Remyelination

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Petr75
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Re: Remyelination

Post by Petr75 » Sat Dec 21, 2019 12:24 pm

2019 Dec 13
Neurobiology Laboratory, Department of Neurology, Institute of Neurosciences, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain
Vitamin D increases remyelination by promoting oligodendrocyte lineage differentiation
https://www.ncbi.nlm.nih.gov/pubmed/31837111

Abstract
INTRODUCTION:
Several experimental studies have suggested the potential remyelinating effects of vitamin D (VitD) supplements regardless of the presence of VitD deficiency. This study aims to analyze neurogenesis in a model of toxic demyelination in order to evaluate the effects of VitD on demyelination and remyelination.
MATERIAL AND METHODS:
We used 24 male Wistar rats that had received surgical lesions to the corpus callosum and were injected with lysolecithin. Rats were divided into three groups: Group 1 included eight rats with lesions to the corpus callosum but not lysolecithin injections (sham group), group 2 included eight rats with lesions to the corpus callosum that were injected with lysolecithin (lysolecithin group), and group 3 included eight rats with lesions that were injected with lysolecithin and received VitD (VitD group). We analyzed neurogenesis both in the subventricular zone and at the lesion site.
RESULTS:
Administration of VitD promotes the proliferation and differentiation of neural stem cells in the subventricular zone and the migration of these cells to the lesion site in the corpus callosum; these cells subsequently differentiate into oligodendrocyte lineage cells and produce myelin basic protein. This phenomenon was not caused by microglial activation, which was less marked in rats receiving VitD. Megalin expression did not increase at the lesion site, which suggests that VitD is internalized by other mechanisms.
CONCLUSION:
Our results support the hypothesis that regardless of the presence of VitD deficiency, treatment with VitD may contribute to remyelination by promoting the proliferation of oligodendrocyte precursor cells.

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Re: Remyelination

Post by Petr75 » Sun Feb 09, 2020 2:59 am

2020 Feb 6
Department of Neurology, The Children's Hospital of Philadelphia, 516D Abramson Center, 3615 Civic Center Blvd, Philadelphia
Inhibitors of Myelination and Remyelination, Bone Morphogenetic Proteins, Are Upregulated in Human Neurological Disease
https://pubmed.ncbi.nlm.nih.gov/3203059 ... l-disease/

Abstract

During demyelinating disease such as multiple sclerosis and stroke, myelin is destroyed and along with it, the oligodendrocytes that synthesize the myelin. Thus, recovery is limited due to both interruptions in neuronal transmission as well as lack of support for neurons. Although oligodendrocyte progenitor cells remain abundant in the central nervous system, they rarely mature and form new functional myelin in the diseased CNS. In cell culture and in experimental models of demyelinating disease, inhibitory signaling factors decrease myelination and remyelination. One of the most potent of these are the bone morphogenetic proteins (BMPs), a family of proteins that strongly inhibits oligodendrocyte progenitor differentiation and myelination in culture. BMPs are highly expressed in the dorsal CNS during pre-natal development and serve to regulate dorsal ventral patterning. Their expression decreases after birth but is significantly increased in rodent demyelination models such as experimental autoimmune encephalomyelitis, cuprizone ingestion and spinal cord injury. However, until recently, evidence for BMP upregulation in human disease has been scarce. This review discusses new human studies showing that in multiple sclerosis and other demyelinating diseases, BMPs are expressed by immune cells invading the CNS as well as resident CNS cell types, mostly astrocytes and microglia. Expression of endogenous BMP antagonists is also regulated. Identification of BMPs in the CNS is correlated with areas of demyelination and inflammation. These studies further support BMP as a potential therapeutic target.

