scholarly journals Biological Functions and Therapeutic Potential of Autophagy in Spinal Cord Injury

2021 ◽  
Vol 9 ◽  
Author(s):  
Hai-Yang Liao ◽  
Zhi-Qiang Wang ◽  
Rui Ran ◽  
Kai-Sheng Zhou ◽  
Chun-Wei Ma ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Biological Therapy ◽  
Therapeutic Potential ◽  
Degradation Pathway ◽  
Neuroprotective Effects ◽  
Current Review ◽  
Cord Injury ◽  
Evolutionarily Conserved

Autophagy is an evolutionarily conserved lysosomal degradation pathway that maintains metabolism and homeostasis by eliminating protein aggregates and damaged organelles. Many studies have reported that autophagy plays an important role in spinal cord injury (SCI). However, the spatiotemporal patterns of autophagy activation after traumatic SCI are contradictory. Most studies show that the activation of autophagy and inhibition of apoptosis have neuroprotective effects on traumatic SCI. However, reports demonstrate that autophagy is strongly associated with distal neuronal death and the impaired functional recovery following traumatic SCI. This article introduces SCI pathophysiology, the physiology and mechanism of autophagy, and our current review on its role in traumatic SCI. We also discuss the interaction between autophagy and apoptosis and the therapeutic effect of activating or inhibiting autophagy in promoting functional recovery. Thus, we aim to provide a theoretical basis for the biological therapy of SCI.

scholarly journals Sonic Hedgehog modulates the inflammatory response and improves functional recovery after spinal cord injury in a thoracic contusion–compression model

2021 ◽  
Author(s):  
Hao Zhang ◽  
Alexander Younsi ◽  
Guoli Zheng ◽  
Mohamed Tail ◽  
Anna-Kathrin Harms ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Sonic Hedgehog ◽  
Functional Recovery ◽  
Intrathecal Administration ◽  
Neuroprotective Effects ◽  
Thoracic Spinal Cord ◽  
Shh Pathway ◽  
Thoracic Spinal ◽  
Cord Injury

Abstract Purpose The Sonic Hedgehog (Shh) pathway has been associated with a protective role after injury to the central nervous system (CNS). We, therefore, investigated the effects of intrathecal Shh-administration in the subacute phase after thoracic spinal cord injury (SCI) on secondary injury processes in rats. Methods Twenty-one Wistar rats were subjected to thoracic clip-contusion/compression SCI at T9. Animals were randomized into three treatment groups (Shh, Vehicle, Sham). Seven days after SCI, osmotic pumps were implanted for seven-day continuous intrathecal administration of Shh. Basso, Beattie and Bresnahan (BBB) score, Gridwalk test and bodyweight were weekly assessed. Animals were sacrificed six weeks after SCI and immunohistological analyses were conducted. The results were compared between groups and statistical analysis was performed (p < 0.05 was considered significant). Results The intrathecal administration of Shh led to significantly increased polarization of macrophages toward the anti-inflammatory M2-phenotype, significantly decreased T-lymphocytic invasion and significantly reduced resident microglia six weeks after the injury. Reactive astrogliosis was also significantly reduced while changes in size of the posttraumatic cyst as well as the overall macrophagic infiltration, although reduced, remained insignificant. Finally, with the administration of Shh, gain of bodyweight (216.6 ± 3.65 g vs. 230.4 ± 5.477 g; p = 0.0111) and BBB score (8.2 ± 0.2 vs. 5.9 ± 0.7 points; p = 0.0365) were significantly improved compared to untreated animals six weeks after SCI as well. Conclusion Intrathecal Shh-administration showed neuroprotective effects with attenuated neuroinflammation, reduced astrogliosis and improved functional recovery six weeks after severe contusion/compression SCI.

scholarly journals High-Dose Neural Stem/Progenitor Cell Transplantation Increases Engraftment and Neuronal Distribution and Promotes Functional Recovery in Rats after Acutely Severe Spinal Cord Injury

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Taoyang Yuan ◽  
Qian Liu ◽  
Jie Kang ◽  
Hua Gao ◽  
Songbai Gui
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Network Formation ◽  
Donor Cell ◽  
High Dose ◽  
Lesion Area ◽  
Neuroprotective Effects ◽  
Cord Injury ◽  
Neuronal Distribution

Severe spinal cord injury (SCI) leads to permanent, complete paraplegia and places considerable mental and economic burdens on patients, compared with mild to moderate SCI. However, the dose-related effects of the neural stem/precursor cell (NSPC) transplantation on the injury microenvironment, NSPC survival, axonal growth, neuronal distribution, the composition of neurons, oligodendrocytes, and astrocytes in the lesion area and functional recovery have not yet been quantitatively evaluated in the context of severe SCI. In our study, we acutely transplanted 2.5×104 or 1.5×105 NSPCs/μl into the site of transection SCI. We found that high-dose NSPC transplantation exerted immunomodulatory and neuroprotective effects in the acute phase of severe SCI. In addition, one week later, a remarkable positive relationship was observed between the transplantation dose and the number of surviving NSPCs in severe SCI. At 8 weeks postgrafting, subjects that received the higher cell dose exhibited abundant nerve regeneration, extensive neuronal distribution, increased proportions of neurons and oligodendrocytes, and nascent functional neural network formation in the lesion area. Notably, a significant functional recovery was also observed. Our data suggest that it is important to consider potential dose-related effects on donor cell survival, neuronal distribution, and locomotor recovery in the development of preclinical NSPC transplantation therapy for severe SCI.

