enhanced remyelination. Overall, we demonstrate that IL-11 is of therapeutic interest for MS and other demyelinating diseases by limiting demyelination and promoting remyelination.
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Del Giovane, Alice, and Antonella Ragnini-Wilson. "Targeting Smoothened as a New Frontier in the Functional Recovery of Central Nervous System Demyelinating Pathologies." International Journal of Molecular Sciences 19, no. 11 (2018): 3677. http://dx.doi.org/10.3390/ijms19113677.
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Myelin sheaths on vertebrate axons provide protection, vital support and increase the speed of neuronal signals. Myelin degeneration can be caused by viral, autoimmune or genetic diseases. Remyelination is a natural process that restores the myelin sheath and, consequently, neuronal function after a demyelination event, preventing neurodegeneration and thereby neuron functional loss. Pharmacological approaches to remyelination represent a promising new frontier in the therapy of human demyelination pathologies and might provide novel tools to improve adaptive myelination in aged individuals. Recent phenotypical screens have identified agonists of the atypical G protein-coupled receptor Smoothened and inhibitors of the glioma-associated oncogene 1 as being amongst the most potent stimulators of oligodendrocyte precursor cell (OPC) differentiation in vitro and remyelination in the central nervous system (CNS) of mice. Here, we discuss the current state-of-the-art of studies on the role of Sonic Hedgehog reactivation during remyelination, referring readers to other reviews for the role of Hedgehog signaling in cancer and stem cell maintenance.
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Fletcher, Jessica, Simon Murray, and Junhua Xiao. "Brain-Derived Neurotrophic Factor in Central Nervous System Myelination: A New Mechanism to Promote Myelin Plasticity and Repair." International Journal of Molecular Sciences 19, no. 12 (2018): 4131. http://dx.doi.org/10.3390/ijms19124131.
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Brain-derived neurotrophic factor (BDNF) plays vitally important roles in neural development and plasticity in both health and disease. Recent studies using mutant mice to selectively manipulate BDNF signalling in desired cell types, in combination with animal models of demyelinating disease, have demonstrated that BDNF not only potentiates normal central nervous system myelination in development but enhances recovery after myelin injury. However, the precise mechanisms by which BDNF enhances myelination in development and repair are unclear. Here, we review some of the recent progress made in understanding the influence BDNF exerts upon the myelinating process during development and after injury, and discuss the cellular and molecular mechanisms underlying its effects. In doing so, we raise new questions for future research.
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Kalafatakis, Ilias, Maria Savvaki, Theodora Velona, and Domna Karagogeos. "Implication of Contactins in Demyelinating Pathologies." Life 11, no. 1 (2021): 51. http://dx.doi.org/10.3390/life11010051.
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Demyelinating pathologies comprise of a variety of conditions where either central or peripheral myelin is attacked, resulting in white matter lesions and neurodegeneration. Myelinated axons are organized into molecularly distinct domains, and this segregation is crucial for their proper function. These defined domains are differentially affected at the different stages of demyelination as well as at the lesion and perilesion sites. Among the main players in myelinated axon organization are proteins of the contactin (CNTN) group of the immunoglobulin superfamily (IgSF) of cell adhesion molecules, namely Contactin-1 and Contactin-2 (CNTN1, CNTN2). The two contactins perform their functions through intermolecular interactions, which are crucial for myelinated axon integrity and functionality. In this review, we focus on the implication of these two molecules as well as their interactors in demyelinating pathologies in humans. At first, we describe the organization and function of myelinated axons in the central (CNS) and the peripheral (PNS) nervous system, further analyzing the role of CNTN1 and CNTN2 as well as their interactors in myelination. In the last section, studies showing the correlation of the two contactins with demyelinating pathologies are reviewed, highlighting the importance of these recognition molecules in shaping the function of the nervous system in multiple ways.
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Velasco-Estevez, Maria, Nina Koch, Ilona Klejbor, et al. "EBI2 Is Temporarily Upregulated in MO3.13 Oligodendrocytes during Maturation and Regulates Remyelination in the Organotypic Cerebellar Slice Model." International Journal of Molecular Sciences 22, no. 9 (2021): 4342. http://dx.doi.org/10.3390/ijms22094342.
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The EBI2 receptor regulates the immune system and is expressed in various immune cells including B and T lymphocytes. It is also expressed in astrocytes in the central nervous system (CNS) where it regulates pro-inflammatory cytokine release, cell migration and protects from chemically induced demyelination. Its signaling and expression are implicated in various diseases including multiple sclerosis, where its expression is increased in infiltrating immune cells in the white matter lesions. Here, for the first time, the EBI2 protein in the CNS cells in the human brain was examined. The function of the receptor in MO3.13 oligodendrocytes, as well as its role in remyelination in organotypic cerebellar slices, were investigated. Human brain sections were co-stained for EBI2 receptor and various markers of CNS-specific cells and the human oligodendrocyte cell line MO3.13 was used to investigate changes in EBI2 expression and cellular migration. Organotypic cerebellar slices prepared from wild-type and cholesterol 25-hydroxylase knock-out mice were used to study remyelination following lysophosphatidylcholine (LPC)-induced demyelination. The data showed that EBI2 receptor is present in OPCs but not in myelinating oligodendrocytes in the human brain and that EBI2 expression is temporarily upregulated in maturing MO3.13 oligodendrocytes. Moreover, we show that migration of MO3.13 cells is directly regulated by EBI2 and that its signaling is necessary for remyelination in cerebellar slices post-LPC-induced demyelination. The work reported here provides new information on the expression and role of EBI2 in oligodendrocytes and myelination and provides new tools for modulation of oligodendrocyte biology and therapeutic approaches for demyelinating diseases.
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Schultz, Verena, Stephanie L. Cumberworth, Quan Gu, et al. "Zika Virus Infection Leads to Demyelination and Axonal Injury in Mature CNS Cultures." Viruses 13, no. 1 (2021): 91. http://dx.doi.org/10.3390/v13010091.
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Understanding how Zika virus (Flaviviridae; ZIKV) affects neural cells is paramount in comprehending pathologies associated with infection. Whilst the effects of ZIKV in neural development are well documented, impact on the adult nervous system remains obscure. Here, we investigated the effects of ZIKV infection in established mature myelinated central nervous system (CNS) cultures. Infection incurred damage to myelinated fibers, with ZIKV-positive cells appearing when myelin damage was first detected as well as axonal pathology, suggesting the latter was a consequence of oligodendroglia infection. Transcriptome analysis revealed host factors that were upregulated during ZIKV infection. One such factor, CCL5, was validated in vitro as inhibiting myelination. Transferred UV-inactivated media from infected cultures did not damage myelin and axons, suggesting that viral replication is necessary to induce the observed effects. These data show that ZIKV infection affects CNS cells even after myelination—which is critical for saltatory conduction and neuronal function—has taken place. Understanding the targets of this virus across developmental stages including the mature CNS, and the subsequent effects of infection of cell types, is necessary to understand effective time frames for therapeutic intervention.
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Schultz, Verena, Stephanie L. Cumberworth, Quan Gu, et al. "Zika Virus Infection Leads to Demyelination and Axonal Injury in Mature CNS Cultures." Viruses 13, no. 1 (2021): 91. http://dx.doi.org/10.3390/v13010091.
