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Unresolved Excess Accumulation of Myelin-Derived Cholesterol Contributes to Scar Formation after Spinal Cord Injury

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Research 2024年第1期2023卷 17-32页

作者： Bolin Zheng Yijing He Shuai Yin Xu Zhu Qing Zhao Huiyi Yang Zhaojie wang Rongrong Zhu Liming Cheng Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration Ministry of EducationDepartment of OrthopedicsTongji HospitalSchool of MedicineTongji UniversityShanghai 200092China Frontier Science Center for Stem Cell Research School of Life Science and TechnologyTongji UniversityShanghai 200092China Clinical Center for Brain and Spinal Cord Research Tongji UniversityShanghai 200092China

Spinal cord injury triggers complex pathological cascades,resulting in destructive tissue damage and incomplete tissue repair.Scar formation is generally considered a barrier for regeneration in the central nervous system.However,the intrinsic mechanism of scar formation after Spinal cord injury has not been fully elucidated.Here,we report that excess cholesterol accumulates in phagocytes and is inefficiently removed from Spinal cord lesions in young adult mice.Interestingly,we observed that excessive cholesterol also accumulates in injured peripheral nerves but is subsequently removed by reverse cholesteroltransport.Meanwhile,preventing reverse cholesterol transport leads to macrophage accumulation and fibrosis in injured peripheral nerves.Furthermore,the neonatal mouse Spinal cord lesions are devoid of myelin-derived lipids and can heal without excess cholesterol accumulation.We found that transplantation of myelin into neonatal lesions disrupts healing with excessive cholesterol accumulation,persistent macrophage activation,and fibrosis.Myelin internalization suppresses macrophage apoptosis mediated by CD5L expression,indicating that myelin-derived cholesterol plays a critical role in impaired wound healing.Taken together,our data suggest that the central nervous system lacks an efficient approach for cholesterol clearance,resulting in excessive accumulation of myelin-derived cholesterol,thereby inducing scar formation after injury.

关键词： healing Spinal impaired

Reversion of Injured Adult Neurons to an Embryonic State by Grafts of Neural Progenitor Cells After Spinal Cord Injury

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Neuroscience Bulletin 2021年第2期37卷 271-274页

作者： Liying Cao Yongjie Wang Zhihui Huang Laboratory of Aging and Cancer Biology of Zhejiang Province School of MedicineHangzhou Normal UniversityHangzhou 311121China Department of Neurosurgery of Affiliated Hospital and Holistic Integrative Pharmacy InstitutesHangzhou Normal UniversityHangzhou 311121China

Spinal cord injury(SCI)is a severe condition characterized by neurological dysfunction,dependence,respiratory failure,psychological morbidities,and an increased mortality rate[1].Globally,its incidence ranges from 250... 详细信息

关键词： Spinal mortality respiratory

Dynamic changes in intramedullary pressure 72 hours after Spinal cord injury

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Neural Regeneration Research 2019年第5期14卷 886-895页

作者： Xin Zhang Chang-Bin Liu De-Gang Yang Chuan Qin Xue-Chao Dong Da-Peng Li Chao Zhang Yun Guo Liang-Jie Du Feng Gao Ming-Liang Yang Jian-Jun Li School of Rehabilitation Medicine Capital Medical University Department of Spinal and Neural Function Reconstruction China Rehabilitation Research Center Center of Neural Injury and Repair Beijing Institute for Brain Disorders China Rehabilitation Science Institute Beijing Key Laboratory of Neural Injury and Rehabilitation

