Important Role In Spinal Cord Injury Research Articles

Identification of Anoikis-Related Genes in Spinal Cord Injury: Bioinformatics and Experimental Validation.

Spinal cord injury (SCI) is a serious disease without effective therapeutic strategies. To identify the potential treatments for SCI, it is extremely important to explore the underlying mechanism. Current studies demonstrate that anoikis might play an important role in SCI. In this study, we aimed to identify the key anoikis-related genes (ARGs) providing therapeutic targets for SCI. The mRNA expression matrix of GSE45006 was downloaded from the Gene Expression Omnibus (GEO) database, and the ARGs were downloaded from the Molecular Signatures Database (MSigDB database). Then, the potential differentially expressed ARGs were identified. Next, correlation analysis, gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) analysis were employed for the differentially expressed ARGs. Moreover, miRNA-gene networks were constructed by the hub ARGs. Finally, RNA expression of the top ten hub ARGs was validated in the SCI cell model and rat SCI model. A total of 27 common differentially expressed ARGs were identified at different time points (1, 3, 7, and 14days) following SCI. The GO and KEGG enrichment analysis of these ARGs indicated several enriched terms related to proliferation, cell cycle, and apoptotic process. The PPI results revealed that most of the ARGs interacted with each other. Ten hub ARGs were further screened, and all the 10 genes were validated in the SCI cell model. In the rat model, only seven genes were validated eventually. We identified 27 differentially expressed ARGs of the SCI through bioinformatic analysis. Seven real hub ARGs (CCND1, FN1, IGF1, MYC, STAT3, TGFB1, and TP53) were identified eventually. These results may expand our understanding of SCI and contribute to the exploration of potential SCI targets.

Autophagy exerts a protective role in cervical spinal cord injury by microglia inhibition through the nuclear factor kappa-B pathway.

Spinal cord injury (SCI) is a serious trauma to the central nervous system. M1/M2 microglial polarization as well as the following neuroinflammatory response are crucial factors in SCI. Autophagy plays an important role in SCI, but its neuroprotective or neurodegenerative role remains controversial. Here, we majorly examined the properties of autophagy in SCI and uncovered the regulatory relationship between autophagy and microglial polarization in SCI. In our study, the Basso-Beattie-Bresnahan (BBB) score was declined in SCI. The cervical contusion SCI stimulated a sustaining neuropathic pain-linked phenotype characterized by thermal hyperalgesia as well as mechanical allodynia. It was revealed the structural damage to the spinal cord in SCI. Besides, the expression of microglia markers as well as inflammatory factor were promoted in SCI. Cervical contusion SCI induced autophagy inhibition and nuclear factor kappa-B (NF-κB) activation in mice. More importantly, enhanced autophagy induced by rapamycin suppressed the NF-κB pathway and alleviated cervical contusion SCI-induced neurological function damage in mice. Additionally, rapamycin promoted microglia M2 polarization and improved microglia-mediated inflammatory response. In conclusion, our study demonstrated that autophagy played a protective role in cervical SCI by promoting microglia polarization toward M2 through the NF-κB pathway. Our study may provide a novel sight for SCI treatment.

Short-chain fatty acids ameliorate spinal cord injury recovery by regulating the balance of regulatory T cells and effector IL-17+ γδ T cells.

Spinal cord injury (SCI) causes motor, sensory, and autonomic dysfunctions. The gut microbiome has an important role in SCI, while short-chain fatty acids (SCFAs) are one of the main bioactive mediators of microbiota. In the present study, we explored the effects of oral administration of exogenous SCFAs on the recovery of locomotor function and tissue repair in SCI. Allen's method was utilized to establish an SCI model in Sprague-Dawley (SD) rats. The animals received water containing a mixture of 150 mmol/L SCFAs after SCI. After 21 d of treatment, the Basso, Beattie, and Bresnahan (BBB) score increased, the regularity index improved, and the base of support (BOS) value declined. Spinal cord tissue inflammatory infiltration was alleviated, the spinal cord necrosis cavity was reduced, and the numbers of motor neurons and Nissl bodies were elevated. Enzyme-linked immunosorbent assay (ELISA), real-time quantitative polymerase chain reaction (qPCR), and immunohistochemistry assay revealed that the expression of interleukin (IL)‍-10 increased and that of IL-17 decreased in the spinal cord. SCFAs promoted gut homeostasis, induced intestinal T cells to shift toward an anti-inflammatory phenotype, and promoted regulatory T (Treg) cells to secrete IL-10, affecting Treg cells and IL-17+ γδ T cells in the spinal cord. Furthermore, we observed that Treg cells migrated from the gut to the spinal cord region after SCI. The above findings confirm that SCFAs can regulate Treg cells in the gut and affect the balance of Treg and IL-17+ γδ T cells in the spinal cord, which inhibits the inflammatory response and promotes the motor function in SCI rats. Our findings suggest that there is a relationship among gut, spinal cord, and immune cells, and the "gut-spinal cord-immune" axis may be one of the mechanisms regulating neural repair after SCI.

