Ultrasound stimulation improves inflammatory resolution, neuroprotection, and functional recovery after spinal cord injury

Abstract Spinal cord injury (SCI) is associated with limited functional recovery. Despite advances in neuroscience, realistic therapeutic treatments for SCI remain unavailable. In this study, the effects of non-invasive ultrasound (US) treatment on behavior and inflammatory responses were evaluated in a rat model of SCI. Adult female Sprague–Dawley rats were subjected to spinal cord contusion injury. Two different US parameters (SCIU5: 5% and SCIU40: 40% duty cycle) were applied, and their effects on behavioral recovery after SCI were quantified. Tissue and neuronal responses were detected. Immunofluorescence was used to detect inflammatory markers. In the rat model of SCI, motor function was more effectively restored, and the lesion cavity area was smaller in the SCIU5 group. Furthermore, the SCIU5 protocol elicited an anti-inflammatory response at the injury site by reducing degenerative FJC-labeled neurons, macrophage/microglia activation, and infiltration. Thus, the lesion area decreased, and tissue density increased. Meanwhile, the SCIU40 protocol did not improve motor function or induce an anti-inflammatory response at the injury site. The SCIU5 protocol effectively accelerated the rate of improved exercise performance in the rat model while reducing inflammation. Accordingly, appropriate US stimulation may represent a promising treatment modality for SCI with beneficial anti-inflammatory effects.

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Neonatal Rats Exhibit a Predominantly Anti-Inflammatory Response following Spinal Cord Injury

Developmental Neuroscience ◽

10.1159/000514612 ◽

2021 ◽

pp. 1-9

Author(s):

Theresa C. Sutherland ◽

Alison Ricafrente ◽

Katarina Gomola ◽

Bronwyn A. O’Brien ◽

Catherine A. Gorrie

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Inflammatory Response ◽

Inflammatory Responses ◽

Neonatal Rats ◽

Adult Rats ◽

Lesion Effect ◽

Cord Injury ◽

Th1 Cytokine ◽

Anti Inflammatory

It has been reported that children may respond better than adults to a spinal cord injury (SCI) of similar severity. There are known biomechanical differences in the developing spinal cord that may contribute to this “infant lesion effect,” but the underlying mechanisms are unknown. Using immunohistochemistry, we have previously demonstrated a different injury progression and immune cell response after a mild thoracic contusion SCI in infant rats, as compared to adult rats. Here, we investigated the acute inflammatory responses using flow cytometry and ELISA at 1 h, 24 h, and 1 week after SCI in neonatal (P7) and adult (9 weeks) rats, and locomotor recovery was examined for 6 weeks after injury. Adult rats exhibited a pronounced pro-inflammatory response characterized by neutrophils and M1-like macrophage infiltration and Th1 cytokine secretion. Neonatal rats exhibited a decreased pro-inflammatory response characterized by a higher proportion of M2-like macrophages and reduced Th1 cytokine responses, as compared to adults. These results suggest that the initial inflammatory response to SCI is predominantly anti-inflammatory in very young animals.

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Regulation of Autophagy and Ubiquitinated Protein Accumulation by bFGF Promotes Functional Recovery and Neural Protection in a Rat Model of Spinal Cord Injury

Molecular Neurobiology ◽

10.1007/s12035-013-8432-8 ◽

2013 ◽

Vol 48 (3) ◽

pp. 452-464 ◽

Cited By ~ 88

Author(s):

Hong-Yu Zhang ◽

Zhou-Guang Wang ◽

Fen-Zan Wu ◽

Xiao-Xia Kong ◽

Jie Yang ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Functional Recovery ◽

Rat Model ◽

Protein Accumulation ◽

Ubiquitinated Protein ◽

Cord Injury

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Inhibiting HMGB1-RAGE axis prevents pro-inflammatory macrophages/microglia polarization and affords neuroprotection after spinal cord injury

Journal of Neuroinflammation ◽

10.1186/s12974-020-01973-4 ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Hong Fan ◽