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Understanding how Zika virus (Flaviviridae; ZIKV) affects neural cells is paramount in comprehending pathologies associated with infection. Whilst the effects of ZIKV in neural development are well documented, impact on the adult nervous system remains obscure. Here, we investigated the effects of ZIKV infection in established mature myelinated central nervous system (CNS) cultures. Infection incurred damage to myelinated fibers, with ZIKV-positive cells appearing when myelin damage was first detected as well as axonal pathology, suggesting the latter was a consequence of oligodendroglia infection. Transcriptome analysis revealed host factors that were upregulated during ZIKV infection. One such factor, CCL5, was validated in vitro as inhibiting myelination. Transferred UV-inactivated media from infected cultures did not damage myelin and axons, suggesting that viral replication is necessary to induce the observed effects. These data show that ZIKV infection affects CNS cells even after myelination—which is critical for saltatory conduction and neuronal function—has taken place. Understanding the targets of this virus across developmental stages including the mature CNS, and the subsequent effects of infection of cell types, is necessary to understand effective time frames for therapeutic intervention.
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Goudarzi, Salman, Andrea Rivera, Arthur M. Butt, and Sassan Hafizi. "Gas6 Promotes Oligodendrogenesis and Myelination in the Adult Central Nervous System and After Lysolecithin-Induced Demyelination." ASN Neuro 8, no. 5 (2016): 175909141666843. http://dx.doi.org/10.1177/1759091416668430.
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Yoo, Seung-Wan, Amit Agarwal, Matthew D. Smith, et al. "Inhibition of neutral sphingomyelinase 2 promotes remyelination." Science Advances 6, no. 40 (2020): eaba5210. http://dx.doi.org/10.1126/sciadv.aba5210.
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Myelination requires a highly organized synthesis of multiple lipid species that regulate myelin curvature and compaction. For reasons that are not understood, central nervous system remyelinated axons often have thin myelin sheaths with a disorganized structure susceptible to secondary demyelination. We found that expression of the sphingomyelin hydrolase neutral sphingomyelinase 2 (nSMase2) during the differentiation of oligodendrocyte progenitor cells (OPCs) to myelinating oligodendrocytes changes their response to inflammatory cytokines. OPCs do not express nSMase2 and exhibit a protective/regenerative response to tumor necrosis factor–α and interleukin-1β. Oligodendrocytes express nSMase2 and exhibit a stress response to cytokine challenge that includes an overproduction of ceramide, a sphingolipid that forms negative curvatures in membranes. Pharmacological inhibition or genetic deletion of nSMase2 in myelinating oligodendrocytes normalized the ceramide content of remyelinated fibers and increased thickness and compaction. These results suggest that inhibition of nSMase2 could improve the quality of myelin and stabilize structure.
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Rosko, Lauren, Tyler Gentile, Victoria Smith, and Jeffrey K. Huang. "86583 The role of creatine in developmental myelination and remyelination." Journal of Clinical and Translational Science 5, s1 (2021): 99. http://dx.doi.org/10.1017/cts.2021.655.
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ABSTRACT IMPACT: This study highlights the importance of creatine in developmental myelination and remyelination to investigate whether creatine provides a therapeutic value during a central nervous system (CNS) demyelinating insult with a potential value in patients with Multiple Sclerosis. OBJECTIVES/GOALS: Creatine is vital for ATP buffering in the brain. Interestingly, the cells that generate myelin express the main enzyme for creatine synthesis, Gamt. Patients with Gamt mutations display intellectual delays and impaired myelination. Therefore, we hypothesize that creatine is essential for developmental myelination and improves remyelination. METHODS/STUDY POPULATION: To investigate these hypotheses, we developed a new transgenic mouse model with LoxP sites flanking exons 2-6 of the guanidinoacetate methyltransferase (Gamt) gene where excision leads to expression of a green fluorescent tag allowing us to track the cells normally expressing Gamt. We used immunohistochemistry techniques to look at the corpus callosum, the main white matter tract in the brain, and evaluate the number of oligodendrocytes (OL), glial cells responsible for generating myelin. We also used the cuprizone model of toxic demyelination to investigate whether dietary creatine and cyclocreatine, a planar analog of creatine that more efficiently crosses the blood-brain barrier, can enhance remyelination. RESULTS/ANTICIPATED RESULTS: In this mouse model, we show a 95% (+/-0.47%, n=3) co-localization of Gamt within mature OL during postnatal (P) day P14 with no co-localization in neurons or other glial cells. This suggests that mature OL are the main cells making creatine in the CNS. Next, we show that knocking out Gamt leads to a significant reduction in OL in the developing corpus callosum, at P14 and P21 (P14: 0.007, n=3; P21: 0.04, n=3). We also show that creatine supplementation causes a trending increase in mature OL density in the corpus callosum following cuprizone demyelination (2% creatine; p=0.052; n=4). Interestingly, cyclocreatine supplementation significantly increased mature OL density in the corpus callosum following cuprizone demyelination (0.1% cyclocreatine; p=0.034; n=4). DISCUSSION/SIGNIFICANCE OF FINDINGS: These studies highlight the important role creatine plays in developmental myelination and remyelination to investigate whether creatine and cyclocreatine provide a therapeutic value during a CNS demyelinating insult. This work investigates a potential therapeutic value of creatine to patients with Multiple Sclerosis.
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Rinaldi, Simon, Alexander Davies, Janev Fehmi, et al. "Overlapping central and peripheral nervous system syndromes in MOG antibody–associated disorders." Neurology - Neuroimmunology Neuroinflammation 8, no. 1 (2020): e924. http://dx.doi.org/10.1212/nxi.0000000000000924.
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ObjectiveAntibodies to myelin oligodendrocyte glycoprotein (MOG) are associated with CNS demyelination inclusive of optic neuritis (ON) and transverse myelitis (TM). To examine whether peripheral nervous system (PNS) involvement is associated with MOG antibody–associated disorders (MOGAD), we performed detailed characterization of an Australasian MOGAD cohort.MethodsUsing a live cell–based assay, we diagnosed 271 adults with MOGAD (2013–2018) and performed detailed clinical and immunologic characterization on those with likely PNS involvement.ResultsWe identified 19 adults with MOGAD and PNS involvement without prior TM. All patients had CNS involvement including ON (bilateral [n = 3], unilateral [n = 3], and recurrent [n = 7]), a cortical lesion (n = 1), meningoencephalitis (n = 1), and subsequent TM (n = 4). Clinical phenotyping and neurophysiology were consistent with acute inflammatory demyelinating polyneuropathy (n = 1), myeloradiculitis (n = 3), multifocal motor neuropathy (n = 1), brachial neuritis (n = 2), migrant sensory neuritis (n = 3), and paresthesia and/or radicular limb pain (n = 10). Onset MRI spine was consistent with myeloradiculitis with nerve root enhancement in 3/19 and normal in 16/19. Immunotherapy resulted in partial/complete PNS symptom resolution in 12/15 (80%) (steroids and/or IV immunoglobulin n = 9, rituximab n = 2, and plasmapheresis n = 1). We identified serum antibodies targeting neurofascin 155, contactin-associated protein 2, or GM1 in 4/16 patients with MOGAD PNS compared with 0/30 controls (p = 0.01). There was no binding to novel cell surface antigens using an in vitro myelinating sensory neuronal coculture model.ConclusionsMyeloradiculitis, combined central and peripheral demyelination syndromes, and inflammatory neuropathies may be associated with MOGAD and may be immunotherapy responsive. We identified a subgroup who may have pathology mediated by coexistent autoantibodies.
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de la Vega Gallardo, Nira, Rosana Penalva, Marie Dittmer, et al. "Dynamic CCN3 expression in the murine CNS does not confer essential roles in myelination or remyelination." Proceedings of the National Academy of Sciences 117, no. 30 (2020): 18018–28. http://dx.doi.org/10.1073/pnas.1922089117.
