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Neural Regeneration Research 2011年第15期6卷 1151-1157页

作者： Yanqing Wu Ying Gao Lingqun Zhu Yonghong Gao Dongmei Zhang Lixia Lou Yanfang Yan Department of Neurology Chinese Medicine Key Research Room of Encephalopathy Syndrome and Treatment of the State Administration of TCM People's Republic of China Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine Beijing 100700 China Key Laboratory of Chinese Internal Medicine Ministry of Education Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine Beijing 100700 China

This study investigated the effects of Yishendaluo decoction on the loss of blood-brain barrier integrity in mice exhibiting experimental autoimmune encephalomyelitis.To this end,we used real-time fluorescent quantitative PCR to measure the levels of mRNAs specific to the T cell markers CD4 and CD8,and the monocyte marker CD11b.In addition,we used Evans blue dye extravasation in the spinal cord and brain tissues to assess blood-brain barrier permeability.The results indicated that an increase in blood-brain barrier permeability was associated with an increase in CD4,CD8 and CD11b mRNA expression in experimental autoimmune encephalomyelitis mice.Yishendaluo decoction administration significantly reversed inflammatory cell accumulation in cerebral tissues of experimental autoimmune encephalomyelitis mice.

关键词： experimental autoimmune encephalomyelitis Yishendaluo decoction blood-brain barrier neurological score spinal cord

Synaptic and blood-brain barrier structural changes in a rat epilepsy model induced by coriaria lacton Replication experiment with animals

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Neural Regeneration Research 2008年第1期3卷 25-28页

作者： Jiyan Cheng Jichun Huang Yi Han Guangyi Liu Ling Yin Furong Zheng Department of Histology and Embryology Luzhou Medical College Luzhou 646000 Sichuan Province China Electron Microscopy Laboratory Luzhou Medical College Luzhou 646000 Sichuan Province China

BACKGROUND： Structural and functional synaptic changes, as well as blood-brain barrier （BBB） changes, affect the micro-environment of nervous tissue and excitation, both of which play an important role in epilepsy. OBJECTIVE： To observe synaptic and BBB ultrastructural changes in the motor cortex of a rat epilepsy model induced by coriaria lacton, and to investigate the synaptic and BBB effects on the mechanism of epilepsy. DESIGN： A randomized controlled animal experiment. SETTING： Department of Histology and Embryology, Luzhou Medical College; and Electron Microscopy Laboratory, Luzhou Medical College. MATERIALS： Twenty healthy male Sprague Dawley rats, aged 8 weeks, were chosen for this study. The rats weighed （280 ± 50） g and were supplied by the Experimental Animal Center of Luzhou Medical College. Experimentation was performed in accordance with the ethical guidelines for the use and care of animals. The animals were randomly divided into a control group and an epilepsy group, with 10 rats in each group. METHODS： This study was performed at the Department of Histology and Embryology, and Electron Microscopy Laboratory, Luzhou Medical College between February and December 2006. According to the protocol, the epilepsy group was injected with 10 μ L/100 g coriaria lacton into the lateral ventricles to establish an epileptic model. The control group rats were not administered anything. Eight days after the model was established, all rats were anesthetized with ether. The motor cortex was removed and sectioned into ultrathin sections. Synaptic and BBB ultrastructural changes were observed by electron microscopy. MAIN OUTCOME MEASURES：（1）Structural changes of three different parts of the synapses, synaptic cleft width, postsynaptic density thickness, proportion of perforation synapses, curvature of synaptic interface, and length of active zones. （2）Capillary and BBB changes （endothelium, basement membrane, pericyte, and the astrocyte endfeet）. RESULTS：（1）Curvature of synaptic interface, length of active zones,

关键词： coriaria lacton epilepsy synapse blood-brain barrier rats

Correlation of vascular endothelial growth factor to permeability of blood-brain barrier and brain edema during high-altitude exposure

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Neural Regeneration Research 2009年第10期4卷 775-779页

作者： Qiquan Zhou Chang'e Liu Jing Wang Yunli Wang Bo Zhou Department of High Altitude Disease College of High Altitude Military Medicine Third Military Medical University of Chinese PLA Chongqing 400038 China Key Laboratory of High Altitude Medicine Ministry of Education and Key Laboratory of High Altitude Physiology and High Altitude Disease of Chinese PLA Chongqing 400038 China Department of Animal Science College of Basic Medicine Third Military Medical University of Chinese PLA Chongqing 400038 China Department of Pathology and Pathophysiology Chengdu Medical College Chengdu 610083 Sichuan Province China Clinical Laboratory the25 Hospital of Chinese PLA Jiuquan 735000 Gansu Province China

