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Roles of extra-cellular signal-regulated protein kinase 5 signaling pathway in the development of spinal cord injury

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Chinese Medical Journal 2019年第21期132卷 2601-2611页

作者： Chen-Jun Liu Hai-Ying Liu Zhen-Qi Zhu Yuan-Yuan Zhang Kai-Feng Wang Wei-Wei Xia Department of spinal Surgery Peking University People’s HospitalBeijing 100044China Department of Pathology Peking University People’s HospitalBeijing 100044China.

Background:In consideration of characteristics and functions,extra-cellular signal-regulated protein kinase 5(ERK5)signaling pathway could be a new target for spinal cord injury(SCI)*** study aimed to evaluate the roles of ERK5 signaling pathway in secondary damage of ***:We randomly divided 70 healthy Wistar rats into five groups:ten in the blank group,15 in the sham surgery+BIX02188(sham+B)group,15 in the sham surgery+dimethyl sulfoxide(DMSO;sham+D)group,15 in the SCI+BIX02188(SCI+B)group,and 15 in the SCI+DMSO(SCI+D)***02188 is a specific inhibitor of the ERK5 signaling *** was induced by the application of vascular clips(with the force of 30 g)to the dura on T10 level,while rats in the sham surgery group underwent only T9-T11 ***02188 or DMSO was intra-thecally injected at 1,6,and 12 h after surgery or *** cord samples were taken for testing at 24 h after surgery or ***:Expression of phosphorylated-ERK5(p-ERK5)significantly increased after *** of BIX02188 indeed inhibited ERK5 signaling pathway and reduced the degree of spinal cord tissue injury,neutrophil infiltration and proinflammatory cytokine expression,nuclear factor-kB(NF-kB)activation and apoptosis(measured by TdT-mediated 20-deoxyuridine 50-triphosphate nickend labeling,expression of Fas-ligand,BCL2-associated X[Bax],and B-cell lymphoma-2[Bcl-2]).Double immunofluorescence revealed activation of ERK5 in neurons and microglia after ***:ERK5 signaling pathway was activated in spinal neurons and microglia,contributing to secondary injury of ***,inhibition of ERK5 signaling pathway could alleviate the degree of SCI,which might be related to its regulation of infiltration of inflammatory cells and release of inflammatory cytokines,expression of NF-kB and cell apoptosis.

关键词： Extracellular signal-regulated protein kinase 5 Mitogen activated protein kinase spinal cord injury Nuclear factor-κB Apoptosis

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Neuroprotective effects of rapamycin on spinal cord injury in rats by increasing autophagy and Akt signaling

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Neural Regeneration Research 2019年第4期14卷 721-727页

作者： Xi-Gong Li Jun-Hua Du Yang Lu Xiang-Jin Lin Department of Orthopedic Surgery The First Affiliated Hospital School of Medicine Zhejiang University

Rapamycin treatment has been shown to increase autophagy activity and activate Akt phosphorylation, suppressing apoptosis in several models of ischemia reperfusion injury. However, little has been studied on the neuroprotective effects on spinal cord injury by activating Akt phosphorylation. We hypothesized that both effects of rapamycin, the increased autophagy activity and Akt signaling, would contribute to its neuroprotective properties. In this study, a compressive spinal cord injury model of rat was created by an aneurysm clip with a 30 g closing force. Rat models were intraperitoneally injected with rapamycin 1 mg/kg, followed by autophagy inhibitor 3-methyladenine 2.5 mg/kg and Akt inhibitor IV 1 μg/kg. Western blot assay, immunofluorescence staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay were used to observe the expression of neuronal autophagy molecule Beclin 1, apoptosis-related molecules Bcl-2, Bax, cytochrome c, casp ase-3 and Akt signaling. Our results demonstrated that rapamycin inhibited the expression of mTOR in injured spinal cord tissue and up-regulated the expression of Beclin 1 and phosphorylated-Akt. Rapamycin prevented the decrease of bcl-2 expression in injured spinal cord tissue, reduced Bax, cytochrome c and caspase-3 expression levels and reduced the number of apoptotic neurons in injured spinal cord tissue 24 hours after spinal cord injury. 3-Methyladenine and Akt inhibitor IV intervention suppressed the expression of Beclin-1 and phosphorylated-Akt in injured spinal cord tissue and reduced the protective effect of rapamycin on apoptotic neurons. The above results indicate that the neuroprotective effect of rapamycin on spinal cord injury rats can be achieved by activating autophagy and the Akt signaling pathway.