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Re: Remyelination

Post by Petr75 » Sun Feb 09, 2020 3:06 am

2020 Feb 6
Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Canada
Niacin-mediated Rejuvenation of Macrophage/Microglia Enhances Remyelination of the Aging Central Nervous System
https://pubmed.ncbi.nlm.nih.gov/3203046 ... us-system/

Abstract

Remyelination following CNS demyelination restores rapid signal propagation and protects axons; however, its efficiency declines with increasing age. Both intrinsic changes in the oligodendrocyte progenitor cell population and extrinsic factors in the lesion microenvironment of older subjects contribute to this decline. Microglia and monocyte-derived macrophages are critical for successful remyelination, releasing growth factors and clearing inhibitory myelin debris. Several studies have implicated delayed recruitment of macrophages/microglia into lesions as a key contributor to the decline in remyelination observed in older subjects. Here we show that the decreased expression of the scavenger receptor CD36 of aging mouse microglia and human microglia in culture underlies their reduced phagocytic activity. Overexpression of CD36 in cultured microglia rescues the deficit in phagocytosis of myelin debris. By screening for clinically approved agents that stimulate macrophages/microglia, we have found that niacin (vitamin B3) upregulates CD36 expression and enhances myelin phagocytosis by microglia in culture. This increase in myelin phagocytosis is mediated through the niacin receptor (hydroxycarboxylic acid receptor 2). Genetic fate mapping and multiphoton live imaging show that systemic treatment of 9-12-month-old demyelinated mice with therapeutically relevant doses of niacin promotes myelin debris clearance in lesions by both peripherally derived macrophages and microglia. This is accompanied by enhancement of oligodendrocyte progenitor cell numbers and by improved remyelination in the treated mice. Niacin represents a safe and translationally amenable regenerative therapy for chronic demyelinating diseases such as multiple sclerosis.

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Re: Remyelination

Post by Petr75 » Fri Feb 21, 2020 10:41 am

2019 Dec 18
Department of Biology, Faculty of Sciences, University of Zabol, Iran
Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Germany
Metformin Accelerates Myelin Recovery and Ameliorates Behavioral Deficits in the Animal Model of Multiple Sclerosis via Adjustment of AMPK/Nrf2/mTOR Signaling and Maintenance of Endogenous Oligodendrogenesis During Brain Self-Repairing Period
https://pubmed.ncbi.nlm.nih.gov/3204824 ... ng-period/

Abstract

Background: Multiple sclerosis (MS) is a devastating autoimmune disorder characterized by oligodendrocytes (OLGs) loss and demyelination. In this study, we have examined the effects of metformin (MET) on the oligodendrogenesis, redox signaling, apoptosis, and glial responses during a self-repairing period (1-week) in the animal model of MS.

Methods: For induction of demyelination, C57BL/6 J mice were fed a 0.2% cuprizone (CPZ) for 5 weeks. Thereafter, CPZ was removed for 1-week and molecular and behavioral changes were monitored in the presence or absence of MET (50 mg/kg body weight/day).

Results: MET remarkably increased the localization of precursor OLGs (NG2+/O4+ cells) and subsequently the renewal of mature OLGs (MOG+ cells) in the corpus callosum via AMPK/mammalian target of rapamycin (mTOR) pathway. Moreover, we observed a significant elevation in the antioxidant responses, especially in mature OLGs (MOG+/nuclear factor erythroid 2-related factor 2 (Nrf2+) cells) after MET intervention. MET also reduced brain apoptosis markers and lessened motor dysfunction in the open-field test. While MET was unable to decrease active astrogliosis (GFAP mRNA), it reduced microgliosis by down-regulation of Mac-3 mRNA a marker of pro-inflammatory microglia/macrophages. Molecular modeling studies, likewise, confirmed that MET exerts its effects via direct interaction with AMPK.

Conclusions: Altogether, our study reveals that MET effectively induces lesion reduction and elevated molecular processes that support myelin recovery via direct activation of AMPK and indirect regulation of AMPK/Nrf2/mTOR pathway in OLGs. These findings facilitate the development of new therapeutic strategies based on AMPK activation for MS in the near future.

