Propitious Therapeutic Modulators to Prevent Blood-Spinal Cord Barrier Disruption in Spinal Cord Injury

Kumar, Hemant; Ropper, Alexander E.; Lee, Soo−Hong; Han, Inbo

doi:10.1007/s12035-016-9910-6

Cited by 76 publications

(45 citation statements)

References 164 publications

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“…The BSCB is similar to the blood–brain barrier and effectively prevents certain substances, especially harmful ones, in the blood circulation from entering the CNS, and this property is conducive to maintaining the stability of the microenvironment in CNS [12]. After SCI, BSCB destruction and increased microvascular permeability lead to the infiltration of inflammatory cells, such as neutrophils and macrophages, leading to spinal cord tissue edema and cell necrosis [27]. The integrity of the BSCB is further impaired by activation of pro-inflammatory cytokines during secondary injury [28].…”

Section: Discussionmentioning

confidence: 99%

Brilliant Blue G Inhibits Inflammasome Activation and Reduces Disruption of Blood–Spinal Cord Barrier Induced by Spinal Cord Injury in Rats

Zhou

Yang

et al. 2019

Med Sci Monit

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Background Brilliant blue G (BBG) is a P2X7 receptor inhibitor that has been reported to improve spinal cord injury (SCI) in previous studies, but the specific mechanism has been unclear. In this study, we investigated the effects of BBG on inflammasomes and blood–spinal cord barrier (BSCB) permeability after SCI. Material/Methods The experimental rats were randomly divided into 3 groups: sham, SCI, and SCI+BBG. The expression of P2X7 and inflammasome-related proteins was measured by Western blot and immunohistochemistry, while IL-1β and IL-18 levels were measured by using an enzyme-linked immunosorbent assay (ELISA) kit. The permeability of the BSCB was evaluated by Evans Blue (EB) exosmosis, and histological alterations were observed by hematoxylin-eosin staining. Motor function recovery was assessed by the Basso, Beattie, Bresnahan (BBB) scale after SCI. Results The expression levels of P2X7, NLRP3, ASC, cleaved XIAP, caspase-1, caspase-11, IL-1β, and IL-18 were increased significantly after SCI, and BBG administration inhibited this increase at 72 h after SCI. BBG administration significantly reduced EB leakage at 24 h after SCI. Furthermore, treatment with BBG significantly attenuated histological alterations and improved motor function recovery after SCI. Conclusions BBG administration promoted motor function recovery and alleviated tissue injury, and these effects might be related to the suppression of inflammasomes and the maintenance of BSCB integrity.

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Section: Discussionmentioning

confidence: 99%

Brilliant Blue G Inhibits Inflammasome Activation and Reduces Disruption of Blood–Spinal Cord Barrier Induced by Spinal Cord Injury in Rats

Zhou

Yang

et al. 2019

Med Sci Monit

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“…These pro-inflammatory factors stimulate nitric oxide synthesis, which leads to increased capillary permeability and blood-spinal cord barrier dysfunction while promoting neuronal apoptosis [ 2 , 3 ]. The inhibition of SCI-induced, the microglial activation, and the subsequent neuroinflammatory response have been shown to improve the recovery in SCI patients [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Valproic acid attenuates traumatic spinal cord injury-induced inflammation via STAT1 and NF-κB pathway dependent of HDAC3