Intramedullary pressure increases after Spinal cord injury, and this can be an important factor for secondary Spinal cord injury. Until now there have been no studies of the dynamic changes of intramedullary pressure after Spinal cord injury. In this study, telemetry systems were used to observe changes in intramedullary pressure in the 72 hours following Spinal cord injury to explore its pathological mechanisms. Spinal cord injury was induced using an aneurysm clip at T10 of the Spinal cord of 30 Japanese white rabbits, while another 32 animals were only subjected to laminectomy. The feasibility of this measurement was assessed. Intramedullary pressure was monitored in anesthetized and conscious animals. The dynamic changes of intramedullary pressure after Spinal cord injury were divided into three stages: stage I(steep rise) 1–7 hours, stage Ⅱ(steady rise) 8–38 hours, and stage Ⅲ(descending) 39–72 hours. Blood-Spinal barrier permeability, edema, hemorrhage, and histological results in the 72 hours following Spinal cord injury were evaluated according to intramedullary pressure changes. We found that Spinal cord hemorrhage was most severe at 1 hour post-Spinal cord injury and then gradually decreased; albumin and aquaporin 4 immunoreactivities first increased and then decreased, peaking at 38 hours. These results confirm that severe bleeding in Spinal cord tissue is the main cause of the sharp increase in intramedullary pressure in early Spinal cord injury. Spinal cord edema and blood-Spinal barrier destruction are important factors influencing intramedullary pressure in stages Ⅱ and Ⅲ of Spinal cord injury.

关键词： nerve regeneration secondary Spinal cord injury telemetry pathological mechanism rabbit conscious anesthetized hemorrhage edema pressure measurement blood-Spinal barrier neural regeneration

Changes in neurological and pathological outcomes in a modified rat Spinal cord injury model with closed canal

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Neural Regeneration Research 2020年第4期15卷 697-704页

作者： Xin Sun Xing-Zhen Liu Jia Wang Hai-Rong Tao Tong Zhu Wen-Jie Jin Kang-Ping Shen Shanghai Key Laboratory of Orthopedic Implants Department of Orthopedic SurgeryShanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Department of Pathology Shanghai Xinhua HospitalShanghai Jiao Tong University School of MedicineShanghaiChina

Most animal Spinal cord injury models involve a laminectomy,such as the weight drop model or the transection model.However,in clinical practice,many patients undergo Spinal cord injury while maintaining a relatively complete Spinal canal.Thus,open Spinal cord injury models often do not simulate real injuries,and few previous studies have investigated whether having a closed Spinal canal after a primary Spinal cord injury may influence secondary processes.Therefore,we aimed to assess the differences in neurological dysfunction and pathological changes between rat Spinal cord injury models with closed and open Spinal canals.Sprague-Dawley rats were randomly divided into three groups.In the sham group,the tunnel was expanded only,without inserting a screw into the Spinal canal.In the Spinal cord injury with open canal group,a screw was inserted into the Spinal canal to cause Spinal cord injury for 5 minutes,and then the screw was pulled out,leaving a hole in the vertebral plate.In the Spinal cord injury with closed canal group,after inserting a screw into the Spinal canal for 5 minutes,the screw was pulled out by approximately 1.5 mm and the flat end of the screw remained in the hole in the vertebral plate so that the Spinal canal remained closed;this group was the modified model,which used a screw both to compress the Spinal cord and to seal the Spinal canal.At 7 days post-operation,the Basso-Beattie-Bresnahan scale was used to measure changes in neurological outcomes.Hematoxylin-eosin staining was used to assess histopathology.To evaluate the degree of local secondary hypoxia,immunohistochemical staining and western blot assays were applied to detect the expression of hypoxia-inducible factor 1α(HIF-1α)and vascular endothelial growth factor(VEGF).Compared with the Spinal cord injury with open canal group,in the closed canal group the Basso-Beattie-Bresnahan scores were lower,cell morphology was more irregular,the percentage of morphologically normal neurons was lower,the percentages of HIF-1α-and VEGF-immunoreacti

关键词： Basso-Beattie-Bresnahan scores closed Spinal canal HIF-1α hypoxia model nerve regeneration open Spinal canal rat secondary injury Spinal cord injury VEGF

Hyperbaric oxygen improves functional recovery of rats after Spinal cord injury via activating stromal cell-derived factor-1/CXC chemokine receptor 4 axis and promoting brain-derived neurothrophic factor expression

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Chinese Medical Journal 2019年第6期132卷 699-706页

作者： Xiang-Long Meng Yong Hai Xi-Nuo Zhang Yun-Sheng Wang Xue-Hua Liu Lin-Lin Ma Rong Yue Gang Xu Zhuo Li Orthopedic Department Beijing Chaoyang Hospital Capital Medical University Beijing 100020 China Hyperbaric Oxygen Department Beijing Chaoyang Hospital Capital Medical University Beijing 100020 China Hyperbaric Oxygen Department Xinjiang Uygur Autonomous Region People's Hospital Urumqi Xinjiang 830001 China