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Re: Remyelination

Post by Petr75 » Tue Feb 25, 2020 10:20 am

2020 Feb 18
Department of Immunology, Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium
Oncostatin M-induced Astrocytic Tissue Inhibitor of metalloproteinases-1 Drives Remyelination
https://pubmed.ncbi.nlm.nih.gov/3207122 ... elination/

Abstract

The brain's endogenous capacity to restore damaged myelin deteriorates during the course of demyelinating disorders. Currently, no treatment options are available to establish remyelination. Chronic demyelination leads to damaged axons and irreversible destruction of the central nervous system (CNS). We identified two promising therapeutic candidates which enhance remyelination: oncostatin M (OSM), a member of the interleukin-6 family, and downstream mediator tissue inhibitor of metalloproteinases-1 (TIMP-1). While remyelination was completely abrogated in OSMRβ knockout (KO) mice, OSM overexpression in the chronically demyelinated CNS established remyelination. Astrocytic TIMP-1 was demonstrated to play a pivotal role in OSM-mediated remyelination. Astrocyte-derived TIMP-1 drove differentiation of oligodendrocyte precursor cells into mature oligodendrocytes in vitro. In vivo, TIMP-1 deficiency completely abolished spontaneous remyelination, phenocopying OSMRβ KO mice. Finally, TIMP-1 was expressed by human astrocytes in demyelinated multiple sclerosis lesions, confirming the human value of our findings. Taken together, OSM and its downstream mediator TIMP-1 have the therapeutic potential to boost remyelination in demyelinating disorders.

-----------------------------------------------
wiki - https://en.wikipedia.org/wiki/Oncostatin_M

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Re: Remyelination

Post by Petr75 » Thu Apr 30, 2020 10:21 am

2020 Apr 8
Department of Molecular Biology and Biochemistry, University of California, Irvine
Regulatory T cells promote remyelination in the murine experimental autoimmune encephalomyelitis model of multiple sclerosis following human neural stem cell transplant.
https://www.ncbi.nlm.nih.gov/pubmed/32276110

Abstract

Multiple sclerosis (MS) is a chronic, inflammatory autoimmune disease that affects the central nervous system (CNS) for which there is no cure. In MS, encephalitogenic T cells infiltrate the CNS causing demyelination and neuroinflammation; however, little is known about the role of regulatory T cells (Tregs) in CNS tissue repair. Transplantation of neural stem and progenitor cells (NSCs and NPCs) is a promising therapeutic strategy to promote repair through cell replacement, although recent findings suggest transplanted NSCs also instruct endogenous repair mechanisms. We have recently described that dampened neuroinflammation and increased remyelination is correlated with emergence of Tregs following human NPC transplantation in a murine viral model of immune-mediated demyelination. In the current study we utilized the prototypic murine autoimmune model of demyelination experimental autoimmune encephalomyelitis (EAE) to test the efficacy of hNSC transplantation. Eight-week-old, male EAE mice receiving an intraspinal transplant of hNSCs during the chronic phase of disease displayed remyelination, dampened neuroinflammation, and an increase in CNS CD4+CD25+FoxP3+ regulatory T cells (Tregs). Importantly, ablation of Tregs abrogated histopathological improvement. Tregs are essential for maintenance of T cell homeostasis and prevention of autoimmunity, and an emerging role for Tregs in maintenance of tissue homeostasis through interactions with stem and progenitor cells has recently been suggested. The data presented here provide direct evidence for collaboration between CNS Tregs and hNSCs promoting remyelination.

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Re: Remyelination

Post by Petr75 » Sun May 03, 2020 1:54 am

2020 Apr 11
Department of Neurology, Hannover Medical School,Hannover, Germany
Delayed Demyelination and Impaired Remyelination in Aged Mice in the Cuprizone Model.
https://www.ncbi.nlm.nih.gov/pubmed/32290524

Abstract

To unravel the failure of remyelination in multiple sclerosis (MS) and to test promising remyelinating treatments, suitable animal models like the well-established cuprizone model are required. However, this model is only standardized in young mice. This does not represent the typical age of MS patients. Furthermore, remyelination is very fast in young mice, hindering the examination of effects of remyelination-promoting agents. Thus, there is the need for a better animal model to study remyelination. We therefore aimed to establish the cuprizone model in aged mice. 6-month-old C57BL6 mice were fed with different concentrations of cuprizone (0.2-0.6%) for 5-6.5 weeks. De- and remyelination in the medial and lateral parts of the corpus callosum were analyzed by immunohistochemistry. Feeding aged mice 0.4% cuprizone for 6.5 weeks resulted in the best and most reliable administration scheme with virtually complete demyelination of the corpus callosum. This was accompanied by a strong accumulation of microglia and near absolute loss of mature oligodendrocytes. Subsequent remyelination was initially robust but remained incomplete. The remyelination process in mature adult mice better represents the age of MS patients and offers a better model for the examination of regenerative therapies.