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CCN3 is a matricellular protein that promotes oligodendrocyte progenitor cell differentiation and myelination in vitro and ex vivo. CCN3 is therefore a candidate of interest in central nervous system (CNS) myelination and remyelination, and we sought to investigate the expression and role of CCN3 during these processes. We found CCN3 to be expressed predominantly by neurons in distinct areas of the CNS, primarily the cerebral cortex, hippocampus, amygdala, suprachiasmatic nuclei, anterior olfactory nuclei, and spinal cord gray matter. CCN3 was transiently up-regulated following demyelination in the brain of cuprizone-fed mice and spinal cord lesions of mice injected with lysolecithin. However, CCN3−/−mice did not exhibit significantly different numbers of oligodendroglia or differentiated oligodendrocytes in the healthy or remyelinating CNS, compared to WT controls. These results suggest that despite robust and dynamic expression in the CNS, CCN3 is not required for efficient myelination or remyelination in the murine CNS in vivo.
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Tepavčević, Vanja. "Oligodendroglial Energy Metabolism and (re)Myelination." Life 11, no. 3 (2021): 238. http://dx.doi.org/10.3390/life11030238.
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Central nervous system (CNS) myelin has a crucial role in accelerating the propagation of action potentials and providing trophic support to the axons. Defective myelination and lack of myelin regeneration following demyelination can both lead to axonal pathology and neurodegeneration. Energy deficit has been evoked as an important contributor to various CNS disorders, including multiple sclerosis (MS). Thus, dysregulation of energy homeostasis in oligodendroglia may be an important contributor to myelin dysfunction and lack of repair observed in the disease. This article will focus on energy metabolism pathways in oligodendroglial cells and highlight differences dependent on the maturation stage of the cell. In addition, it will emphasize that the use of alternative energy sources by oligodendroglia may be required to save glucose for functions that cannot be fulfilled by other metabolites, thus ensuring sufficient energy input for both myelin synthesis and trophic support to the axons. Finally, it will point out that neuropathological findings in a subtype of MS lesions likely reflect defective oligodendroglial energy homeostasis in the disease.
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Chen, Civia Z., Björn Neumann, Sarah Förster, and Robin J. M. Franklin. "Schwann cell remyelination of the central nervous system: why does it happen and what are the benefits?" Open Biology 11, no. 1 (2021): 200352. http://dx.doi.org/10.1098/rsob.200352.
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Myelin sheaths, by supporting axonal integrity and allowing rapid saltatory impulse conduction, are of fundamental importance for neuronal function. In response to demyelinating injuries in the central nervous system (CNS), oligodendrocyte progenitor cells (OPCs) migrate to the lesion area, proliferate and differentiate into new oligodendrocytes that make new myelin sheaths. This process is termed remyelination. Under specific conditions, demyelinated axons in the CNS can also be remyelinated by Schwann cells (SCs), the myelinating cell of the peripheral nervous system. OPCs can be a major source of these CNS-resident SCs—a surprising finding given the distinct embryonic origins, and physiological compartmentalization of the peripheral and central nervous system. Although the mechanisms and cues governing OPC-to-SC differentiation remain largely undiscovered, it might nevertheless be an attractive target for promoting endogenous remyelination. This article will (i) review current knowledge on the origins of SCs in the CNS, with a particular focus on OPC to SC differentiation, (ii) discuss the necessary criteria for SC myelination in the CNS and (iii) highlight the potential of using SCs for myelin regeneration in the CNS.
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Cheli, Veronica T., J. Correale, Pablo M. Paez, and Juana M. Pasquini. "Iron Metabolism in Oligodendrocytes and Astrocytes, Implications for Myelination and Remyelination." ASN Neuro 12 (January 2020): 175909142096268. http://dx.doi.org/10.1177/1759091420962681.
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Iron is a key nutrient for normal central nervous system (CNS) development and function; thus, iron deficiency as well as iron excess may result in harmful effects in the CNS. Oligodendrocytes and astrocytes are crucial players in brain iron equilibrium. However, the mechanisms of iron uptake, storage, and efflux in oligodendrocytes and astrocytes during CNS development or under pathological situations such as demyelination are not completely understood. In the CNS, iron is directly required for myelin production as a cofactor for enzymes involved in ATP, cholesterol and lipid synthesis, and oligodendrocytes are the cells with the highest iron levels in the brain which is linked to their elevated metabolic needs associated with the process of myelination. Unlike oligodendrocytes, astrocytes do not have a high metabolic requirement for iron. However, these cells are in close contact with blood vessel and have a strong iron transport capacity. In several pathological situations, changes in iron homoeostasis result in altered cellular iron distribution and accumulation and oxidative stress. In inflammatory demyelinating diseases such as multiple sclerosis, reactive astrocytes accumulate iron and upregulate iron efflux and influx molecules, which suggest that they are outfitted to take up and safely recycle iron. In this review, we will discuss the participation of oligodendrocytes and astrocytes in CNS iron homeostasis. Understanding the molecular mechanisms of iron uptake, storage, and efflux in oligodendrocytes and astrocytes is necessary for planning effective strategies for iron management during CNS development as well as for the treatment of demyelinating diseases.
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Chen, Yan, Wenjie Guo, Liangzhi Xu та ін. "17β-Estradiol Promotes Schwann Cell Proliferation and Differentiation, Accelerating Early Remyelination in a Mouse Peripheral Nerve Injury Model". BioMed Research International 2016 (2016): 1–13. http://dx.doi.org/10.1155/2016/7891202.
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Estrogen induces oligodendrocyte remyelination in response to demyelination in the central nervous system. Our objective was to determine the effects of 17β-estradiol (E2) on Schwann cell function and peripheral nerve remyelination after injury. Adult male C57BL/6J mice were used to prepare the sciatic nerve transection injury model and were randomly categorized into control and E2 groups. To study myelination in vitro, dorsal root ganglion (DRG) explant culture was prepared using 13.5-day-old mouse embryos. Primary Schwann cells were isolated from the sciatic nerves of 1- to 3-day-old Sprague–Dawley rats. Immunostaining for myelin basic protein (MBP) expression and toluidine blue staining for myelin sheaths demonstrated that E2 treatment accelerates early remyelination in the “nerve bridge” region between the proximal and distal stumps of the transection injury site in the mouse sciatic nerve. The 5-bromo-2′-deoxyuridine incorporation assay revealed that E2 promotes Schwann cell proliferation in the bridge region and in the primary culture, which is blocked using AKT inhibitor MK2206. The in vitro myelination in the DRG explant culture determined showed that the MBP expression in the E2-treated group is higher than that in the control group. These results show that E2 promotes Schwann cell proliferation and myelination depending on AKT activation.
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Tondo, Giacomo, Daniela Perani, and Cristoforo Comi. "TAM Receptor Pathways at the Crossroads of Neuroinflammation and Neurodegeneration." Disease Markers 2019 (September 15, 2019): 1–13. http://dx.doi.org/10.1155/2019/2387614.
