scholarly journals Parthenolide promotes the repair of spinal cord injury by modulating M1/M2 polarization via the NF-κB and STAT 1/3 signaling pathway

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Tao Gaojian ◽  
Qian Dingfei ◽  
Li Linwei ◽  
Wang Xiaowei ◽  
Zhou Zheng ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Mechanism Study ◽  
Microglia Cell ◽  
M2 Polarization ◽  
Macrophages Polarization ◽  
Bv2 Cells ◽  
Cord Injury

Abstract Spinal cord injury (SCI) is a severe neurological disease; however, there is no effective treatment for spinal cord injury. Neuroinflammation involves the activation of resident microglia and the infiltration of macrophages is the major pathogenesis of SCI secondary injury and considered to be the therapeutic target of SCI. Parthenolide (PN) has been reported to exert anti-inflammatory effects in fever, migraines, arthritis, and superficial inflammation; however, the role of PN in SCI therapeutics has not been clarified. In this study, we showed that PN could improve the functional recovery of spinal cord in mice as revealed by increased BMS scores and decreased cavity of spinal cord injury in vivo. Immunofluorescence staining experiments confirmed that PN could promote axonal regeneration, increase myelin reconstitution, reduce chondroitin sulfate formation, inhibit scar hyperplasia, suppress the activation of A1 neurotoxic reactive astrocytes and facilitate shift from M1 to M2 polarization of microglia/macrophages. To verify how PN exerts its effects on microglia/macrophages polarization, we performed the mechanism study in vitro in microglia cell line BV-2. PN could significantly reduce M1 polarization in BV2 cells and partially rescue the decrease in the expression of M2 phenotype markers of microglia/macrophage induced by LPS, but no significant effect on M2 polarization stimulated with IL-4 was observed. Further study demonstrated PN inhibited NF-κB signal pathway directly or indirectly, and suppressed activation of signal transducer and activator of transcription 1 or 3 (STAT1/3) via reducing the expression of HDAC1 and subsequently increasing the levels of STAT1/3 acetylation. Overall, our study illustrated that PN may be a promising strategy for traumatic SCI.

scholarly journals CD73 alleviates GSDMD-mediated pyroptosis in spinal cord injury through PI3K/AKT/Foxo1 signaling

2020 ◽  
Author(s):  
Shun Xu ◽  
Minghao Shao ◽  
Xiaosheng Ma ◽  
Jianyuan Jiang ◽  
Fan Zhang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Transcriptional Level ◽  
Inflammasome Activation ◽  
Bv2 Cells ◽  
Cord Injury ◽  
Underlying Mechanisms ◽  
Regulatory Loop

Abstract Background: Neuroinflammation-induced secondary injury is responsible for the sustained progression of spinal cord injury (SCI). Inflammatory programmed cell death or pyroptosis triggered by the pore-forming protein gasdermin D (GSDMD) is an essential step in neuroinflammation. The aim of this study was to determine the role of the immunosuppressive receptor CD73 in GSDMD-mediated pyroptosis following SCI. Methods: CD73 deficient mice and LPS-stimulated BV2 cells were respectively used as the in vivo and in vitro models of microglial pyroptosis. Molecular and histological assays were performed to assess pyroptosis and inflammasome activation, and to explore the underlying mechanisms.Results: CD73 inhibited the NLRP3 inflammasome and GSDMD, and decreased pyroptosis in the microglia via the adenosine-A2B adenosine receptor (AR)-PI3K-AKT-FOXO1 pathway. Specifically, CD73 suppressed GSDMD at the transcriptional level through FOXO1. Furthermore, HIF-1α accumulation after SCI upregulated CD73, which in turn increased the expression of HIF-1α, resulting in a positive feedback regulatory loop.Conclusion: CD73 alleviates microglial pyroptosis after SCI by inhibiting GSDMD via the adenosine- A2BAR-PI3K-AKT-FOXO1 pathway.

scholarly journals CD73 alleviates GSDMD-mediated pyroptosis in spinal cord injury through PI3K/AKT/Foxo1 signaling

