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Ferroptosis inhibition protects vascular endothelial cells and maintains integrity of the blood-spinal cord barrier after spinal cord injury

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Neural Regeneration Research 2023年第11期18卷 2474-2481页

作者： Wenxiang Li Xiaoqing Zhao Rong Zhang Xinjie Liu Zhangyang Qi Yang Zhang Weiqi Yang Yilin Pang Chenxi Zhao Baoyou Fan Ning Ran Jiawei Zhang Xiaohong Kong Shiqing Feng Xue Yao Shandong University Center for Orthopedics Department of OrthopedicsQilu Hospital of Shandong UniversityCheeloo College of MedicineShandong UniversityJinanShandong ProvinceChina Tianjin Key Laboratory of Spine and spinal cord National Spinal Cord Injury International Cooperation BaseDepartment of OrthopedicsTianjin Medical University General HospitalTianjinChina

Maintaining the integrity of the blood-spinal cord barrier is critical for the recove ry of spinal cord *** ptosis contributes to the pathogenesis of spinal cord *** hypothesized that ferroptosis is involved in disruption of the blood-s pinal cord *** this study,we administe red the ferroptosis inhibitor liproxstatin-1 intraperitoneally after contusive spinal co rd injury in ***-1 improved locomotor recovery and somatosensory evoked potential electrophysiological performance after spinal cord inju ***-1 maintained blood-spinal cord barrier integrity by upregulation of the expression of tight junction ***-1 inhibited ferroptosis of endothelial cell after spinal cord injury,as shown by the immunofluorescence of an endothelial cell marker(rat endothelium cell antigen-1,RECA-1) and fe rroptosis markers Acyl-CoA synthetase long-chain family member 4 and ***-1reduced brain endothelial cell ferroptosis in vitro by upregulating glutathione peroxidase 4 and downregulating Acyl-CoA synthetase long-chain family member4 and ***,inflammatory cell recruitment and astrogliosis were mitigated after liproxstatin-1 *** summary,liproxstatin-1im proved spinal cord injury recovery by inhibiting ferroptosis in endothelial cells and maintaining blood-s pinal co rd barrier integrity.

关键词： blood-spinal cord barrier ferroptosis liproxstatin-1 neuroinflammation spinal cord injury vascular endothelial cells

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Mertk Reduces blood-spinal cord barrier Permeability Through the Rhoa/Rock1/P-MLC Pathway After spinal cord Injury

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Neuroscience Bulletin 2024年第9期40卷 1230-1244页

作者： Jiezhao Lin Yuanfang Sun Bin Xia Yihan Wang Changnan Xie Jinfeng Wang Jinwei Hu Lixin Zhu Department of spinal Surgery Orthopedic Medical CenterZhujiang HospitalSouthern Medical UniversityGuangzhou510280China Department of Orthopedics Chengdu Seventh People’s Hospital(Affiliated Cancer Hospital of Chengdu Medical College)Chengdu610299China

Disruption of the blood-spinal cord barrier(BSCB)is a critical event in the secondary injury following spinal cord injury(SCI).Mertk has been reported to play an important role in regulating inflammation and cytoskeletal ***,the specific involvement of Mertk in BSCB remains ***,we demonstrated a distinct role of Mertk in the repair of *** expression is decreased in endothelial cells following *** of Mertk upregulated tight junction proteins(TJs),reducing BSCB permeability and subsequently inhibiting inflammation and ***,this led to enhanced neural regeneration and functional *** experiments revealed that the RhoA/Rock1/P-MLC pathway plays a key role in the effects of *** findings highlight the role of Mertk in promoting SCI recovery through its ability to mitigate BSCB permeability and may provide potential targets for SCI repair.

