Dexmedetomidine alleviates inflammation-induced neuropathic pain by suppressing NLRP3 via activation of Nrf2

Abstract Objective: To investigate the mechanism of dexmedetomidine (DEX) involving Nrf2-dependent inhibition of NLRP3 in relieving neuropathic pain in chronic constriction injury (CCI) rat models.Methods: The CCI rat models were constructed through sciatic nerve ligation. The CCI rats were treated with DEX, Nrf2 inhibitor (ML385), NLRP3 antagonist (MCC950) and NLRP3 activator (Nigericin). Mechanical withdrawal threshold (MWT) was measured to test the pain sensitivity of CCI rats. H&E staining detected spinal injury of the rats and TUNEL staining was applied to test apoptosis in the spinal cords. ELISA measured the expressions of inflammatory factors. The expressions of Nrf2 and NLRP3 were also detected.Results: Decreased MWT, enhanced spinal cord injury, promoted apoptosis and increased inflammatory factors were detected in CCI rats. The expressions of the above indicators were retraced in DEX-treated CCI rats. Increased MWT, reduced spinal cord injury, inhibited apoptosis and decreased inflammatory factors were detected in rats treated with MCC950 or ML385 while opposite expression patterns were found in rats treated with Nigericin. The expressions of these indicators were retraced in both DEX+ML385 group and MCC950+ML385 group compared to ML385 group and MCC950 group respectively.Conclusion: DEX reduces neuropathic pain of CCI rats by suppressing NLRP3 through activation of Nrf2.

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Catalpol Protects Against Spinal Cord Injury in Mice Through Regulating MicroRNA-142-Mediated HMGB1/TLR4/NF-κB Signaling Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2020.630222 ◽

2021 ◽

Vol 11 ◽

Author(s):

Hougang Xia ◽

Dandan Wang ◽

Xiaohui Guo ◽

Kaidi Wu ◽

Fuwei Huang ◽

...

Keyword(s):

Oxidative Stress ◽

Spinal Cord ◽

Spinal Cord Injury ◽

Inflammatory Response ◽

Inflammatory Factors ◽

Tunel Staining ◽

Ros Generation ◽

Bv2 Cells ◽

Cord Injury ◽

Oxidative Response

Background: Spinal cord injury (SCI) is a devastating condition that leads to paralysis, disability and even death in severe cases. Inflammation, apoptosis and oxidative stress in neurons are key pathogenic processes in SCI. Catalpol (CTP), an iridoid glycoside extracted from Rehmannia glutinosa, has many pharmacological activities, such as anti-inflammatory, anti-oxidative and anti-apoptotic properties.Purpose: Here, we investigated whether CTP could exert neuroprotective effects against SCI, and explored the underlying mechanism involved.Methods: SCI was induced by a weight-drop device and treated with CTP (10 mg and 60 mg/kg). Then the locomotor function of SCI mice was evaluated by the BBB scores, spinal cord edema was measured by the wet/dry weight method, oxidative stress markers and inflammatory factors were detected by commercial kits and neuronal death was measured by TUNEL staining. Moreover, the microRNA expression profile in spinal cords from mice following SCI was analyzed using miRNA microarray. In addition, reactive oxygen species (ROS) generation, inflammatory response and cell apoptosis were detected in murine microglia BV2 cells under oxygen-glucose deprivation (OGD) and CTPtreatment.Results: Our data showed that CTP treatment could improve the functional recovery, as well as suppress the apoptosis, alleviate inflammatory and oxidative response in SCI mice. In addition, CTP was found to be up-regulated miR-142 and the protective effects of CTP on apoptosis, inflammatory and oxidative response may relate to its regulation of HMGB1/TLR4/NF-κB pathway through miR-142.Conclusion: Our findings suggest that CTP may protect the spinal cord from SCI by suppression of apoptosis, oxidative stress and inflammatory response via miR-142/HMGB1/TLR4/NF-κB pathway.

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Critical role of microglia in the inflammatory response after spinal injury

American Journal of BioMedicine ◽

10.18081/2333-5106/015-03/453-462 ◽

2015 ◽

Vol 3 (3) ◽

pp. 453-462

Author(s):

Ya-Yun Shi

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Inflammatory Responses ◽

Spinal Injury ◽

Critical Role ◽

Cell Types ◽

Inflammatory Factors ◽

Cytokines And Chemokines ◽

Cord Injury

Spinal cord injury induces a robust neuroinflammatory response that includes marked changes in the variety of endogenous CNS cell types specially microglia. In response to spinal injury, microglia undergo dramatic changes in cell morphology and promote inflammatory responses, which result in production of inflammatory factors and oxidative stress including reactive oxygen species. Further pro-inflammatory cytokines and chemokines are also rapidly up-regulated and likely contribute to microglial activation. This topic review will explore the current research on microglial responses to spinal injury and the recent progress in the pharmacologic and molecular targeting of microglia in spinal injury. Finally, we explore the argument for a positive versus negative role of microglia after spinal cord injury.

