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Neural Regeneration Research 2014年第10期9卷 1025-1030页

作者： Luigi Aloe Patrizia Bianchi Alberto De Bellis Marzia Soligo Maria Luisa Rocco Cellular Biology and Neurobiology Institute National Research Council(CNR) Maria Rosaria Maglione Foundation Onlus NapoliItaly Intitute of Translational Pharmacology National Research Council(CNR)

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.

关键词： nerve regeneration spinal cord injury nerve growth factor intranasal delivery blood-brain barrier motor function leptin neuroprotection rats neural regeneration

The effects of aerobic exercise training on oxidant-antioxidant balance, neurotrophic factor levels, and blood-brain barrier function in obese and non-obese men

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Journal of Sport and Health Science 2017年第4期6卷 447-453页

作者： Hee-Tae Roh Wi-Young So Department of Physical Education College of Arts and Physical Education Dong-A University Busan 604-714 Republic of Korea Sports and Health Care Major College of Humanities and Arts Korea National University of Transportation Chungju-si 380-702 Republic of Korea

Purpose: The purpose of this study was to investigate the effects of obesity and aerobic exercise training on oxidant-antioxidant balance,neurotrophic factor levels, and blood-brain barrier(BBB) function.Methods: Ten non-obese healthy men(body mass index blood samples were collected to examine oxidant-antioxidant balance(reactive oxygen species(ROS) and superoxide dismutase(SOD) activity levels), neurotrophic factors(brain-derived neurotrophic factor(BDNF), nerve growth factor, and glial cell line-derived neurotrophic factor levels), and BBB function(S100βand neuron-specific enolase(NSE) levels) before and after exercise training.Results: The obese group showed significantly greater changes than the non-obese group in serum ROS(-0.46 ± 0.31 mmol/L vs.-0.10 ±0.17 mmol/L,p=0.005),serum S100 p levels(-8.50 ± 5.92 ng/L vs.-0.78 ± 5.45 ng/L,p=0.007),and serum NSE levels(-0.89 ± 0.54 μg/L vs.-0.01 ± 0.74 μg/L,p= 0.007) after training. At baseline,the obese group showed significantly higher serum ROS and S100β levels and significantly lower serum SOD activity and BDNF levels than the non-obese group(p < 0.05). The obese group showed significantly lower serum ROS, S100β,and NSE levels and significantly higher serum SOD activity and BDNF levels after training compared with baseline(p < 0.05).Conclusion: These results suggest that obesity can reduce serum neurotrophic factor levels and can induce BBB dysfunction. On the other hand,aerobic exercise can improve an oxidant-antioxidant imbalance in obese subjects and limit BBB dysfunction.

关键词： blood-brain barrier Exercise training Neurotrophic factor Obesity Oxidative stress Redox balance

Limb remote ischemic postconditioning protects integrity of the blood-brain barrier after stroke

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Neural Regeneration Research 2018年第9期13卷 1585-1593页

作者： Juan Li Xiao-Song Hu Fang-Fang Zhou Shuai Li You-Sheng Lin Wen-Qian Qi Cun-Fang Qi Xiao Zhang Experiment Technology Center of Preclinical Medicine of Chengdu Medical College Chengdu Sichuan Province China Department of Anatomy Qinghai University Xining Qinghai Province China

Integrity of the blood-brain barrier structure is essential for maintaining the internal environment of the brain.Development of cerebral infarction and brain edema is strongly associated with blood-brain barrier leakage.Therefore,studies have suggested that protecting the blood-brain barrier may be an effective method for treating acute stroke.To examine this possibility,stroke model rats were established by middle cerebral artery occlusion and reperfusion.Remote ischemic postconditioning was immediately induced by three cycles of 10-minute ischemia/10-minute reperfusion of bilateral hind limbs at the beginning of middle cerebral artery occlusion reperfusion.Neurological function of rat models was evaluated using Zea Longa’s method.Permeability of the blood-brain barrier was assessed by Evans blue leakage.Infarct volume and brain edema were evaluated using 2,3,5-triphenyltetrazolium chloride staining.Expression of matrix metalloproteinase-9 and claudin-5 m RNA was determined by real-time quantitative reverse transcription-polymerase chain reaction.Expression of matrix metalloproteinase-9 and claudin-5 protein was measured by western blot assay.The number of matrix metalloproteinase-9-and claudin-5-positive cells was analyzed using immunohistochemistry.Our results showed that remote ischemic postconditioning alleviated disruption of the blood-brain barrier,reduced infarct volume and edema,decreased expression of matrix metalloproteinase-9 m RNA and protein and the number of positive cells,increased expression of claudin-5 m RNA and protein and the number of positive cells,and remarkably improved neurological function.These findings confirm that by suppressing expression of matrix metalloproteinase-9 and claudin-5 induced by acute ischemia/reperfusion,remote ischemic postconditioning reduces blood-brain barrier injury,mitigates ischemic injury,and exerts protective effects on the brain.

