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

Maintaining the integrity of the blood-spinal cord barrier is critical for the recove ry of spinal cord injury.Ferro ptosis contributes to the pathogenesis of spinal cord injury.We hypothesized that ferroptosis is involved in disruption of the blood-s pinal cord barrier.In this study,we administe red the ferroptosis inhibitor liproxstatin-1 intraperitoneally after contusive spinal co rd injury in rats.Liproxstatin-1 improved locomotor recovery and somatosensory evoked potential electrophysiological performance after spinal cord inju ry.Liproxstatin-1 maintained blood-spinal cord barrier integrity by upregulation of the expression of tight junction protein.Liproxstatin-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 15-lipoxygenase.Liproxstatin-1reduced brain endothelial cell ferroptosis in vitro by upregulating glutathione peroxidase 4 and downregulating Acyl-CoA synthetase long-chain family member4 and 15-lipoxygenase.Furthermore,inflammatory cell recruitment and astrogliosis were mitigated after liproxstatin-1 treatment.In summary,liproxstatin-1im proved spinal cord injury recovery by inhibiting ferroptosis in endothelial cells and maintaining blood-s pinal co rd barrier integrity.

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

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 diseases.However,the mechanism behind the neuroprotective effects remains unclear.In this study,rat models of spinal cord injury were established using a modified Allen's impact method and then treated with intraperitoneal injection of Baicalin.The 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 injury.SH-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 Baicalin.The 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 phosphorylation.These effects on Bax,Bcl-2,and Caspase-3 were blocked by pretreatment with the PI3 K inhibitor LY294002.These 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 pathway.This study was approved by Animal Ethics Committee of Xi'an Jiaotong University on March 6,2014.

Morphological and functional changes in the blood-spinal cord barrier of rabbits in an experimental spinal cord presyrinx state

BACKGROUND: Presyrinx state of spinal cord can reflect the initial lesion of syringomyelia (SM). The early trials has proved that ischamia and edema are main pathological changes of presyrinx state. OBJECTIVE: To establish SM model of rabbits for investigating the relationship between changes of morphous and function of blood-spinal cord barrier and the edema degree, histological changes in presyrinx state of SM, and to explore the mechanism of the presyrinx state of SM. DESIGN: Randomized controlled animal experiment. SETTING: Department of Neurosurgery, Fourth Hospital, Heibei Medical University. MATERIALS: Sixty Chinese healthy white rabbits, aged 3.5-4.5 months, weighing 1.5-2.0 kg, were provided by Experimental Animal Center of Hebei Medical University [certification: (SYXK(Ji)2003-0026)]. Evan's blue (EB) and dimethylformamide (DMF) were purchased from Jingmei Biotech Co., Ltd. RM2125 paraffin section cutter (Leica Company, Japan), H-7500 transmission electron microscope (Hitachi Company, Japan), PM-20 light microscope photograph system (Olympus Company, Japan). METHODS: The experiment was carried out in the Laboratory of Neurosurgery Department, Second Hospital of Hebei Medical University from January to June 2006. ① All the rabbits were randomly divided into two groups: model group (n =40), control group (n =20). Rabbits in two groups were divided into five subgroups once again at five time points (1st, 3rd, 7th, 14th, 21st days, n =8 and n =4 at each time point in the model group and control group, respectively). Under ketamine anesthesia, 0.6 mL Kaolin solution (250 g/L, 37 ℃) was injected into the cisterna magna of rabbits in model group, while 0.6 mL physiological saline (37 ℃) was injected into the rabbits of control group. ② On the 1st, 3rd, 7th, 14th, 21st days after kaolin injection, cervical cord samples were harvested after sacrifice of animal. Quantitative analysis on the function of blood-spinal cord barrier was performed by Evan's blue technique. Water content of spinal cord was measured by dry-wet weighing technique. Samples were fixed in 40 g/L paraform for haematoxylin and eosin staining. Pathological and ultramicrostructural observation was carried out under a light microscope and H-7500 electron microscope, respectively. ③ The comparison of measurement data was performed with analysis of variance. MAIN OUTCOME MEASURES: The changes of water content, Evan's blue content and pathology in upper cervical cord of presyrinx state at different time points. RESULTS: All the 60 rabbits were involved in the result analysis. ① Ultramicrostructural observation: During the whole process of occurrence and development of presyrinx state of spinal cord, no obvious morphological changes of blood-spinal cord barrier were found. Microvascular endothelial cells were in integrity in morphology, basal membrane was continuous and smooth, and the structure of tight junction was not destructed remarkably. ②Water content of spinal cord: Compared with control group, the water content of spinal cord was increased on the 1st day [(68.35±0.7)% vs.(66.51±0.32)%, F =7.387, P =0.026] after kaolin injection, more prominent on the 3rd day [(72.70±0.88)%, F =123.48, P =0.000], reached its peak on the 7th-14th day [(72.92±0.86)%, F =135.94, P =0.000; (72.18±0.55)%, F =28.18, P =0.001], and was declined slowly after 21 days[(70.03±0.77)%,F =11.51, P =0.009], but it was still higher than that of control group [(65.98±0.56)%, F = 11.51, P =0.009].③ Evan's blue content in spinal cord tissue: It started to rise on the 3rd day after operation [(2.79±0.42) mg/L, F =61.35, P =0.000], reached its peak on the 7th day [(3.53±0.45) mg/L, F =528.35, P =0.000], and kept this high level till the 14th day [(3.45± 0.35) mg/L, F =326.57, P =0.000]. It decreased on the 21st day [(3.36±0.27) mg/L], but was still higher than normal level[(1.69±0.16)mg/L,F = 58.63,P =0.000]. ④ Neurologic function score: The neurologic function score of rabbits in the model group was close to that in the control group preoperatively and on the postoperative 1st and 3rd days (F =2.667, P =0.141);Abnormal nerve function appeared on the postoperative 7th day (F =32.667, P =0.00), and the neurologic function scores were gradually decreased with the elongation of time. The neurologic function scores in the model group were significantly lower than those in the control group on the postoperative 14th and 21st days (F =42.667, 34.571,P =0.00). CONCLUSION: Under the presyrinx state of spinal cord of experimental rabbits, the destruction of blood-spinal cord barrier of spinal cord and spinal edema co-exist with the same changing tendency. Although morphological integrity of blood-spinal cord barrier is kept, the function of blood-spinal cord barrier was destroyed in the early stage and permeability is increased. This functional disorder plays an important role in the occurrence and development of presyrinx state of SM.

