Therapeutic Effects of Azithromycin on Spinal Cord Injury in Male Wistar Rats: A Role for Inflammatory Pathways

2021 ◽  
Author(s):  
Ali Rismanbaf ◽  
Khashayar Afshari ◽  
Mehdi Ghasemi ◽  
Abolfazl Badripour ◽  
Arvin Haj-Mirzaian ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Wistar Rats ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Therapeutic Effects ◽  
Spinal Cord Tissue ◽  
Cord Injury ◽  
Male Wistar Rats

Abstract Background Inflammatory responses, including macrophages/microglia imbalance, are associated with spinal cord injury (SCI) complications. Accumulating evidence also suggests an anti-inflammatory property of azithromycin (AZM). Material and Methods Male Wistar rats were subjected to T9 vertebra laminectomy. SCI was induced by spinal cord compression at this level with an aneurysmal clip for 60 seconds. They were divided into three groups: the sham-operated group and two SCI treatment (normal saline as a vehicle control vs. AZM at 180 mg/kg/d intraperitoneally for 3 days postsurgery; first dose: 30 minutes after surgery) groups. Locomotor scaling and behavioral tests for neuropathic pain were evaluated and compared through a 28-day period. At the end of the study, tissue samples were taken to assess neuroinflammatory changes and neural demyelination using ELISA and histopathologic examinations, respectively. In addition, the proportion of M1/M2 macrophage polarization was assessed by using flow cytometry. Results Post-SCI AZM treatment (180 mg/kg/d for 3 days) significantly improved locomotion (p < 0.01) and decreased sensitivity to mechanical (p < 0.01) and thermal allodynia (p < 0.001). Moreover, there was a significant tumor necrosis factor-α (TNF-α) decline (p < 0.01) and interleukin-10 (IL-10) elevation (p < 0.01) in the spinal cord tissue of the AZM-treated group compared with the control groups 28 days post-SCI. AZM significantly improved neuroinflammation as evidenced by reduction of the M1 expression, elevation of M2 macrophages, and reduction of the M1/M2 ratio in both the dorsal root ganglion and the spinal cord tissue after SCI compared with controls (p < 0.01). Conclusion AZM treatment can be considered a therapeutic agent for SCI, as it could reduce neuroinflammation and SCI sensory/locomotor complications.

scholarly journals Mechanism of mesenchymal stem cells in spinal cord injury repair through macrophage polarization

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nan An ◽  
Jiaxu Yang ◽  
Hequn Wang ◽  
Shengfeng Sun ◽  
Hao Wu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Spinal Cord Injury ◽  
Mesenchymal Stem Cells ◽  
Clinical Medicine ◽  
Macrophage Polarization ◽  
Modern Medicine ◽  
Therapeutic Effects ◽  
Inflammatory Reactions ◽  
Cord Injury

AbstractTreatment and rehabilitation of spinal cord injury (SCI) is a major problem in clinical medicine. Modern medicine has achieved minimal progress in improving the functions of injured nerves in patients with SCI, mainly due to the complex pathophysiological changes that present after injury. Inflammatory reactions occurring after SCI are related to various functions of immune cells over time at different injury sites. Macrophages are important mediators of inflammatory reactions and are divided into two different subtypes (M1 and M2), which play important roles at different times after SCI. Mesenchymal stem cells (MSCs) are characterized by multi-differentiation and immunoregulatory potentials, and different treatments can have different effects on macrophage polarization. MSC transplantation has become a promising method for eliminating nerve injury caused by SCI and can help repair injured nerve tissues. Therapeutic effects are related to the induced formation of specific immune microenvironments, caused by influencing macrophage polarization, controlling the consequences of secondary injury after SCI, and assisting with function recovery. Herein, we review the mechanisms whereby MSCs affect macrophage-induced specific immune microenvironments, and discuss potential avenues of investigation for improving SCI treatment.

scholarly journals Mmu-miR-27a-5p Promotes the Polarization of Macrophages to the M2 Phenotype at the Site of Spinal Cord Injury in Mice

