scholarly journals Ryanodine Receptor 2 Plays a Critical Role in Spinal Cord Injury via Induction of Oxidative Stress

2016 ◽  
Vol 38 (3) ◽  
pp. 1129-1137 ◽  
Author(s):  
Bo Liao ◽  
Yong Zhang ◽  
Honghui Sun ◽  
Baoan Ma ◽  
Jixian Qian
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Molecular Mechanisms ◽  
Ryanodine Receptors ◽  
Critical Role ◽  
Ros Generation ◽  
Lesion Volume ◽  
Activating Transcription Factor 3 ◽  
Cord Injury

Background/Aims: Spinal cord injury (SCI) is a severe health problem worldwide. Ryanodine receptors (RyRs) are a class of intracellular calcium channels in various excitable tissues such as muscles and nervous tissues. The current study was designed to investigate the possible role of RyR2 upregulation in SCI and to elucidate the possible molecular mechanisms. Methods: Rats were injected with LVshRNAi- RyR2 and then exposed to spinal cord contusion injury. Results: The results showed that knockdown of RyR2 significantly promoted the recovery of structural and functional injury in spinal cord, as evidenced by reduction of lesion volume and increase of Basso, Beattie and Bresnahan (BBB) and combined behavioral score (CBS) scores. Knockdown of RyR2 inhibited the increase of proinflammatory cytokines, including IL-1β and TNFα. Moreover, downregulation of RyR2 increased oxygen consumption rate and decreased the expression of glucose-regulated protein 78 (GRP78), activating transcription factor 3 (ATF3) and ATF6, indicating the improvement of mitochondrial dysfunction and endoplasmic reticulum stress after SCI. Furthermore, silence of RyR2 reduced oxidative stress, as reflected by decrease of TBARS and GSSG content and increase of GSH level. The expression of NADPH oxidase 2 (NOX2), NOX4 and p66shc were increased in SCI rats. Knockdown of RyR2 significantly decreased NOX2 expression, but had no evident effect on NOX4 and p66shc expression. These results indicated NOX2 may be involved in RyR2-induced ROS generation which mediated contusion-induced spinal cord injury. Conclusion: The data provide novel insights into the mechanism of RyR2-mediated injury and the potential therapeutic targets for injury in spinal cord.

scholarly journals Catalpol Protects Against Spinal Cord Injury in Mice Through Regulating MicroRNA-142-Mediated HMGB1/TLR4/NF-κB Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Hougang Xia ◽  
Dandan Wang ◽  
Xiaohui Guo ◽  
Kaidi Wu ◽  
Fuwei Huang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Inflammatory Factors ◽  
Tunel Staining ◽  
Ros Generation ◽  
Bv2 Cells ◽  
Cord Injury ◽  
Oxidative Response

Background: Spinal cord injury (SCI) is a devastating condition that leads to paralysis, disability and even death in severe cases. Inflammation, apoptosis and oxidative stress in neurons are key pathogenic processes in SCI. Catalpol (CTP), an iridoid glycoside extracted from Rehmannia glutinosa, has many pharmacological activities, such as anti-inflammatory, anti-oxidative and anti-apoptotic properties.Purpose: Here, we investigated whether CTP could exert neuroprotective effects against SCI, and explored the underlying mechanism involved.Methods: SCI was induced by a weight-drop device and treated with CTP (10 mg and 60 mg/kg). Then the locomotor function of SCI mice was evaluated by the BBB scores, spinal cord edema was measured by the wet/dry weight method, oxidative stress markers and inflammatory factors were detected by commercial kits and neuronal death was measured by TUNEL staining. Moreover, the microRNA expression profile in spinal cords from mice following SCI was analyzed using miRNA microarray. In addition, reactive oxygen species (ROS) generation, inflammatory response and cell apoptosis were detected in murine microglia BV2 cells under oxygen-glucose deprivation (OGD) and CTPtreatment.Results: Our data showed that CTP treatment could improve the functional recovery, as well as suppress the apoptosis, alleviate inflammatory and oxidative response in SCI mice. In addition, CTP was found to be up-regulated miR-142 and the protective effects of CTP on apoptosis, inflammatory and oxidative response may relate to its regulation of HMGB1/TLR4/NF-κB pathway through miR-142.Conclusion: Our findings suggest that CTP may protect the spinal cord from SCI by suppression of apoptosis, oxidative stress and inflammatory response via miR-142/HMGB1/TLR4/NF-κB pathway.