BACKGROUND： Many studies have evaluated the role of vascular endothelial growth factor （VEGF） in traumatic brain edema and hemorrhagic brain edema. OBJECTIVE： To observe the effects of VEGF expression on permeability of the blood-brain barrier （BBB） during high-altitude and hypoxia exposure, and to investigate the correlation between VEGF expression and BBB permeability with regard to Evans blue staining and brain edema during high-altitude exposure. DESIGN, TIME AND SETTING： The randomized, controlled, animal study was performed at the Tanggula Etape, Central Laboratory of Chengdu Medical College, and Central Laboratory of General Hospital of Chengdu Military Area Command of Chinese PLA, China, from July 2003 to November 2004. MATERIALS： Quantitative RT-PCR kit （Sigma, USA）, VEGF ELISA kit （Biosource, USA）, and Evans blue （Jingchun, China） were acquired for this study. METHODS： A total of 180 Wistar rats were equally and randomly assigned to 15 groups： low-altitude （500 m）, middle-altitude （2 880 m）, high-altitude （4 200 m）, super-high-altitude （5 000 m）, 1,3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 days of super high-altitude exposure. Wistar rats were exposed to various altitude gradients to establish a hypoxia model. MAIN OUTCOME MEASURES： brain water content was calculated according to the wet-to-dry weight ratio. BBB permeability to Evans blue was determined by colorimetric method. VEGF mRNA and protein levels in brain tissues were detected using RT-PCR and double-antibody sandwich ELISA. RESULTS： brain water content, BBB permeability to Evans blue, and VEGF mRNA and protein levels in brain tissues increased with increasing altitude and prolonged exposure to altitude. The greatest increase was determined on day 9 upon ascending 5 000 m. Simultaneously, VEGF expression positively correlated to BBB permeability of Evans blue and brain water content （r = 0.975, 0.917, P〈 0.01）. CONCLUSION： Increased VEGF protein and mRNA expression was responsible for increased BBB permeability, which may be an important mechanism

关键词： high-altitude blood-brain barrier permeability vascular endothelial growth factor

Identification of blood-brain barrier function following subarachnoid hemorrhage in rats at different stages

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Neural Regeneration Research 2008年第4期3卷 444-448页

作者： Zongyi Xie Weiwei Shen Ying Ma Yuan Cheng Department of Neurosurgery the Second Affiliated Hospital of Chongqing University of Medical Sciences Chongqing 400010 China Department of Internal Medicine the Sixth People＇s Hospital of Chongqing City Chongqing 400060 China

BACKGROUND： Recent studies have indicated that blood-brain barrier （BBB） disruption following subarachnoid hemorrhage （SAH） significantly correlates with the development of brain injury and poor prognosis of patients subjected to SAH. OBJECTIVE： To investigate both functional and structural changes related to BBB in various phases after SAH in rats through quantitative and qualitative methods. DESIGN, TIME AND SETTING： This experiment, a completely randomized design and controlled experiment, was performed at the Department of Neurosurgery, the Second Affiliated Hospital of Chongqing University of Medical Sciences from June 2006 to March 2007. MATERIALS： A total of 128 female, healthy, Sprague-Dawley rats were selected for this study. Main reagents and instruments： Evans Blue dye （Sigma Company, USA）, fluorescence spectrophotometer （Shimadzu Company, Japan）, and transmission electron microscope （Olympus Company, Japan）. METHODS： The included 128 rats were randomly divided into two groups： sham-operated group （n = 16） and SAH group （n = 112）. Rats in the SAH group were divided into seven subgroups： 6, 12, 24, 36, 48, 60, and 72 hours after SAH （16 rats for each time point）. Experimental SAH was induced by blood injection into the pre-chiasmatic cistern （300 μ L）. The sham-operated group received an equivalent volume of normal saline solution （300 μ L） injected into the subarachnoid space. MAIN OUTCOME MEASURES： brain tissue water content was determined by the wet-dry method. BBB permeability in the cerebral cortex was determined by Evans Blue dye and fluorescent spectrophotometer. The ultrastructural changes in BBB were observed with transmission electron microscope. RESULTS： Compared with the sham-operated group, SAH induced a significant increase in brain water content between 24 and 60 hours （F = 888.32, P 〈 0.05）. brain water content increased to a maximum by 36 hours after SAH, normalizing by 72 hours. Evans Blue content in the cerebral cortex of SAH group rats began to increase by 24 hours after SAH, peaked