2021 ◽  
Author(s):  
Mingkun Yang ◽  
Xiaoqian Dang ◽  
Xu Zhang ◽  
Chuan Liu ◽  
Min He
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Function ◽  
Macrophage Polarization ◽  
Spinal Cord Tissue ◽  
Injured Spinal Cord ◽  
Arginase 1 ◽  
Tnf Α ◽  
Cord Injury ◽  
M2 Phenotype

Abstract BackgroundTo investigate the effect of mmu-miR-27a-5p on macrophage polarization in the injured spinal cord and the recovery of motor function after spinal cord injury (SCI) in mice.MethodsA total of 160 specific-pathogen-free male mice were randomly divided into sham, model, mmu-miR-27a-5p, mmu-miR-27a-5p-negative control (NC) groups, with 40 mice in each group. Hindlimb motor function was assessed using the Basso Mouse scale (BMS) before injury and at 1, 3, 7, and 14 days after surgery. Spinal cord tissue samples were obtained at 1, 3, 7, and 14 days after surgery, and macrophage polarization types were detected by using western blot analysis, immunofluorescence, flow cytometry and RT-qPCR.ResultsThe BMS score in the mmu-miR-27a-5p group was significantly higher than that in the model and mmu-miR-27a-5p-NC groups at 7 and 14 days after SCI (X2=26.45-57.62, P<0.05). No significant changes in the expression of M1 markers IL-1β, TNF-α and M2 markers IL-10, Arginase-1 at each time point in the sham group (P=0.96). The expression of IL-1β and TNF-α was significantly lower, while the expression of IL-10 and Arginase-1 were significantly higher in the mmu-miR-27a-5p group as compared to the model and mmu-miR-27a-5p-NC groups at 7 and 14 days after SCI (P<0.05).ConclusionAdministration of mmu-miR-27a-5p can promote the polarization of macrophages to the M2 phenotype in the injured spinal cord, and improve motor function recovery within 14 days after SCI in mice.

scholarly journals Modulation of inflammatory factors predicts the outcome following spinal cord injury

2020 ◽  
Author(s):  
Zepeng Yu ◽  
Xingwei Sun ◽  
Rui Xia ◽  
Qian Chen ◽  
Qin Wu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Axonal Regeneration ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Serum Levels ◽  
High Serum ◽  
Inflammatory Factors ◽  
Mhc I ◽  
Cord Injury

Abstract BACKGROUND : The correlation between inflammatory responses caused by spinal cord injury (SCI) and the prognosis of patients with SCI still remains controversial. METHODS : In the present study, we preliminary investigated the serum levels of interleukin (IL)-4, IL-10, major histocompatibility complex (MHC)-I and inducible nitric oxide synthase (iNOS), and compared the serum IL-4 and IL-10 expression in rats of high BBB scores with these of low Basso-Beattie-Bresnahan(BBB) scores. Besides, the infiltration of macrophage and the axonal regeneration of the injuried spinal cord were observed from day10 to day30. RESULTS : We found that higher serum levels of IL-4 and IL-10 can reflect the restorability degree of SCI and could be potential biomarkers for the prognosis of SCI. The infiltration of M2 subtype of macrophage and the axons regrowth might contribute to better prognosis. CONCLUSIONS ： Collectively, the current study demonstrates that the serum levels of IL-4 and IL-10 are preliminary adopted as serologic markers to forecast SCI, and high serum levels of IL-4 and IL-10 may indicate a better prognosis. Moreover, the way to promote macrophage polarization from M1 to M2 may contribute to better axonal regeneration.

scholarly journals Sodium Tanshinone IIA Sulfonate Promotes Spinal Cord Injury Repair  by Inhibiting BSCB Disruption In Vitro and In Vivo

2020 ◽  
Author(s):  
Dan Luo ◽  
Xing Li ◽  
Jiheng Zhan ◽  
Yonghui Hou ◽  
Jiyao Luan ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Tanshinone Iia ◽  
Neurological Deficits ◽  
Drug Candidate ◽  
Therapeutic Effects ◽  
Spinal Cord Tissue ◽  
Cord Injury ◽  
Sodium Tanshinone Iia Sulfonate

