Guanabenz modulates microglia and macrophages during demyelination

Thompson, Kaitlyn Koenig; Tsirka, Stella E.

doi:10.1038/s41598-020-76383-w

Cited by 15 publications

(10 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nevertheless, the enhancement of the ISR had no effect on remyelination in the absence of IFN-γ. This is consistent with a recent study that showed that guanabenz, a drug closely related to Sephin1 ( Das et al, 2015 ), did not improve remyelination in the non-inflammatory cuprizone model of demyelination ( Thompson and Tsirka, 2020 ).…”

Section: Discussionsupporting

confidence: 93%

Prolonging the integrated stress response enhances CNS remyelination in an inflammatory environment

Chen

Kunjamma

Weiner

et al. 2021

eLife

View full text Add to dashboard Cite

The inflammatory environment of demyelinated lesions in multiple sclerosis (MS) patients contributes to remyelination failure. Inflammation activates a cytoprotective pathway, the integrated stress response (ISR), but it remains unclear whether enhancing the ISR can improve remyelination in an inflammatory environment. To examine this possibility, the remyelination stage of experimental autoimmune encephalomyelitis (EAE), as well as a mouse model that incorporates cuprizone-induced demyelination along with CNS delivery of the proinflammatory cytokine IFN-γ were used here. We demonstrate that either genetic or pharmacological ISR enhancement significantly increased the number of remyelinating oligodendrocytes and remyelinated axons in the inflammatory lesions. Moreover, the combined treatment of the ISR modulator Sephin1 with the oligodendrocyte differentiation enhancing reagent bazedoxifene increased myelin thickness of remyelinated axons to pre-lesion levels. Taken together, our findings indicate that prolonging the ISR protects remyelinating oligodendrocytes and promotes remyelination in the presence of inflammation, suggesting that ISR enhancement may provide reparative benefit to MS patients.

show abstract

Section: Discussionsupporting

confidence: 93%

Prolonging the integrated stress response enhances CNS remyelination in an inflammatory environment

Chen

Kunjamma

Weiner

et al. 2021

eLife

View full text Add to dashboard Cite

show abstract

“…This resulted in D = 0.15 and P = 0.04, thus detecting a small but significant shift in phagocytic activity, which can be seen by the rightward shift in the histogram, density curve, and ECDF. While not as large of an increase relative to that observed after GCM treatment, this result agrees with published literature (Wu et al, 2009;Scheraga et al, 2016;Caponegro et al, 2019;Thompson et al, 2020)…”

Section: Comparing Ks Test To Reported Methodssupporting

confidence: 93%

A Rigorous Quantitative Approach to Analyzing Phagocytosis Assays

Caponegro¹,

Thompson²,

Tayyab³

et al. 2020

BIO-PROTOCOL

View full text Add to dashboard Cite

Studying monocytic cells in isolated systems in vitro contributes significantly to the understanding of innate immune physiology. Functional assays produce read outs which can be used to measure responses to selected stimuli, such as pathogen exposure, antigen loading, and cytokine stimulation. Integration of these results with high quality in vivo models allows for the development of therapeutics which target these cell populations. Current methodologies to quantify phagocytic function of monocytic cells in vitro either measure phagocytic activity of individual cells (average number of beads or particles/cell), or a population outcome (% cells that contain phagocytosed material). Here we address technical challenges and shortcomings of these methods and present a protocol for collecting and analyzing data derived from a functional assay which measures phagocytic activity of macrophage and macrophage-like cells. We apply this method to two different experimental conditions, and compare to existing work flows. We also provide an online tool for users to upload and analyze data using this method.

show abstract

“…Microglia and astrocytes play a major role in the pathogenesis of MS and EAE [75]. Their activation and maturation are critical to disease development and progression [76] and ablation of microglia suppresses EAE development [77].…”

Section: Discussionmentioning

confidence: 99%

Piperine Improves Experimental Autoimmune Encephalomyelitis (EAE) in Lewis Rats Through its Neuroprotective, Anti-inflammatory, and Antioxidant Effects

et al. 2021

View full text Add to dashboard Cite

In ammation, demyelination, glial activation, and oxidative damage are the most pathological hallmarks of multiple sclerosis (MS). Piperine, a main bioactive alkaloid of black pepper, possesses antioxidant, anti-in ammatory and neuroprotective properties whose therapeutic potential has been less studied in the experimental autoimmune encephalomyelitis (EAE) models. In this study, the e ciency of peprine on progression of EAE model and myelin repair mechanisms was investigated. EAE was induced in female Lewis rats and piperine and its vehicle were daily administrated intraperitoneally from day 8 to 29 post immunization. We found that peperine alleviated neurological de cits and EAE disease progression. Luxol fast blue and H&E staining and immuno-staining of lumbar spinal cord cross sections con rmed that piperine signi cantly reduced the extent of demyelination, in ammation and immune cell in ltration and inhibited microglia and astrocyte activation. Gene expression analysis in lumbar spinal cord showed that piperine treatment decreased the level of pro-in ammatory cytokines (TNF-α, IL-1β) and iNOS and enhanced IL-10, Nrf-2, HO-1and MBP expressions. Piperine supplementation also enhanced the total antioxidant capacity (FRAP) and reduced the level of oxidative stress marker (MDA) in the CNS of EAE rats. Finally, we found that piperine has anti-apoptotic and neuroprotective effect in EAE through reducing caspase-3 (apoptosis marker) and enhancing BDNF and NeuN expressing cells. This study strongly indicates that piperine has a bene cial effect on the EAE progression and could be considered as a potential therapeutic target for MS treatment. Upcoming clinical trials will provide the deep understanding of piperine's role for the treatment of the MS.

show abstract

Guanabenz modulates microglia and macrophages during demyelination

Cited by 15 publications

References 43 publications

Prolonging the integrated stress response enhances CNS remyelination in an inflammatory environment

Prolonging the integrated stress response enhances CNS remyelination in an inflammatory environment

A Rigorous Quantitative Approach to Analyzing Phagocytosis Assays

Piperine Improves Experimental Autoimmune Encephalomyelitis (EAE) in Lewis Rats Through its Neuroprotective, Anti-inflammatory, and Antioxidant Effects

Contact Info

Product

Resources

About