关键词： spinal cord injury Mertk blood-spinal cord barrier RhoA/Rock1/P-MLC pathway Apoptosis Inflammation

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Baicalin attenuates blood-spinal cord barrier disruption and apoptosis through PI3K/Akt signaling pathway after spinal cord injury

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Neural Regeneration Research 2022年第5期17卷 1080-1087页

作者： Rui Zhao Xue Wu Xue-Yuan Bi Hao Yang Qian Zhang College of Pharmacy Shaanxi University of Chinese MedicineXi’anShaanxi ProvinceChina Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest ChinaCollege of Life SciencesShaanxi Normal UniversityXi’anShaanxi ProvinceChina Translational Medicine Center Hong Hui HospitalXi’an Jiaotong UniversityXi’anShaanxi ProvinceChina Department of Pharmacy Hong Hui HospitalXi’an Jiaotong UniversityXi’anShaanxi ProvinceChina

Baicalin is a natural active ingredient isolated from Scutellariae Radix that can cross the blood-brain barrier and exhibits neuroprotective effects on multiple central nervous system ***,the mechanism behind the neuroprotective effects remains *** this study,rat models of spinal cord injury were established using a modified Allen's impact method and then treated with intraperitoneal injection of *** results revealed that Baicalin greatly increased the Basso,Beattie,Bresnahan Locomotor Rating Scale score,reduced blood-spinal cord barrier permeability,decreased the expression of Bax,Caspase-3,and nuclear factorκB,increased the expression of Bcl-2,and reduced neuronal apoptosis and pathological spinal cord ***-SY5 Y cell models of excitotoxicity were established by application of 10 m M glutamate for 12 hours and then treated with 40μM Baicalin for 48 hours to investigate the mechanism of action of *** results showed that Baicalin reversed tight junction protein expression tendencies(occludin and ZO-1)and apoptosis-related protein expression(Bax,Bcl-2,Caspase-3,and nuclear factor-κB),and also led to up-regulation of PI3 K and Akt *** effects on Bax,Bcl-2,and Caspase-3 were blocked by pretreatment with the PI3 K inhibitor *** findings suggest that Baicalin can inhibit bloodspinal cord barrier permeability after spinal cord injury and reduce neuronal apoptosis,possibly by activating the PI3 K/Akt signaling *** study was approved by Animal Ethics Committee of Xi'an Jiaotong University on March 6,2014.

关键词： apoptosis baicalin blood-spinal cord barrier natural products neuron PI3K/Akt signaling pathway spinal cord injury tight junction

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Role of hypoxia-induced VEGF in blood-spinal cord barrier disruption in chronic spinal cord injury

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Chinese Journal of Traumatology 2015年第5期18卷 293-295页

作者： Hou-Qing Long Guang-Sheng Li Xing Cheng Jing-Hui Xu Fo-Bao Li Department of spinal Surgery The First Affiliated Hospital of Sun Yat-Sen University China

Chronic spinal cord lesions （CSCL） which result in irreversible neurologic deficits remain one of tbe most devastating clinical problems. Its patbophysiological mechanism has not been fully clarified. As a crucial factor in the outcomes following traumatic spinal cord injury （SCI）, the blood-spinal cord barrier （BSCB） disruption is considered as an important pathogenic factor contributing to the neurologic impairment in SCI. Vascular endothelial growth factor （VEGF） is a multirole element in the spinal cord vascular event. On one hand, VEGF administrations can result in rise of BSCB permeability in acute or sub-acute periods and even last for chronic process. On the other band, VEGF is regarded to be correlated with anglo- genesis, neurogenesis and improvement of locomotor ability. Hypoxia inducible factor-I （HIFq） is a primary regulator of VEGF during hypoxic conditions. Therefore, hypoxia-mediated up-regulation of VEGF may play multiple roles in the BSCB disruption and react on functional restoration of CSCL. The purpose of this article is to further explore the relationship among HIF-1, hypoxia-mediated VEGF and BSCB dysfunction, and investigate the roles of these elements on CSCL.

关键词： VEGF blood-spinal cord barrier Chronic spinal cord lesions

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Spared Nerve Injury alters the blood-spinal cord barrier permeability:light-,electro-microscopy

Spared Nerve Injury alters the blood-spinal cord barrier per...