2019 ◽  
Author(s):  
Shun Xu ◽  
Minghao Shao ◽  
Xiaosheng Ma ◽  
Jianyuan Jiang ◽  
Fan Zhang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Disease Process ◽  
Molecular Evidence ◽  
Transcriptional Level ◽  
Bv2 Cells ◽  
Cord Injury ◽  
Regulatory Loop

Abstract BackgroundNeuroinflammation-induced secondary injury is an important cause of sustained progression of spinal cord injury. Inflammatory programmed cell death pyroptosis executed by the pore-forming protein gasdermin D (GSDMD) is an essential step of neuroinflammation. However, it is unclear whether CD73, a widely accepted immunosuppressive molecule, can inhibit pyroptosis via mediating GSDMD. MethodsCD73 deficient mice and LPS induced BV2 cells were respectively used to illustrate the effect of CD73 on macrophages/microglia pyroptosis in vivo and in vitro. A combination of molecular and histological methods was performed to assess pyroptosis and explore the mechanism both in vivo and in vitro.ResultsWe showed molecular evidence for CD73 suppresses the activation of NLRP3 inflammasome complexes to reduce the maturation of GSDMD, leading to decreased pyroptosis in macrophages/microglia. Further analysis reveals that adenosine-A2B adenosine receptor-PI3K-AKT-Foxo1 cascade is a possible mechanism of CD73 regulation. Importantly, we determine that CD73 inhibits the expression of GSDMD at the transcriptional level through Foxo1. What’s more, we confirm the accumulation of HIF-1α promotes the overexpression of CD73 after SCI, and the increased CD73 in turn upregulates the expression of HIF-1α, eventually forming a positive feedback regulatory loop.ConclusionOur data reveal a novel function of CD73 on microphages/microglia pyroptosis, suggesting a unique therapeutic opportunity for mitigating the disease process in SCI.

scholarly journals A Collagen-Based Scaffold for Promoting Neural Plasticity in a Rat Model of Spinal Cord Injury

Polymers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2245
Author(s):  
Jue-Zong Yeh ◽  
Ding-Han Wang ◽  
Juin-Hong Cherng ◽  
Yi-Wen Wang ◽  
Gang-Yi Fan ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Rat Model ◽  
Neural Plasticity ◽  
Collagen Scaffold ◽  
Glial Scar ◽  
Beneficial Effects ◽  
Cord Injury

In spinal cord injury (SCI) therapy, glial scarring formed by activated astrocytes is a primary problem that needs to be solved to enhance axonal regeneration. In this study, we developed and used a collagen scaffold for glial scar replacement to create an appropriate environment in an SCI rat model and determined whether neural plasticity can be manipulated using this approach. We used four experimental groups, as follows: SCI-collagen scaffold, SCI control, normal spinal cord-collagen scaffold, and normal control. The collagen scaffold showed excellent in vitro and in vivo biocompatibility. Immunofluorescence staining revealed increased expression of neurofilament and fibronectin and reduced expression of glial fibrillary acidic protein and anti-chondroitin sulfate in the collagen scaffold-treated SCI rats at 1 and 4 weeks post-implantation compared with that in untreated SCI control. This indicates that the collagen scaffold implantation promoted neuronal survival and axonal growth within the injured site and prevented glial scar formation by controlling astrocyte production for their normal functioning. Our study highlights the feasibility of using the collagen scaffold in SCI repair. The collagen scaffold was found to exert beneficial effects on neuronal activity and may help in manipulating synaptic plasticity, implying its great potential for clinical application in SCI.

scholarly journals Immunosuppressants Affect Human Neural Stem Cells In Vitro but Not in an In Vivo Model of Spinal Cord Injury

2013 ◽  
Vol 2 (10) ◽  
pp. 731-744 ◽  
Author(s):  
Christopher J. Sontag ◽  
Hal X. Nguyen ◽  
Noriko Kamei ◽  
Nobuko Uchida ◽  
Aileen J. Anderson ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Spinal Cord Injury ◽  
Neural Stem Cells ◽  
In Vivo Model ◽  
Human Neural Stem Cells ◽  
Cord Injury

scholarly journals Depolarization and electrical stimulation enhance in vitro and in vivo sensory axon growth after spinal cord injury

