Vitamin C promotes oligodendrocytes generation and remyelination

Guo, Yue; Suo, Na; Cui, Xue; Yuan, Qianting; Xie, Xin

doi:10.1002/glia.23306

Cited by 63 publications

(47 citation statements)

References 61 publications

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“…Remyelinated axons in the cuprizone model recapitulate some of these modifications in lipid content. We found that remyelination was incomplete and many of the remyelinated axons in the posterior corpus callosum were thinly myelinated, or the myelin was disorganized and not compacted, similar to findings by other groups (Guo, Suo et al, 2018, Mullin, Cui et al, 2017, Tagge, O’Connor et al, 2016). This disorganization was accompanied by an abnormal lipid content with increased ceramide, increased sphingomyelin, reduced hexosylceramide and sulfatide.…”

Section: Discussionsupporting

confidence: 89%

Inhibition of neutral sphingomyelinase-2 facilitates remyelination

Yoo

Agarwal

Smith

et al. 2019

Preprint

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For reasons that are not completely understood, remyelination is often incomplete, producing thin myelin sheaths with disorganized structure. We investigated the cellular basis for this altered myelin structure, and found that the response of oligodendrocyte progenitor cells (OPCs), and mature oligodendrocytes to TNFα and IL-1β is modified by the expression of the sphingomyelin hydrolase nSMase2. OPCs do not express nSMase2, and exhibit a protective response to these cytokines manifest by decreased ceramide, increased sphingosine 1-phosphate, and increased cell motility. Mature oligodendrocytes express nSMase2, and respond to TNFα and IL-1β with a stress phenotype, evidenced by increased ceramide, decreased sphingosine, and active caspase 3. Pharmacological inhibition or a targeted genetic deletion of nSMase2 in vivo increased myelin thickness, and enhanced myelin compaction. These results suggest that inhibition of nSMase2 improves the quality of new myelin by protecting maturing/myelinating oligodendrocytes. Pharmacological inhibition of nSMase2 following a demyelinating event could stabilize the structure of these newly formed myelin sheaths and protect them from secondary demyelination.Electrostatic interactions between negatively charged phosphatidyl serine (PS) head groups, and positively charged surface groups on MBP, combined with attractive van der Walls force creates a highly stable interface (Min, Kristiansen et al., 2009). Adhesion at the intraperiod line is less stable, and relies heavily on the interactions of proteolipid protein (PLP) with membrane lipids through van der Walls force to overcome repulsive energies originating from thermal undulations. Small changes in the lipid components can modify these adhesive forces and result in the decompaction and/or degeneration of myelin. We previously reported modifications in the lipid composition of normal appearing white matter (NAWM) at sights adjacent to lesions in multiple sclerosis (MS) brains, and calculated that this change in lipid composition would produce an order of magnitude increase in the repulsive energy between bilayers, that would destabilize myelin structure (Bandaru, Mielke et al., 2013). Although these results were compelling, using autopsy material we were unable to determine the mechanism(s) that contributed to these perturbations in the lipid content of regenerated myelin. In this study we show that pharmacological inhibition or genetic deletion of the sphingomyelin hydrolase neutral sphingomyelinase 2 (nSMase2) protects oligodendrocytes during re-myelination, resulting in a partial normalization of myelin lipid content and restoration of myelin compaction. Results Modifications in the lipid composition of myelin following remyelinationCompared with control mice fed a standard diet, we observed an 89 ± 9.5% reduction of black gold staining in the posterior corpus callosum (pCC) of mice fed a cuprizone containing diet for 4 weeks, consistent with a robust demyelination in this brain region. Four weeks after return to a standard die...

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Section: Discussionsupporting

confidence: 89%

Inhibition of neutral sphingomyelinase-2 facilitates remyelination

Yoo

Agarwal

Smith

et al. 2019

Preprint

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“…To identify drug‐like small molecules that can induce OPC differentiation, we developed a high‐content imaging assay based on MBP expression (Guo et al, ). Briefly, cortical NPCs from mouse E14.5 embryos were expended in vitro as neurospheres.…”

Section: Resultsmentioning

confidence: 99%

“…Another screen of NIH Clinical Collection I and II libraries has also identified two drugs—miconazole and clobetasol—which are effective in promoting OL generation in vitro and remyelination in vivo (Najm et al, ). We also developed a high‐throughput screening assay based on the induction of MBP during OPC to OL differentiation, and vitamin C has been found to greatly promote OL differentiation, maturation, and remyelination (Guo, Suo, Cui, Yuan, & Xie, ).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of MAPK/ERK pathway promotes oligodendrocytes generation and recovery of demyelinating diseases

Suo

Guo

et al. 2019

Glia

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Oligodendrocytes (OLs) are the myelinating glia of the central nervous system. Injury to OLs causes myelin loss. In demyelinating diseases, such as multiple sclerosis, the remyelination is hindered principally due to a failure of the oligodendrocyte precursor cells (OPCs) to differentiate into mature OLs. To identify inducers of OPC to OL differentiation, a high‐throughput screening based on myelin basic protein expression using neural progenitor cells‐derived OPCs has been performed and, PD0325901—an MEK (MAPK kinase) inhibitor—is found to significantly enhance OPC to OL differentiation in a dose‐ and time‐dependent manner. Other MEK inhibitors also display similar effect, indicating blockade of MAPK–ERK signaling is sufficient to induce OPC differentiation into OLs. PD0325901 facilitates the formation of myelin sheaths in OPC–neuron co‐culture in vitro. And in experimental autoimmune encephalomyelitis model and cuprizone‐induced demyelination model, PD0325901 displays significant therapeutic effect by promoting myelin regeneration. Our results suggest that targeting the MAPK–ERK pathway might be an intriguing way to develop new therapies for demyelinating diseases.

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“…Essential nutrient (ascorbic acid) Scavenges ROS and RNS [196] Serum levels are low in MS patients during relapses [193]. It promotes OLGs generation and remyelination [197].…”

Section: Vitamin Cmentioning

confidence: 99%

Inflammation and Oxidative Stress in Multiple Sclerosis: Consequences for Therapy Development

Pegoretti

Swanson

Bethea

et al. 2020

Oxidative Medicine and Cellular Longevity

109

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CNS inflammation is a major driver of MS pathology. Differential immune responses, including the adaptive and the innate immune system, are observed at various stages of MS and drive disease development and progression. Next to these immune-mediated mechanisms, other mediators contribute to MS pathology. These include immune-independent cell death of oligodendrocytes and neurons as well as oxidative stress-induced tissue damage. In particular, the complex influence of oxidative stress on inflammation and vice versa makes therapeutic interference complex. All approved MS therapeutics work by modulating the autoimmune response. However, despite substantial developments in the treatment of the relapsing-remitting form of MS, approved therapies for the progressive forms of MS as well as for MS-associated concomitants are limited and much needed. Here, we summarize the contribution of inflammation and oxidative stress to MS pathology and discuss consequences for MS therapy development.

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Vitamin C promotes oligodendrocytes generation and remyelination

Cited by 63 publications

References 61 publications

Inhibition of neutral sphingomyelinase-2 facilitates remyelination

Inhibition of neutral sphingomyelinase-2 facilitates remyelination

Inhibition of MAPK/ERK pathway promotes oligodendrocytes generation and recovery of demyelinating diseases

Inflammation and Oxidative Stress in Multiple Sclerosis: Consequences for Therapy Development

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