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中国神经科学学会第四次会员代表大会暨第八届全国学术会议

作者： Li DUAN~1,Yan XU~2,Ying-Fei XIONG~1,Rong CAO~1,Ling-Feng TU~1,Zhi-Ren RAO~(1,*) 1 Institute of Neurosciences Fourth Military Medical University,Xi''an,710032. 2 Departement of Neurology,Xijing Hospital.Fourth Military Medical University Xi''an 710032

＜正＞Objective To investigate the change of blood-spinal cord barrier permeability after the Spared Nerve Injury （SNI） in adult ***（1） Male SD rats were divided into 3 groups randomly（control,sham-SNI group and SNI group） .The rats were performed SNI and survived for 3d,10d and 20d *** blue was injected into caudal vein,after 30 min,the rats were perfused and spinal cord were removed,L4 segment of spinal cord were cut into 30μm frontal sections on a *** section was detected under Olympus BX-51 fluorescent microscope.（2） ImmunoelectromocroOscopic DAB staining of IgG was performed at 10d,20d after SNI and detected under electron ***（1） Red fluorescent staining-blood vessel and effusion could not be found in the spinal cord dorsal horn of control *** 3d group,weak red fluorescent staining-blood vessel was *** 10d group,obvious red fluorescent staining-blood vessel was detected with few *** 20d group,the dorsal horn exhibited wide enlarge capillaries with obvious red- staining vessel wall and many clear effusion（P＞0.05）.（2） At SNI 10d group,weak electron density IgG was detected in the capillary endothelium,but at SNI 20d group,electron density IgG was higher,the granule and flocculent *** three type ultrastructures for IgG exudation from the capillary were found using electron microscopy,（a） The first means was IgG from endothelium,through pericytes and basement membrane exudates to perivascular space,（b） The second means was adsorptive-mediated transcytosis（AMT） processes,the endothelial performs AMT through "endocytosis" and transport and / or "exocytosis" steps.（c）The third means was through the tight junctions open of endothelium. Conclusion BSCB is not unusual open after SNI 3d;at SNI 10d,BSCB is mild opened unusual;at SNI 20d,the opened BSCB is peak,local BSCB permeability increased and subsequently increase the activity of neurons and *** open window can provide effective ther

关键词： blood-spinal cord barrier Evans blue SNI endothelial cell rat

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Exogenous platelet-derived growth factor improves neurovascular unit recovery after spinal cord injury

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Neural Regeneration Research 2021年第4期16卷 757-763页

作者： Lu-Xia Ye Ning-Chen An Peng Huang Duo-Hui Li Zhi-Long Zheng Hao Ji Hao Li Da-Qing Chen Yan-Qing Wu Jian Xiao Ke Xu Xiao-Kun Li Hong-Yu Zhang School of Pharmaceutical Sciences Wenzhou Medical UniversityWenzhouZhejiang ProvinceChina Department of Pharmacy Ruian People’s HospitalThe Third Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang ProvinceChina Institute of Life Sciences Wenzhou UniversityWenzhouZhejiang ProvinceChina Department of Orthopedics Surgery Lishui People’s HospitalThe sixth affiliated hospital of Wenzhou Medical UniversityLishuiZhejiang ProvinceChina Department of Emergency The Second Affiliated Hospital and Yuying Children’s HospitalWenzhou Medical UniversityWenzhouZhejiang ProvinceChina