Propofol protects against blood-spinal cord barrier disruption induced by ischemia/reperfusion injury

Propofol has been shown to exert neuroprotective effects on the injured spinal cord.However,the effect of propofol on the blood-spinal cord barrier（BSCB） after ischemia/reperfusion injury（IRI） is poorly understood.Therefore,we investigated whether propofol could maintain the integrity of the BSCB.Spinal cord IRI（SCIRI） was induced in rabbits by infrarenal aortic occlusion for 30 minutes.Propofol,30 mg/kg,was intravenously infused 10 minutes before aortic clamping as well as at the onset of reperfusion.Then,48 hours later,we performed histological and m RNA/protein analyses of the spinal cord.Propofol decreased histological damage to the spinal cord,attenuated the reduction in BSCB permeability,downregulated the m RNA and protein expression levels of matrix metalloprotease-9（MMP-9） and nuclear factor-κB（NF-κB）,and upregulated the protein expression levels of occludin and claudin-5.Our findings suggest that propofol helps maintain BSCB integrity after SCIRI by reducing MMP-9 expression,by inhibiting the NF-κB signaling pathway,and by maintaining expression of tight junction proteins.

Magnetic resonance imaging-guided focused ultrasound to increase localized blood-spinal cord barrier permeability

Spinal cord injury（SCI） affects thousands of people every year in the USA, and most patients are left with some permanent paralysis. Therapeutic options are limited and only modestly affect outcome. To address this issue, we used magnetic resonance imaging-guided focused ultrasound（MRg FUS） as a non-invasive approach to increase permeability in the blood-spinal cord barrier（BSCB）. We hypothesize that localized, controlled sonoporation of the BSCB by MRg FUS will aid delivery of therapeutics to the injury. Here, we report our preliminary findings for the ability of MRg FUS to increase BSCB permeability in the thoracic spinal cord of a normal rat model. First, an excised portion of normal rat spinal column was used to characterize the acoustic field and to estimate the insertion losses that could be expected in an MRg FUS blood spinal cord barrier opening. Then, in normal rats, MRg FUS was applied in combination with intravenously administered microbubbles to the spinal cord region. Permeability of the BSCB was indicated as signal enhancement by contrast administered prior to T1-weighted magnetic resonance imaging and verified by Evans blue dye. Neurological testing using the Basso, Beattie, and Breshnahan scale and the ladder walk was normal in 8 of 10 rats tested. Two rats showed minor impairment indicating need for further refinement of parameters. No gross tissue damage was evident by histology. In this study, we have opened successfully the blood spinal cord barrier in the thoracic region of the normal rat spine using magnetic resonance-guided focused ultrasound combined with microbubbles.