Full textAbstract:
Increasing evidence suggests that pathogenic mechanisms underlying neurodegeneration are strongly linked with neuroinflammatory responses. Tyro3, Axl, and Mertk (TAM receptors) constitute a subgroup of the receptor tyrosine kinase family, cell surface receptors which transmit signals from the extracellular space to the cytoplasm and nucleus. TAM receptors and the corresponding ligands, Growth Arrest Specific 6 and Protein S, are expressed in different tissues, including the nervous system, playing complex roles in tissue repair, inflammation and cell survival, proliferation, and migration. In the nervous system, TAM receptor signalling modulates neurogenesis and neuronal migration, synaptic plasticity, microglial activation, phagocytosis, myelination, and peripheral nerve repair, resulting in potential interest in neuroinflammatory and neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Multiple Sclerosis. In Alzheimer and Parkinson diseases, a role of TAM receptors in neuronal survival and pathological protein aggregate clearance has been suggested, while in Multiple Sclerosis TAM receptors are involved in myelination and demyelination processes. To better clarify roles and pathways involving TAM receptors may have important therapeutic implications, given the fine modulation of multiple molecular processes which could be reached. In this review, we summarise the roles of TAM receptors in the central nervous system, focusing on the regulation of immune responses and microglial activities and analysing in vitro and in vivo studies regarding TAM signalling involvement in neurodegeneration.
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Rosko, Lauren, Victoria N. Smith, and Jeffrey K. Huang. "4492 The role of creatine in developmental myelination and remyelination." Journal of Clinical and Translational Science 4, s1 (2020): 103. http://dx.doi.org/10.1017/cts.2020.318.
Full textAbstract:
OBJECTIVES/GOALS: Oligodendrocytes (OL) are glial cells of the central nervous system (CNS) responsible for the energy demanding task of generating myelin sheaths during development and remyelination after demyelinating injury. One metabolite shown to significantly increase ATP production in OL is the nitrogenous organic acid, creatine. Creatine plays an essential role in ATP buffering within tissues with highly fluctuating energy demands such as brain and muscle. Interestingly, mature OL, which are the cells capable of myelin production, are the main cells in the CNS expressing the rate-limiting enzyme for creatine synthesis, guanidinoacetate methyltransferase (Gamt). Patients with mutations in Gamt display intellectual disabilities, impaired myelination and seizures. Therefore, we hypothesize that creatine may be essential for developmental myelination and improve remyelination. METHODS/STUDY POPULATION: To investigate these hypotheses, we developed a new transgenic mouse model with LoxP sites flanking exons 2-6 of the Gamt gene where excision leads to expression of a green fluorescent tag allowing us to track the cells normally expressing Gamt. RESULTS/ANTICIPATED RESULTS: In this mouse model, we show a 95% (±0.47%, n = 3) co-localization of Gamt within mature OL during postnatal (P) day P14. Next, we show that knocking out Gamt leads to a significant reduction in OL in the major CNS white matter tract, the corpus callosum, at P14 and P21 (P14: 0.007, n = 3; P21: 0.04, n = 3). Here, we also investigate whether dietary creatine can enhance remyelination in the cuprizone model of toxic demyelination. DISCUSSION/SIGNIFICANCE OF IMPACT: These studies highlight the important role creatine plays in developmental myelination and investigate whether creatine can provide a therapeutic value during a CNS demyelinating insult.
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Russell, Lauren N., and Kyle J. Lampe. "Engineering Biomaterials to Influence Oligodendroglial Growth, Maturation, and Myelin Production." Cells Tissues Organs 202, no. 1-2 (2016): 85–101. http://dx.doi.org/10.1159/000446645.
Full textAbstract:
Millions of people suffer from damage or disease to the nervous system that results in a loss of myelin, such as through a spinal cord injury or multiple sclerosis. Diminished myelin levels lead to further cell death in which unmyelinated neurons die. In the central nervous system, a loss of myelin is especially detrimental because of its poor ability to regenerate. Cell therapies such as stem or precursor cell injection have been investigated as stem cells are able to grow and differentiate into the damaged cells; however, stem cell injection alone has been unsuccessful in many areas of neural regeneration. Therefore, researchers have begun exploring combined therapies with biomaterials that promote cell growth and differentiation while localizing cells in the injured area. The regrowth of myelinating oligodendrocytes from neural stem cells through a biomaterials approach may prove to be a beneficial strategy following the onset of demyelination. This article reviews recent advancements in biomaterial strategies for the differentiation of neural stem cells into oligodendrocytes, and presents new data indicating appropriate properties for oligodendrocyte precursor cell growth. In some cases, an increase in oligodendrocyte differentiation alongside neurons is further highlighted for functional improvements where the biomaterial was then tested for increased myelination both in vitro and in vivo.
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Calzà, Laura, Mercedes Fernandez, and Luciana Giardino. "Cellular approaches to central nervous system remyelination stimulation: thyroid hormone to promote myelin repair via endogenous stem and precursor cells." Journal of Molecular Endocrinology 44, no. 1 (2009): 13–23. http://dx.doi.org/10.1677/jme-09-0067.
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Brain and spinal cord repair is a very difficult task in view of the extremely limited repair capability of the mature central nervous system (CNS). Thus, cellular therapies are regarded as a new frontier for both acute and chronic neurological diseases characterized by neuron or oligodendroglia degeneration. Although cell replacement has been considered as the primary goal of such approaches, in recent years greater attention has been devoted to the possibility that new undifferentiated cells in damaged nervous tissue might also act in autocrine–paracrine fashion, regulating the micro-environment through the release of growth factor and cytokines, also regulating immune response and local inflammation. In this review, repair of demyelinating disease using endogenous cells will be discussed in view of the critical role played by thyroid hormones (THs) during developmental myelination, focusing on the following points: 1) endogenous stem and precursor cells during demyelinating diseases; 2) TH homeostasis in the CNS; 3) cellular and molecular mechanism regulated by TH during developmental myelination and 4) a working hypothesis to develop a rationale for the use of THs to improve remyelination through endogenous stem and precursor cells in the course of demyelinating diseases.
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Campbell, Graham R., and Don J. Mahad. "Mitochondria as Crucial Players in Demyelinated Axons: Lessons from Neuropathology and Experimental Demyelination." Autoimmune Diseases 2011 (2011): 1–9. http://dx.doi.org/10.4061/2011/262847.
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Mitochondria are the most efficient producers of energy in the form of ATP. Energy demands of axons, placed at relatively great distances from the neuronal cell body, are met by mitochondria, which when functionally compromised, produce reactive oxygen species (ROS) in excess. Axons are made metabolically efficient by myelination, which enables saltatory conduction. The importance of mitochondria for maintaining the structural integrity of myelinated axons is illustrated by neuroaxonal degeneration in primary mitochondrial disorders. When demyelinated, the compartmentalisation of ion channels along axons is disrupted. The redistribution of electrogenic machinery is thought to increase the energy demand of demyelinated axons. We review related studies that focus on mitochondria within unmyelinated, demyelinated and dysmyelinated axons in the central nervous system. Based on neuropathological observations we propose the increase in mitochondrial presence within demyelinated axons as an adaptive process to the increased energy need. An increased presence of mitochondria would also increase the capacity to produce deleterious agents such as ROS when functionally compromised. Given the lack of direct evidence of a beneficial or harmful effect of mitochondrial changes, the precise role of increased mitochondrial presence within axons due to demyelination needs to be further explored in experimental demyelinationin-vivoandin-vitro.
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Avila, Mirla, Arpana Bansal, John Culberson, and Alan N. Peiris. "The Role of Sex Hormones in Multiple Sclerosis." European Neurology 80, no. 1-2 (2018): 93–99. http://dx.doi.org/10.1159/000494262.
