scholarly journals Bazedoxifene, a Selective Estrogen Receptor Modulator, Promotes Functional Recovery in a Spinal Cord Injury Rat Model

2021 ◽  
Vol 22 (20) ◽  
pp. 11012
Author(s):  
Yiyoung Kim ◽  
Eun Ji Roh ◽  
Hari Prasad Joshi ◽  
Hae Eun Shin ◽  
Hyemin Choi ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Therapeutic Potential ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
Sprague Dawley ◽  
Post Injury ◽  
Static Compression ◽  
Cord Injury

In research on various central nervous system injuries, bazedoxifene acetate (BZA) has shown two main effects: neuroprotection by suppressing the inflammatory response and remyelination by enhancing oligodendrocyte precursor cell differentiation and oligodendrocyte proliferation. We examined the effects of BZA in a rat spinal cord injury (SCI) model. Anti-inflammatory and anti-apoptotic effects were investigated in RAW 264.7 cells, and blood-spinal cord barrier (BSCB) permeability and angiogenesis were evaluated in a human brain endothelial cell line (hCMEC/D3). In vivo experiments were carried out on female Sprague Dawley rats subjected to moderate static compression SCI. The rats were intraperitoneally injected with either vehicle or BZA (1mg/kg pre-SCI and 3mg/kg for 7 days post-SCI) daily. BZA decreased the lipopolysaccharide-induced production of proinflammatory cytokines and nitric oxide in RAW 264.7 cells and preserved BSCB disruption in hCMEC/D3 cells. In the rats, BZA reduced caspase-3 activity at 1 day post-injury (dpi) and suppressed phosphorylation of MAPK (p38 and ERK) at dpi 2, hence reducing the expression of IL-6, a proinflammatory cytokine. BZA also led to remyelination at dpi 20. BZA contributed to improvements in locomotor recovery after compressive SCI. This evidence suggests that BZA may have therapeutic potential to promote neuroprotection, remyelination, and functional outcomes following SCI.

scholarly journals Combined Treatment with Fasudil and Menthol Improves Functional Recovery in Rat Spinal Cord Injury Model

Biomedicines ◽  
2020 ◽  
Vol 8 (8) ◽  
pp. 258
Author(s):  
JeongHoon Kim ◽  
Hari Prasad Joshi ◽  
Kyoung-Tae Kim ◽  
Yi Young Kim ◽  
Keundong Yeo ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Combined Treatment ◽  
Scar Formation ◽  
Sprague Dawley ◽  
Static Compression ◽  
Cord Injury ◽  
Fibrotic Scar ◽  
Spinal Cord Dysfunction

Neuroprotective measures by preventing secondary spinal cord injury (SCI) are one of the main strategies for repairing an injured spinal cord. Fasudil and menthol may be potent neuroprotective agents, which act by inhibiting a rho-associated protein kinase (ROCK) and suppressing the inflammatory response, respectively. We hypothesized that combined treatment of fasudil and menthol could improve functional recovery by decreasing inflammation, apoptosis, and glial scar formation. We tested our hypothesis by administering fasudil and menthol intraperitoneally (i.p.) to female Sprague Dawley rats after moderate static compression (35 g of impounder for 5 min) of T10 spinal cord. The rats were randomly divided into five experimental groups: (i) sham animals received laminectomy alone, (ii) injured (SCI) and untreated (saline 0.2 mL/day, i.p.) rats, (iii) injured (SCI) rats treated with fasudil (10 mg/kg/day, i.p.) for two weeks, (iv) injured (SCI) rats treated with menthol (10 mg/kg/day, i.p.) for twoweeks, (v) injured (SCI) rats treated with fasudil (5 mg/kg/day, i.p.) and menthol (10 mg/kg/day, i.p.) for two weeks. Compared to single treatment groups, combined treatment of fasudil and menthol demonstrated significant functional recovery and pain amelioration, which, thereby, significantly reduced inflammation, apoptosis, and glial/fibrotic scar formation. Therefore, combined treatment of fasudil and menthol may provide effective amelioration of spinal cord dysfunction by a synergistic effect of fasudil and menthol.

scholarly journals Progranulin deficiency exacerbates spinal cord injury by promoting neuroinflammation and cell apoptosis in mice

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Chao Wang ◽  
Lu Zhang ◽  
Jean De La Croix Ndong ◽  
Aubryanna Hettinghouse ◽  
Guodong Sun ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Western Blotting ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Neurological Recovery ◽  
Post Injury ◽  
Nissl Staining ◽  
Promising Therapeutic Approach ◽  
Cord Injury