Abstract Background:Spinal cord injury (SCI) leads to microvascular damage and the destruction of blood spinal cord barrier (BSCB), which progresses to secondary injuries like apoptosis and necrosis of neurons and glia, culminating in permanent neurological deficits. BSCB restoration is the primary goal of SCI therapy, although very few drugs can repair the damaged barrier structure and permeability. Sodium tanshinone IIA sulfonate (STS) is commonly used to treat cardiovascular disease. We found that STS restored BSCB integrity and promoted microvessel recovery 7 days after SCI in a mouse model. However, the therapeutic effects of STS on damaged BSCB in the early stage of SCI remained uncertain. Methods: we exposed spinal cord microvascular endothelial cells (SCMECs) to H2O2 and treated them with different doses of STS. The mice received intraperitoneal injection of STS after SCI in vivo model. Spinal cord tissue was taken 1 and 3d post-SCI. HE, Nissl staining, BSCB permeability, and the expression levels of tight junction (TJ) and adherens junction (AJ), MMP2, MMP9, NeuN, and C-caspase-3 were analyzed.Results: In addition to protecting the cells from H2O2-induced apoptosis, STS also reduced cellular permeability. In the in vivo model of SCI as well, STS reduced BSCB permeability, relieved tissue edema and hemorrhage, suppressed MMPs activation and prevented TJ and AJ the loss of proteins. Conclusions:Our findings indicate that STS treatment promotes SCI recovery, and should be investigated further as a drug candidate against traumatic SCI.

scholarly journals The CatWalk XT® Gait Analysis Is Closely Correlated with Tissue Damage after Cervical Spinal Cord Injury in Rats

2021 ◽  
Vol 11 (9) ◽  
pp. 4097
Author(s):  
Guoli Zheng ◽  
Alexander Younsi ◽  
Moritz Scherer ◽  
Lennart Riemann ◽  
Johannes Walter ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Gait Analysis ◽  
Tissue Damage ◽  
Wistar Rats ◽  
Spontaneous Recovery ◽  
Cervical Spinal Cord ◽  
Spinal Cord Tissue ◽  
Cord Injury ◽  
Consistent Assessment

Objective and consistent assessment of locomotion recovery remains challenging in rodent spinal cord injury (SCI). We, therefore, studied the validity and relevance of the CatWalk XT® gait analysis as a tool for assessing functional outcome in a clinically relevant cervical SCI model in rats. In total, 20 Wistar rats were randomly assigned to either a C6 clip compression/contusion SCI or a sham laminectomy. Locomotion recovery was assessed weekly using the CatWalk XT® gait analysis and the BBB open field score. Six weeks after SCI, the percentage of preserved spinal cord tissue was measured by glial fibrillary acidic protein (GFAP) immunohistochemistry (IHC) staining. Statistical analyses were performed to assess the correlation of the BBB and the percentage of preserved tissue with 30 different CatWalk XT® parameters. SCI caused a bilateral and significant functional impairment in all studied CatWalk XT® parameters. Similar to the BBB, a significant spontaneous recovery could be observed in most of the CatWalk XT® parameters in the following weeks. Correlation between the hindlimb CatWalk XT® parameters and the BBB was good (53% of r values > 0.6) while the correlation between the forelimb and the hindlimb CatWalk XT® parameters and the percentage of preserved tissue was even stronger (83% of r values > 0.6). The CatWalk XT® gait analysis is closely correlated with tissue damage after cervical contusion/compression SCI and can be used as an objective and consistent tool for assessing locomotion recovery.

scholarly journals Modulation of inflammatory factors predicts the outcome following spinal cord injury

2020 ◽  
Author(s):  
Zepeng Yu ◽  
Xingwei Sun ◽  
Rui Xia ◽  
Qian Chen ◽  
Qin Wu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Axonal Regeneration ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Serum Levels ◽  
High Serum ◽  
Inflammatory Factors ◽  
Mhc I ◽  
Cord Injury