Full textAbstract:
Multiple sclerosis (MS) is a chronic inflammatory demyelination disorder with an immune-mediated pathophysiology that affects the central nervous system (CNS). Like other autoimmune conditions, it has a predilection for female gender. This suggests a gender bias and a possible hormonal association. Inflammation and demyelination are hallmarks of MS. Oligodendrocytes are the myelinating cells of the CNS and these continue to be generated by oligodendrocyte precursor cells (OPCs). The process of remyelination represents a major form of plasticity in the developing adult CNS. Remyelination does occur in MS, but the process is largely inadequate and/or incomplete. Current treatment strategies primarily focus on reducing inflammation or immunosuppression, but there is a need for more extensive research on re-myelination as a possible mechanism of treatment. Previous studies have shown that pregnancy leads to an increase in OPC proliferation, oligodendrocyte generation and the number of myelinated axons in the maternal CNS. Studies have also suggested that this remyelination is possibly mediated by estriol. Sex hormones in particular have been shown to have an immuno-protective effect in TH1-driven autoimmunity diseases. The aim of our article is to review the available research on sex hormone-specific immune modulatory effects, assess its remyelination potential in MS, and suggest a future path for more extensive research on sex hormone as a target for therapeutics in MS.
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Stadelmann, Christine, Sebastian Timmler, Alonso Barrantes-Freer, and Mikael Simons. "Myelin in the Central Nervous System: Structure, Function, and Pathology." Physiological Reviews 99, no. 3 (2019): 1381–431. http://dx.doi.org/10.1152/physrev.00031.2018.
Full textAbstract:
Oligodendrocytes generate multiple layers of myelin membrane around axons of the central nervous system to enable fast and efficient nerve conduction. Until recently, saltatory nerve conduction was considered the only purpose of myelin, but it is now clear that myelin has more functions. In fact, myelinating oligodendrocytes are embedded in a vast network of interconnected glial and neuronal cells, and increasing evidence supports an active role of oligodendrocytes within this assembly, for example, by providing metabolic support to neurons, by regulating ion and water homeostasis, and by adapting to activity-dependent neuronal signals. The molecular complexity governing these interactions requires an in-depth molecular understanding of how oligodendrocytes and axons interact and how they generate, maintain, and remodel their myelin sheaths. This review deals with the biology of myelin, the expanded relationship of myelin with its underlying axons and the neighboring cells, and its disturbances in various diseases such as multiple sclerosis, acute disseminated encephalomyelitis, and neuromyelitis optica spectrum disorders. Furthermore, we will highlight how specific interactions between astrocytes, oligodendrocytes, and microglia contribute to demyelination in hereditary white matter pathologies.
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Gemert, Marciavan, and James Killeen. "Chemically Induced Myelinopathies." International Journal of Toxicology 17, no. 3 (1998): 231–75. http://dx.doi.org/10.1080/109158198226567.
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The diverse, structurally unrelated chemicals that cause toxic myelinopathies have been investigated and can be categorized into two types of primary demyelinators. Some demyelinating chemicals seem to leave intact the myeli-nating cells (oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system), while others damage the myelinating cells as well as the myelin. The significance between the two is that with the myelinating cells still in tact, repair of the myelin sheath can occur. However, if the myelinating cells are destroyed, repair and reversal of the neuropathy may not occur. Histologically, these chemicals produce an edema of the white matter of the brain, and in some cases the peripheral nervous system, that appears spongy by light microscopy. By electron microscopy, vacuoles can be seen in the myelin surrounding axons. These vacuoles are characterized as fluid-filled separations (splitting) of myelin lamellae at the intraperiod line. In some cases these vacuoles can degenerate further to full demyelination, affecting conduction through those axons. Regeneration of the myelin layers can occur, and in some cases occurs at the same time other axons are undergoing toxic demyelination. Several of these chemicals, however, have been shown to increase cerebrospinal fluid pressure in the brain, optic nerve, and spinal cord, and/or intraneuronal pressure in the perineurium surrounding the axons in the peripheral nervous system. This increased pressure has been correlated with decreased conduction capacity through the axon, ischemia to the neuronal tissue from decreased blood flow because of pressure against the blood vessels, and, if unrelieved, permanent axonal damage. Several of these chemicals havebeen shown to inhibit oxidative phosphorylation, while others uncouple oxidative phosphorylation. One chemical appears to inhibit an enzyme critical to cholesterol synthesis, thus destabilizing myelin. Another hypothesis for a mechanism of action may be in the ability of these compounds to alter membrane permeability.
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Tepavčević, V., and W. F. Blakemore. "Glial grafting for demyelinating disease." Philosophical Transactions of the Royal Society B: Biological Sciences 360, no. 1461 (2005): 1775–95. http://dx.doi.org/10.1098/rstb.2005.1700.
Full textAbstract:
Remyelination of demyelinated central nervous system (CNS) axons is considered as a potential treatment for multiple sclerosis, and it has been achieved in experimental models of demyelination by transplantation of pro-myelinating cells. However, the experiments undertaken have not addressed the need for tissue-type matching in order to achieve graft-mediated remyelination since they were performed in conditions in which the chance for graft rejection was minimized. This article focuses on the factors determining survival of allogeneic oligodendrocyte lineage cells and their contribution to the remyelination of demyelinating CNS lesions. The immune status of the CNS as well as the suitability of different models of demyelination for graft rejection studies are discussed, and ways of enhancing allogeneic oligodendrocyte-mediated remyelination are presented. Finally, the effects of glial graft rejection on host remyelination are described, highlighting the potential benefits of the acute CNS inflammatory response for myelin repair.
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Graça, Dominguita Lühers, Eduardo Fernandes Bondan, Luis Antonio Violin Dias Pereira, Cristina Gevehr Fernandes, and Paulo César Maiorka. "Behaviour of oligodendrocytes and Schwann cells in an experimental model of toxic demyelination of the central nervous system." Arquivos de Neuro-Psiquiatria 59, no. 2B (2001): 358–61. http://dx.doi.org/10.1590/s0004-282x2001000300009.
Full textAbstract:
Oligodendrocytes and Schwann cells are engaged in myelin production, maintenance and repairing respectively in the central nervous system (CNS) and the peripheral nervous system (PNS). Whereas oligodendrocytes act only within the CNS, Schwann cells are able to invade the CNS in order to make new myelin sheaths around demyelinated axons. Both cells have some limitations in their activities, i.e. oligodendrocytes are post-mitotic cells and Schwann cells only get into the CNS in the absence of astrocytes. Ethidium bromide (EB) is a gliotoxic chemical that when injected locally within the CNS, induce demyelination. In the EB model of demyelination, glial cells are destroyed early after intoxication and Schwann cells are free to approach the naked central axons. In normal Wistar rats, regeneration of lost myelin sheaths can be achieved as early as thirteen days after intoxication; in Wistar rats immunosuppressed with cyclophosphamide the process is delayed and in rats administered cyclosporine it may be accelerated. Aiming the enlightening of those complex processes, all events concerning the myelinating cells in an experimental model are herein presented and discussed.
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Bolton, Christopher, and Carolyn Paul. "Glutamate Receptors in Neuroinflammatory Demyelinating Disease." Mediators of Inflammation 2006 (2006): 1–12. http://dx.doi.org/10.1155/mi/2006/93684.
Full textAbstract:
Multiple sclerosis (MS) is a chronic demyelinating disease of the human central nervous system (CNS). The condition predominantly affects young adults and is characterised by immunological and inflammatory changes in the periphery and CNS that contribute to neurovascular disruption, haemopoietic cell invasion of target tissues, and demyelination of nerve fibres which culminate in neurological deficits that relapse and remit or are progressive. The main features of MS can be reproduced in the inducible animal counterpart, experimental autoimmune encephalomyelitis (EAE). The search for new MS treatments invariably employs EAE to determine drug activity and provide a rationale for exploring clinical efficacy. The preclinical development of compounds for MS has generally followed a conventional, immunotherapeutic route. However, over the past decade, a group of compounds that suppress EAE but have no apparent immunomodulatory activity have emerged. These drugs interact with the N-methyl-D-aspartate (NMDA) andα-amino-3-hydroxy-5-isoxazolepropionic acid (AMPA)/kainate family of glutamate receptors reported to control neurovascular permeability, inflammatory mediator synthesis, and resident glial cell functions including CNS myelination. The review considers the importance of the glutamate receptors in EAE and MS pathogenesis. The use of receptor antagonists to control EAE is also discussed together with the possibility of therapeutic application in demyelinating disease.