关键词： subarachnoid hemorrhage blood-brain barrier rats

Correlation of aquaporin-4 expression to blood-brain barrier permeability in rats with focal cerebral ischemia

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Neural Regeneration Research 2008年第6期3卷 629-633页

作者： Pengcheng Xu Haorong Feng Jinbu Xu Yongping Wu Jiangsu Province Key Laboratory of Anesthesiology Xuzhou Medical College Xuzhou 221002 Jiangsu Province China Department of Anesthesiology the 98 Hospital of Chinese PLA Huzhou 313000 Zhejiang Province China

BACKGROUND： Ischemic cerebrovascular disease causes injury to the blood-brain barrier. The occurrence of brain edema is associated with aquaporin expression following cerebral ischemia/reperfusion. OBJECTIVE： To analyze the correlation of aquaporin-4 expression to brain edema and blood-brain barrier permeability in brain tissues of rat models of ischemia/reperfusion. DESIGN, TIME AND SETTING： The randomized control experiment was performed at the Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, China from December 2006 to October 2007. MATERIALS： A total of 112 adult, male, Sprague-Dawley rats, weighing 220-250 g, were used to establish rat models of middle cerebral artery occlusion and reperfusion by the suture method. Rabbit anti-aquaporin-4 （Santa Cruz, USA） and Evans blue （Sigma, USA） were used to analyze the tissue. METHODS： The rats were randomized into sham-operated （n = 16） and ischemia/reperfusion （n = 96） groups. There were 6 time points in the ischemia/reperfusion group, comprising 4, 6, 12, 24, 48, and 72 hours after reperfusion, with 16 rats for each time point. Rat models in the sham-operated group at 4 hours after surgery and rat models in the ischemia/reperfusion group at different time points were equally and randomly assigned into 4 different subgroups. MAIN OUTCOME MEASURES： brain water content on the ischemic side and the control side was measured using the dry-wet weight method. blood-brain barrier function was determined by Evans Blue. Aquaporin-4 expression surrounding the ischemic focus, as well as the correlation of aquaporin-4 expression with brain water content and Evans blue staining, were measured using immunohistochemistry and Western blot analysis. RESULTS： brain water content on the ischemic side significantly increased at 12 hours after reperfusion, reached a peak at 48 hours, and was still high at 72 hours. brain water content was greater on the ischemic hemispheres, compared with the control hemispheres at 6, 12, 24, 48, and 72 hours after reperfusion,

关键词： aquaporin-4 blood-brain barrier Evans blue brain edema

Changes in blood-brain barrier permeability and expression of related factors in a rat model of intracerebral hemorrhage following minocycline treatment

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Neural Regeneration Research 2010年第17期5卷 1308-1312页

作者： Wei Shi Zizhang Wang Jingnan Pu Ruizhi Wang Zhenyu Guo Chongxiao Liu Jianjun Sun Ligui Gao Ren Zhou Department of Neurosurgery Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'an 710004Shaanxi ProvinceChina

Inflammatory factor aggregation and blood-brain barrier（BBB）damage occur around hematoma foci following intracerebral hemorrhage.Minocycline is lipophilic,can pass through the BBB,and shows anti-inflammatory effects in models of central nervous system disease.We found that minocycline application at 6 hours after intracerebral hemorrhage reduced BBB permeability,decreased vascular endothelial growth factor expression,and increased nerve growth factor and heat shock protein 70 expression,primarily in neurons and microglia.Early intraperitoneal injection of minocycline attenuated BBB damage possibly by reducing vascular endothelial growth factor expression and enhancing nerve growth factor and heat shock protein 70 expression.