Hai-Bin Tang ◽

Zhe Chen ◽

Hu-Qing Wang ◽

Lei Zhang ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Western Blot ◽

Functional Recovery ◽

Sterile Inflammation ◽

Qrt Pcr ◽

Cord Injury ◽

Microglia Polarization ◽

Anti Inflammatory ◽

Inflammatory Macrophages

Abstract Background Spinal cord injury (SCI) favors a persistent pro-inflammatory macrophages/microglia-mediated response with only a transient appearance of anti-inflammatory phenotype of immune cells. However, the mechanisms controlling this special sterile inflammation after SCI are still not fully elucidated. It is known that damage-associated molecular patterns (DAMPs) released from necrotic cells after injury can trigger severe inflammation. High mobility group box 1(HMGB1), a ubiquitously expressed DNA binding protein, is an identified DAMP, and our previous study demonstrated that reactive astrocytes could undergo necroptosis and release HMGB1 after SCI in mice. The present study aimed to explore the effects and the possible mechanism of HMGB1on macrophages/microglia polarization, as well as the neuroprotective effects by HMGB1 inhibition after SCI. Methods In this study, the expression and the concentration of HMGB1 was determined by qRT-PCR, ELISA, and immunohistochemistry. Glycyrrhizin was applied to inhibit HMGB1, while FPS-ZM1 to suppress receptor for advanced glycation end products (RAGE). The polarization of macrophages/microglia in vitro and in vivo was detected by qRT-PCR, immunostaining, and western blot. The lesion area was detected by GFAP staining, while neuronal survival was examined by Nissl staining. Luxol fast blue (LFB) staining, DAB staining, and western blot were adopted to evaluate the myelin loss. Basso-Beattie-Bresnahan (BBB) scoring and rump-height Index (RHI) assay was applied to evaluate locomotor functional recovery. Results Our data showed that HMGB1 can be elevated and released from necroptotic astrocytes and HMGB1 could induce pro-inflammatory microglia through the RAGE-nuclear factor-kappa B (NF-κB) pathway. We further demonstrated that inhibiting HMGB1 or RAGE effectively decreased the numbers of detrimental pro-inflammatory macrophages/microglia while increased anti-inflammatory cells after SCI. Furthermore, our data showed that inhibiting HMGB1 or RAGE significantly decreased neuronal loss and demyelination, and improved functional recovery after SCI. Conclusions The data implicated that HMGB1-RAGE axis contributed to the dominant pro-inflammatory macrophages/microglia-mediated pro-inflammatory response, and inhibiting this pathway afforded neuroprotection for SCI. Thus, therapies designed to modulate immune microenvironment based on this cascade might be a prospective treatment for SCI.

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Overexpression of Rictor in the injured spinal cord promotes functional recovery in a rat model of spinal cord injury

The FASEB Journal ◽

10.1096/fj.201903171r ◽

2020 ◽

Vol 34 (5) ◽

pp. 6984-6998

Author(s):

Ningning Chen ◽

Pengxiang Zhou ◽

Xizhe Liu ◽

Jiachun Li ◽

Yong Wan ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Functional Recovery ◽

Rat Model ◽

Injured Spinal Cord ◽

Cord Injury

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Anti‑inflammatory effect of delphinidin on intramedullary spinal pressure in a spinal cord injury rat model

Experimental and Therapeutic Medicine ◽

10.3892/etm.2017.5206 ◽

2017 ◽

Cited By ~ 4

Author(s):

Cheng‑Hu Wang ◽

Lin‑Lin Zhu ◽

Ke‑Feng Ju ◽

Jin‑Long Liu ◽

Kun‑Peng Li

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Rat Model ◽

Cord Injury ◽

Anti Inflammatory ◽

Inflammatory Effect

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Galantamine improves functional recovery and reduces lesion size in a rat model of spinal cord injury

Brain Research ◽

10.1016/j.brainres.2019.146424 ◽

2019 ◽

Vol 1724 ◽

pp. 146424 ◽

Cited By ~ 1

Author(s):

Laura E. Sperling ◽

Karina Pires Reis ◽

Fabricio Nicola ◽

Cristian Euzebio Teixeira ◽

Gabriele Gulielmin Didó ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Functional Recovery ◽