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Kerman, Bilal Ersen, Stéphane Genoud, Burcu Kurt Vatandaslar, et al. "Motoneuron expression profiling identifies an association between an axonal splice variant of HDGF-related protein 3 and peripheral myelination." Journal of Biological Chemistry 295, no. 34 (2020): 12233–46. http://dx.doi.org/10.1074/jbc.ra120.014329.
Full textAbstract:
Disorders that disrupt myelin formation during development or in adulthood, such as multiple sclerosis and peripheral neuropathies, lead to severe pathologies, illustrating myelin's crucial role in normal neural functioning. However, although our understanding of glial biology is increasing, the signals that emanate from axons and regulate myelination remain largely unknown. To identify the core components of the myelination process, here we adopted a microarray analysis approach combined with laser-capture microdissection of spinal motoneurons during the myelinogenic phase of development. We identified neuronal genes whose expression was enriched during myelination and further investigated hepatoma-derived growth factor-related protein 3 (HRP3 or HDGFRP3). HRP3 was strongly expressed in the white matter fiber tracts of the peripheral (PNS) and central (CNS) nervous systems during myelination and remyelination in a cuprizone-induced demyelination model. The dynamic localization of HPR3 between axons and nuclei during myelination was consistent with its axonal localization during neuritogenesis. To study this phenomenon, we identified two splice variants encoded by the HRP3 gene: the canonical isoform HRP3-I and a newly recognized isoform, HRP3-II. HRP3-I remained solely in the nucleus, whereas HRP3-II displayed distinct axonal localization both before and during myelination. Interestingly, HRP3-II remained in the nuclei of unmyelinated neurons and glial cells, suggesting the existence of a molecular machinery that transfers it to and retains it in the axons of neurons fated for myelination. Overexpression of HRP3-II, but not of HRP3-I, increased Schwann cell numbers and myelination in PNS neuron–glia co-cultures. However, HRP3-II overexpression in CNS co-cultures did not alter myelination.
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Chesnut, Megan, Hélène Paschoud, Cendrine Repond, et al. "Human IPSC-Derived Model to Study Myelin Disruption." International Journal of Molecular Sciences 22, no. 17 (2021): 9473. http://dx.doi.org/10.3390/ijms22179473.
Full textAbstract:
Myelin is of vital importance to the central nervous system and its disruption is related to a large number of both neurodevelopmental and neurodegenerative diseases. The differences observed between human and rodent oligodendrocytes make animals inadequate for modeling these diseases. Although developing human in vitro models for oligodendrocytes and myelinated axons has been a great challenge, 3D cell cultures derived from iPSC are now available and able to partially reproduce the myelination process. We have previously developed a human iPSC-derived 3D brain organoid model (also called BrainSpheres) that contains a high percentage of myelinated axons and is highly reproducible. Here, we have further refined this technology by applying multiple readouts to study myelination disruption. Myelin was assessed by quantifying immunostaining/confocal microscopy of co-localized myelin basic protein (MBP) with neurofilament proteins as well as proteolipid protein 1 (PLP1). Levels of PLP1 were also assessed by Western blot. We identified compounds capable of inducing developmental neurotoxicity by disrupting myelin in a systematic review to evaluate the relevance of our BrainSphere model for the study of the myelination/demyelination processes. Results demonstrated that the positive reference compound (cuprizone) and two of the three potential myelin disruptors tested (Bisphenol A, Tris(1,3-dichloro-2-propyl) phosphate, but not methyl mercury) decreased myelination, while ibuprofen (negative control) had no effect. Here, we define a methodology that allows quantification of myelin disruption and provides reference compounds for chemical-induced myelin disruption.
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Muñoz-Esquivel, Jonathan, Peter Göttle, Lucinda Aguirre-Cruz, et al. "Sildenafil Inhibits Myelin Expression and Myelination of Oligodendroglial Precursor Cells." ASN Neuro 11 (January 2019): 175909141983244. http://dx.doi.org/10.1177/1759091419832444.
Full textAbstract:
Phosphodiesterases (PDEs) have previously been implicated in oligodendrocyte maturation and myelination of central nervous system axons. Sildenafil citrate is a phosphodiesterase inhibitor known to block PDE5, which also reduces inflammation in the experimental autoimmune encephalomyelitis demyelinating model. To find out whether this inhibitor might exert beneficial effects on central nervous system myelin repair activities, we investigated to what degree sildenafil modulates differentiation and maturation of cultured primary rat oligodendroglial precursor cells (OPCs). To this end, gene and protein expression of 2′,3′-cyclic-nucleotide 3′-phosphodiesterase, myelin basic protein, and myelin oligodendrocyte glycoprotein, as well as of negative regulators of myelin expression (Hes1, Hes5, Id2, Id4, Rock2, and p57Kip2) were measured in OPCs treated with sildenafil. Moreover, the subcellular distribution of the p57kip2 protein was determined after sildenafil treatment, as this revealed to be an early predictor of the oligodendroglial differentiation capacity. In vitro myelination assays were done to measure the myelination capacity of oligodendrocytes treated with sildenafil. We found that sildenafil significantly diminished myelin gene expression and protein expression. Moreover, sildenafil also increased the expression of Id2 and Id4 negative transcriptional regulators, and the degree of OPCs with cytoplasmic p57kip2 protein localization was reduced, providing evidence that the PDE blocker impaired the differentiation capacity. Finally, sildenafil also interfered with the establishment of internodes as revealed by in vitro myelination assays. We therefore conclude that blocking PDE5 activities exerts a negative impact on intrinsic oligodendroglial differentiation processes.
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O'Meara, Ryan W., John-Paul Michalski, and Rashmi Kothary. "Integrin Signaling in Oligodendrocytes and Its Importance in CNS Myelination." Journal of Signal Transduction 2011 (December 20, 2011): 1–11. http://dx.doi.org/10.1155/2011/354091.
Full textAbstract:
Multiple sclerosis is characterized by repeated demyelinating attacks of the central nervous system (CNS) white matter tracts. To tailor novel therapeutics to halt or reverse disease process, we require a better understanding of oligodendrocyte biology and of the molecular mechanisms that initiate myelination. Cell extrinsic mechanisms regulate CNS myelination through the interaction of extracellular matrix proteins and their transmembrane receptors. The engagement of one such receptor family, the integrins, initiates intracellular signaling cascades that lead to changes in cell phenotype. Oligodendrocytes express a diverse array of integrins, and the expression of these receptors is developmentally regulated. Integrin-mediated signaling is crucial to the proliferation, survival, and maturation of oligodendrocytes through the activation of downstream signaling pathways involved in cytoskeletal remodeling. Here, we review the current understanding of this important signaling axis and its role in oligodendrocyte biology and ultimately in the myelination of axons within the CNS.
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Pan, Ruangang, Qinran Zhang, Scott M. Anthony, et al. "Oligodendrocytes that survive acute coronavirus infection induce prolonged inflammatory responses in the CNS." Proceedings of the National Academy of Sciences 117, no. 27 (2020): 15902–10. http://dx.doi.org/10.1073/pnas.2003432117.
