An efficient device to experimentally model compression injury of mammalian spinal cord

Ropper, Alexander E.; Zeng, Xiang; Anderson, Jamie E.; Yu, Di; Han, Inbo; Haragopal, Hariprakash; Teng, Yang D.

doi:10.1016/j.expneurol.2015.07.012

Cited by 29 publications

(25 citation statements)

References 32 publications

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“…Both compression and contusion models simulate the biomechanics and neuropathology of human injury (Sharif-Alhoseini et al, 2017). In the current study, we used clinically relevant SCI via controlled mechanical compression (Yu et al, 2013;Ropper et al, 2015). The advantage of the current method is that delivered force is precisely known at the time of application compared with other compression models.…”

Section: Discussionmentioning

confidence: 99%

Elevated TRPV4 Levels Contribute to Endothelial Damage and Scarring in Experimental Spinal Cord Injury

et al. 2020

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Currently, the role of transient receptor potential vanilloid type 4 (TRPV4), a nonselective cation channel in the pathology of spinal cord injury (SCI), is not recognized. Herein, we report the expression and contribution of TRPV4 in the pathology of scarring and endothelial and secondary damage after SCI. TRPV4 expression increased during the inflammatory phase in female rats after SCI and was expressed primarily by cells at endothelial-microglial junctions. Two-photon microscopy of intracellular-free Ca 2ϩ levels revealed a biphasic increase at similar time points after SCI. Expression of TRPV4 at the injury epicenter, but not intracellular-free Ca 2ϩ , progressively increases with the severity of the injury. Activation of TRPV4 with specific agonist altered the organization of endothelial cells, affected tight junctions in the hCMEC/D3 BBB cell line in vitro, and increases the scarring in rat spinal cord as well as induced endothelial damage. By contrast, suppression of TRPV4 with a specific antagonist or in female Trpv4 KO mouse attenuated inflammatory cytokines and chemokines, prevented the degradation of tight junction proteins, and preserve blood-spinal cord barrier integrity, thereby attenuate the scarring after SCI. Likewise, secondary damage was reduced, and behavioral outcomes were improved in Trpv4 KO mice after SCI. These results suggest that increased TRPV4 expression disrupts endothelial cell organization during the early inflammatory phase of SCI, resulting in tissue damage, vascular destabilization, blood-spinal cord barrier breakdown, and scarring. Thus, TRPV4 inhibition/knockdown represents a promising therapeutic strategy to stabilize/protect endothelial cells, attenuate nociception and secondary damage, and reduce scarring after SCI.

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Section: Discussionmentioning

confidence: 99%

Elevated TRPV4 Levels Contribute to Endothelial Damage and Scarring in Experimental Spinal Cord Injury

et al. 2020

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“…After skin preparation and precise positioning of anesthetized rats, a laminectomy was performed to expose T10 spinal cord. The vertebral column was supported and stabilized by Allis clamps at T8 and T12 spinous processes as described previously [ 48 , 75 ]. A metal impounder (35 g × 5 min) was then gently applied on T10 dura, resulting in moderate standing weight compression.…”

Section: Methodsmentioning

confidence: 99%

Neutrophil elastase inhibition effectively rescued angiopoietin-1 decrease and inhibits glial scar after spinal cord injury