Rat Model ◽

Lesion Size ◽

Cord Injury

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Limited functional recovery in rats with complete spinal cord injury after transplantation of whole-layer olfactory mucosa

Journal of Neurosurgery Spine ◽

10.3171/2009.9.spine09233 ◽

2010 ◽

Vol 12 (2) ◽

pp. 122-130 ◽

Cited By ~ 30

Author(s):

Masanori Aoki ◽

Haruhiko Kishima ◽

Kazuhiro Yoshimura ◽

Masahiro Ishihara ◽

Masaki Ueno ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Lamina Propria ◽

Motor Function ◽

Functional Recovery ◽

Olfactory Mucosa ◽

Respiratory Mucosa ◽

Locomotor Recovery ◽

Cord Injury ◽

Complete Spinal Cord Injury

Object The olfactory mucosa (OM) consists of 2 layers, the epithelium and the lamina propria. Attempts have been made to restore motor function in rat models of spinal cord injury (SCI) by transplanting olfactory ensheathing cells from the lamina propria, but there has been no attempt to transplant the OM in animal models. To investigate the potential of the OM to restore motor function, the authors developed a rat model of SCI and delayed transplantation of syngenic OM. Methods Two weeks after complete transection of the spinal cord at the T-10 level in Wistar rats, pieces of syngenic whole-layer OM were transplanted into the lesion. Rats that underwent respiratory mucosa transplantation were used as controls. The authors evaluated the locomotor activity according to the Basso-Beattie-Bresnahan scale for 8 weeks after transplantation. Obtained spinal cords were analyzed histologically. Results The OM transplantation rats showed significantly greater hindlimb locomotor recovery than the respiratory mucosa–transplanted rats. However, the recovery was limited according to the Basso-Beattie-Bresnahan scale. In the histological examination, the serotonergic raphespinal tract was regenerated. The pseudocyst cavity volume in the vicinity of the SCI lesion correlated negatively with the functional recovery. Conclusions Transplantation of whole-layer OM in rats contributes to functional recovery from SCI, but the effect is limited. In addition to OM transplantation, other means would be necessary for better outcomes in clinical situations.

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Effect of Shikonin on Spinal Cord Injury in Rats Via Regulation of HMGB1/TLR4/NF-kB Signaling Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000480474 ◽

2017 ◽

Vol 43 (2) ◽

pp. 481-491 ◽

Cited By ~ 13

Author(s):

Yihui Bi ◽

Yapeng Zhu ◽

Mingkai Zhang ◽

Keke Zhang ◽

Xingyi Hua ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Inflammatory Response ◽

Signaling Pathway ◽

Motor Function ◽

Tissue Repair ◽

Underlying Mechanism ◽

Molecular Signaling ◽

Cord Injury

Background/Aims: Shikonin, a compound extracted from Zicao, has been demonstrated to hold anti-bacterial, anti-inflammatory, and anti-tumor activities in various diseases and it has been shown to protect human organs from injuries. However, the effect of shikonin on the recovery of spinal cord injury (SCI) remains unknown. This study was designed to estimate the potential therapeutic effect and underlying mechanism of shikonin on SCI in vivo. Methods: In the study, we used HE staining, ELISA assay, transfection assay, TUNEL assay, real time PCR and Western blot to detect the effects of shikonin on spinal cord injury in rats. Results: we showed that shikonin could promote the recovery of motor function and tissue repair after SCI treatment in rats SCI model. Moreover, we demonstrated that shikonin inhibited the spinal cord edema in SCI model of rats. According to further investigation, shikonin induced the reduction of inflammatory response through decreasing the expression levels of HMGB1, TLR4 and NF-κB after SCI injury. In addition, we also found that shikonin could suppress the apoptosis and expression of caspase-3 protein in SCI model of rats. Conclusion: Our results demonstrated that shikonin induced the recovery of tissue repair and motor function via inactivation of HMGB1/TLR4/NF-κB signaling pathway in SCI model of rats. Meanwhile, shikonin regulated the inflammation response in SCI by suppressing the HMGB1/TLR4/NF-κB signaling pathway. The described mechanism sheds novel light on molecular signaling pathway in spinal cord injury and secondary injury including inflammatory response.

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