2018 ◽  
Vol 300 ◽  
pp. 247-258 ◽  
Author(s):  
Ioana Goganau ◽  
Beatrice Sandner ◽  
Norbert Weidner ◽  
Karim Fouad ◽  
Armin Blesch
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Electrical Stimulation ◽  
Axon Growth ◽  
Sensory Axon ◽  
Cord Injury

scholarly journals Cytokine and Growth Factor Activation In Vivo and In Vitro after Spinal Cord Injury

2016 ◽  
Vol 2016 ◽  
pp. 1-21 ◽  
Author(s):  
Elisa Garcia ◽  
Jorge Aguilar-Cevallos ◽  
Raul Silva-Garcia ◽  
Antonio Ibarra
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Critical Role ◽  
Glutamate Excitotoxicity ◽  
Signaling Proteins ◽  
Neurodegenerative Process ◽  
Cord Injury ◽  
Ion Imbalance

Spinal cord injury results in a life-disrupting series of deleterious interconnected mechanisms encompassed by the primary and secondary injury. These events are mediated by the upregulation of genes with roles in inflammation, transcription, and signaling proteins. In particular, cytokines and growth factors are signaling proteins that have important roles in the pathophysiology of SCI. The balance between the proinflammatory and anti-inflammatory effects of these molecules plays a critical role in the progression and outcome of the lesion. The excessive inflammatory Th1 and Th17 phenotypes observed after SCI tilt the scale towards a proinflammatory environment, which exacerbates the deleterious mechanisms present after the injury. These mechanisms include the disruption of the spinal cord blood barrier, edema and ion imbalance, in particular intracellular calcium and sodium concentrations, glutamate excitotoxicity, free radicals, and the inflammatory response contributing to the neurodegenerative process which is characterized by demyelination and apoptosis of neuronal tissue.

scholarly journals Docosahexaenoic Acid-Loaded Polylactic Acid Core-Shell Nanofiber Membranes for Regenerative Medicine after Spinal Cord Injury: In Vitro and In Vivo Study

2020 ◽  
Vol 21 (19) ◽  
pp. 7031
Author(s):  
Zhuo-Hao Liu ◽  
Yin-Cheng Huang ◽  
Chang-Yi Kuo ◽  
Chao-Ying Kuo ◽  
Chieh-Yu Chin ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Docosahexaenoic Acid ◽  
Neurite Outgrowth ◽  
Polylactic Acid ◽  
In Vivo Study ◽  
Core Shell ◽  
Cord Injury

Spinal cord injury (SCI) is associated with disability and a drastic decrease in quality of life for affected individuals. Previous studies support the idea that docosahexaenoic acid (DHA)-based pharmacological approach is a promising therapeutic strategy for the management of acute SCI. We postulated that a nanostructured material for controlled delivery of DHA at the lesion site may be well suited for this purpose. Toward this end, we prepare drug-loaded fibrous mats made of core-shell nanofibers by electrospinning, which contained a polylactic acid (PLA) shell for encapsulation of DHA within the core, for delivery of DHA in situ. In vitro study confirmed sustained DHA release from PLA/DHA core-shell nanofiber membrane (CSNM) for up to 36 days, which could significantly increase neurite outgrowth from primary cortical neurons in 3 days. This is supported by the upregulation of brain-derived neurotropic factor (BDNF) and neurotrophin-3 (NT-3) neural marker genes from qRT-PCR analysis. Most importantly, the sustained release of DHA could significantly increase the neurite outgrowth length from cortical neuron cells in 7 days when co-cultured with PLA/DHA CSNM, compared with cells cultured with 3 μM DHA. From in vivo study with a SCI model created in rats, implantation of PLA/DHA CSNM could significantly improve neurological functions revealed by behavior assessment in comparison with the control (no treatment) and the PLA CSNM groups. According to histological analysis, PLA/DHA CSNM also effectively reduced neuron loss and increased serotonergic nerve sprouting. Taken together, the PLA/DHA CSNM may provide a nanostructured drug delivery system for DHA and contribute to neuroprotection and promoting neuroplasticity change following SCI.

scholarly journals Alterations of protein composition along the rostro-caudal axis after spinal cord injury: proteomic, in vitro and in vivo analyses