Transactivating-transduction protein-polyethylene glycol modified liposomes traverse the blood-spinal cord and blood-brain barriers

Naive liposomes can cross the blood-brain barrier and blood-spinal cord barrier in small amounts. Liposomes modified by a transactivating-transduction protein can deliver antibiotics for the treatment of acute bacterial infection-induced brain inflammation. Liposomes conjugated with polyethylene glycol have the capability of long-term circulation. In this study we prepared transactivating-transduction protein-polyethylene glycol-modified liposomes labeled with fiuorescein isothiocyanate. Thus, liposomes were characterized by transmembrane, long-term circulation and fluorescence tracing. Uptake, cytotoxicity, and the ability of traversing blood-spinal cord and blood-brain barriers were observed following coculture with human breast adenocarcinoma cells （MCF-7）. Results demonstrated that the liposomes had good biocompatibility, and low cytotoxicity when cocultured with human breast adenocarcinoma cells. Liposomes could traverse cell membranes and entered the central nervous system and neurocytes through the blood-spinal cord and blood-brain barriers of rats via the systemic circulation. These results verified that fluorescein isothiocyanate-modified transactivating-transduction protein-polyethylene glycol liposomes have the ability to traverse the blood-spinal cord and blood-brain barriers.

Pharmacological interventions targeting the microcirculation following traumatic spinal cord injury

Traumatic spinal cord injury is a devastating disorder chara cterized by sensory,motor,and autonomic dysfunction that seve rely compromises an individual's ability to perform activities of daily living.These adve rse outcomes are closely related to the complex mechanism of spinal cord injury,the limited regenerative capacity of central neurons,and the inhibitory environment fo rmed by traumatic injury.Disruption to the microcirculation is an important pathophysiological mechanism of spinal cord injury.A number of therapeutic agents have been shown to improve the injury environment,mitigate secondary damage,and/or promote regeneration and repair.Among them,the spinal cord microcirculation has become an important target for the treatment of spinal cord injury.Drug inte rventions targeting the microcirculation can improve the microenvironment and promote recovery following spinal cord injury.These drugs target the structure and function of the spinal cord microcirculation and are essential for maintaining the normal function of spinal neuro ns,axons,and glial cells.This review discusses the pathophysiological role of spinal cord microcirculation in spinal cord injury,including its structure and histopathological changes.Further,it summarizes the progress of drug therapies targeting the spinal cord mic rocirc ulation after spinal cord injury.

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

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 diseases.The family of ATP-binding cassette(ABC)transporters has been widely studied regarding efflux of medications at blood-central nervous system barriers.These 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 tissue.Recent 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 challenge.This 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 exist.In 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.

Reviving the use of inhibitors of matrix metalloproteases in spinal cord injury:a case for specificity

At present,there are no resto rative therapies in the clinic for spinal cord injury,with current treatments offering only palliative treatment options.The role of matrix metalloproteases is well established in spinal cord injury,howeve r,translation into the clinical space was plagued by early designs of matrix metalloprotease inhibitors that lacked specificity and fears of musculos keletal syndrome prevented their further development.Newe r,much more specific matrix metalloprotease inhibitors have revived the possibility of using these inhibitors in the clinic since they are much more specific to their to rget matrix metalloproteases.Here,the evidence for use of matrix metalloproteases after spinal cord injury is reviewed and researche rs are urged to overcome their old fears rega rding matrix metalloprotease inhibition and possible side effects for the field to progress.Recently published work by us shows that inhibition of specific matrix metalloproteases after spinal cord injury holds promise since four key consequences of spinal cord injury could be alleviated by specific,next-gene ration matrix metalloprotease inhibitors.For example,specific inhibition of matrix metalloprotease-9 and matrix metalloprotease-12 within 24 hours after injury and for 3 days,alleviates spinal cord injury-induced edema,blood-s pinal co rd barrier breakdown,neuro pathic pain and resto res sensory and locomotor function.Attempts are now underway to translate this therapy into the clinic.