scholarly journals HDAC6 Regulates the Chaperone-Mediated Autophagy to Prevent Oxidative Damage in Injured Neurons after Experimental Spinal Cord Injury

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Min Su ◽  
Huaqing Guan ◽  
Fan Zhang ◽  
Yarong Gao ◽  
Xiaomei Teng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Potential Role ◽  
Mechanical Trauma ◽  
Ros Generation ◽  
Histone Deacetylase 6 ◽  
Cord Injury ◽  
Chaperone Mediated Autophagy

Hypoxia-ischemia- (HI-) induced oxidative stress plays a role in secondary pathocellular processes of acute spinal cord injury (SCI) due to HI from many kinds of mechanical trauma. Increasing evidence suggests that the histone deacetylase-6 (HDAC6) plays an important role in cell homeostasis in both physiological and abnormal, stressful, pathological conditions. This paper found that inhibition of HDAC6 accelerated reactive oxygen species (ROS) generation and cell apoptosis in response to the HI. Deficiency of HDAC6 hindered the chaperone-mediated autophagy (CMA) activity to resistance of HI-induced oxidative stress. Furthermore, this study provided the experimental evidence for the potential role of HDAC6 in the regulation of CMA by affecting HSP90 acetylation. Therefore, HDAC6 plays an important role in the function of CMA pathway under the HI stress induced by SCI and it may be a potential therapeutic target in acute SCI model.

scholarly journals Inhibiting microglia proliferation after spinal cord injury improves recovery in mice and nonhuman primates

2021 ◽  
Author(s):  
Gaëtan Poulen ◽  
Emilie Aloy ◽  
Claire M. Bringuier ◽  
Nadine Mestre-Francés ◽  
Emaëlle V.F. Artus ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Function ◽  
Functional Recovery ◽  
Nonhuman Primates ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Post Injury ◽  
Function Recovery ◽  
Cord Injury

AbstractNo curative treatment is available for any deficits induced by spinal cord injury (SCI). Following injury, microglia undergo highly diverse activation processes, including proliferation, and play a critical role on functional recovery.In a translational objective, we investigated whether a transient pharmacological reduction of microglia proliferation after injury is beneficial for functional recovery after SCI in mice and nonhuman primates. The colony stimulating factor-1 receptor (CSF1R) regulates proliferation, differentiation, and survival of microglia, we thus used an oral administration of GW2580, a CSF1R inhibitor.First, transient post-injury GW2580 administration in mice improves motor function recovery, promotes tissues preservation and/or reorganization (identified by coherent anti-stokes Raman scattering microscopy), and modulates glial reactivity.Second, post-injury GW2580-treatment in nonhuman primates reduces microglia proliferation, improves functional motor function recovery, and promotes tissue protection. Notably, three months after lesion microglia reactivity returned to baseline value.Finally, to initiate the investigation on molecular mechanisms induced by a transient post-SCI GW2580-treatment, we used microglia-specific transcriptomic analysis in mice. Notably, we detected a downregulation in the expression of inflammatory-associated genes and we identified genes that were up-regulated by SCI and further downregulated by the treatment.Thus, a transient oral GW2580 treatment post-injury may provide a promising therapeutic strategy for SCI patients and may also be extended to other central nervous system disorders displaying microglia activation.

scholarly journals GAS5 knockdown alleviates spinal cord injury by reducing VAV1 expression via RNA binding protein CELF2

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dan Wang ◽  
Xiaoxiao Xu ◽  
Junwei Pan ◽  
Shixin Zhao ◽  
Yu Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Cell Injury ◽  
Glucose Deprivation ◽  
Nucleotide Exchange ◽  
Coding Region ◽  
Cord Injury