关键词： blood-brain barrier intracerebral hemorrhage vascular endothelial growth factor nerve growth factor heat shock protein 70 therapy

Regulation of pathological blood-brain barrier for intracranial enhanced drug delivery and anti-glioblastoma therapeutics

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Oncology Research 2021年第5期29卷 351-363页

作者： KAI WANG FENGTIAN ZHANG CHANGLONG WEN ZHIHUA HUANG ZHIHAO HU YUWEN ZHANG FUQIANG HU LIJUAN WEN Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of Education Gannan Medical UniversityGanzhou341000China College of Pharmaceutical Sciences Zhejiang UniversityHangzhou310058China Department of Orthopedics First Affiliated Hospital of Gannan Medical UniversityGanzhou341000China Medical College of Soochow University Suzhou215123China Department of Infectious Diseases Ganzhou People’s HospitalGanzhou341000China Ganzhou Key Laboratory of Neuroinflammation Research Gannan Medical UniversityGanzhou341000China

The blood-brain barrier(BBB)is an essential component in regulating and maintaining the homeostatic microenvironment of the central nervous system(CNS).During the occurrence and development of glioblastoma(GBM),BBB is pathologically destroyed with a marked increase in permeability.Due to the obstruction of the BBB,current strategies for GBM therapeutics still obtain a meager success rate and may lead to systemic toxicity.Moreover,chemotherapy could promote pathological BBB functional restoration,which results in signiﬁcantly reduced intracerebral transport of therapeutic agents during multiple administrations of GBM and the eventual failure of GBM chemotherapy.The effective delivery of intracerebral drugs still faces severe challenges.However,strategies that regulate the pathological BBB to enhance the transport of therapeutic agents across the barrier may provide new opportunities for the effective and safe treatment of GBM.This article reviews the structure and function of BBB in physiological states,the mechanisms underlying BBB pathological fenestration during the development of GBM,and the therapeutic strategies of GBM based on BBB intervention and medicinal drugs transporting across the BBB.

关键词： blood-brain barrier Physiological Pathological Glioblastoma Intervention

Protein-S-100-beta is increased in patients with decompensated cirrhosis admitted to ICU

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Journal of Intensive Medicine 2024年第2期4卷 222-230页

作者： Nicolas Weiss Simona Tripon Maxime Mallet Françoise Imbert-Bismut Mehdi Sakka Dominique Bonnefont-Rousselot Philippe Sultanik Sarah Mouri Marika Rudler Dominique Thabut Sorbonne Université AP-HP.Sorbonne UniversitéHôpital de la Pitié-SalpêtrièreDépartement de NeurologieUnitéde Médecine Intensive RéanimationàOrientation NeurologiqueParisFrance brain Liver Pitié-Salpêtrière(BLIPS)Study Group INSERM UMR_S 938Centre de recherche Saint-AntoineMaladies métaboliquesBiliaires et Fibro-Inflammatoire du FoieInstitute of Cardiometabolism and Nutrition(ICAN)ParisFrance Groupe de Recherche Clinique en REanimation et Soins intensifs du Patient en Insuffisance Respiratoire aiguE(GRC-RESPIRE)Sorbonne Université ParisFrance Assistance Publique-Hôpitaux de Paris AP-HP.Sorbonne UniversitéHôpital de la Pitié-SalpêtrièreService d'hépato-GastroentérologieUnitéde Soins Intensifs d'HépatologieParisFrance Assistance Publique-Hôpitaux de Paris AP-HP.Sorbonne UniversitéService de Biochimie MétaboliqueHôpitaux Universitaires Pitié-Salpêtrière-Charles FoixDMU BioGeMParis F-75013France UniversitéParis Cité UFR de PharmacieCNRSInsermUTCBSParisFrance

Background Hepatic encephalopathy(HE)is highly prevalent in patients with liver diseases.The pathophysiology of HE is centered on the synergic role of hyperammonemia and systemic inflammation.However,some data suggest altered functioning of the blood–brain barrier(BBB).Assessing BBB function is challenging in clinical practice and at the bedside.Protein-S-100 Beta(PS100-Beta)could be a useful peripheral marker of BBB permeability in HE.This study aimed to assess plasmatic PS100-Beta levels in a prospective cohort of patients admitted to the intensive care unit(ICU)with decompensated cirrhosis with and without overt HE.Methods We retrospectively evaluated a prospective cohort of cirrhotic patients admitted to the ICU from October 2013 to September 2015 that had an available plasmatic PS100-Beta measurement.Patients with previous neurological impairment or limitation of intensive or resuscitative measures were excluded.Overt HE was defined as West-Haven grades 2 to 4.The patients were compared to a control cohort of outpatient clinic cirrhotic and non-cirrhotic patients explored for isolated elevation of liver enzymes.After ICU discharge,the patients were followed for at least 3 months for the occurrence of overt HE.Adverse outcomes(liver transplantation or death)were collected.The ability of PS100-Beta–in combination with other factors–to predict overt HE was evaluated in a multivariate analysis using logistic regression.Likelihood ratios were used to determine the effects and calculate odds ratios(OR).Survival analysis was performed by using the Kaplan–Meier method and survival between groups was compared using a Log-rank test.Results A total of 194 ICU patients and 207 outpatients were included in the study.Increased levels of plasmatic PS100-Beta were detected in the ICU decompensated cirrhotic patients compared with the outpatients([0.15±0.01]mg/L vs.[0.08±0]mg/L,P<0.001).ICU patients with overt HE had higher levels of PS100-Beta([0.19±0.03]mg/L)compared with the ICU patients without overt HE([0.13±0.01]mg/L)(