Intranasal nerve growth factor bypasses the blood-brain barrier and affects spinal cord neurons in spinal cord injury

The purpose of this work was to investigate whether, by intranasal administration, the nerve growth factor bypasses the blood-brain barrier and turns over the spinal cord neurons and if such therapeutic approach could be of value in the treatment of spinal cord injury. Adult Sprague-Dawley rats with intact and injured spinal cord received daily intranasal nerve growth factor administration in both nostrils for 1 day or for 3 consecutive weeks. We found an in-creased content of nerve growth factor and enhanced expression of nerve growth factor receptor in the spinal cord 24 hours after a single intranasal administration of nerve growth factor in healthy rats, while daily treatment for 3 weeks in a model of spinal cord injury improved the deifcits in locomotor behaviour and increased spinal content of both nerve growth factor and nerve growth factor receptors. These outcomes suggest that the intranasal nerve growth factor bypasses blood-brain barrier and affects spinal cord neurons in spinal cord injury. They also suggest exploiting the possible therapeutic role of intranasally delivered nerve growth factor for the neuroprotection of damaged spinal nerve cells.

Exercise awareness and barriers after spinal cord injury

Exercise is an essential element in managing several of the non-communicable diseases after spinal cord injury(SCI).Awareness of the importance of prescribing a customized exercise program that meets the goals of persons with SCI should be highly considered in the rehabilitation community.The barriers of implementing specific exercise program as well as the factors that may mask the outcomes of regular exercise regimen need to be continuously addressed as a part of patients’rehabilitation care.The focus of this editorial is to encourage the medical community to consider routine physical activity as one of the necessary vital signs that needs to be routinely checked in patients with SCI.Providing education tips,nutritional counseling and engaging in recreational programs may provide motivational route to the community of SCI.This may result in reinforcing active lifestyle in survivors with SCI as well as to reduce the impact of chronic life threatening medical disorders.

Regulatory effect of vascular endothelial growth factor on blood spinal cord barrier in presyrinx state of experimental syringomyelia

BACKGROUND： Vascular endothelial growth factor （VEGF） is able to regulate blood spinal cord barrier function as well as influence neovascularization and cause edema. OBJECTIVE： Through establishment of a rabbit model of syringomyelia, to explore the correlation between VEGF protein and mRNA expressions and function of blood spinal cord barrier and edema degree of spinal cord in presyrinx state. DESIGN, TIME AND SETTING： Randomized controlled animal study was performed in the Tumor Institute of the Fourth Hospital, Hebei Medical University from January to June 2007. MATERIALS： Atotal of 0.6 mL Kaolin solution （250 g/L, 37℃） was injected into the cisterna magna of 40 rabbits in the kaolin group to establish syringomyelia models. Goat anti-rabbit VEGF monoclonal antibody was provided by DIACLONE Company, USA; RT-PCR related reagents were provided by Huamei Bioengineering Co., Ltd., Beijing. METHODS： Sixty Chinese white rabbits were divided randomly into two groups： Kaolin group （n = 40） and control group （n = 20）. Physiological saline （0.6 mL at 37℃） was injected in rabbits of control group. On days 1,3, 7, 14 and 21 after kaolin injection, cervical cords samples were harvested after sacrifice of animal. MAIN OUTCOME MEASURES： VEGF protein and mRNA expressions were detected by immunohistochemistry and RT-PCR on days 1, 3, 7, 14, and 21 after kaolin injection. A quantitative analysis of blood spinal cord barrier function was performed by Evans blue technique. Water content of the spinal cord was measured by dry-wet weight technique. The correlation between the expression of VEGF protein and mRNA and the function of blood spinal cord barrier in the upper cervical cord of the presyrinx state was analyzed by linear correlation analysis. RESULTS： The water content and Evans blue content increased in the kaolin group on days 1 and 3 postoperatively compared with the control group （F = 7.387, 61.35, P 〈 0.05, 0.01）, and reached a peak on day 7 （F = 135.94, 528.35, P 〈 0.01）. They declined slowly to day 21 postoperatively, but both contents were still higher than the control group （F = 11.51, 58.63, P 〈 0.01）. VEGF protein expression increased on day 1, and stronger positive expression was seen on days 3, 7 and 14. It decreased on day 21. VEGF protein expression was higher than the control group at each time point （F = 137.4-468.5, P 〈 0.01 ）. VEGF mRNA expression showed the same pattern in the cervical cord at different time points. By statistical analysis, the expression of VEGF protein and mRNA had a significantly positive correlation with the structural and functional changes of the blood spinal cord barrier in the presyrinx state （r = 0.604-0.979, P 〈 0.05）. CONCLUSION： In the presyrinx state of syringomyelia, the expressions of VEGF protein and mRNA can influence the structure and function of the blood spinal cord barrier and play an important role in the formation and development of spinal cord edema and syringomyelia.