The blood-spinal cord barrier plays a vital role in recovery after spinal cord *** neurovascular unit concept emphasizes the relationship between nerves and vessels in the brain,while the effect of the blood-spinal cord barrier on the neurovascular unit is rarely reported in spinal cord injury *** models of spinal cord injury were established by heavy object impact and then immediately injected with plateletderived growth factor(80μg/kg)at the injury *** results showed that after platelet-derived growth factor administration,spinal cord injury,neuronal apoptosis,and blood-spinal cord barrier permeability were reduced,excessive astrocyte proliferation and the autophagyrelated apoptosis signaling pathway were inhibited,collagen synthesis was increased,and mouse locomotor function was *** vitro,human umbilical vein endothelial cells were established by exposure to 200μM *** 2 hours prior to injury,in vitro cell models were treated with 5 ng/mL platelet-derived growth *** results showed that expression of blood-spinal cord barrier-related proteins,including Occludin,Claudin 5,andβ-catenin,was significantly decreased and autophagy was significantly ***,the protective effects of platelet-derived growth factor could be reversed by intraperitoneal injection of 80 mg/kg chloroquine,an autophagy inhibitor,for 3 successive days prior to spinal cord *** findings suggest that platelet-derived growth factor can promote endothelial cell repair by regulating autophagy,improve the function of the blood-spinal cord barrier,and promote the recovery of locomotor function post-spinal cord *** for animal experiments was obtained from the Animal Ethics Committee,Wenzhou Medical University,China(approval ***2018-0043)in July 2018.

关键词： autophagy blood-spinal cord barrier central nervous system locomotor function neurovascular unit platelet-derived growth factor spinal cord spinal cord injury

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Exosomes derived from bone marrow mesenchymal stem cells protect the injured spinal cord by inhibiting pericyte pyroptosis

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Neural Regeneration Research 2022年第1期17卷 194-202页

作者： Yan Zhou Lu-Lu Wen Yan-Fei Li Kai-Min Wu Ran-Ran Duan Yao-Bing Yao Li-Jun Jing Zhe Gong Jun-Fang Teng Yan-Jie Jia Department of Radiology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina Department of Neurology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina

Mesenchymal stem cell(MSC)transplantation is a promising treatment strategy for spinal cord injury,but immunological rejection and possible tumor formation limit its *** therapeutic effects of MSCs mainly depend on their release of soluble paracrine *** are essential for the secretion of these paracrine *** marrow mesenchymal stem cell-derived exosomes(BMSC-EXOs)can be substituted for BMSCs in cell ***,the underlying mechanisms remain *** this study,a rat model of T10 spinal cord injury was established using the impact ***,30 minutes and 1 day after spinal cord injury,the rats were administered 200μL exosomes via the tail vein(200μg/mL;approximately 1×106 BMSCs).Treatment with BMSC-EXOs greatly reduced neuronal cell death,improved myelin arrangement and reduced myelin loss,increased pericyte/endothelial cell coverage on the vascular wall,decreased bloodspinal cord barrier leakage,reduced caspase 1 expression,inhibited interleukin-1βrelease,and accelerated locomotor functional recovery in rats with spinal cord *** the cell culture experiment,pericytes were treated with interferon-γand tumor necrosis factor-α.Then,Lipofectamine 3000 was used to deliver lipopolysaccharide into the cells,and the cells were co-incubated with adenosine triphosphate to simulate injury in ***-treatment with BMSC-EXOs for 8 hours greatly reduced pericyte pyroptosis and increased pericyte survival *** findings suggest that BMSC-EXOs may protect pericytes by inhibiting pyroptosis and by improving blood-spinal cord barrier integrity,thereby promoting the survival of neurons and the extension of nerve fibers,and ultimately improving motor function in rats with spinal cord *** protocols were conducted with the approval of the Animal Ethics Committee of Zhengzhou University on March 16,2019.

关键词： blood-spinal cord barrier edema exosome pericyte NOD1 pro-caspase 1 pyroptosis spinal cord injury

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The roles of microRNAs in spinal cord ischemia-reperfusion injury

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Neural Regeneration Research 2022年第12期17卷 2593-2599页