Abstract Purpose Spinal cord injury (SCI) often results in significant and catastrophic dysfunction and disability and imposes a huge economic burden on society. This study aimed to determine whether progranulin (PGRN) plays a role in the progressive damage following SCI and evaluate the potential for development of a PGRN derivative as a new therapeutic target in SCI. Methods PGRN-deficient (Gr−/−) and wild-type (WT) littermate mice were subjected to SCI using a weight-drop technique. Local PGRN expression following injury was evaluated by Western blotting and immunofluorescence. Basso Mouse Scale (BMS), inclined grid walking test, and inclined plane test were conducted at indicated time points to assess neurological recovery. Inflammation and apoptosis were examined by histology (Hematoxylin and Eosin (H&E) staining and Nissl staining, TUNEL assays, and immunofluorescence), Western blotting (from whole tissue protein for iNOS/p-p65/Bax/Bcl-2), and ex vivo ELISA (for TNFα/IL-1β/IL-6/IL-10). To identify the prophylactic and therapeutic potential of targeting PGRN, a PGRN derived small protein, Atsttrin, was conjugated to PLGA-PEG-PLGA thermosensitive hydrogel and injected into intrathecal space prior to SCI. BMS was recorded for neurological recovery and Western blotting was applied to detect the inflammatory and apoptotic proteins. Results After SCI, PGRN was highly expressed in activated macrophage/microglia and peaked at day 7 post-injury. Grn−/− mice showed a delayed neurological recovery after SCI at day 21, 28, 35, and 42 post-injury relative to WT controls. Histology, TUNEL assay, immunofluorescence, Western blotting, and ELISA all indicated that Grn−/− mice manifested uncontrolled and expanded inflammation and apoptosis. Administration of control-released Atsttrin could improve the neurological recovery and the pro-inflammatory/pro-apoptotic effect of PGRN deficiency. Conclusion PGRN deficiency exacerbates SCI by promoting neuroinflammation and cellular apoptosis, which can be alleviated by Atsttrin. Collectively, our data provide novel evidence of using PGRN derivatives as a promising therapeutic approach to improve the functional recovery for patients with spinal cord injury.

scholarly journals Comprehensive Effects of Suppression of MicroRNA-383 in Human Bone-Marrow-Derived Mesenchymal Stem Cells on Treating Spinal Cord Injury

2018 ◽  
Vol 47 (1) ◽  
pp. 129-139 ◽  
Author(s):  
Guo-Jun Wei ◽  
Ke-wen Zheng ◽  
Gang An ◽  
Zuo-Wei Shi ◽  
Kai-Fu Wang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Bone Marrow ◽  
Spinal Cord Injury ◽  
Mesenchymal Stem Cells ◽  
Therapeutic Potential ◽  
Luciferase Reporter ◽  
Therapeutic Effects ◽  
Cord Injury

Background/Aims: Transplantation of bone-marrow-derived mesenchymal stem cells (MSCs) promotes neural cell regeneration after spinal cord injury (SCI). Recently, we showed that suppression of microRNA-383 (miR-383) in MSCs increased the protein levels of glial cell line derived neurotrophic factor (GDNF), resulting in improved therapeutic effects on SCI. However, the overall effects of miR-383 suppression in MSCs on SCI therapy were not determined yet. Here, we addressed this question. Methods: We used bioinformatics tools to predict all miR-383-targeting genes, confirmed the functional bindings in a dual luciferase reporter assay. The effects of alteration of candidate genes in MSCs on cell proliferation were analyzed by MTT assay and by Western blotting for PCNA. The effects on angiogenesis were assessed by HUVEC assay. The effects on SCI in vivo were analyzed by transplantation of the modified MSCs into nude rats that underwent SCI. Results: Suppression of miR-383 in MSCs not only upregulated GDNF protein, but also increased vascular endothelial growth factor A (VEGF-A) and cyclin-dependent kinase 19 (CDK19), two other miR-383 targets. MiR-383-suppression-induced increases in CDK19 resulted in a slight but significant increase in MSC proliferation, while miR-383-suppression-induced increases in VEGF-A resulted in a slight but significant increase in MSC-mediated angiogenesis. Conclusions: Upregulation of CDK19 and VEGF-A by miR-383 suppression in MSCs further improve the therapeutic potential of MSCs in treating SCI in rats.