Effect of platelet activating factor on blood spinal cord barrier following cervical cord injury

Effect of platelet activating factor(PAF) on blood spinal cord barrier in cervical cord injury was investigated. Methods: Spinal cord injury at C6 segment was induced with Allen’s ’method in cats. PAF and PAF receptor antagonist BN52021 were administered by arachnoid space and intravenous injection respectively, and their effects on PAF levels, blood spinal cord barrier and cervical cord edema in the injuried zone and adjacent cervical cord tissue following cervical cord injury were investigated. Results: PAF levels, Evens content and water content in the injuried and adjacent cervical cord tissues significantly increased following trauma. PAF levels, Evens content and water content were evidently elevated with PAF by arachnoid space injection. PAF receptor antagonist BN52021 could inhibit the increase in PAF levels and reduce Evens and water content in the cervical cord tissue following trauma. Conclusion: PAF is an important contributing factor causing post-traumatic damage to the blood spinal cord barrier, while PAF receptor antagonist can effectively relieve post-traumatic damage to the blood spinal cord barrier.

人脐带间充质干细胞来源外泌体降低脊髓损伤后血脊髓屏障的通透性

背景:研究发现,内皮素参与了脊髓损伤后血脊髓屏障的破坏,干细胞来源外泌体可降低血脊髓屏障的通透性,修复脊髓损伤。目的:观察人脐带间充质干细胞来源外泌体是否可以通过抑制内皮素1表达降低血脊髓屏障的通透性,进而修复脊髓损伤。方法:用超速离心法从人脐带间充质干细胞培养上清液中提取外泌体,透射电子显微镜观察其形态,Western blot检测tsg101、CD63的表达。80只SD大鼠随机分成假手术组、模型组、外泌体组、内皮素1组(n=20),采用改良Allen’s法制备大鼠脊髓损伤模型,内皮素1组用微量注射器直接向损伤部位注射10μL(1μg/mL)内皮素1,术后即刻及1,2 d,分别给予假手术组、模型组尾静脉注射200μL PBS,外泌体组、内皮素1组尾静脉注射200μL外泌体(200μg/mL)。脊髓损伤后第1,3,7,14,21天进行后肢运功功能评分;损伤后第7天通过伊文思蓝染色观察血脊髓屏障通透性,Western blot检测脊髓组织中紧密连接蛋白ZO-1、β-Catenin、Occludin和内皮素1的表达。结果与结论:①外泌体组BBB评分在损伤后3-21 d显著高于模型组(P<0.05),苏木精-伊红染色显示外泌体组脊髓损伤较模型组明显减轻;内皮素1组BBB评分较外泌体组显著降低(P<0.05),内皮素1组脊髓损伤较外泌体组加重;②模型组内皮素1表达量较假手术组显著增加(P<0.05),外泌体组内皮素1表达量较模型组显著降低(P<0.05);③与模型组比较,外泌体组血脊髓屏障伊文思蓝渗出量显著减少(P<0.05),紧密连接蛋白β-Catenin、Occludin、ZO-1的表达增加(P<0.05);与外泌体组比较,内皮素1组伊文思蓝渗出量显著增加(P<0.05),上述紧密连接蛋白表达量显著减少(P<0.05);④结果表明,人脐带间充质细胞来源外泌体通过下调内皮素1表达来保护血脊髓屏障的通透性,起到了修复脊髓损伤的作用。

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

Mesenchymal stem cell(MSC)transplantation is a promising treatment strategy for spinal cord injury,but immunological rejection and possible tumor formation limit its application.The therapeutic effects of MSCs mainly depend on their release of soluble paracrine factors.Exosomes are essential for the secretion of these paracrine effectors.Bone marrow mesenchymal stem cell-derived exosomes(BMSC-EXOs)can be substituted for BMSCs in cell transplantation.However,the underlying mechanisms remain unclear.In this study,a rat model of T10 spinal cord injury was established using the impact method.Then,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 injury.In 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 vitro.Pre-treatment with BMSC-EXOs for 8 hours greatly reduced pericyte pyroptosis and increased pericyte survival rate.These 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 injury.All protocols were conducted with the approval of the Animal Ethics Committee of Zhengzhou University on March 16,2019.