作者： Feng-Shou Chen Xiang-Yi Tong Bo Fang Dan Wang Xiao-Qian Li Zai-Li Zhang Department of Anesthesiology the First Hospital of China Medical UniversityShenyangLiaoning ProvinceChina

spinal cord ischemia/reperfusion injury is a devastating medical disorder with poor prognosis that is associated with several pathophysiological ***,multiple stimuli can trigger SCII,so the underlying mechanism of this pathology has not yet been fully ***(miRNAs)are a class of non-coding RNAs that mediate a variety of nervous system diseases and regulate numerous physiological functions,including apoptosis,autophagy,inflammation,and blood-spinal cord barrier *** expression profiles are known to be altered after spinal cord ischemia/reperfusion ***,gaining a better understanding of the significant roles that miRNAs play in spinal cord ischemia/reperfusion injury could help develop potential preventive and therapeutic strategies for spinal cord ischemia/reperfusion *** review summarizes the current state of our knowledge about the relationship between miRNAs and spinal cord ischemia/reperfusion injury,as well as potential miRNAs that could be targeted to treat spinal cord ischemia/reperfusion injury.

关键词： apoptosis autophagy blood-spinal cord barrier inflammation microRNAs pathophysiology review spinal cord ischemia-reperfusion injury

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ABC efflux transporters at blood-central nervous system barriers and their implications for treating spinal cord disorders

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Neural Regeneration Research 2020年第7期15卷 1235-1242页

作者： Liam M. Koehn Department of Pharmacology and Therapeutics the University of Melbourne

The barriers present in the interfaces between the blood and the central nervous system form a major hurdle for the pharmacological treatment of central nervous system injuries and *** family of ATP-binding cassette(ABC)transporters has been widely studied regarding efflux of medications at blood-central nervous system *** efflux transporters include P-glycoprotein(abcb1),‘breast cancer resistance protein'(abcg2)and the various‘multidrug resistance-associated proteins'(abccs).Understanding which efflux transporters are present at the blood-spinal cord,blood-cerebrospinal fluid and cerebrospinal fluid-spinal cord barriers is necessary to determine their involvement in limiting drug transfer from blood to the spinal cord *** developments in the blood-brain barrier field have shown that barrier systems are dynamic and the profile of barrier defenses can alter due to conditions such as age,disease and environmental *** means that a true understanding of ABC efflux transporter expression and localization should not be one static value but instead a range that represents the complex patient subpopulations that *** the present review,the blood-central nervous system barrier literature is discussed with a focus on the impact of ABC efflux transporters on:(i)protecting the spinal cord from adverse effects of systemically directed drugs,and(ii)limiting centrally directed drugs from accessing their active sites within the spinal cord.

关键词： ABC transporters ATP-binding cassette BCRP blood-brain barrier blood-spinal cord barrier efflux MRP P-glycoprotein PGP spinal cord injury

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Elevated intraspinal pressure in traumatic spinal cord injury is a promising therapeutic target

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Neural Regeneration Research 2022年第8期17卷 1703-1710页

作者： Chao-Hua Yang Zheng-Xue Quan Gao-Ju Wang Tao He Zhi-Yu Chen Qiao-Chu Li Jin Yang Qing Wang Department of Orthopedics The Affiliated Hospital of Southwest Medical UniversityLuzhouSichuan ProvinceChina Department of Orthopedics The First Affiliated Hospital of Chongqing Medical UniversityChongqingChina

The currently recommended management for acute traumatic spinal cord injury aims to reduce the incidence of secondary injury and promote functional *** intraspinal pressure(ISP)likely plays an important role in the processes involved in secondary spinal cord injury,and should not be ***,the factors and detailed time course contributing to elevated ISP and its impact on pathophysiology after traumatic spinal cord injury have not been reviewed in the ***,we review the etiology and progression of elevated ISP,as well as potential therapeutic measures that target elevated *** ISP is a time-dependent process that is mainly caused by hemorrhage,edema,and blood-spinal cord barrier destruction and peaks at 3 days after traumatic spinal cord *** and hypertonic saline may be promising treatments for reducing ISP within this time *** potential treatments such as decompression,spinal cord incision,hemostasis,and methylprednisolone treatment require further validation.

关键词： blood-spinal cord barrier decompression duraplasty durotomy edema hemorrhage intraspinal pressure myelotomy spinal cord injury therapeutic target

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