关键词： nerve regeneration rapamycin mammalian target of rapamycin,mTOR autophagy Beclin 1 3-methyladenine acute spinal cord injury apoptosis Bax Akt neural regeneration

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Matrine promotes neural circuit remodeling to regulate motor function in a mouse model of chronic spinal cord injury

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Neural Regeneration Research 2019年第11期14卷 1961-1967页

作者： Norio Tanabe Tomoharu Kuboyama Chihiro Tohda Division of Neuromedical Science Institute of Natural Medicine University of Toyama

In chronic phase of spinal cord injury, functional recovery is more untreatable compared with early intervention in acute phase of spinal cord injury. In the last decade, several combination therapies successfully improved motor dysfunction in chronic spinal cord injury. However, their effectiveness is not sufficient. We previously found a new effective compound for spinal cord injury, matrine, which induced axonal growth and functional recovery in acute spinal cord injury mice via direct activation of extracellular heat shock protein 90. Although our previous study clarified that matrine was an activator of extracellular heat shock protein 90, the potential of matrine for spinal cord injury in chronic phase has not been sufficiently evaluated. Thus, this study aimed to investigate whether matrine ameliorates chronic spinal cord injury in mice. Once daily intragastric administration of matrine(100 μmol/kg per day) to spinal cord injury mice were starte at 28 days after injury, and continued for 154 days. Continuous mat rine treatment improved hindlimb motor function in chronic spinal cord injury mice. In injured spinal cords of the matrine-treated mice, the density of neurofilament-H-positive axons was increased. Moreover, matrine treatment increased the density of bassoon-positive presynapses in contact with choline acetyltransferase-positive motor neurons in the lumbar spinal cord. These findings suggest that matrine promotes remodeling and reconnection of neural circuits to regulate hindlimb movement. All protocols were approved by the Committee for Animal Care and Use of the Sugitani Campus of the University of Toyama(approval No. A2013 INM-1 and A2016 INM-3) on May 7, 2013 and May 17, 2016, respectively.

关键词： matrine chronic spinal cord injury axonal growth synaptogenesis hindlimb locomotor presynapse immunohistochemistry Basso Mouse Scale Body Support Score Sophora flavescens

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Serum and cerebrospinal fluid tau protein level as biomarkers for evaluating acute spinal cord injury severity and motor function outcome

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Neural Regeneration Research 2019年第5期14卷 896-902页

作者： Ying Tang Hong-Liang Liu Ling-Xia Min Hao-Shi Yuan Lei Guo Peng-Bo Han Yu-Xin Lu Jian-Feng Zhong Dong-Lin Wang Key Laboratory of Biorheological Science and Technology Ministry of Education (Chongqing University) Chongqing University Cancer Hospital Department of Rehabilitation Southwest Hospital Third Military Medical University Department of Spine Surgery Second Affiliated Hospital of Xi'an Medical University Department of Orthopedics Chinese PLA Beijing Army General Hospital

Tau protein, a microtubule-associated protein, has a high specific expression in neurons and axons. Because traumatic spinal cord injury mainly affects neurons and axons, we speculated that tau protein may be a promising biomarker to reflect the degree of spinal cord injury and prognosis of motor function. In this study, 160 female Sprague-Dawley rats were randomly divided into a sham group, and mild, moderate, and severe spinal cord injury groups. A laminectomy was performed at the T8 level to expose the spinal cord in all groups. A contusion lesion was made with the NYU-MASCIS impactor by dropping a 10 g rod from heights of 12.5 mm(mild), 25 mm(moderate) and 50 mm(severe) upon the exposed dorsal surface of the spinal cord. Tau protein levels were measured in serum and cerebrospinal fluid samples at 1, 6, 12, 24 hours, 3, 7, 14 and 28 days after operation. Locomotor function of all rats was assessed using the Basso, Beattie and Bresnahan locomotor rating scale. Tau protein concentration in the three spinal cord injury groups(both in serum and cerebrospinal fluid) rapidly increased and peaked at 12 hours after spinal cord injury. Statistically significant positive linear correlations were found between tau protein level and spinal cord injury severity in the three spinal cord injury groups, and between the tau protein level and Basso, Beattie, and Bresnahan locomotor rating scale scores. The tau protein level at 12 hours in the three spinal cord injury groups was negatively correlated with Basso, Beattie, and Bresnahan locomotor rating scale scores at 28 days(serum: r =-0.94; cerebrospinal fluid: r =-0.95). Our data suggest that tau protein levels in serum and cerebrospinal fluid might be a promising biomarker for predicting the severity and functional outcome of traumatic spinal cord injury.