2014 ◽  
Vol 8 ◽  
Author(s):  
Dasa Cizkova ◽  
Françoise Le Marrec-Croq ◽  
Julien Franck ◽  
Lucia Slovinska ◽  
Ivana Grulova ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Protein Composition ◽  
Cord Injury

scholarly journals VDAC1 is essential for neurite maintenance and the inhibition of its oligomerization protects spinal cord from demyelination and facilitates locomotor function recovery after spinal cord injury

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Vera Paschon ◽  
Beatriz Cintra Morena ◽  
Felipe Fernandes Correia ◽  
Giovanna Rossi Beltrame ◽  
Gustavo Bispo dos Santos ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Cell Death ◽  
Conformational Changes ◽  
Secondary Response ◽  
Disulfonic Acid ◽  
Function Recovery ◽  
Cord Injury

Abstract During the progression of the neurodegenerative process, mitochondria participates in several intercellular signaling pathways. Voltage-dependent anion-selective channel 1 (VDAC1) is a mitochondrial porin involved in the cellular metabolism and apoptosis intrinsic pathway in many neuropathological processes. In spinal cord injury (SCI), after the primary cell death, a secondary response that comprises the release of pro-inflammatory molecules triggers apoptosis, inflammation, and demyelination, often leading to the loss of motor functions. Here, we investigated the functional role of VDAC1 in the neurodegeneration triggered by SCI. We first determined that in vitro targeted ablation of VDAC1 by specific morpholino antisense nucleotides (MOs) clearly promotes neurite retraction, whereas a pharmacological blocker of VDAC1 oligomerization (4, 4′-diisothiocyanatostilbene-2, 2′-disulfonic acid, DIDS), does not cause this effect. We next determined that, after SCI, VDAC1 undergoes conformational changes, including oligomerization and N-terminal exposition, which are important steps in the triggering of apoptotic signaling. Considering this, we investigated the effects of DIDS in vivo application after SCI. Interestingly, blockade of VDAC1 oligomerization decreases the number of apoptotic cells without interfering in the neuroinflammatory response. DIDS attenuates the massive oligodendrocyte cell death, subserving undisputable motor function recovery. Taken together, our results suggest that the prevention of VDAC1 oligomerization might be beneficial for the clinical treatment of SCI.

scholarly journals Molecular Mechanism of MiR-136-5p Targeting NF-κB/A20 in the IL-17-Mediated Inflammatory Response after Spinal Cord Injury

2017 ◽  
Vol 44 (3) ◽  
pp. 1224-1241 ◽  
Author(s):  
Jichen He ◽  
Jinmin Zhao ◽  
Xiaoming Peng ◽  
Xiongzhi Shi ◽  
Shaohui Zong ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Factors ◽  
Scoring Method ◽  
Histological Changes ◽  
Cord Injury ◽  
Rat Astrocytes ◽  
Underlying Mechanisms

Background/Aims: The pathophysiology of spinal cord injury (SCI) results in serious damage to the human body via an increase in the secondary biological processes imposed by activated astrocytes. Abnormal expression of microRNAs after SCI has become a potential research focus. However, the underlying mechanisms are poorly understood. Methods: SCI models were established in rats using Allen’s method, and the BBB scoring method was employed to assess locomotor function. Lentivirus was used to infect rat astrocytes and SCI rats. Real-time PCR and antibody chip were used to measure gene expression and cytokine secretion. Western blot analysis was employed to detect protein expression. HE staining was used to assess the histological changes in SCI. The immunohistochemical staining of A20 and p-NF-κB in SCI was also analyzed. Results: The in vitro experiment showed that miR-136-5p up-regulated the expression of p-NF-κB by down-regulating the expression of A20 so that astrocytes produced inflammatory factors and chemokines. The in vivo experiment indicated that overexpressed miR-136-5p promoted the production of inflammatory factors, chemokines and p-NF-κB in SCI rats, whereas it inhibited the expression of A20 protein and increased inflammatory cell infiltration and injuries in the spinal cord. Conclusion: The current findings indicate that silencing miR-136-5p effectively decreased inflammatory factors and chemokines and protected the spinal cord via NF-κB/A20 signaling in vivo and in vitro. In contrast, overexpression of miR-136-5p had the opposite effect.

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