Chen

et al. 2018

J Neuroinflammation

215

155

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BackgroundMicroglial polarization with M1/M2 phenotype shifts and the subsequent neuroinflammatory responses are vital contributing factors for spinal cord injury (SCI)-induced secondary injury. Nuclear factor-κB (NF-κB) is considered the central transcription factor of inflammatory mediators, which plays a crucial role in microglial activation. Lysine acetylation of STAT1 seems necessary for NF-kB pathway activity, as it is regulated by histone deacetylases (HDACs). There have been no studies that have explained if HDAC inhibition by valproic acid (VPA) affects the NF-κB pathway via acetylation of STAT1 dependent of HDAC activity in the microglia-mediated central inflammation following SCI. We investigated the potential molecular mechanisms that focus on the phenotypic transition of microglia and the STAT1-mediated NF-κB acetylation after a VPA treatment.MethodsThe Basso-Beattie-Bresnahan locomotion scale, the inclined plane test, the blood-spinal cord barrier, and Nissl staining were employed to determine the neuroprotective effects of VPA treatment after SCI. Assessment of microglia polarization and pro-inflammatory markers, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and interferon (INF)-γ was used to evaluate the neuroinflammatory responses and the anti-inflammatory effects of VPA treatment. Immunofluorescent staining and Western blot analysis were used to detect HDAC3 nuclear translocation, activity, and NF-κB signaling pathway activation to evaluate the effects of VPA treatment. The impact of STAT1 acetylation on NF-kB pathway and the interaction between STAT1 and NF-kB were assessed to evaluate anti-inflammation effects of VPA treatment and also whether these effects were dependent on a STAT1/NF-κB pathway to gain further insight into the mechanisms underlying the development of the neuroinflammatory response after SCI.ResultsThe results showed that the VPA treatment promoted the phenotypic shift of microglia from M1 to M2 phenotype and inhibited microglial activation, thus reducing the SCI-induced inflammatory factors. The VPA treatment upregulation of the acetylation of STAT1/NF-κB pathway was likely caused by the HDAC3 translocation to the nucleus and activity. These results indicated that the treatment with the VPA suppressed the expression and the activity of HDAC3 and enhanced STAT1, as well as NF-κB p65 acetylation following a SCI. The acetylation status of NF-kB p65 and the complex with NF-κB p65 and STAT1 inhibited the NF-kB p65 transcriptional activity and attenuated the microglia-mediated central inflammatory response following SCI.ConclusionsThese results suggested that the VPA treatment attenuated the inflammatory response by modulating microglia polarization through STAT1-mediated acetylation of the NF-κB pathway, dependent of HDAC3 activity. These effects led to neuroprotective effects following SCI.

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“…The initial mechanical trauma usually triggers a secondary damage cascade, where a sustained inflammatory response to the secondary injury could contribute to neuronal apoptosis, demyelination, and formation of glial scars [3,4]. Since the initial mechanical trauma is uncontrollable, the treatment of SCI is mainly focused on preventing the secondary damage [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Macrophage MSR1 promotes the formation of foamy macrophage and neuronal apoptosis after spinal cord injury

Kong

Líu

et al. 2020

J Neuroinflammation

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Background: A sustained inflammatory response following spinal cord injury (SCI) contributes to neuronal damage, inhibiting functional recovery. Macrophages, the major participants in the inflammatory response, transform into foamy macrophages after phagocytosing myelin debris, subsequently releasing inflammatory factors and amplifying the secondary injury. Here, we assessed the effect of macrophage scavenger receptor 1 (MSR1) in phagocytosis of myelin debris after SCI and explained its possible mechanism. Methods: The SCI model was employed to determine the critical role of MSR1 in phagocytosis of myelin debris in vivo. The potential functions and mechanisms of MSR1 were explored using qPCR, western blotting, and immunofluorescence after treating macrophages and RAW264.7 with myelin debris in vitro. Results: In this study, we found improved recovery from traumatic SCI in MSR1-knockout mice over that in MSR1 wild-type mice. Furthermore, MSR1 promoted the phagocytosis of myelin debris and the formation of foamy macrophage, leading to pro-inflammatory polarization in vitro and in vivo. Mechanistically, in the presence of myelin debris, MSR1-mediated NF-κB signaling pathway contributed to the release of inflammatory mediators and subsequently the apoptosis of neurons. Conclusions:Our study elucidates a previously unrecognized role of MSR1 in the pathophysiology of SCI and suggests that its inhibition may be a new treatment strategy for this traumatic condition.

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Propitious Therapeutic Modulators to Prevent Blood-Spinal Cord Barrier Disruption in Spinal Cord Injury

Cited by 76 publications

References 164 publications

Brilliant Blue G Inhibits Inflammasome Activation and Reduces Disruption of Blood–Spinal Cord Barrier Induced by Spinal Cord Injury in Rats

Brilliant Blue G Inhibits Inflammasome Activation and Reduces Disruption of Blood–Spinal Cord Barrier Induced by Spinal Cord Injury in Rats

Valproic acid attenuates traumatic spinal cord injury-induced inflammation via STAT1 and NF-κB pathway dependent of HDAC3

Macrophage MSR1 promotes the formation of foamy macrophage and neuronal apoptosis after spinal cord injury

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