Ca2+ Regulates Autophagy Through CaMKKβ/AMPK/mTOR Signaling Pathway in Mechanical Spinal cord Injury: An in vitro Study.

Spinal cord injury (SCI), resulting in damage of the normal structure and function of the spinal cord, would do great harm to patients, physically and psychologically. The mechanism of SCI is very complex. At present, lots of studies have reported that autophagy was involved in the secondary injury process of SCI, and several researchers also found that calcium ions (Ca2+) played an important role in SCI by regulating necrosis, autophagy, or apoptosis. However, to our best of knowledge, no studies have linked the spinal cord mechanical injury, intracellular Ca2+, and autophagy in series. In this study, we have established an in vitro model of SCI using neural cells from fetal rats to explore the relationship among them, and found that mechanical injury could promote the intracellular Ca2+ concentration, and the increased Ca2+ level activated autophagy through the CaMKKβ/AMPK/mTOR pathway. Additionally, we found that apoptosis was also involved in this pathway. Thus, our study provides new insights into the specific mechanisms of SCI and may open up new avenues for the treatment of SCI.

Triad1 Promotes the Inflammatory Response and Neuronal Apoptosis to Aggravate Acute Spinal Cord Injury in Rats.

Objective Spinal cord injury (SCI) is one of the most devastating central injuries, resulting in serious locomotor deficits. Triad1 is known to play an important role in SCI, but its effects on the inflammatory response and physiological behavior have not been thoroughly studied. This study is aimed at examining the effects of Triad1 on the inflammatory response and neuronal injury in acute SCI in rats. Methods Twenty-four male Sprague–Dawley (SD) rats were randomly divided into a control group, SCI group, sh-NC group, and Triad1 knockout group (sh-Triad1). The Basso Beattie Bresnahan locomotor rating scale was utilized for the assessment of the motor ability of rats. Hematoxylin and eosin (H&E), Luxol fast blue (LFB), and TUNEL staining were used to assess the pathological injury, demyelination, and neuronal apoptosis, respectively. ELISA was used to detect the levels of IL-1β, IL-10, and TNF-α, and qRT-PCR was used to examine the expression level of Triad1. Furthermore, the protein levels of Triad1, Bax, Bcl-2, and cleaved caspase-3 were determined using western blotting. Results The Triad1 expression level was upregulated in damaged spinal cord tissue. Knockdown of Triad1 improved motor function and reduced SCI as well as apoptosis of spinal cord neurons. In addition, the knockdown of Triad1 inhibited the inflammatory response caused by SCI. Conclusion Knockdown of Triad1 can reduce SCI in rats with acute SCI by inhibiting the inflammatory response and apoptosis.

Wogonin inhibits inflammation and apoptosis through STAT3 signal pathway to promote the recovery of spinal cord injury

Spinal cord injury (SCI) is a complex central traumatic disease. STAT3 signal transduction pathway plays an important role in SCI. Wogonin has been reported to exhibit neuroprotection. However, the molecular mechanism of its potential therapeutic effect after SCI remains unclear. In this study, rats were divided into the following groups: Sham; SCI; SCI + wogonin; and SCI + wogonin + colivelin (Colivelin is an effective activator of the STAT3 pathway). Motor function was evaluated by Basso Beattie Bresnahan (BBB) score. Histomorphological changes in the spinal cords were observed by Hematoxylin-eosin (HE) staining and Nissl staining. Western blot, Transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining, and immunofluorescence were used to detect changes in the neuronal inflammation, apoptosis, and STAT3 signal pathway. Western blot and immunofluorescence techniques were also performed to detect the regulatory effect and the underlying mechanism of wogonin on the inflammation and apoptosis of PC12 cells. Experimental results in vivo and in vitro showed that wogonin could promote the recovery of motor function, improve the histopathological morphology, inhibit the activation of the STAT3 signal pathway, and reduce the neuronal inflammation and apoptosis in the rats with SCI. Activation of the STAT3 signal pathway by colivelin reversed the therapeutic effect of wogonin. Therefore, wogonin could inhibit inflammation and apoptosis by inhibiting the STAT3 signal pathway and promote the functional recovery of rats with SCI.

