scholarly journals RXRα Blocks Nerve Regeneration after Spinal Cord Injury by Targeting p66shc

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Pei Yu ◽  
Kai Yang ◽  
Min Jiang
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Nerve Regeneration ◽  
Motor Neurons ◽  
Regulation Of Gene Expression ◽  
Hippocampal Neurogenesis ◽  
Luciferase Assay ◽  
Cord Injury

Nerve regeneration after spinal cord injury is regulated by many factors. Studies have found that the expression of retinoid X receptor α (RXRα) does not change significantly after spinal cord injury but that the distribution of RXRα in cells changes significantly. In undamaged tissues, RXRα is distributed in motor neurons and the cytoplasm of glial cells. RXRα migrates to the nucleus of surviving neurons after injury, indicating that RXRα is involved in the regulation of gene expression after spinal cord injury. p66shc is an important protein that regulates cell senescence and oxidative stress. It can induce the apoptosis and necrosis of many cell types, promoting body aging. The absence of p66shc enhances the resistance of cells to reactive oxygen species (ROS) and thus prolongs life. It has been found that p66shc deletion can promote hippocampal neurogenesis and play a neuroprotective role in mice with multiple sclerosis. To verify the function of RXRα after spinal cord injury, we established a rat T9 spinal cord transection model. After RXRα agonist or antagonist administration, we found that RXRα agonists inhibited nerve regeneration after spinal cord injury, while RXRα antagonists promoted the regeneration of injured neurites and the recovery of motor function in rats. The results showed that RXRα played an impeding role in repair after spinal cord injury. Immunofluorescence staining showed that p66shc expression was upregulated in neurons after spinal cord injury (in vivo and in vitro) and colocalized with RXRα. RXRα overexpression in cultured neurons promoted the expression of p66shc, while RXRα interference inhibited the expression of p66shc. Using a luciferase assay, we found that RXRα could bind to the promoter region of p66shc and regulate the expression of p66shc, thereby regulating nerve regeneration after spinal cord injury. The above results showed that RXRα inhibited nerve regeneration after spinal cord injury by promoting p66shc expression, and interference with RXRα or p66shc promoted functional recovery after spinal cord injury.

scholarly journals MP Resulting in Autophagic Cell Death of Microglia through Zinc Changes against Spinal Cord Injury

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Dingding Li ◽  
Guannan Wang ◽  
Donghe Han ◽  
Jing Bi ◽  
Chenyuan Li ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Cell Death ◽  
Motor Neurons ◽  
Neuroprotective Effect ◽  
Pulse Therapy ◽  
Autophagic Cell Death ◽  
Cord Injury

Methylprednisolone pulse therapy (MPPT), as a public recognized therapy of spinal cord injury (SCI), is doubted recently, and the exact mechanism of MP on SCI is unclear. This study sought to investigate the exact effect of MP on SCI. We examined the effect of MP in a model of SCI in vivo and an LPS induced model in vitro. We found that administration of MP produced an increase in the Basso, Beattie, and Bresnahan scores and motor neurons counts of injured rats. Besides the number of activated microglia was apparently reduced by MP in vivo, and Beclin-1 dependent autophagic cell death of microglia was induced by MP in LPS induced model. At the same time, MP increases cellular zinc concentration and level of ZIP8, and TPEN could revert effect of MP on autophagic cell death of microglia. Finally, we have found that MP could inhibit NF-κβin LPS induced model. These results show that the MP could result in autophagic cell death of microglia, which mainly depends on increasing cellular labile zinc, and may be associated with inhibition of NF-κβ, and that MP can produce neuroprotective effect 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.

scholarly journals Zinc Regulates Glucose Metabolism of the Spinal Cord and Neurons and Promotes Functional Recovery after Spinal Cord Injury through the AMPK Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-27
Author(s):  
Hengshuo Hu ◽  
Nan Xia ◽  
Jiaquan Lin ◽  
Daoyong Li ◽  
Chuanjie Zhang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Nervous System ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Functional Recovery ◽  
Glucose Metabolism Disorders ◽  
Cord Injury

Spinal cord injury (SCI) is a traumatic disease that can cause severe nervous system dysfunction. SCI often causes spinal cord mitochondrial dysfunction and produces glucose metabolism disorders, which affect neuronal survival. Zinc is an essential trace element in the human body and plays multiple roles in the nervous system. This experiment is intended to evaluate whether zinc can regulate the spinal cord and neuronal glucose metabolism and promote motor functional recovery after SCI. Then we explore its molecular mechanism. We evaluated the function of zinc from the aspects of glucose uptake and the protection of the mitochondria in vivo and in vitro. The results showed that zinc elevated the expression level of GLUT4 and promoted glucose uptake. Zinc enhanced the expression of proteins such as PGC-1α and NRF2, reduced oxidative stress, and promoted mitochondrial production. In addition, zinc decreased neuronal apoptosis and promoted the recovery of motor function in SCI mice. After administration of AMPK inhibitor, the therapeutic effect of zinc was reversed. Therefore, we concluded that zinc regulated the glucose metabolism of the spinal cord and neurons and promoted functional recovery after SCI through the AMPK pathway, which is expected to become a potential treatment strategy for SCI.

Sign in / Sign up

Export Citation Format

Share Document