Full textAbstract:
Neurotropic strains of mouse hepatitis virus (MHV), a coronavirus, cause acute and chronic demyelinating encephalomyelitis with similarities to the human disease multiple sclerosis. Here, using a lineage-tracking system, we show that some cells, primarily oligodendrocytes (OLs) and oligodendrocyte precursor cells (OPCs), survive the acute MHV infection, are associated with regions of demyelination, and persist in the central nervous system (CNS) for at least 150 d. These surviving OLs express major histocompatibility complex (MHC) class I and other genes associated with an inflammatory response. Notably, the extent of inflammatory cell infiltration was variable, dependent on anatomic location within the CNS, and without obvious correlation with numbers of surviving cells. We detected more demyelination in regions with larger numbers of T cells and microglia/macrophages compared to those with fewer infiltrating cells. Conversely, in regions with less inflammation, these previously infected OLs more rapidly extended processes, consistent with normal myelinating function. Together, these results show that OLs are inducers as well as targets of the host immune response and demonstrate how a CNS infection, even after resolution, can induce prolonged inflammatory changes with CNS region-dependent impairment in remyelination.
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Spaas, Jan, Lieve van Veggel, Melissa Schepers, et al. "Oxidative stress and impaired oligodendrocyte precursor cell differentiation in neurological disorders." Cellular and Molecular Life Sciences 78, no. 10 (2021): 4615–37. http://dx.doi.org/10.1007/s00018-021-03802-0.
Full textAbstract:
AbstractOligodendrocyte precursor cells (OPCs) account for 5% of the resident parenchymal central nervous system glial cells. OPCs are not only a back-up for the loss of oligodendrocytes that occurs due to brain injury or inflammation-induced demyelination (remyelination) but are also pivotal in plastic processes such as learning and memory (adaptive myelination). OPC differentiation into mature myelinating oligodendrocytes is controlled by a complex transcriptional network and depends on high metabolic and mitochondrial demand. Mounting evidence shows that OPC dysfunction, culminating in the lack of OPC differentiation, mediates the progression of neurodegenerative disorders such as multiple sclerosis, Alzheimer’s disease and Parkinson’s disease. Importantly, neurodegeneration is characterised by oxidative and carbonyl stress, which may primarily affect OPC plasticity due to the high metabolic demand and a limited antioxidant capacity associated with this cell type. The underlying mechanisms of how oxidative/carbonyl stress disrupt OPC differentiation remain enigmatic and a focus of current research efforts. This review proposes a role for oxidative/carbonyl stress in interfering with the transcriptional and metabolic changes required for OPC differentiation. In particular, oligodendrocyte (epi)genetics, cellular defence and repair responses, mitochondrial signalling and respiration, and lipid metabolism represent key mechanisms how oxidative/carbonyl stress may hamper OPC differentiation in neurodegenerative disorders. Understanding how oxidative/carbonyl stress impacts OPC function may pave the way for future OPC-targeted treatment strategies in neurodegenerative disorders.
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Li, Ning, and Gilberto K. K. Leung. "Oligodendrocyte Precursor Cells in Spinal Cord Injury: A Review and Update." BioMed Research International 2015 (2015): 1–20. http://dx.doi.org/10.1155/2015/235195.
Full textAbstract:
Spinal cord injury (SCI) is a devastating condition to individuals, families, and society. Oligodendrocyte loss and demyelination contribute as major pathological processes of secondary damages after injury. Oligodendrocyte precursor cells (OPCs), a subpopulation that accounts for 5 to 8% of cells within the central nervous system, are potential sources of oligodendrocyte replacement after SCI. OPCs react rapidly to injuries, proliferate at a high rate, and can differentiate into myelinating oligodendrocytes. However, posttraumatic endogenous remyelination is rarely complete, and a better understanding of OPCs’ characteristics and their manipulations is critical to the development of novel therapies. In this review, we summarize known characteristics of OPCs and relevant regulative factors in both health and demyelinating disorders including SCI. More importantly, we highlight current evidence on post-SCI OPCs transplantation as a potential treatment option as well as the impediments against regeneration. Our aim is to shed lights on important knowledge gaps and to provoke thoughts for further researches and the development of therapeutic strategies.
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Williams, Jessica L., Jigisha R. Patel, Brian P. Daniels, and Robyn S. Klein. "Targeting CXCR7/ACKR3 as a therapeutic strategy to promote remyelination in the adult central nervous system." Journal of Experimental Medicine 211, no. 5 (2014): 791–99. http://dx.doi.org/10.1084/jem.20131224.
Full textAbstract:
Current treatment modalities for the neurodegenerative disease multiple sclerosis (MS) use disease-modifying immunosuppressive compounds but do not promote repair. Although several potential targets that may induce myelin production have been identified, there has yet to be an approved therapy that promotes remyelination in the damaged central nervous system (CNS). Remyelination of damaged axons requires the generation of new oligodendrocytes from oligodendrocyte progenitor cells (OPCs). Although OPCs are detected in MS lesions, repair of myelin is limited, contributing to progressive clinical deterioration. In the CNS, the chemokine CXCL12 promotes remyelination via CXCR4 activation on OPCs, resulting in their differentiation into myelinating oligodendrocytes. Although the CXCL12 scavenging receptor CXCR7/ACKR3 (CXCR7) is also expressed by OPCs, its role in myelin repair in the adult CNS is unknown. We show that during cuprizone-induced demyelination, in vivo CXCR7 antagonism augmented OPC proliferation, leading to increased numbers of mature oligodendrocytes within demyelinated lesions. CXCR7-mediated effects on remyelination required CXCR4 activation, as assessed via both phospho-S339-CXCR4–specific antibodies and administration of CXCR4 antagonists. These findings identify a role for CXCR7 in OPC maturation during remyelination and are the first to use a small molecule to therapeutically enhance myelin repair in the demyelinated adult CNS.
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Larochelle, Catherine, Beatrice Wasser, Hélène Jamann, et al. "Pro-inflammatory T helper 17 directly harms oligodendrocytes in neuroinflammation." Proceedings of the National Academy of Sciences 118, no. 34 (2021): e2025813118. http://dx.doi.org/10.1073/pnas.2025813118.
Full textAbstract:
T helper (Th)17 cells are considered to contribute to inflammatory mechanisms in diseases such as multiple sclerosis (MS). However, the discussion persists regarding their true role in patients. Here, we visualized central nervous system (CNS) inflammatory processes in models of MS live in vivo and in MS brains and discovered that CNS-infiltrating Th17 cells form prolonged stable contact with oligodendrocytes. Strikingly, compared to Th2 cells, direct contact with Th17 worsened experimental demyelination, caused damage to human oligodendrocyte processes, and increased cell death. Importantly, we found that in comparison to Th2 cells, both human and murine Th17 cells express higher levels of the integrin CD29, which is linked to glutamate release pathways. Of note, contact of human Th17 cells with oligodendrocytes triggered release of glutamate, which induced cell stress and changes in biosynthesis of cholesterol and lipids, as revealed by single-cell RNA-sequencing analysis. Finally, exposure to glutamate decreased myelination, whereas blockade of CD29 preserved oligodendrocyte processes from Th17-mediated injury. Our data provide evidence for the direct and deleterious attack of Th17 cells on the myelin compartment and show the potential for therapeutic opportunities in MS.
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Rodríguez-Pascau, Laura, Anna Vilalta, Marc Cerrada та ін. "The brain penetrant PPARγ agonist leriglitazone restores multiple altered pathways in models of X-linked adrenoleukodystrophy". Science Translational Medicine 13, № 596 (2021): eabc0555. http://dx.doi.org/10.1126/scitranslmed.abc0555.