Attenuation of Activated eIF2\u03b1 Signaling by ISRIB Treatment After Spinal Cord Injury Improves Locomotor Function

Following spinal cord injury (SCI), multiple signaling cascades are activated instantaneously in the injured segments of the spinal cord to create a complex and pathogenic microenvironment, making it difficult to treat SCI. Nevertheless, the significance of the integrated stress response (ISR) to the series of physiological and pathological changes that occur after SCI remains unclear. Through western blotting (WB), we determined that the autophosphorylation of stress receptors (GCN2, PERK, PKR, and HRI) was enhanced after SCI, leading to increased phosphorylation of eIF2α at Ser51. Strikingly, we found that eIF2α was highly phosphorylated at 1 day post injury (dpi) and that this hypophosphorylation was maintained thereafter in the spinal cord, especially in neurons, which suggests that intervening with eIF2α phosphorylation may be a treatment strategy for SCI. Therefore, we employed the small molecule ISRIB, which inhibits eIF2α phosphorylation when the ISR is activated at moderate or low levels but not when the ISR is highly activated. Daily intraperitoneal injection of ISRIB significantly inhibited ISR signaling after SCI, reduced the cytosolic localization of RNA-binding proteins, and decreased neuronal apoptosis. Histological and functional experiments further demonstrated that treatment with ISRIB after SCI effectively curbed morphological deterioration and promoted the recovery of locomotor function. In summary, the ISR plays an important role in SCI, and ISRIB is a promising drug for the treatment of SCI.

Ischemic damage may play an important role in spinal cord injury during dancing

Study designRetrospective analysis.SettingChina Rehabilitation Research Center, Beijing, China.ObjectiveTo explore possible mechanisms underlying spinal cord injury (SCI) in children caused by hyperextension of the spine while dancing.MethodsThe clinical records of 88 children with SCI (mean age, 5.97 years; age range, 4–10 years) admitted to our hospital from January 1989 to October 2019 were retrospectively reviewed. Computed tomography and magnetic resonance imaging were performed on the day of injury. The time from injury to development of paralysis, as well as post-injury activities were surveyed, while abnormal patterns on images, the range of the involved vertebrae, and the extents of edema and atrophy were assessed.ResultsAmong the 88 patients, 6 (6.8%) were unable to move immediately after SCI, while paralysis occurred in 42, 23, and 17 patients at <30, 30–60, and >60 min after SCI, respectively. The neurological level of injury of 84 patients was between T4 and T12. On sagittal T2-weighted images (T2WIs), the longitudinal range of spinal cord edema was more than one vertebral body in 65 patients, while spinal cord atrophy below T8 was found in 40 patients. On axial T2WIs, although three patients had none, long T2 signals were found in the central gray matter of seven patients. Meanwhile, necrosis of the central area combined with the peripheral white matter was observed in 57 patients, while three patients had total involvement on a cross section.ConclusionIschemia-related damage, rather than direct trauma to the spinal cord, may play an important role in SCI due to spinal hyperextension during dancing.

The Function and Mechanisms of Autophagy in Spinal Cord Injury.

Spinal cord injury (SCI) is one of the major causes of death and long-term disability in the world. Numerous studies have reported that autophagy plays an important role in SCI. However, the understanding of underlying mechanisms of autophagy after SCI and autophagy mechanism-based preclinical pharmacological intervention needs to be updated. This part provides an overview of current knowledge about the mechanisms of autophagy and autophagy flux as well as its potential molecular mechanisms based on the pharmacological regulation of autophagy. Although autophagic activation and the disruption of autophagy flux exist in SCI, whether autophagy is beneficial and detrimental is still under debate. We also focus on the existing and developing therapeutic options based on the potential molecular mechanisms of autophagy.