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Re: Remyelination

Post by Petr75 » Mon Jun 15, 2020 8:26 am

2020 May 19
Center for Translational Neuromedicine and the Department of Neurology, University of Rochester Medical Center, Rochester, NY
Human Glial Progenitor Cells Effectively Remyelinate the Demyelinated Adult Brain
https://www.cell.com/cell-reports/pdf/S ... 0611-2.pdf

Abstract

Neonatally transplanted human glial progenitor cells (hGPCs) can myelinate the brains of myelin-deficient shiverer mice, rescuing their phenotype and survival. Yet, it has been unclear whether implanted hGPCs are similarly able to remyelinate the diffusely demyelinated adult CNS. We, therefore, ask if hGPCs could remyelinate both congenitally hypomyelinated adult shiverers and normal adult mice after cuprizone demyelination. In adult shiverers, hGPCs broadly disperse and differentiate as myelinating oligodendrocytes after subcortical injection, improving both host callosal conduction and ambulation. Implanted hGPCs similarly remyelinate denuded axons after cuprizone demyelination, whether delivered before or after demyelination. RNA sequencing (RNA-seq) of hGPCs back from cuprizone-demyelinated brains reveals their transcriptional activation of oligodendrocyte differentiation programs, while distinguishing them from hGPCs not previously exposed to demyelination. These data indicate the ability of transplanted hGPCs to disperse throughout the adult CNS, to broadly myelinate regions of dysmyelination, and also to be recruited as myelinogenic oligodendrocytes later in life, upon demyelination-associated demand.

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Re: Remyelination

Post by NHE » Tue Jun 16, 2020 5:11 pm

Petr75 wrote:
Mon Jun 15, 2020 8:26 am
2020 May 19
Center for Translational Neuromedicine and the Department of Neurology, University of Rochester Medical Center, Rochester, NY
Human Glial Progenitor Cells Effectively Remyelinate the Demyelinated Adult Brain
https://www.cell.com/cell-reports/pdf/S ... 0611-2.pdf
This paper looks like one of the more hopeful areas of research I've seen in a while.

How do I convince these researchers that I'm really just an overgrown mouse in disguise? :roll:

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Re: Remyelination

Post by NHE » Fri Jun 19, 2020 12:28 am

Petr75 wrote:
Mon Jun 15, 2020 8:26 am
2020 May 19
Center for Translational Neuromedicine and the Department of Neurology, University of Rochester Medical Center, Rochester, NY
Human Glial Progenitor Cells Effectively Remyelinate the Demyelinated Adult Brain
https://www.cell.com/cell-reports/pdf/S ... 0611-2.pdf
Some background research from the same author.

Glial Progenitor Cell-Based Treatment and Modeling of Neurological Disease
Science. 2012 Oct 26;338(6106):491-5.

The diseases of myelin are among the most prevalent and disabling conditions in neurology. These diseases include both the vascular and inflammatory demyelinating disorders of adulthood, as well as the childhood leukodystrophies and cerebral palsy. These fundamentally glial disorders may be amenable to treatment by glial progenitor cells (GPCs), which give rise to astroglia and myelin-producing oligodendrocytes. Given the development of new methods for generating and isolating human GPCs, the myelin disorders may now be compelling targets for cell-based therapy. In addition, the efficient engraftment and expansion of human GPCs in murine hosts has led to the development of human glial chimeric mouse brains, which provides new opportunities for studying the species-specific roles of human glia in cognition, as well as in disease pathogenesis.

