Pifithrin‐μ modulates microglial activation and promotes histological recovery following spinal cord injury

Caponegro, Michael; Torres, Luisa; Rastegar, Cyrus; Rath, Nisha; Anderson, Monica; Robinson, John K.; Tsirka, Stella E.

doi:10.1111/cns.13000

Cited by 9 publications

(5 citation statements)

References 60 publications

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“…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

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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.

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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

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“…For example, zinc can change the polarization of microglia and play an anti‐inflammatory effect. The protective effect of zinc on astrocytes inhibits demyelination damage 47 . Zinc directly or indirectly affects the expression of related proteins, such as the regulation of the tumor necrosis factor receptor 2 48 .…”

Section: Discussionmentioning

confidence: 99%

“…The protective effect of zinc on astrocytes inhibits demyelination damage. 47 Zinc directly or indirectly affects the expression of related proteins, such as the regulation of the tumor necrosis factor receptor 2. 48 The changes in some central nervous system cells and related protein factors in the acute phase of spinal cord injury can effectively affect the pathological changes of spinal cord injury and promote wound healing.…”

Section: Discussionmentioning

confidence: 99%

Zinc attenuates ferroptosis and promotes functional recovery in contusion spinal cord injury by activating Nrf2/GPX4 defense pathway

Ge¹,

Tian

Mao³

et al. 2021

CNS Neurosci Ther

155

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Aim Spinal cord injury (SCI) involves multiple pathological processes. Ferroptosis has been shown to play a critical role in the injury process. We wanted to explore whether zinc can inhibit ferroptosis, reduce inflammation, and then exert a neuroprotective effect. Methods The Alice method was used to establish a spinal cord injury model. The Basso Mouse Scale (BMS), Nissl staining, hematoxylin‐eosin staining, and immunofluorescence analysis were used to investigate the protective effect of zinc on neurons on spinal cord neurons and the recovery of motor function. The regulation of the nuclear factor E2/heme oxygenase‐1 (NRF2/HO‐1) pathway was assessed, the levels of essential ferroptosis proteins were measured, and the changes in mitochondria were confirmed by transmission electron microscopy and 5,5′,6,6′‐tetrachloro‐1,1′,3,3′‐tetraethyl‐imidacarbocyanine iodide (JC‐1) staining. In vitro experiments using VSC4.1 (spinal cord anterior horn motor neuroma cell line), 4‐hydroxynonenal (4HNE), reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), lipid peroxides, and finally the levels of inflammatory factors were detected to assess the effect of zinc. Results Zinc reversed behavioral and structural changes after SCI. Zinc increased the expression of NRF2/HO‐1, thereby increasing the content of glutathione peroxidase 4 (GPX4), SOD, and GHS and reducing the levels of lipid peroxides, MDA, and ROS. Zinc also rescued injured mitochondria and effectively reduced spinal cord injury and the levels of inflammatory factors, and the NRF2 inhibitor Brusatol reversed the effects of zinc. Conclusion Zinc promoted the degradation of oxidative stress products and lipid peroxides through the NRF2/HO‐1 and GPX4 signaling pathways to inhibit ferroptosis in neurons.

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“…Spinal cord injury (SCI) usually results in dysfunction of the limbs and causes disability in many cases, mainly including primary and secondary injuries [1,2]. The secondary injuries involve multiple mechanisms, mainly blood-brain barrier dysfunction, neuroinflammation response, microglia activation, and neuronal death [3,4], among which the neuroinflammatory response induced by SCI is an important factor that boosts the occurrence and development of SCI [5,6]. Therefore, the elucidation of the potential mechanism of neuroinflammation is expected to alleviate SCI.…”

Section: Introductionmentioning

confidence: 99%

lncRNA MEG3 restrained the M1 polarization of microglia in acute spinal cord injury through the HuR/A20/NF‐κB axis

et al. 2022

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The M1 polarization of microglia and neuroinflammation restrict the treatment of acute spinal cord injury (ASCI), and long non‐coding ribonucleic acid (lncRNA) maternally expressed gene 3 (MEG3) expression is lessened in ASCI. However, the function and mechanism of lncRNA MEG3 in the M1 polarization of microglia and neuroinflammation in ASCI are unclear. The expressions of lncRNA MEG3 in ASCI mouse spinal cord tissues and lipopolysaccharide (LPS)‐treated primary microglia and BV2 cells were quantified through a quantitative real‐time polymerase chain reaction. In‐vitro assays were conducted to explore the function of lncRNA MEG3 in the M1 polarization of microglia and neuroinflammation in ASCI. RNA degradation, RNA immunoprecipitation, RNA pull‐down, cycloheximide‐chase, and ubiquitination analyses were carried out to probe into the mechanism of lncRNA MEG3 in the M1 polarization of microglia and neuroinflammation in ASCI. The lncRNA MEG3 expression was lessened in the ASCI mouse spinal cord tissues and LPS‐treated primary microglia and BV2 cells, and the overexpression of lncRNA MEG3 restrained the M1 polarization of microglia and the neuroinflammation by regulating the NF‐κB signaling pathway. For the investigation of the potential mechanism of such, the overexpression of lncRNA MEG3 restrained the M1 polarization of microglia through the HuR/A20/NF‐κB axis and boosted the motor function recovery and neuroinflammation relief in the mice with SCI. The overexpression of lncRNA MEG3 restrained the M1 polarization of microglia through the HuR/A20/NF‐κB axis.

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Pifithrin‐μ modulates microglial activation and promotes histological recovery following spinal cord injury

Abstract: Our results indicate that a small molecule reagent PFT-μ has sustained immunomodulatory effects following a single dose after injury.

Cited by 9 publications

References 60 publications

A Rigorous Quantitative Approach to Analyzing Phagocytosis Assays

A Rigorous Quantitative Approach to Analyzing Phagocytosis Assays

Zinc attenuates ferroptosis and promotes functional recovery in contusion spinal cord injury by activating Nrf2/GPX4 defense pathway

lncRNA MEG3 restrained the M1 polarization of microglia in acute spinal cord injury through the HuR/A20/NF‐κB axis

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