scholarly journals Microglia limit lesion expansion and promote functional recovery after spinal cord injury in mice

2018 ◽  
Author(s):  
Faith H. Brennan ◽  
Jodie C.E. Hall ◽  
Zhen Guan ◽  
Phillip G. Popovich
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Spontaneous Recovery ◽  
Recovery Of Function ◽  
Experimental Models ◽  
Post Injury ◽  
Thoracic Spinal ◽  
Cord Injury

AbstractTraumatic spinal cord injury (SCI) elicits a robust intraspinal inflammatory reaction that is dominated by at least two major subpopulations of macrophages, i.e., those derived from resident microglia and another from monocytes that infiltrate the injury site from the circulation. Previously, we implicated monocyte-derived macrophages (MDMs) as effectors of acute post-injury pathology after SCI; however, it is still unclear whether microglia also contribute to lesion pathology. Assigning distinct functional roles to microglia and MDMs in vivo has been difficult because these CNS macrophage subsets are morphologically and phenotypically similar. Here, to characterize the role that microglia play in experimental models of thoracic spinal contusion or lumbar crush injury, mice were fed vehicle chow or chow laced with a CSF1R receptor antagonist, PLX5622. Feeding PLX5622 depletes microglia. In both groups, spontaneous recovery of hindlimb motor function was evaluated for up to 8 weeks post-SCI using open-field and horizontal ladder tests. Histopathological assessment of intraspinal pathology was assessed in 8 week post-injury tissues. In both SCI models, microglia depletion exacerbated lesion pathology and impaired spontaneous recovery of hind limb function. Notably, the loss of microglia prevented astroglial encapsulation of the lesion core, which was associated with larger lesions, enhanced demyelination and neuron loss and a larger inflammatory response that was dominated by monocyte-derived macrophages. The neuroprotective and healing properties of microglia become obvious in the subacute phases of recovery; microglia depletion up to 7 days post-injury (dpi) had no apparent effect on recovery while delayed depletion from 8-28dpi exacerbated lesion pathology and significantly impaired functional recovery. These data suggest that microglia have essential tissue repair functions after SCI. Selective enhancement of microglial activities may be a novel strategy to preserve tissue and promote recovery of function after neurotrauma.

scholarly journals Microglia Response and In Vivo Therapeutic Potential of Methylprednisolone-Loaded Dendrimer Nanoparticles in Spinal Cord Injury

Small ◽  
2016 ◽  
Vol 12 (8) ◽  
pp. 972-972 ◽  
Author(s):  
Susana R. Cerqueira ◽  
Joaquim M. Oliveira ◽  
Nuno A. Silva ◽  
Hugo Leite-Almeida ◽  
Silvina Ribeiro-Samy ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Therapeutic Potential ◽  
Cord Injury

scholarly journals Neural Stem Cell-Conditioned Medium Suppresses Inflammation and Promotes Spinal Cord Injury Recovery

2017 ◽  
Vol 26 (3) ◽  
pp. 469-482 ◽  
Author(s):  
Zhijian Cheng ◽  
Dale B. Bosco ◽  
Li Sun ◽  
Xiaoming Chen ◽  
Yunsheng Xu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Stem Cell ◽  
Conditioned Medium ◽  
Neural Stem Cell ◽  
Therapeutic Potential ◽  
Secondary Injury ◽  
Cord Injury

Spinal cord injury (SCI) causes functional impairment as a result of the initial injury followed by secondary injury mechanism. SCI provokes an inflammatory response that causes secondary tissue damage and neurodegeneration. While the use of neural stem cell (NSC) engraftment to mitigate secondary injury has been of interest to many researchers, it still faces several limitations. As such, we investigated if NSC-conditioned medium (NSC-M) possesses therapeutic potential for the treatment of SCI. It has been proposed that many of the beneficial effects attributed to stem cell therapies are due to secreted factors. Utilizing primary cell culture and murine models of SCI, we determined that systemic treatment with NSC-M was able to significantly improve motor function and lesion healing. In addition, NSC-M demonstrated significant anti-inflammatory potential in vitro and in vivo, reducing inflammatory cytokine expression in both activated macrophages and injured spinal cord tissues. NSC-M was also able to reduce the expression of inducible nitric oxide synthase (iNOS) within the spleen of injured animals, indicating an ability to reduce systemic inflammation. Thus, we believe that NSC-M offers a possible alternative to direct stem cell engraftment for the treatment of SCI.