Abstract BACKGROUND: The correlation between inflammatory responses caused by spinal cord injury (SCI) and the prognosis of patients with SCI still remains controversial.METHODS: In the present study, we preliminary investigated the serum levels of interleukin (IL)-4, IL-10, major histocompatibility complex (MHC)-I and inducible nitric oxide synthase (iNOS), and compared the serum IL-4 and IL-10 expression in rats of high Basso-Beattie-Bresnahan (BBB) scores with these of low BBB scores. Besides, the infiltration of macrophage and the axonal regeneration of the injured spinal cord were observed from day10 to day30.RESULTS: We found that higher serum levels of IL-4 and IL-10 can reflect the restorability degree of SCI and could be potential biomarkers for the prognosis of SCI. The infiltration of the M2 subtype of macrophage and the axons regrowth might contribute to a better prognosis.CONCLUSIONS：The current study demonstrates that the serum levels of IL-4 and IL-10 are preliminary adopted as serologic markers to forecast SCI, and high serum levels of IL-4 and IL-10 may indicate a better prognosis. Moreover, the way to promote macrophage polarization from M1 to M2 may contribute to better axonal regeneration.

scholarly journals The Conditioned Medium of Lactobacillus rhamnoides GG Regulates Microglia/Macrophage Polarization and Improves Functional Recovery after Spinal Cord Injury in Rats

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Fangqi Lin ◽  
Baokun Zhang ◽  
Qiang Shi ◽  
Jiaming Liang ◽  
Xin Wang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Conditioned Medium ◽  
Rating Scale ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Mrna Level ◽  
Treated Group ◽  
Cord Injury ◽  
Lower Ratio

Lactobacillus rhamnoides, a human intestinal colonizer, can act through various pathways to induce microglia/macrophages to produce cytokines and to polarize microglia/macrophages to different phenotypes to reduce the inflammatory response. In this article, we evaluated the treatment potential of the Lactobacillus rhamnoides GG conditioned medium (LGG-CM) in rat model with SCI (acute spinal cord injury), including functional, neurophysiological, and histological outcomes and the underlying neuroprotective mechanisms. In our experiment, LGG-CM (30 mg/kg) was injected directly into the injury site in rats immediately after SCI. Measured by the BBB scale (Basso, Beattie, and Bresnahan locomotor rating scale) and inclined plane test, rats in the LGG-CM-treated group showed better locomotor scores. Moreover, compared to the vehicle treatment group, LGG-CM increased the mRNA level of the M2 marker (CD206), and decreased that of the M1 marker (iNOS). Western blot assays showed that LGG-CM-treated SCI rats had a higher grayscale ratio of p65 and a lower ratio of p-IκBα/IκBα. Our study shows that local injection of LGG-CM after acute SCI can inhibit inflammatory responses and improve motor function recovery. These effects may be related with the inhibition to the NF-κB (The nuclear factor-kappa B) signal pathway which leads to M2 microglia/macrophage polarization.

scholarly journals The Repression of the HMGB1-TLR4-NF-κB Signaling Pathway by Safflower Yellow May Improve Spinal Cord Injury

2021 ◽  
Vol 15 ◽  
Author(s):  
Lu Wang ◽  
Benson O. A. Botchway ◽  
Xuehong Liu
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Signaling Pathway ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Nerve Tissue ◽  
Inflammatory Factors ◽  
Spinal Cord Tissue ◽  
Pathophysiological Mechanism ◽  
Cord Injury

Spinal cord injury (SCI) often results in abnormal sensory and motor functions. Current interventions for SCI in the clinical setting are not effective partly due to the complexity concerning its pathophysiological mechanism. In the wake of SCI, considerable inflammatory cells assemble around the injured area that induces a series of inflammatory reactions and aggravates tissue lesions, thereby affecting the recovery of the damaged nerve tissue. Therefore, the inhibition of inflammatory responses can improve the repair of the injured spinal cord tissue. Safflower Yellow (SY) is the main active ingredient of Carthamus tinctorius. SY has anti-inflammatory effect, as it can inhibit IκBα phosphorylation to impede the NF-κB signaling pathway and p53 nuclear translocation. Besides, SY can limit the release of pro-inflammatory factors, which in turn may alleviate secondary SCI and prevent further complications. In this report, we analyze the pathophysiological mechanism of SCI, the role of inflammatory responses, and how SY interferes with the HMGB1-TLR-4-NF-κB signaling pathway to attenuate inflammatory responses in SCI.

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