Background: Spinal cord injury (SCI) is a worldwide medical concern. This study aimed to elucidate the mechanism underlying protective effect of hyperbaric oxygen (HBO) against SCI-induced neurologic defects in rats via exploring the stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis and expression of brain-derived neurotrophic factor (BDNF). Methods: An acute SCI rat model was established in Sprague-Dawley rats using the Allen method. Sixty rats were divided into four groups (w = 15 in each group): sham-operated, SCI, SCI treated with HBO (SCI + HBO), and SCI treated with both HBO and AMD3100 (an antagonist of CXCR4;SCI + HBO + AMD) groups. The rats were treated with HBO twice a day for 3 days and thereafter once a day after the surgery for up to 28 days. Following the surgery, neurologic assessments were performed with the Basso-Bettie-Bresnahan (BBB) scoring system on postoperative day (POD) 7, 14, 21, and 28. Spinal cord tissues were harvested to assess the expression of SDF-1, CXCR4, and BDNF at mRNA and protein levels, using quantitative real-time polymerase chain reaction, Western blot analysis, and histopathologic analysis. Results: HBO treatment recovered SCI-induced descent of BBB scores on POD 14,(1.25±0.75 vs. 1.03 ±0.66, P< 0.05), 21 (5.27± 0.89 vs. 2.56± 1.24, P< 0.05), and 28 (11.35±0.56 vs. 4.23± 1.20, P<0.05) compared with the SCI group. Significant differences were found in the mRNA levels of SDF-1 (mRNA: day 21, SCI + HBO vs. SCI + HBO + AMD, 2.89± 1.60 vs. 1.56±0.98, P<0.05), CXCR4 (mRNA: day 7, SCI + HBO vs. SCI, 2.99± 1.60 vs. 1.31 ±0.98, P<0.05;day 14, SCI + HBO vs. SCI + HBO + AMD, 4.18± 1.60 vs. 0.80±0.34, P<0.05;day 21, SCI + HBO vs. SCI, 2.10±1.01 vs.1.15±0.03, P<0.05), and BDNF (mRNA: day 7, SCI + HBO vs. SCI, 3.04±0.41 vs. 2.75±0.31, P<0.05;day 14, SCI + HBO vs. SCI, 3.88± 1.59 vs. 1.11 ±0.40, P<0.05), indicating the involvement of SDF-1/CXCR4 axis in the protective effect of HBO. Conclusions: HBO might promote the recovery of neurologic function after SCI in

关键词： Brain-derived neurotrophic factor CXC chemokine receptor 4 Hyperbaric oxygen Neurotrophic Stromal cell-derived factor-1 Spinal cord injury

Different protein expression patterns in rat Spinal nerves during wallerian degeneration assessed using isobaric tags for relative and absolute quantitation proteomics profiling

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Neural Regeneration Research 2020年第2期15卷 315-323页

作者： Shuai Wei Xue-Zhen Liang Qian Hu Wei-Shan Wang Wen-Jing Xu Xiao-Qing Cheng Jiang Peng Quan-Yi Guo Shu-Yun Liu Wen Jiang Xiao Ding Gong-Hai Han Ping Liu Chen-Hui Shi Yu Wang The First Affiliated Hospital of Medical College Shihezi UniversityShiheziXinjiang Uygur Autonomous RegionChina Institute of Orthopedics Chinese PLA General HospitalBeijingChina Co-Innovation Center of Neuroregeneration Nantong UniversityNantongJiangsu ProvinceChina The First Clinical Medical School Shandong University of Traditional Chinese MedicineJinanShandong ProvinceChina Kunming Medical University KunmingYunnan ProvinceChina Shanxi Medical University TaiyuanShanxi ProvinceChina