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Re: Remyelination

Post by NHE » Fri Jun 19, 2020 2:09 am

How to Make an Oligodendrocyte
Development. 2015 Dec 1;142(23):3983-95.

Oligodendrocytes produce myelin, an insulating sheath required for the saltatory conduction of electrical impulses along axons. Oligodendrocyte loss results in demyelination, which leads to impaired neurological function in a broad array of diseases ranging from pediatric leukodystrophies and cerebral palsy, to multiple sclerosis and white matter stroke. Accordingly, replacing lost oligodendrocytes, whether by transplanting oligodendrocyte progenitor cells (OPCs) or by mobilizing endogenous progenitors, holds great promise as a therapeutic strategy for the diseases of central white matter. In this Primer, we describe the molecular events regulating oligodendrocyte development and how our understanding of this process has led to the establishment of methods for producing OPCs and oligodendrocytes from embryonic stem cells and induced pluripotent stem cells, as well as directly from somatic cells. In addition, we will discuss the safety of engrafted stem cell-derived OPCs, as well as approaches by which to modulate their differentiation and myelinogenesis in vivo following transplantation.

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Re: Remyelination

Post by Petr75 » Fri Jun 19, 2020 9:59 am

2020 May 19
Department of Medicine, University of Wisconsin, School of Medicine and Public Health and University of Wisconsin Carbone Cancer Center
Regulatory B Cells Normalize CNS Myeloid Cell Content in a Mouse Model of Multiple Sclerosis and Promote Oligodendrogenesis and Remyelination
https://pubmed.ncbi.nlm.nih.gov/32430295/


Abstract

The unmet medical need of patients with multiple sclerosis (MS) is the inexorable loss of CNS myelin and latterly neurons leading to permanent neurological disability. Solicitation of endogenous oligodendrocytes progenitor cells (OPC), the precursor of oligodendrocytes, to remyelinate axons may abort the onset of disability. In female mice with experimental autoimmune encephalomyelitis (EAE), a murine model of MS, adoptive transfer of IL-10+ regulatory B cells (Bregs) has been shown to reverse EAE by promoting the expansion of peripheral and CNS-infiltrating IL-10+ T cells. Here, we examined whether Bregs treatment and its bystander effect on regulatory T-cells are associated with CNS repair as reflected by oligodendrogenesis and remyelination. We have found that transfusion of Bregs reverses established clinical EAE and that clinical improvement is associated with a significant increase in spinal cord remyelination as reflected by g-ratio analysis within the thoracic and lumbar spine. We further observed in the spinal cords of EAE Bregs treated mice that CNS resident CD11b/CD45intLy6C- microglia, and infiltrating CD11b+/CD45high monocytes/macrophages content reverts to normal and polarize to a M2-like CD206+ phenotype. Concurrently, there was a substantial increase in neo-oligodendrogenesis as manifest by an increase in CD45-/low CNS cells expressing A2B5, an early marker in OPC differentiation as well as GalC+/O1+ pre-myelinating and MBP+/MOG+ mature oligodendrocytes with reciprocal downregulation of paired related homeobox protein 1 (PRXX1). These results demonstrate that the clinical benefit of Bregs is associated with normalization of CNS immune milieu and concurrent activation of oligodendrocyte progenitor cells with subsequent remyelination. SIGNIFICANCE STATEMENT: In multiple sclerosis (MS) patients, demyelination progresses with aging and disease course leading to irreversible disability. In this study, we have discovered, using a mouse model of MS, that the transfusion of autologous regulatory B cells (Bregs) is able to ameliorate, cure and sustain the durable remission of the disease. We show that the adoptive transfer of Bregs dramatically decreased the frequency of myeloid-derived cells, both infiltrating monocytes/macrophages, and resident microglia, and converted their phenotype to an immunosuppressive-like phenotype. Moreover, we showed that central nervous system oligodendrocyte progenitor cells are activated following Bregs treatment and differentiate into myelinating oligodendrocytes which results in neo-oligodendrogenesis and remyelination of spinal cords.