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PD-L1 Improves Motor Function and Alleviates Neuropathic Pain in Male Mice After Spinal Cord Injury by Inhibiting MAPK Pathway

10.21203/rs.3.rs-227701/v1 ◽

2021 ◽

Author(s):

Jiangang Shi ◽

FanQi Kong ◽

Kaiqiang Sun ◽

Jian Zhu ◽

FuDong Li ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Neuropathic Pain ◽

Inflammatory Response ◽

Mapk Pathway ◽

Expression Patterns ◽

Motor Dysfunction ◽

Locomotor Recovery ◽

Cord Injury

Abstract Background Traumatic spinal cord injury (SCI) causes severe motor dysfunction and persistent central neuropathic pain (Nep) that remains uncured yet. Programmed cell death ligand-1 (PD-L1) is typically produced by cancer cells and contributes to the immune-suppressive in tumor microenvironment, and the role of PD-L1 in regulating inflammatory response and Nep after SCI remains unclear. A growing amount of research has begun to investigate the effect of PD-L1 on macrophages and microglia. Considering the pivotal role of macrophages/microglia in the inflammatory response after SCI, we tested the hypothesis that PD-L1 improved the recovery of locomotor and sensory functions after SCI through macrophages and microglia. Methods The mice SCI model was employed to determine the changes in expression patterns of PD-L1. Meanwhile, we constructed PD-L1 knockout mice to observe differences in functional recovery and phenotypes of macrophages/microglia post-SCI. Results In present study, PD-L1 was significantly upregulated after SCI and highly expressed on macrophages/microglia. PD-L1 knockout (KO) mice showed poor locomotor recovery and serious pathological pain compared with wild-type (WT) mice. Furthermore, deletion of PD-L1 significantly increased the polarization of M1-like macrophages/microglia. Mechanistic analysis revealed that PD-L1 may improve functional outcomes following SCI by inhibiting phosphorylation of p38 and ERK1/2. Conclusions Our observations implicate the involvement of PD-L1 in recovery of SCI and provide a new treatment strategy for prevention and treatment of this traumatic condition.

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PD-L1 Improves Motor Function and Alleviates Neuropathic Pain in Male Mice After Spinal Cord Injury by Inhibiting MAPK Pathway

Frontiers in Immunology ◽

10.3389/fimmu.2021.670646 ◽

2021 ◽

Vol 12 ◽

Author(s):

Fanqi Kong ◽

Kaiqiang Sun ◽

Jian Zhu ◽

Fudong Li ◽

Feng Lin ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Neuropathic Pain ◽

Inflammatory Response ◽

Mapk Pathway ◽

Expression Patterns ◽

Motor Dysfunction ◽

Locomotor Recovery ◽

Cord Injury

BackgroundTraumatic spinal cord injury (SCI) causes severe motor dysfunction and persistent central neuropathic pain (Nep), which has not yet been effectively cured. Programmed cell death ligand-1 (PD-L1) is typically produced by cancer cells and contributes to the immune-suppressive in tumor microenvironment. However, the role of PD-L1 in regulating inflammatory response and Nep after SCI remains unclear. A growing amount of researches have begun to investigate the effect of PD-L1 on macrophages and microglia in recent years. Considering the pivotal role of macrophages/microglia in the inflammatory response after SCI, we proposed the hypothesis that PD-L1 improved the recovery of locomotor and sensory functions after SCI through regulating macrophages and microglia.MethodsThe mice SCI model was established to determine the changes in expression patterns of PD-L1. Meanwhile, we constructed PD-L1 knockout mice to observe differences in functional recovery and phenotypes of macrophages/microglia post-SCI.ResultsIn present study, PD-L1 was significantly upregulated after SCI and highly expressed on macrophages/microglia at the injury epicenter. PD-L1 knockout (KO) mice showed worse locomotor recovery and more serious pathological pain compared with wild-type (WT) mice. Furthermore, deletion of PD-L1 significantly increased the polarization of M1-like macrophages/microglia. Mechanistic analysis revealed that PD-L1 may improve functional outcomes following SCI by inhibiting phosphorylation of p38 and ERK1/2.ConclusionsOur observations implicate the involvement of PD-L1 in recovery of SCI and provide a new treatment strategy for the prevention and treatment of this traumatic condition.