Sensory and motor nerve fibers of peripheral nerves have different anatomies and regeneration functions after injury. To gain a clear understanding of the biological processes behind these differences, we used a labeling technique termed isobaric tags for relative and absolute quantitation to investigate the protein profiles of Spinal nerve tissues from Sprague-Dawley rats. In response to Wallerian degeneration, a total of 626 proteins were screened in sensory nerves, of which 368 were upregulated and 258 were downregulated. In addition, 637 proteins were screened in motor nerves, of which 372 were upregulated and 265 were downregulated. All identified proteins were analyzed using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis of bioinformatics, and the presence of several key proteins closely related to Wallerian degeneration were tested and verified using quantitative real-time polymerase chain reaction analyses. The differentially expressed proteins only identified in the sensory nerves were mainly relevant to various biological processes that included cell-cell adhesion, carbohydrate metabolic processes and cell adhesion, whereas differentially expressed proteins only identified in the motor nerves were mainly relevant to biological processes associated with the glycolytic process, cell redox homeostasis, and protein folding. In the aspect of the cellular component, the differentially expressed proteins in the sensory and motor nerves were commonly related to extracellular exosomes, the myelin sheath, and focal adhesion. According to the Kyoto Encyclopedia of Genes and Genomes, the differentially expressed proteins identified are primarily related to various types of metabolic pathways. In conclusion, the present study screened differentially expressed proteins to reveal more about the differences and similarities between sensory and motor nerves during Wallerian degeneration. The present findings could provide a reference point for a future investigation into the differences between s

关键词： gene ontology Kyoto Encyclopedia of Genes and Genomes isobaric tags for relative and absolute quantitation motor nerve proteomics sensory nerve Spinal nerve Wallerian degeneration

Muscovite nanoparticles mitigate neuropathic pain by modulating the inflammatory response and neuroglial activation in the Spinal cord

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Neural Regeneration Research 2020年第11期15卷 2162-2168页

作者： Ju-Young Oh Tae-Yeon Hwang Jae-Hwan Jang Ji-Yeun Park Yeonhee Ryu HyeJung Lee Hi-Joon Park Acupuncture and Meridian Science Research Center Kyung Hee University26 Kyungheedae-roDongdaemun-guSeoulRepublic of Korea Department of Korean Medical Science Graduate School of Korean MedicineKyung Hee UniversitySeoulRepublic of Korea BK21 PLUS Korean Medicine Science Center College of Korean MedicineKyung Hee UniversitySeoulRepublic of Korea College of Korean Medicine Daejeon UniversityDaejeonRepublic of Korea Korean Institute of Oriental Medicine DaejeonRepublic of Korea

Despite numerous efforts to overcome neuropathic pain,various pharmacological drugs often fail to meet the needs and have many side effects.Muscovite is an aluminosilicate mineral that has been reported to have an anti-inflammatory effect,but the efficacy of muscovite for neuropathic pain has not been investigated.Here,we assessed whether muscovite nanoparticles can reduce the symptoms of pain by controlling the inflammatory process observed in neuropathic pain.The analgesic effects of muscovite nanoparticles were explored using partial sciatic nerve ligation model of neuropathic pain,in which one-third to onehalf of the nerve trifurcation of the sciatic nerve was tightly tied to the dorsal side.Muscovite nanoparticles(4 mg/100μL)was given intramuscularly to evaluate its effects on neuropathic pain(3 days per week for 4 weeks).The results showed that the muscovite nanoparticle injections significantly alleviated partial sciatic nerve ligation-induced mechanical and cold allodynia.In the Spinal cord,the muscovite nanoparticle injections exhibited inhibitory effects on astrocyte and microglia activation and reduced the expression of pro-inflammatory cytokines,such as interleukin-1β,tumor necrosis factor-α,interleiukin-6 and monocyte chemoattractant protein-1,which were upregulated in the partial sciatic nerve ligation model.Moreover,the muscovite nanoparticle injections resulted in a decrease in activating transcription factor 3,a neuronal injury marker,in the sciatic nerve.These results suggest that the analgesic effects of muscovite nanoparticle on partial sciatic nerve ligation-induced neuropathic pain may result from inhibiting activation of astrocytes and microglia as well as pro-inflammatory cytokines.We propose that muscovite nanoparticle is a potential anti-nociceptive candidate for neuropathic pain.All experimental protocols in this study were approved by the Institutional Animal Ethics Committee(IACUC)at Dongguk University,South Korea(approval No.2017-022-1)on September 28,2017.