scholarly journals MicroRNA-92a-3p enhances functional recovery and suppresses apoptosis after spinal cord injury via targeting phosphatase and tensin homolog

2020 ◽  
Vol 40 (5) ◽  
Author(s):  
Shaoxuan He ◽  
Zhihua Wang ◽  
Yunxuan Li ◽  
Junjie Dong ◽  
Dong Xiang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Mammalian Target Of Rapamycin ◽  
Mice Model ◽  
Neuroprotective Effects ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Cord Injury ◽  
Underlying Mechanisms

Abstract Spinal cord injury (SCI) is a neurological disease commonly caused by traumatic events on spinal cords. MiRNA-92a-3p is reported to be down-regulated after SCI. Our study investigated the effects of up-regulated miR-92a-3p on SCI and the underlying mechanisms. SCI mice model was established to evaluate the functional recovery of hindlimbs of mice through open-field locomotion and scored by Basso, Beattie, and Bresnahan (BBB) locomotion scale. Apoptosis of spinal cord cells was determined by flow cytometry. The effects of miR-92a-3p on SCI were detected by intrathecally injecting miR-92a-3p agomiR (agomiR-92) into the mice prior to the establishment of SCI. Phosphatase and tensin homolog (PTEN) was predicted as a target of miR-29a-3p by TargetScan. We further assessed the effects of agomiR-92 or/and overexpressed PTEN on apoptosis rates and apoptotic protein expressions in SCI mice. Moreover, the activation of protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling was determined by Western blot. The results showed that compared with the sham-operated mice, SCI mice had much lower BBB scores, and theapoptosis rate of spinal cord cells was significantly increased. After SCI, the expression of miR-92a-3p was down-regulated, and increased expression of miR-92a-3p induced by agomiR-92 further significantly increased the BBB score and decreased apoptosis. PTEN was specifically targeted by miR-92a-3p. In addition, the phosphorylation levels of Akt and mTOR were up-regulated under the treatment of agomiR-92. Our data demonstrated that the neuroprotective effects of miR-92a-3p on spinal cord safter SCI were highly associated with the activation of the PTEN/AKT/mTOR pathway.

scholarly journals Diosgenin Glucoside Protects against Spinal Cord Injury by Regulating Autophagy and Alleviating Apoptosis

2018 ◽  
Vol 19 (8) ◽  
pp. 2274 ◽  
Author(s):  
Xian-Bing Chen ◽  
Zi-Li Wang ◽  
Qing-Yu Yang ◽  
Fang-Yu Zhao ◽  
Xiao-Li Qin ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Therapeutic Potential ◽  
Tissue Injury ◽  
Treated Group ◽  
Control Group ◽  
Sprague Dawley ◽  
Neuroprotective Effects ◽  
Traumatic Lesion ◽  
Cord Injury

Spinal cord injury (SCI) is a severe traumatic lesion of central nervous system (CNS) with only a limited number of restorative therapeutic options. Diosgenin glucoside (DG), a major bioactive ingredient of Trillium tschonoskii Max., possesses neuroprotective effects through its antioxidant and anti-apoptotic functions. In this study, we investigated the therapeutic benefit and underlying mechanisms of DG treatment in SCI. We found that in Sprague-Dawley rats with traumatic SCI, the expressions of autophagy marker Light Chain 3 (LC3) and Beclin1 were decreased with concomitant accumulation of autophagy substrate protein p62 and ubiquitinated proteins, indicating an impaired autophagic activity. DG treatment, however, significantly attenuated p62 expression and upregulated the Rheb/mTOR signaling pathway (evidenced as Ras homolog enriched in brain) due to the downregulation of miR-155-3p. We also observed significantly less tissue injury and edema in the DG-treated group, leading to appreciable functional recovery compared to that of the control group. Overall, the observed neuroprotection afforded by DG treatment warrants further investigation on its therapeutic potential in SCI.

scholarly journals Trehalose Augments Neuron Survival and Improves Recovery from Spinal Cord Injury via mTOR-Independent Activation of Autophagy

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Kailiang Zhou ◽  
Huanwen Chen ◽  
Huazi Xu ◽  
Xiaofeng Jia
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Therapeutic Potential ◽  
Neurological Dysfunction ◽  
Tissue Loss ◽  
Compression Injury ◽  
Autophagy Flux ◽  
Nissl Staining ◽  
Cord Injury