Critical role of regulator of calcineurin 1 in spinal cord injury.

Spinal cord injury (SCI) is a severe clinical problem worldwide. The pathogenesis of SCI is complicated and much is unknown. The current study was designed to investigate the possible role of regulator of calcineurin 1 (RCAN1) in SCI and to explore the possible molecular mechanisms. Rats were injected with LVshRNAi-RCAN1 and then contusion-induced SCI was established. We found that RCAN1 was significantly increased in spinal cord of rats with SCI. Knockdown of RCAN1 markedly facilitated the structural and functional recovery in the spinal cord, as illustrated by decrease of lesion volume and increase of Basso, Beattie, and Bresnahan (BBB) and combined behavioral score (CBS) scores. Downregulation of RCAN1 suppressed the increase of pro-inflammatory cytokines, including IL-1β and TNF-α, and inhibited the increase of TUNEL-positive cell numbers and caspases 3 and 9 activities. The decrease of oxygen consumption rate and increase of expression of glucose-regulated protein 78 (GRP78) and phosphorylation of protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK) in rats with SCI were inhibited by LVshRNAi-RCAN1. Moreover, knockdown of RCAN1 ameliorated oxidative stress in rats with SCI, as evidenced by decrease of TBA reactive substances (TBARS) and GSSG content and increase of glutathione (GSH) level. These results suggested that RCAN1 played an important role in SCI through regulation of various pathological processes. Overall, the data provide novel insights into the role of RCAN1 in SCI and novel therapeutic targets of the treatment of injury in the spinal cord.

Persistent phosphorylation of NKCC1 and WNK1 in the epicenter of the spinal cord following contusion injury

Background contextNKCC1 regulates neuronal homeostasis of chloride ions and mediates GABAergic activities in nociceptive processing. WNK1 is an upstream regulator of NKCC1 and acts via SPAK (STE20/SPS1-related proline/alanine-rich kinase) and oxidative stress-responsive kinase 1. NKCC1 activity has been shown to be important in edema formation and nociception following spinal cord injury (SCI). PurposeTo determine the role of NKCC1 and WNK1 in spinal cord tissues in the acute and chronic phases following contusional SCI. Study designAn experimental study investigating the phosphorylation profile of an important Cl-regulatory protein Na+-K+-Cl− cotransporter 1 (NKCC1) and its regulatory-kinase WNK1 (kinase with-no-lysine). MethodsSprague-Dawley rats underwent a contusive SCI at T9. The epicenter spinal cord tissues were harvested at Days 1, 3, and 7 for acute phase of injury or Days 35 and 42 in the chronic phase of injury. Western blot was used to compare phosphorylated levels of both NKCC1 and WNK1 in injured tissues compared with those of sham. ResultsA sustained increase in phosphorylation of NKCC1 and WNK1 was detected in the lesion epicenter in spinal cord during both acute and chronic phases following SCI. ConclusionsThese results suggest that persistent activation of NKCC1 and WNK1 may play an important role in SCI.

Neurotrophic factors attenuate microvascular permeability disturbances and axonal injury following trauma to the rat spinal cord.

Alterations of the blood-spinal cord barrier (BSCB) following spinal cord injury (SCI) and leakage of serum proteins induce vasogenic edema and cell damage. The possibility that two members of the neurotrophin family, BDNF or IGF-1 induce neuroprotection by attenuating the BSCB permeability following trauma was examined in a rat model. Repeated topical application of BDNF or IGF-1 (0.1 1microg, 0.5 microg or 1 microg in 10 microl) onto the spinal cord 30 min before SCI or 2, 5, 10 or 30 min thereafter significantly attenuated BSCB permeability to Evans blue and iodine. In the neurotrophin treated rats. edema formation, degradation of MBP, and myelin vesiculation were much less frequent compared to the untreated traumatised rats. The protective effect of BDNF and IGF-1 was most pronounced at the high dose (1 microg in 10 microl) given either 30 min before or within 10 min after SCI. The observations suggest that early intervention with neurotrophins in high doses following trauma (within 10 min) attenuates disturbances of the fluid microenvironment of the spinal cord. This indicates that BSCB opening plays an important role in SCI induced myelin vesiculation and cord pathology.