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Re: Remyelination

Post by Petr75 » Wed Jun 24, 2020 11:29 am

2020 May 27
The Solomon Snyder Department of Neuroscience, Johns Hopkins University, Baltimore
Remyelination Alters the Pattern of Myelin in the Cerebral Cortex
https://pubmed.ncbi.nlm.nih.gov/32459173/

Abstract

Destruction of oligodendrocytes and myelin sheaths in cortical gray matter profoundly alters neural activity and is associated with cognitive disability in multiple sclerosis (MS). Myelin can be restored by regenerating oligodendrocytes from resident progenitors; however, it is not known whether regeneration restores the complex myelination patterns in cortical circuits. Here, we performed time lapse in vivo two photon imaging in somatosensory cortex of adult mice to define the kinetics and specificity of myelin regeneration after acute oligodendrocyte ablation. These longitudinal studies revealed that the pattern of myelination in cortex changed dramatically after regeneration, as new oligodendrocytes were formed in different locations and new sheaths were often established along axon segments previously lacking myelin. Despite the dramatic increase in axonal territory available, oligodendrogenesis was persistently impaired in deeper cortical layers that experienced higher gliosis. Repeated reorganization of myelin patterns in MS may alter circuit function and contribute to cognitive decline.

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Re: Remyelination

Post by Petr75 » Sat Jun 27, 2020 10:14 am

2020 Jan
Department of Neurology, First Affiliated Hospital, Shanxi Medical University, Taiyuan, China
Effect of Fasudil on Remyelination Following Cuprizone-Induced Demyelination

Abstract

Background: Multiple sclerosis is characterized by demyelination/remyelination, neuroinflammation, and neurodegeneration. Cuprizone (CPZ)-induced toxic demyelination is an experimental animal model commonly used to study demyelination and remyelination in the central nervous system. Fasudil is one of the most thoroughly studied Rho kinase inhibitors.

Methods: Following CPZ exposure, the degree of demyelination in the brain of male C57BL/6 mice was assessed by Luxol fast blue, Black Gold II, myelin basic protein immunofluorescent staining, and Western blot. The effect of Fasudil on behavioral change was determined using elevated plus maze test and pole test. The possible mechanisms of Fasudil action were examined by immunohistochemistry, flow cytometry, ELISA, and dot blot.

Results: Fasudil improved behavioral abnormalities, inhibited microglia-mediated neuroinflammation, and promoted astrocyte-derived nerve growth factor and ciliary neurotrophic factor, which should contribute to protection and regeneration of oligodendrocytes. In addition, Fasudil inhibited the production of myelin oligodendrocyte glycoprotein antibody and the infiltration of peripheral CD4+ T cells and CD68+ macrophages, which appears to be related to the integrity of the blood-brain barrier.

Conclusion: These results provide evidence for the therapeutic potential of Fasudil in CPZ-induced demyelination. However, how Fasudil acts on microglia, astrocytes, and immune cells remains to be further explored.

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Re: Remyelination

Post by Petr75 » Sun Jul 05, 2020 11:45 am

2020 Jun 11
Department of Biochemistry and Biophysics, Institute of Health Sciences, Federal University of Bahia, Brazil
The Flavonoid Agathisflavone Modulates the Microglial Neuroinflammatory Response and Enhances Remyelination
https://pubmed.ncbi.nlm.nih.gov/32534098/

Abstract

Myelin loss is the hallmark of the demyelinating disease multiple sclerosis (MS) and plays a significant role in multiple neurodegenerative diseases. A common factor in all neuropathologies is the central role of microglia, the intrinsic immune cells of the central nervous system (CNS). Microglia are activated in pathology and can have both pro- and anti-inflammatory functions. Here, we examined the effects of the flavonoid agathisflavone on microglia and remyelination in the cerebellar slice model following lysolecithin induced demyelination. Notably, agathisflavone enhances remyelination and alters microglial activation state, as determined by their morphology and cytokine profile. Furthermore, these effects of agathisflavone on remyelination and microglial activation were inhibited by blockade of estrogen receptor α. Thus, our results identify agathisflavone as a novel compound that may act via ER to regulate microglial activation and enhance remyelination and repair.

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