Spinal cord injury (SCI) is a major cause of irreversible nerve injury and leads to serious tissue loss and neurological dysfunction. Thorough investigation of cellular mechanisms, such as autophagy, is crucial for developing novel and effective therapeutics. We administered trehalose, an mTOR-independent autophagy agonist, in SCI rats suffering from moderate compression injury to elucidate the relationship between autophagy and SCI and evaluate trehalose’s therapeutic potential. 60 rats were divided into 4 groups and were treated with either control vehicle, trehalose, chloroquine, or trehalose + chloroquine 2 weeks prior to administration of moderate spinal cord crush injury. 20 additional sham rats were treated with control vehicle. H&E staining, Nissl staining, western blot, and immunofluorescence studies were conducted to examine nerve morphology and quantify autophagy and mitochondrial-dependent apoptosis at various time points after surgery. Functional recovery was assessed over a period of 4 weeks after surgery. Trehalose promotes autophagosome recruitment via an mTOR-independent pathway, enhances autophagy flux in neurons, inhibits apoptosis via the intrinsic mitochondria-dependent pathway, reduces lesion cavity expansion, decreases neuron loss, and ultimately improves functional recovery following SCI (all p < 0.05 ). Furthermore, these effects were diminished upon administration of chloroquine, an autophagy flux inhibitor, indicating that trehalose’s beneficial effects were due largely to activation of autophagy. This study presents new evidence that autophagy plays a critical neuroprotective and neuroregenerative role in SCI, and that mTOR-independent activation of autophagy with trehalose leads to improved outcomes. Thus, trehalose has great translational potential as a novel therapeutic agent after SCI.

Neuroprotective Effects of Caspase-3 Inhibition on Functional Recovery and Tissue Sparing After Acute Spinal Cord Injury

Spine ◽  
2008 ◽  
Vol 33 (21) ◽  
pp. 2269-2277 ◽  
Author(s):  
Bruce A. Citron ◽  
Paul M. Arnold ◽  
Neal G. Haynes ◽  
Syed Ameenuddin ◽  
Mohammed Farooque ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Caspase 3 ◽  
Acute Spinal Cord Injury ◽  
Neuroprotective Effects ◽  
Cord Injury ◽  
Tissue Sparing

scholarly journals Therapeutic potential of flavonoids in spinal cord injury

2017 ◽  
Vol 28 (1) ◽  
pp. 87-101 ◽  
Author(s):  
Peng Zhang ◽  
Christian Hölscher ◽  
Xun Ma
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Therapeutic Potential ◽  
Economic Effects ◽  
Pharmacological Properties ◽  
Plant Metabolites ◽  
Neuroprotective Effects ◽  
Cord Injury ◽  
Anti Oxidant ◽  
Novel Therapeutic Strategies

AbstractSpinal cord injury (SCI) is a catastrophic event that can profoundly affect a patient’s life, with far-reaching social and economic effects. A consequential sequence of SCI is the significant neurological or psychological deficit, which obviously contributes to the overall burden of this condition. To date, there is no effective treatment for SCI. Therefore, developing novel therapeutic strategies for SCI is highly prioritized. Flavonoids, one of the most numerous and ubiquitous groups of plant metabolites, are the active ingredients of traditional Chinese medicine such as Scutellaria baicalensis Georgi (Huang Qin) or Ginkgo biloba (Ying Xin). Accumulated research data show that flavonoids possess a range of key pharmacological properties such as anti-inflammatory, anti-oxidant, anti-tumor, anti-viral, anti-cardiovascular disease, immunomodulatory, and neuroprotective effects. Based on this, the flavonoids show therapeutic potential for SCI diseases. In this paper, we will review the pharmacological properties of different types of flavonoids for the treatment of SCI diseases, and potential underlying biochemical mechanisms of action will also be described.

scholarly journals Peptide OM-LV20 promotes structural and functional recovery of spinal cord injury in rats

2021 ◽  
Author(s):  
Jian Zhao ◽  
Ailang Pang ◽  
Meifeng Yang ◽  
Xuemei Zhang ◽  
Rong Zhang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Acute Stage ◽  
Neuroprotective Effects ◽  
Adult Rats ◽  
Hind Limbs ◽  
Cord Injury

Abstract At present, there are no satisfactory therapeutic drugs for the functional recovery of spinal cord injury (SCI). We previously identified a novel peptide (OM-LV20) that accelerated the regeneration of injured skin tissues of mice and exerts neuroprotective effects against cerebral ischemia/reperfusion injury in rats. Here, the intraperitoneal injection of OM-LV20 (1 µg/kg) markedly improved motor function recovery in the hind limbs of rats with traumatic SCI, and further enhanced spinal cord repair. Administration of OM-LV20 increased the number of surviving neuron bodies, as well as the expression levels of brain-derived neurotrophic factor and its receptor tyrosine receptor kinase B. In the acute stage of SCI, OM-LV20 treatment also increased superoxide dismutase and glutathione content but decreased the levels of malonaldehyde and nitric oxide. Thus, OM-LV20 significantly promoted structural and functional recovery of SCI in adult rats by increasing neuronal survival and BDNF and TrkB expression, and thereby regulating the balance of oxidative stress. Based on our knowledge, this research is the first report on the effects of amphibian-derived peptide on the recovery of SCI and our results highlight the potential of peptide OM-LV20 administration in the acceleration of the recovery of SCI.

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