Microglia Response and In Vivo Therapeutic Potential of Methylprednisolone-Loaded Dendrimer Nanoparticles in Spinal Cord Injury

Small ◽  
2012 ◽  
Vol 9 (5) ◽  
pp. 738-749 ◽  
Author(s):  
Susana R. Cerqueira ◽  
Joaquim M. Oliveira ◽  
Nuno A. Silva ◽  
Hugo Leite-Almeida ◽  
Silvina Ribeiro-Samy ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Therapeutic Potential ◽  
Cord Injury

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 The Effect of Neural Stem Cell Treatment on Astrocyte Phenotypes morphology and Galectin Expression in Following Rat Spinal Cord Injury

2021 ◽  
Author(s):  
Michelle Kilcoyne ◽  
Dearbhaile Dooley ◽  
Azim Patar ◽  
Niall Bergin ◽  
Laura Duane ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Lipid Binding ◽  
Neurological Dysfunction ◽  
Sprague Dawley ◽  
Post Injury ◽  
Vimentin Expression ◽  
Beneficial Effects ◽  
Cord Injury ◽  
Stem Cell Treatment

Abstract Traumatic spinal cord injury (SCI) results in complex neurological dysfunction. Astrocytes react in response to SCI by undergoing proliferation and migrating to the injury site, resulting in astrogliosis. Neural stem cells (NSCs) have been proposed as a promising therapeutic strategy to promote neurogenesis following transplantation post SCI. In this study the antigenic and morphological phenotype of astrocytes, and the pattern of galectin expression was examined following SCI. Female Sprague Dawley rats were contused at thoracic (T) level T9 and treated with Cyclosporin-A (CsA) and/or NSCs 1 week post-injury. CsA and NSC treatment led to increased glial fibrillary acidic protein (GFAP), brain lipid binding protein (BLBP) and vimentin expression. Quiescent and reactive astrocytes were the most abundant cell morphology observed. Astrocytes co-localised with galectin-1 (Gal-1) and galectin-3 (Gal-3). Gal-1 expression was increased in both CsA and CSA + NSC treated animals 2 weeks post-treatment. Treatment with CsA and/or NSCs offers many prospective beneficial effects. A detailed revelation of how astrocytes are heterogeneously responsive to SCI, in addition to their affinity to galectins and response to CsA and NSCs is shown in this study. The current study’s findings support the potential application of NSCs as a novel therapeutic tool in the treatment of SCI.

scholarly journals CRISPR gRNA phenotypic screening in zebrafish reveals pro-regenerative genes in spinal cord injury

PLoS Genetics ◽  
2021 ◽  
Vol 17 (4) ◽  
pp. e1009515
Author(s):  
Marcus Keatinge ◽  
Themistoklis M. Tsarouchas ◽  
Tahimina Munir ◽  
Nicola J. Porter ◽  
Juan Larraz ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Spinal Injury ◽  
Spinal Cord Regeneration ◽  
Post Injury ◽  
Highly Active ◽  
Cord Injury ◽  
Mechanistic Basis ◽  
Acute Injection

Zebrafish exhibit robust regeneration following spinal cord injury, promoted by macrophages that control post-injury inflammation. However, the mechanistic basis of how macrophages regulate regeneration is poorly understood. To address this gap in understanding, we conducted a rapid in vivo phenotypic screen for macrophage-related genes that promote regeneration after spinal injury. We used acute injection of synthetic RNA Oligo CRISPR guide RNAs (sCrRNAs) that were pre-screened for high activity in vivo. Pre-screening of over 350 sCrRNAs allowed us to rapidly identify highly active sCrRNAs (up to half, abbreviated as haCRs) and to effectively target 30 potentially macrophage-related genes. Disruption of 10 of these genes impaired axonal regeneration following spinal cord injury. We selected 5 genes for further analysis and generated stable mutants using haCRs. Four of these mutants (tgfb1a, tgfb3, tnfa, sparc) retained the acute haCR phenotype, validating the approach. Mechanistically, tgfb1a haCR-injected and stable mutant zebrafish fail to resolve post-injury inflammation, indicated by prolonged presence of neutrophils and increased levels of il1b expression. Inhibition of Il-1β rescues the impaired axon regeneration in the tgfb1a mutant. Hence, our rapid and scalable screening approach has identified functional regulators of spinal cord regeneration, but can be applied to any biological function of interest.

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