The ROCK inhibitor Y-27632 ameliorates blood-spinal cord barrier disruption by reducing tight junction protein degradation via the MYPT1-MLC2 pathway after spinal cord injury in rats

Chang, Sheng Yung; Cao, Yang

doi:10.1016/j.brainres.2021.147684

Cited by 6 publications

(5 citation statements)

References 58 publications

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“…Moreover, infiltration of inflammatory cells and increased expression of MMPs exacerbate the destruction of BSCB ( Zhang et al, 2011 ). Although the exact mechanism associated with BSCB disruption is currently unknown, it is closely related to MMPs, ER stress, and the Akt pathway ( Zhou et al, 2016a ; Chang et al, 2018 ; Chang and Cao, 2021 ; Xin et al, 2021 ). Regulation of related proteins can significantly reduce EB leakage and increase TJ protein expression ( Xin et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Experimental treatments to attenuate blood spinal cord barrier rupture in rats with traumatic spinal cord injury: A meta-analysis and systematic review

Deng

Sun

2022

Front. Pharmacol.

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Background: Traumatic spinal cord injury (t-SCI) is a severe injury that has a devastating impact on neurological function. Blood spinal cord barrier (BSCB) destruction following SCI aggravates the primary injury, resulting in a secondary injury. A series of experimental treatments have been proven to alleviate BSCB destruction after t-SCI.Methods: From a screen of 1,189 papers, which were retrieved from Pubmed, Embase, and Web of science, we identified 28 papers which adhered to strict inclusion and exclusion criteria. Evans blue (EB) leakage on the first day post-SCI was selected as the primary result. Secondary outcomes included the expression of tight junction (TJ) proteins and adhesion junction (AJ) proteins in protein immunoblotting. In addition, we measured functional recovery using the Basso, Beattie, Besnahan (BBB) score and we analyzed the relevant mechanisms to explore the similarities between different studies.Result: The forest plot of Evans blue leakage (EB leakage) reduction rate: the pooled effect size of the 28 studies was 0.54, 95% CI: 0.47–0.61, p < 0.01. This indicates that measures to mitigate BSCB damage significantly improved in reducing overall EB leakage. In addition TJ proteins (Occludin, Claudin-5, and ZO-1), AJ proteins (P120 and β-catenin) were significantly upregulated after treatment in all publications. Moreover, BBB scores were significantly improved. Comprehensive studies have shown that in t-SCI, inhibition of matrix metalloproteinases (MMPs) is the most commonly used mechanism to mitigate BSCB damage, followed by endoplasmic reticulum (ER) stress and the Akt pathway. In addition, we found that bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos), which inhibit the TIMP2/MMP signaling pathway, may be the most effective way to alleviate BSCB injury.Conclusion: This study systematically analyzes the experimental treatments and their mechanisms for reducing BSCB injury in the early stage of t-SCI. BMSC-Exos, which inhibit MMP expression, are currently the most effective therapeutic modality for alleviating BSCB damage. In addition, the regulation of MMPs in particular as well as the Akt pathway and the ER stress pathway play important roles in alleviating BSCB injury.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022324794.

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Section: Discussionmentioning

confidence: 99%

Experimental treatments to attenuate blood spinal cord barrier rupture in rats with traumatic spinal cord injury: A meta-analysis and systematic review

Deng

Sun

2022

Front. Pharmacol.

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“…They discovered that the early rapid increase may be related to spinal cord bleeding, while edema and disruption of the blood-spinal cord barrier were key factors in the subsequent slow increase. After the disruption of the blood-spinal cord barrier, significant leakage can occur, reaching its peak at 24 h post-injury and showing a second peak on the fifth day ( Chang and Cao, 2021 ). It was found that most of the leakage occurs in the pericellular space, and intercellular pathways are less common, with TJ proteins being the main component connecting BSCB cells ( Zhou et al, 2023 ).…”

Section: The Mechanisms Underlying Disruption Of the Blood-spinal Cor...mentioning

confidence: 99%

“…The decrease in TJ expression, along with changes in TJ localization or post-transcriptional modifications, are the main reasons leading to an increased permeability of the BSCB ( Deli et al, 2005 ; Chio et al, 2019 ; Zhou et al, 2023 ). Chang and Cao (2021) indicates that spinal cord anterior horn damage often leads to more severe lower limb symptoms and blood-spinal cord barrier (BSCB) disruption. The main reason for this may be that tight junction (TJ) proteins are primarily produced by anterior horn gray matter cells.…”

Section: The Mechanisms Underlying Disruption Of the Blood-spinal Cor...mentioning

confidence: 99%

Teriparatide: an innovative and promising strategy for protecting the blood-spinal cord barrier following spinal cord injury

Xiong,

Feng,

Luo

et al. 2024

Front. Pharmacol.

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“…[ 65 ] Furthermore, in a rat model of SCI, inhibition of ROCK ameliorated blood–spinal cord barrier disruption and improved motor outcomes. [ 66 ] These results were attributed to inhibition of ROCK‐mediated activation of the actin cytoskeletal modulating activities of ADF/cofilin and myosin phosphatase. Recent work has also suggested that RhoA activation downstream of the SARS CoV‐2 spike protein contributes to blood–brain barrier disruption.…”

Section: Pathological Rhoa Activation In Neurological Diseasesmentioning

confidence: 99%

TRPV4: A trigger of pathological RhoA activation in neurological disease

2022

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Transient receptor potential vanilloid 4 (TRPV4), a member of the TRP superfamily, is a broadly expressed, cell surface-localized cation channel that is activated by a variety of environmental stimuli. Importantly, TRPV4 has been increasingly implicated in the regulation of cellular morphology. Here we propose that TRPV4 and the cytoskeletal remodeling small GTPase RhoA together constitute an environmentally sensitive signaling complex that contributes to pathological cell cytoskeletal alterations during neurological injury and disease. Supporting this hypothesis is our recent work demonstrating direct physical and bidirectional functional interactions of TRPV4 with RhoA, which can lead to activation of RhoA and reorganization of the actin cytoskeleton.Furthermore, a confluence of evidence implicates TRPV4 and/or RhoA in pathological responses triggered by a range of acute neurological insults ranging from stroke to traumatic injury. While initiated by a variety of insults, TRPV4-RhoA signaling may represent a common pathway that disrupts axonal regeneration and blood-brain barrier integrity. These insights also suggest that TRPV4 inhibition may represent a safe, feasible, and precise therapeutic strategy for limiting pathological TRPV4-RhoA activation in a range of neurological diseases.

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The ROCK inhibitor Y-27632 ameliorates blood-spinal cord barrier disruption by reducing tight junction protein degradation via the MYPT1-MLC2 pathway after spinal cord injury in rats

Cited by 6 publications

References 58 publications

Experimental treatments to attenuate blood spinal cord barrier rupture in rats with traumatic spinal cord injury: A meta-analysis and systematic review

Experimental treatments to attenuate blood spinal cord barrier rupture in rats with traumatic spinal cord injury: A meta-analysis and systematic review

Teriparatide: an innovative and promising strategy for protecting the blood-spinal cord barrier following spinal cord injury

TRPV4: A trigger of pathological RhoA activation in neurological disease

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