Kumar

Choi

et al. 2018

acta neuropathol commun

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After spinal cord injury (SCI), neutrophil elastase (NE) released at injury site disrupts vascular endothelium integrity and stabilization. Angiopoietins (ANGPTs) are vascular growth factors that play an important role in vascular stabilization. We hypothesized that neutrophil elastase is one of the key determinants of vascular endothelium disruption/destabilization and affects angiopoietins expression after spinal cord injury. To test this, tubule formation and angiopoietins expression were assessed in endothelial cells exposed to different concentrations of recombinant neutropil elastase. Then, the expression of angiopoietin-1, angiopoietin-2, and neutrophil elastase was determined at 3 h and at 1, 3, 5, 7, 14, 21, and 28 days in a clinically relevant model of moderate compression (35 g for 5 min at T10) spinal cord injury. A dichotomy between the levels of angiopoietin-1 and angiopoietin-2 was observed; thus, we utilized a specific neutrophil elastase inhibitor (sivelestat sodium; 30 mg/kg, i.p., b.i.d.) after spinal cord injury. The expression levels of neutropil elastase and angiopoietin-2 increased, and that of angiopoietin-1 decreased after spinal cord injury in rats. The sivelestat regimen, optimized via a pharmacokinetics study, had potent effects on vascular stabilization by upregulating angiopoietin-1 via the AKT pathway and preventing tight junction protein degradation. Moreover, sivelestat attenuated the levels of inflammatory cytokines and chemokines after spinal cord injury and hence subsequently alleviated secondary damage observed as a reduction in glial scar formation and the promotion of blood vessel formation and stabilization. As a result, hindlimb locomotor function significantly recovered in the sivelestat-treated animals as determined by the Basso, Beattie, and Bresnahan scale and footprint analyses. Furthermore, sivelestat treatment attenuated neuropathic pain as assessed by responses to von Frey filaments after spinal cord injury. Thus, our result suggests that inhibiting neutropil elastase by administration of sivelestat is a promising therapeutic strategy to inhibit glial scar and promote functional recovery by upregulating angiopoietin-1 after spinal cord injury.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0576-3) contains supplementary material, which is available to authorized users.

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“…Pathological neuropathic pain is more common after spinal cord injury, and there is currently no effective and effective treatment [2]. At present, the research on neuropathic pain related to spinal cord injury is mostly concentrated in mice, and research reports on human whole blood are rare [27,28].…”

Section: Discussionmentioning

confidence: 99%

Screening of disease-related biomarkers related to neuropathic pain (NP) after spinal cord injury (SCI)

Zhao

Huang

et al. 2021

Hum Genomics

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Background Based on the molecular expression level, this paper compares lncRNA and mRNA expressions respectively in peripheral blood samples of the patients after SCI with NP and without NP, and screens disease-related biomarkers related to NP after SCI in peripheral blood samples of patients. Method The expression spectrum of 25 human peripheral blood samples (12 samples of refractory NP patients after SCI) was downloaded and data were normalized. Screening of GO annotations significantly associated with significant differentially expressed mRNAs and significant involvement of the KEGG pathway. The WGCNA algorithm was used to screen for modules and RNAs that were significantly associated with disease characterization. A co-expression network was constructed to extract the genes involved in the disease pathway from the co-expression network, construct a network of SCI pain-related pathways, and screen important disease-related biomarkers. Quantitative real-time PCR was used to detect the mRNA expression of hub genes. Results Data were normalized and re-annotated by detection of platform information, resulting in a total of 289 lncRNA and 18197 mRNAs. Screening resulted in 338 significant differentially expressed RNAs that met the threshold requirements. Differentially expressed RNAs were significantly enriched with the brown and magenta modules. Six KEGG signaling pathways were screened in the co-expression network, and three KEGG pathways with direct neuropathic pain were identified. The expression levels of E2F1, MAX, MITF, CTNNA1, and ADORA2B in the disease group were all significantly upregulated (p < 0.01). Compared with the normal group, the expression of OXTR was upregulated. Conclusion We speculate that there are 7 genes and 2 lncRNAs directly involved in the pain pathway: E2F1, MAX, MITF, CTNNA1, ADORA2B, GRIK3, OXTR, LINC01119, and LINC02447. These molecules may be important for NP after SCI.

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An efficient device to experimentally model compression injury of mammalian spinal cord

Cited by 29 publications

References 32 publications

Elevated TRPV4 Levels Contribute to Endothelial Damage and Scarring in Experimental Spinal Cord Injury

Elevated TRPV4 Levels Contribute to Endothelial Damage and Scarring in Experimental Spinal Cord Injury

Neutrophil elastase inhibition effectively rescued angiopoietin-1 decrease and inhibits glial scar after spinal cord injury

Screening of disease-related biomarkers related to neuropathic pain (NP) after spinal cord injury (SCI)

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