关键词： nerve regeneration spinal cord injury tau injury severity outcome cerebrospinal fluid serum biomarker Basso,Beattie,and Bresnahan locomotor rating scale neural regeneration

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The hypothalamic-spinal dopaminergic system:a target for pain modulation

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Neural Regeneration Research 2019年第6期14卷 925-930页

作者： Michelino Puopolo Department of Anesthesiology Stony Brook Medicine

Nociceptive signals conveyed to the dorsal horn of the spinal cord by primary nociceptors are subject to extensive modulation by local neurons and by supraspinal descending pathways to the spinal cord before being relayed to higher brain centers. Descending modulatory pathways to the spinal cord comprise,among others, noradrenergic, serotonergic, γ-aminobutyric acid(GABA)ergic, and dopaminergic *** contributions of noradrenaline, serotonin, and GABA to pain modulation have been extensively investigated. In contrast, the contributions of dopamine to pain modulation remain poorly *** focus of this review is to summarize the current knowledge of the contributions of dopamine to pain modulation. Hypothalamic A11 dopaminergic neurons project to all levels of the spinal cord and provide the main source of spinal dopamine. Dopamine receptors are expressed in primary nociceptors as well as in spinal neurons located in different laminae in the dorsal horn of the spinal cord, suggesting that dopamine can modulate pain signals by acting at both presynaptic and postsynaptic targets. Here, I will review the literature on the effects of dopamine and dopamine receptor agonists/antagonists on the excitability of primary nociceptors, the effects of dopamine on the synaptic transmission between primary nociceptors and dorsal horn neurons, and the effects of dopamine on pain in rodents. Published data support both anti-nociceptive effects of dopamine mediated by D2-like receptors and pro-nociceptive effects mediated by D1-like receptors.

关键词： A11 nucleus descending modulation dopamine dorsal horn dorsal root ganglia D2 receptors D1 receptors nociceptors pain spinal cord

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Management of autonomic hyperreflexia during cesarean section in a woman with spinal cord injury:a case report

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Chinese Medical Journal 2002年第8期115卷 137-138页

作者：李胜平唐小丽柏朝益韩仕碧 Department of Obstetric/Gynecology Chengdu PLA General Hospital Chengdu 610083 China

Labor is rarely encountered among women with spinal cord injury. Even the report by Goller and Paeslack dealt with 175 cases from 42 centers in 24 countries.1 Management and control methods of this rare condition have not been defined. Autonomic hyperreflexia (AH) is the most serious complication of labor among women with paraplegia and should be carefully controlled. We found epidural anesthesia can safely control AH during labor and delivery.

关键词： autonomic hyperreflexia · spinal cord injuries· labor

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spinal intraosseous schwannoma without spinal canal and neuroforamina involvement:A case report

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World Journal of Clinical Cases 2020年第7期8卷 1271-1277页

作者： Zhong-Qi Xu Ping Zhang Zhi-Hong Zhong Wei Zhou Hao-Tao Yu Department of Orthopedics The Third Affiliated Hospital of Guangzhou Medical UniversityGuanzhou 510000Guandong ProvinceChina

BACKGROUND spinal intraosseous schwannomas(SIS)are rare,and as yet have not been fully described in the *** first case of SIS was reported in 1971,and 24 cases of SIS have been reported so ***,including the present case,there are only seven cases without spinal canal and neuroforamina *** SUMMARY A 56-year-old man presented with a history of neck pain for 2 *** obvious osteolytic destruction of the seventh cervical(C7)vertebra was observed on imaging *** resonance imaging of the cervical spine showed space-occupying lesions in the C7 vertebra,and destruction of the anterior cortex of the *** lesions had an exophytic component that extended from the C7 vertebra into the soft tissue on the front *** foramen transversarium on both sides were *** patient underwent surgical biopsy and focal excision of the C7 *** diagnosis of“schwannoma”was verified by postoperative pathological *** a review of the literature,this is the seventh case of SIS without spinal canal and neuroforamina involvement,and the third reported case of type VIII *** discussed our case with respect to reported classification characteristics of *** SIS is a very rare *** report a rare case that may be important for further classification of *** establishment of a complete disease classification is of high importance for the treatment and prognosis of this ***,more basic studies and retrospective analysis of related cases are necessary.