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Faculty Opinions recommendation of Comparison of the effectiveness of amitriptyline and gabapentin on chronic neuropathic pain in persons with spinal cord injury.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1098590.554694 ◽

2007 ◽

Author(s):

Nanna Finnerup

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Neuropathic Pain ◽

Chronic Neuropathic Pain ◽

Cord Injury

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Bone marrow mesenchymal stem cells-derived exosomes reduce apoptosis and inflammatory response during spinal cord injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway

Human & Experimental Toxicology ◽

10.1177/09603271211003311 ◽

2021 ◽

pp. 096032712110033

Author(s):

Liying Fan ◽

Jun Dong ◽

Xijing He ◽

Chun Zhang ◽

Ting Zhang

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Bone Marrow ◽

Spinal Cord Injury ◽

Mesenchymal Stem Cells ◽

Motor Function ◽

Inflammatory Factors ◽

Cord Injury ◽

Marrow Mesenchymal Stem Cells ◽

Apoptosis And Inflammation

Spinal cord injury (SCI) is one of the most common destructive injuries, which may lead to permanent neurological dysfunction. Currently, transplantation of bone marrow mesenchymal stem cells (BMSCs) in experimental models of SCI shows promise as effective therapies. BMSCs secrete various factors that can regulate the microenvironment, which is called paracrine effect. Among these paracrine substances, exosomes are considered to be the most valuable therapeutic factors. Our study found that BMSCs-derived exosomes therapy attenuated cell apoptosis and inflammation response in the injured spinal cord tissues. In in vitro studies, BMSCs-derived exosomes significantly inhibited lipopolysaccharide (LPS)-induced PC12 cell apoptosis, reduced the secretion of pro-inflammatory factors including tumor necrosis factor (TNF)-α and IL (interleukin)-1β and promoted the secretion of anti-inflammatory factors including IL-10 and IL-4. Moreover, we found that LPS-induced protein expression of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and nuclear transcription factor-κB (NF-κB) was significantly downregulated after treatment with BMSCs-derived exosomes. In in vivo studies, we found that hindlimb motor function was significantly improved in SCI rats with systemic administration of BMSCs-derived exosomes. We also observed that the expression of pro-apoptotic proteins and pro-inflammatory factors was significantly decreased, while the expression of anti-apoptotic proteins and anti-inflammatory factors were upregulated in SCI rats after exosome treatment. In conclusion, BMSCs-derived exosomes can inhibit apoptosis and inflammation response induced by injury and promote motor function recovery by inhibiting the TLR4/MyD88/NF-κB signaling pathway, which suggests that BMSCs-derived exosomes are expected to become a new therapeutic strategy for SCI.

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1-kHz high-frequency spinal cord stimulation alleviates chronic refractory pain after spinal cord injury: a case report

JA Clinical Reports ◽

10.1186/s40981-021-00451-x ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Chiaki Yamada ◽

Aiko Maeda ◽

Katsuyuki Matsushita ◽

Shoko Nakayama ◽

Kazuhiro Shirozu ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Neuropathic Pain ◽

Spinal Cord Stimulation ◽

High Frequency ◽

Cervical Vertebrae ◽

Intractable Pain ◽

Target Area ◽

Positive Effects ◽

Cord Injury

Abstract Background Patients with spinal cord injury (SCI) frequently complain of intractable pain that is resistant to conservative treatments. Here, we report the successful application of 1-kHz high-frequency spinal cord stimulation (SCS) in a patient with refractory neuropathic pain secondary to SCI. Case presentation A 69-year-old male diagnosed with SCI (C4 American Spinal Injury Association Impairment Scale A) presented with severe at-level bilateral upper extremity neuropathic pain. Temporary improvement in his symptoms with a nerve block implied peripheral component involvement. The patient received SCS, and though the tip of the leads could not reach the cervical vertebrae, a 1-kHz frequency stimulus relieved the intractable pain. Conclusions SCI-related symptoms may include peripheral components; SCS may have a considerable effect on intractable pain. Even when the SCS electrode lead cannot be positioned in the target area, 1-kHz high-frequency SCS may still produce positive effects.

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Rehabilitation of the canine patient following spinal cord injury: a practical guide

Companion Animal ◽

10.12968/coan.2020.0060 ◽

2021 ◽

Vol 26 (1) ◽

pp. 1-6

Author(s):

Cheryl Corral

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Spinal Injury ◽

Neurological Deficits ◽

Practical Guide ◽

Cord Injury ◽

Physical Therapies

This article forms part of a series exploring the rehabilitation of the canine shoulder, elbow, back, hip and stifle following injury or disease. Discussed here are different rehabilitation techniques used to address neurological deficits, pain and weakness following spinal injury, including physical therapies, electrotherapies and acupuncture.

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