AbstractLong non-coding RNA growth arrest specific transcript 5 (GAS5) has been found to be implicated in the pathogenesis of central nervous diseases and to be a contributor to hypoxic brain injury. However, the roles and molecular mechanisms of GAS5 in spinal cord injury (SCI) have not thoroughly investigated. Here, we reported that GAS5 knockdown improved rat locomotor function and alleviated pathological damage of spinal cord tissues by reducing oxidative stress, caspase-3 activity and vav guanine nucleotide exchange factor 1 (VAV1) expression in SCI rat models. GAS5 knockdown inhibited the increase of malondialdehyde (MDA) level and cell apoptotic rate induced by oxygen–glucose deprivation (OGD) and weakened the inhibitory effects of OGD on superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and cell viability in RN-Sc cells, suggesting that GAS5 loss mitigated OGD-triggered oxidative stress and cell injury in RN-Sc cells. Molecular mechanism explorations revealed that GAS5 recruited CUGBP, Elav-like family member 2 (CELF2) to the coding region of VAV1 mRNA, resulting in the increase of VAV1 mRNA stability and expression levels. VAV1 knockdown weakened OGD-induced oxidative stress and cell injury in RN-Sc cells. VAV1 loss alleviated GAS5-induced oxidative stress and cell injury in OGD-treated RN-Sc cells. As a conclusion, our findings suggested that GAS5 aggravated SCI by increasing VAV1 expression via binding with CELF2, deepening our understanding on function and molecular basis of GAS5 in SCI.

scholarly journals Critical role of mitochondrial aldehyde dehydrogenase 2 in acrolein sequestering in rat spinal cord injury

2022 ◽  
Vol 17 (7) ◽  
pp. 1505
Author(s):  
Riyi Shi ◽  
SethA Herr ◽  
Liangqin Shi ◽  
Thomas Gianaris ◽  
Yucheng Jiao ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Aldehyde Dehydrogenase ◽  
Critical Role ◽  
Aldehyde Dehydrogenase 2 ◽  
Rat Spinal Cord ◽  
Cord Injury

scholarly journals pH-responsive delivery of H2 through ammonia borane-loaded mesoporous silica nanoparticles improves recovery after spinal cord injury by moderating oxidative stress and regulating microglial polarization

2021 ◽  
Author(s):  
Yi Liu ◽  
Yeying Wang ◽  
Bing Xiao ◽  
Guoke Tang ◽  
Jiangming Yu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Mesoporous Silica ◽  
Silica Nanoparticles ◽  
Mesoporous Silica Nanoparticles ◽  
Ammonia Borane ◽  
Neural Regeneration ◽  
Dependent Manner ◽  
Cord Injury

Abstract Imbalance of oxidative and inflammatory regulation is the main contributor to neurofunctional deterioration and failure of rebuilding spared neural networks after spinal cord injury (SCI). As an emerging biosafe strategy for protecting against oxidative and inflammatory damage, hydrogen (H2) therapy is a promising approach for improving the microenvironment to allow neural regeneration. However, achieving release of H2 at sufficient concentrations specifically into the injured area is critical for the therapeutic effect of H2. Thus, we assembled SiO2@mSiO2 mesoporous silica nanoparticles and loaded them with ammonia borane (AB), which has abundant capacity and allows controllable release of H2 in an acid-dependent manner. The release of H2 from AB/SiO2@mSiO2 was satisfactory at pH 6.6, which is approximately equal to the microenvironmental acidity after SCI. After AB/SiO2@mSiO2 were intrathecally administered to rat models of SCI, continuous release of H2 from these nanoparticles synergistically enhanced neurofunctional recovery, reduced fibrotic scar formation and promoted neural regeneration by suppressing oxidative stress reaction. Furthermore, in the subacute phase of SCI, microglia were markedly polarized toward the M2 phenotype by H2 via inhibition of TLR9 expression in astrocytes. In conclusion, H2 delivery through AB/SiO2@mSiO2 has the potential to efficiently treat SCI through comprehensive modulation of the oxidative and inflammatory imbalance in the microenvironment.

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