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

The blood-spinal cord barrier plays a vital role in recovery after spinal cord injury.The 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 studies.Mouse models of spinal cord injury were established by heavy object impact and then immediately injected with plateletderived growth factor(80μg/kg)at the injury site.Our 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 improved.In vitro,human umbilical vein endothelial cells were established by exposure to 200μM H2O2.At 2 hours prior to injury,in vitro cell models were treated with 5 ng/mL platelet-derived growth factor.Our results showed that expression of blood-spinal cord barrier-related proteins,including Occludin,Claudin 5,andβ-catenin,was significantly decreased and autophagy was significantly reduced.Additionally,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 injury.Our 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 injury.Approval for animal experiments was obtained from the Animal Ethics Committee,Wenzhou Medical University,China(approval No.wydw2018-0043)in July 2018.

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

The currently recommended management for acute traumatic spinal cord injury aims to reduce the incidence of secondary injury and promote functional recovery.Elevated intraspinal pressure(ISP)likely plays an important role in the processes involved in secondary spinal cord injury,and should not be overlooked.However,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 literature.Here,we review the etiology and progression of elevated ISP,as well as potential therapeutic measures that target elevated ISP.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 injury.Duraplasty and hypertonic saline may be promising treatments for reducing ISP within this time window.Other potential treatments such as decompression,spinal cord incision,hemostasis,and methylprednisolone treatment require further validation.

人脐带间充质干细胞对糖尿病肾病大鼠肠道屏障功能的调节作用

背景:糖尿病肾病是引起终末期肾病的重要原因,其中肠道屏障损伤在糖尿病肾病的发生发展中起到了重要作用。目的:观察人脐带间充质干细胞对糖尿病肾病大鼠肠道屏障的保护作用。方法:30只8周龄雄性SD大鼠随机分配至健康对照组、模型组和人脐带间充质干细胞组,每组10只。人脐带间充质干细胞组大鼠在糖尿病肾病成模后经尾静脉注射1×106个人脐带间充质干细胞,每周1次,连续4周,健康对照组和模型组大鼠在相同时间注射等体积PBS。末次注射后1周,光镜下观察肾脏和结肠组织形态学改变情况,免疫组化法检测大鼠结肠组织中ZO-1和Occludin的表达;ELISA法检测大鼠血清D-乳酸和脂多糖水平。此外,还利用活体成像系统观察DiR染料标记的人脐带间充质干细胞在大鼠体内的示踪分布,以及应用免疫组化法检测结肠组织中人源性间充质干细胞表面标志抗原CD44和CD90的表达。结果与结论:①与模型组比较,人脐带间充质干细胞移植显著抑制了糖尿病肾病大鼠尿素氮、血肌酐、24 h尿蛋白水平和尿白蛋白/肌酐比值的增加(均P<0.05);②在糖尿病肾病大鼠结肠中发现了人源间充质干细胞表面标志物CD44和CD90的表达;③与健康对照组相比,模型组大鼠结肠组织中紧密连接蛋白Occludin与ZO-1蛋白表达水平显著减少,而人脐带间充质干细胞治疗后显著提高了Occludin和ZO-1的表达;④与模型组比较,人脐带间充质干细胞移植后显著降低了糖尿病肾病大鼠血清D-乳酸和脂多糖水平;⑤结果提示,人脐带间充质干细胞可能通过增强糖尿病肾病大鼠肠道紧密连接蛋白的表达来保护肠道屏障功能。

The roles of microRNAs in spinal cord ischemia-reperfusion injury

Spinal cord ischemia/reperfusion injury is a devastating medical disorder with poor prognosis that is associated with several pathophysiological conditions.However,multiple stimuli can trigger SCII,so the underlying mechanism of this pathology has not yet been fully established.MicroRNAs(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 damage.miRNA expression profiles are known to be altered after spinal cord ischemia/reperfusion injury.Therefore,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 injury.This 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.