关键词： spinal intraosseous schwannoma Neurilemmoma spinal tumor Classification Case report Cervical

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Combination of biomaterial transplantation and genetic enhancement of intrinsic growth capacities to promote CNS axon regeneration after spinal cord injury

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Frontiers of Medicine 2019年第2期13卷 131-137页

作者： Bin Yu Xiaosong Gu Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Co-innovation Center of Neuroregeneration Nantong UniversityNantong 226001China

The inhibitory environment that surrounds the lesion site and the lack of intrinsic regenerative capacity of the adult mammalian central nervous system (CNS) impede the regrowth of injured axons and thereby the reestablishment of neural circuits required for functional recovery after spinal cord injuries (SCI). To circumvent these barriers, biomaterial scaffolds are applied to bridge the lesion gaps for the regrowing axons to follow, and, often by combining stem cell transplantation, to enable the local environment in the growth-supportive direction. Manipulations, such as the modulation of PTEN/mTOR pathways, can also enhance intrinsic CNS axon regrowth after injury. Given the complex pathophysiology of SCI, combining biomaterial scaffolds and genetic manipulation may provide synergistic effects and promote maximal axonal regrowth. Future directions will primarily focus on the translatability of these approaches and promote therapeutic avenues toward the functional rehabilitation of patients with SCIs.

关键词： spinal cord injury biomaterial extrinsic barrier intrinsic regeneration capacity

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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 *** 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 ***,we assessed whether muscovite nanoparticles can reduce the symptoms of pain by controlling the inflammatory process observed in neuropathic *** 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 *** 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 *** 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 ***,the muscovite nanoparticle injections resulted in a decrease in activating transcription factor 3,a neuronal injury marker,in the sciatic *** 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 *** propose that muscovite nanoparticle is a potential anti-nociceptive candidate for neuropathic *** experimental protocols in this study were approved by the Institutional Animal Ethics Committee(IACUC)at Dongguk University,South Korea(approval No.2017-022-1)

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

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Mesenchymal stem cells and the neuronal microenvironment in the area of spinal cord injury

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Neural Regeneration Research 2019年第2期14卷 227-237页

作者： Yana O.Mukhamedshina Olga A.Gracheva Dina M.Mukhutdinova Yurii A.Chelyshev Albert A.Rizvanov OpenLab Gene and Cell Technologies Institute of Fundamental Medicine and Biology Kazan (Volga Region)Federal University Department of Histology Cytology and Embryology Kazan State Medical University Department of Therapy and Clinical Diagnostics with radiology Faculty of Veterinary Medicine Bauman Kazan State Academy of Veterinary Medicine OpenLab Gene and Cell Technologies Institute of Fundamental Medicine and Biology Kazan (Volga Region) Federal University

Cell-based technologies are used as a therapeutic strategy in spinal cord injury(SCI). Mesenchymal stem cells(MSCs), which secrete various neurotrophic factors and cytokines, have immunomodulatory, anti-apoptotic and anti-inflammatory effects, modulate reactivity/phenotype of astrocytes and the microglia, thereby promoting neuroregeneration seem to be the most promising. The therapeutic effect of MSCs is due to a paracrine mechanism of their action, therefore the survival of MSCs and their secretory phenotype is of particular importance. Nevertheless, these data are not always reported in efficacy studies of MSC therapy in SCI. Here, we provide a review with summaries of preclinical trials data evaluating the efficacy of MSCs in animal models of SCI. Based on the data collected, we have tried(1) to establish the behavior of MSCs after transplantation in SCI with an evaluation of cell survival, migration potential, distribution in the area of injured and intact tissue and possible differentiation;(2) to determine the effects MSCs on neuronal microenvironment and correlate them with the efficacy of functional recovery in SCI;(3) to ascertain the conditions under which MSCs demonstrate their best survival and greatest efficacy.

关键词： spinal cord injury mesenchymal stem cells survival migration Rho/ROCK/PTEN astrocytes microglia myelin-forming cells axon growth tissue integrity

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