Full textAbstract:
X-linked adrenoleukodystrophy (X-ALD), a potentially fatal neurometabolic disorder with no effective pharmacological treatment, is characterized by clinical manifestations ranging from progressive spinal cord axonopathy [adrenomyeloneuropathy (AMN)] to severe demyelination and neuroinflammation (cerebral ALD-cALD), for which molecular mechanisms are not well known. Leriglitazone is a recently developed brain penetrant full PPARγ agonist that could modulate multiple biological pathways relevant for neuroinflammatory and neurodegenerative diseases, and particularly for X-ALD. We found that leriglitazone decreased oxidative stress, increased adenosine 5′-triphosphate concentration, and exerted neuroprotective effects in primary rodent neurons and astrocytes after very long chain fatty acid–induced toxicity simulating X-ALD. In addition, leriglitazone improved motor function; restored markers of oxidative stress, mitochondrial function, and inflammation in spinal cord tissues from AMN mouse models; and decreased the neurological disability in the EAE neuroinflammatory mouse model. X-ALD monocyte–derived patient macrophages treated with leriglitazone were less skewed toward an inflammatory phenotype, and the adhesion of human X-ALD monocytes to brain endothelial cells decreased after treatment, suggesting the potential of leriglitazone to prevent the progression to pathologically disrupted blood-brain barrier. Leriglitazone increased myelin debris clearance in vitro and increased myelination and oligodendrocyte survival in demyelination-remyelination in vivo models, thus promoting remyelination. Last, leriglitazone was clinically tested in a phase 1 study showing central nervous system target engagement (adiponectin increase) and changes on inflammatory biomarkers in plasma and cerebrospinal fluid. The results of our study support the use of leriglitazone in X-ALD and, more generally, in other neuroinflammatory and neurodegenerative conditions.
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Knoll, W., F. Natali, J. Peters, R. Nanekar, C. Wang, and P. Kursula. "Dynamic properties of a reconstituted myelin sheath." Spectroscopy 24, no. 6 (2010): 585–92. http://dx.doi.org/10.1155/2010/317525.
Full textAbstract:
Myelin is a multilamellar membrane which, wrapping the nerve axons, increases the efficiency of nervous signal transmission. Indeed, the molecular components of the myelin sheath interact tightly with each other and molecules on the axonal surface to drive myelination, to keep both myelin and the axon intact, and to transduce signals from myelin to the axon and vice versa. Myelin is strongly affected in human demyelinating diseases in both the central and peripheral nervous system (CNS and PNS, respectively). Despite the presence of a well-defined set of myelin-specific proteins, little is known about the structure and the dynamics of these proteins, their interactions with the membrane and their influence on myelin stability. We present here the first neutron scattering results on the dynamics of the myelin sheath in PNS and of the interaction between its constituents. Specifically, the human P2 protein is shown to stabilize the lipid membrane upon binding to it.
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Ljunggren-Rose, Åsa, Chandramohan Natarajan, Pranathi Matta, Akansha Pandey, Isha Upender, and Subramaniam Sriram. "Anacardic acid induces IL-33 and promotes remyelination in CNS." Proceedings of the National Academy of Sciences 117, no. 35 (2020): 21527–35. http://dx.doi.org/10.1073/pnas.2006566117.
Full textAbstract:
Given the known neuroreparative actions of IL-33 in experimental models of central nervous system (CNS) injury, we predicted that compounds which induce IL-33 are likely to promote remyelination. We found anacardic acid as a candidate molecule to serve as a therapeutic agent to promote remyelination. Addition of anacardic acid to cultured oligodendrocyte precursor cells (OPCs) rapidly increased expression of myelin genes and myelin proteins, suggesting a direct induction of genes involved in myelination by anacardic acid. Also, when added to OPCs, anacardic acid resulted in the induction of IL-33. In vivo, treatment of with anacardic acid in doses which ranged from 0.025 mg/kg to 2.5 mg/kg,improved pathologic scores in experimental allergic encephalitis (EAE) and in the cuprizone model of demyelination/remyelination. Electron microscopic studies performed in mice fed with cuprizone and treated with anacardic acid showed lower g-ratio scores when compared to controls, suggesting increased remyelination of axons. In EAE, improvement in paralytic scores was seen when the drug was given prior to or following the onset of paralytic signs. In EAE and in the cuprizone model, areas of myelin loss, which are likely to remyelinate, was associated with a greater recruitment of IL-33–expressing OPCs in mice which received anacardic acid when compared to controls.
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Montecchi, Tommaso, Enxhi Shaba, Domiziana De Tommaso, et al. "Differential Proteomic Analysis of Astrocytes and Astrocytes-Derived Extracellular Vesicles from Control and Rai Knockout Mice: Insights into the Mechanisms of Neuroprotection." International Journal of Molecular Sciences 22, no. 15 (2021): 7933. http://dx.doi.org/10.3390/ijms22157933.
Full textAbstract:
Reactive astrocytes are a hallmark of neurodegenerative disease including multiple sclerosis. It is widely accepted that astrocytes may adopt alternative phenotypes depending on a combination of environmental cues and intrinsic features in a highly plastic and heterogeneous manner. However, we still lack a full understanding of signals and associated signaling pathways driving astrocyte reaction and of the mechanisms by which they drive disease. We have previously shown in the experimental autoimmune encephalomyelitis mouse model that deficiency of the molecular adaptor Rai reduces disease severity and demyelination. Moreover, using primary mouse astrocytes, we showed that Rai contributes to the generation of a pro-inflammatory central nervous system (CNS) microenvironment through the production of nitric oxide and IL-6 and by impairing CD39 activity in response to soluble factors released by encephalitogenic T cells. Here, we investigated the impact of Rai expression on astrocyte function both under basal conditions and in response to IL-17 treatment using a proteomic approach. We found that astrocytes and astrocyte-derived extracellular vesicles contain a set of proteins, to which Rai contributes, that are involved in the regulation of oligodendrocyte differentiation and myelination, nitrogen metabolism, and oxidative stress. The HIF-1α pathway and cellular energetic metabolism were the most statistically relevant molecular pathways and were related to ENOA and HSP70 dysregulation.
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Cherchi, Federica, Irene Bulli, Martina Venturini, Anna Maria Pugliese, and Elisabetta Coppi. "Ion Channels as New Attractive Targets to Improve Re-Myelination Processes in the Brain." International Journal of Molecular Sciences 22, no. 14 (2021): 7277. http://dx.doi.org/10.3390/ijms22147277.
Full textAbstract:
Multiple sclerosis (MS) is the most demyelinating disease of the central nervous system (CNS) characterized by neuroinflammation. Oligodendrocyte progenitor cells (OPCs) are cycling cells in the developing and adult CNS that, under demyelinating conditions, migrate to the site of lesions and differentiate into mature oligodendrocytes to remyelinate damaged axons. However, this process fails during disease chronicization due to impaired OPC differentiation. Moreover, OPCs are crucial players in neuro-glial communication as they receive synaptic inputs from neurons and express ion channels and neurotransmitter/neuromodulator receptors that control their maturation. Ion channels are recognized as attractive therapeutic targets, and indeed ligand-gated and voltage-gated channels can both be found among the top five pharmaceutical target groups of FDA-approved agents. Their modulation ameliorates some of the symptoms of MS and improves the outcome of related animal models. However, the exact mechanism of action of ion-channel targeting compounds is often still unclear due to the wide expression of these channels on neurons, glia, and infiltrating immune cells. The present review summarizes recent findings in the field to get further insights into physio-pathophysiological processes and possible therapeutic mechanisms of drug actions.