关键词： astrocyte microglia muscovite nanoparticle neuropathic pain partial sciatic nerve ligation pharmacopuncture pro-inflammatory cytokine Spinal cord

Comparison of walking quality variables between incomplete Spinal cord injury patients and healthy subjects by using a footscan plantar pressure system

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Neural Regeneration Research 2019年第2期14卷 354-360页

作者： Xiang-Nan Yuan Wei-Di Liang Feng-Hua Zhou Han-Ting Li Li-Xin Zhang Zhi-Qiang Zhang Jian-Jun Li Rehabilitation Department Shengjing Hospital of China Medical University Department of Orthopedics Shengjing Hospital of China Medical University

The main goal of Spinal cord rehabilitation is to restore walking ability and improve walking quality after Spinal cord injury(SCI). The spatiotemporal parameters of walking and the parameters of plantar pressure can be obtained using a plantar pressure analysis system. Previous studies have reported step asymmetry in patients with bilateral SCI. However, the asymmetry of other parameters in patients with SCI has not been reported. This was a prospective, cross-sectional study, which included 23 patients with SCI, aged 48.1 ± 14.5 years, and 28 healthy subjects, aged 47.1 ± 9.8 years. All subjects underwent bare foot walking on a plantar pressure measurement device to measure walking speed and spatiotemporal parameters. Compared with healthy subjects, SCI patients had slower walking speed, longer stride time and stance time, larger stance phase percentage, and shorter stride length. The peak pressures under the metatarsal heads and toe were lower in SCI patients than in healthy subjects. In the heel, regional impulse and the contact area percentage in SCI patients were higher than those in healthy subjects. The symmetry indexes of stance time, step length, maximum force, impulse and contact area were increased in SCI patients, indicating a decline in symmetry. The results confirm that the gait quality, including spatiotemporal variables and plantar pressure parameters, and symmetry index were lower in SCI patients compared with healthy subjects. Plantar pressure parameters and symmetry index could be sensitive quantitative parameters to improve gait quality of SCI patients. The protocols were approved by the Clinical Research Ethics Committee of Shengjing Hospital of China Medical University(approval No. 2015 PS54 J) on August 13, 2015. This trial was registered in the ISRCTN Registry(ISRCTN42544587) on August 22, 2018. Protocol version: 1.0.

关键词： nerve regeneration Spinal cord injury walking gait quality plantar pressure system plantar pressure distribution speed plantar pressure impulse contact area symmetry index neural regeneration

Up-regulation of P2X7 Receptors Contributes to Spinal Microglial Activation and the Development of Pain Induced by BmK-I

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Neuroscience Bulletin 2019年第4期35卷 624-636页

作者： Jingjing Zhou Xiaoxue Zhang You Zhou Bin Wu Zhi-Yong Tan Laboratory of Neuropharmacology and Neurotoxicology Shanghai University Shanghai 200444 China Department of Pharmacology and Toxicology and Stark Neurosciences Research Institute Indiana University School of Medicine Indianapolis IN 46202 USA

Previous work has demonstrated that the sensitization of Spinal neurons and microglia is important in the development of pain behaviors induced by BmK I,a Na^+ channel activator and a major peptide component of the venom of the scorpion Buthus martensi Karsch(BmK).We found that the expression of P2X7 receptors(P2X7Rs)was up-regulated in the ipsilateral Spinal dorsal horn after BmK I injection in rats.P2X7R was selectively localized in microglia but not astrocytes or neurons.Similarly,interleukin 1β(IL-1β)was selectively up-regulated in microglia in the Spinal dorsal horn after BmK I injection.Intrathecal injection of P2X7R antagonists largely reduced BmK I-induced spontaneous and evoked pain behaviors,and the up-regulation of P2X7R and IL-1β in the Spinal cord.These data suggested that the up-regulation of P2X7Rs mediates microglial activation in the Spinal dorsal horn,and therefore contributes to the development of BmK I-induced pain.

关键词： P2X7 receptor BmK I Spinal dorsal horn Interleukin 1β Microglia Brilliant Blue G