关键词： Girrhosis Hepatic encephalopathy blood-brain barrier PS100 Beta Liver disease

Fluorescent bovine serum albumin-silver nanoclusters loaded with paclitaxel can traverse the blood-brain barrier to inhibit the migration of glioma

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Journal of Bio-X Research 2020年第4期3卷 183-192页

作者： Yu Liu Yu Liu Yini Zhang Weichang Xie Yalan Yang Kaigeng Hu Hongbo Xin Ping Hu Fanrong Ai School of Mechanical&Electronic Engineering Nanchang UniversityNanchangJiangxi ProvinceChina Rehabilitation Department The Second Affiliated HospitalNanchang UniversityNanchangJiangxi ProvinceChina Institute of Translational Medicine Nanchang UniversityNanchangJiangxi ProvinceChina

Objective::Glioma is the most common and aggressive primary brain tumor. Here, we aimed to establish a nano-drug carrier system to traverse the blood-brain barrier for the treatment and inhibition of glioma migration.Methods::The synthesis of bovine serum albumin protected-silver nanoclusters (BSA-AgNCs) was performed using chemical reduction. The drug paclitaxel (PTX) can be loaded into BSA-AgNCs through electrostatic and hydrophobic interactions to formulate spherical BSA-AgNC-PTX nanoparticles (BSA-AgNC-PTX NPs). A glioma mouse model was established by injecting U251-GFP-Luc cells into the mouse striatum, and all surgical procedures were approved by the Animal Ethics Committee of Nanchang University (SYXK2019-0003) on December 29, 2019.Results::The BSA-AgNC-PTX NPs were able to efficiently pass through the blood-brain barrier, both in vitro and in vivo, to deliver the drug to the tumor site. The in vivo assessment of BSA-AgNC-PTX NPs in glioblastoma multiforme-bearing mice revealed the significant inhibition of tumor growth and migration, prolonging the survival of the mice.Conclusion::These results indicated that BSA-AgNCs might represent an ideal nanocarrier for the treatment of glioma and has the potential to be used in the treatment of a variety of central nervous system diseases.

关键词： blood-brain barrier glioma paclitaxel renal clearable silver nanoclusters

Advances in the Mechanisms of Hemorrhagic Transformation and Therapeutic Agents after Intravenous Thrombolysis in Ischemic Stroke

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Yangtze Medicine 2024年第1期8卷 29-40页

作者： Yue Dai Yongyi Zhan Mingtian Lu Zehua He Yu Liu Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital) Zhuhai China

Ischemic stroke is an important disease leading to death and disability for all human beings, and the key to its treatment lies in the early opening of obstructed vessels and restoration of perfusion to the local infarcted area. Intravenous thrombolysis with tissue plasminogen activator (tPA) is one of the effective therapies to achieve revascularization, but it faces strict indications with a narrow therapeutic time window, and significantly increases the incidence of hemorrhagic transformation, HT, after reperfusion of the infarcted foci, which greatly reduces the incidence of patients with ischemic stroke. which significantly increases the incidence of hemorrhagic transformation (HT) after reperfusion of the infarcted focus, greatly reducing patient utilization and clinical benefit. Since the mechanism of HT has not been fully elucidated, and the related molecular mechanisms are complex and interactive, there is no specific and effective therapy to avoid the occurrence of HT. In this article, we focus on the research progress on the mechanism of HT after tPA intravenous thrombolysis in ischemic stroke patients from the aspects of vascular integrity disruption, oxidative stress, and neuroinflammatory response and the corresponding therapeutic strategies, in order to improve the safety and prognosis of tPA intravenous thrombolysis in the clinic.

关键词： Hemorrhagic Transformation Tissue-Type Fibrinogen Activator Acute Ischemic Stroke blood-brain barrier