关键词： nerve regeneration remote ischemic postconditioning middle cerebral artery occlusion cerebral ischemia/reperfusion blood-brain barrier acute cerebral ischemia stroke matrix metalloproteinase-9 claudin-5 neural regeneration

TIMP1 preserves the blood-brain barrier through interacting with CD63/integrin β1 complex and regulating downstream FAK/RhoA signaling

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Acta Pharmaceutica Sinica B 2020年第6期10卷 987-1003页

作者： Jingshu Tang Yuying Kang Longjian Huang Lei Wu Ying Peng State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China

blood-brain barrier(BBB)breakdown and the associated microvascular hyperpermeability are hallmark features of several neurological disorders,including traumatic brain injury(TBI).However,there is no viable therapeutic strategy to rescue BBB function.Tissue inhibitor of metalloproteinase-1(TIMP1)has been considered to be beneficial for vascular integrity,but the molecular mechanisms underlying the functions of TIMP1 remain elusive.Here,we report that TIMP1 executes a protective role on neuroprotective function via ameliorating BBB disruption in mice with experimental TBI.In human brain microvessel endothelial cells(HBMECs)exposed to hypoxia and inflammation injury,the recombinant TIMP1(rTIMP1)treatment maintained integrity of junctional proteins and trans-endothelial tightness.Mechanistically,TIMP1 interacts with CD63/integrinβ1 complex and activates downstream FAK signaling,leading to attenuation of RhoA activation and F-actin depolymerization for endothelial cells structure stabilization.Notably,these effects depend on CD63/integrinβ1 complex,instead of the MMP-inhibitory function.Together,our results identified a novel MMP-independent function of TIMP1 in regulating endothelial barrier integrity.Therapeutic interventions targeting TIMP1 and its downstream signaling may be beneficial to protect BBB function following brain injury and neurological disorders.

关键词： Tissue inhibitor of metalloproteinase-1 blood-brain barrier Junctional proteins CD63 Integrinβ1

Relationship Between Hematoma Expansion Induced by Hypertension and Hyperglycemia and blood-brain barrier Disruption in Mice and Its Possible Mechanism:Role of Aquaporin-4 and Connexin43

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Neuroscience Bulletin 2020年第11期36卷 1369-1380页

作者： Heling Chu Zidan Gao Chuyi Huang Jing Dong Yuping Tang Qiang Dong Department of Neurology Huashan HospitalState Key Laboratory of Medical NeurobiologyFudan UniversityShanghai 200040China Department of Neurology North Huashan HospitalFudan UniversityShanghai 201907China Department of Neurology Affiliated Hospital of Guizhou Medical UniversityGuiyang 550004China Department of Neurology Shanghai East HospitalTongji University School of MedicineShanghai 200120China

We aimed to select an optimized hematoma expansion(HE)model and investigate the possible mechanism of blood-brain barrier(BBB)damage in mice.The results showed that HE occurred in the group with hypertension combined with hyperglycemia(HH-HE)from3 to 72 h after intracerebral hemorrhage;this was accompanied by neurological deficits and hardly influenced the survival rate.The receiver operating characteristic curve suggested the criterion for this model was hematoma volume expansion≥45.0%.Meanwhile,HH-HE aggravated BBB disruption.A protector of the BBB reduced HH-HE,while a BBB disruptor induced a further HH-HE.Aquaporin-4(AQP4)knock-out led to larger hematoma volume and more severe BBB disruption.Furthermore,hematoma volume and BBB disruption were reduced by multiple connexin43(Cx43)inhibitors in the wild-type group but not in the AQP4 knock-out group.In conclusion,the optimized HE model is induced by hypertension and hyperglycemia with the criterion of hematoma volume expanding≥45.0%.HH-HE leads to BBB disruption,which is dependent on AQP4 and Cx43.

关键词： Intracerebral hemorrhage Hematoma expansion Animal model blood-brain barrier Aquaporin-4 Connexin43

Aquaporin 4 expression and ultrastructure of the blood-brain barrier following cerebral contusion injury

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Neural Regeneration Research 2013年第4期8卷 338-345页

作者： Xinjun Li Yangyun Han Hong Xu Zhongshu Sun Zengjun Zhou Xiaodong Long Yumin Yang Linbo Zou Department of Neurosurgery Deyang People's Hospital Department of Neurosurgery West China Hospital of Sichuan University

This study aimed to investigate aquaporin 4 expression and the ultrastructure of the blood-brain barrier at 2-72 hours following cerebral contusion injury, and correlate these changes to the formation of brain edema. Results revealed that at 2 hours after cerebral contusion and laceration injury, aquaporin 4 expression significantly increased, brain water content and blood-brain barrier permeability increased, and the number of pinocytotic vesicles in cerebral microvascular endothelia cells increased. In addition, the mitochondrial accumulation was observed. As contusion and laceration injury became aggravated, aquaporin 4 expression continued to increase, brain water content and blood-brain barrier permeability gradually increased, brain capillary endothelial cells and astrocytes swelled, and capillary basement membrane injury gradually increased. The above changes were most apparent at 12 hours after injury, after which they gradually attenuated. Aquaporin 4 expression positively correlated with brain water content and the blood-brain barrier index. Our experimental findings indicate that increasing aquaporin 4 expression and blood-brain barrier permeability after cerebral contusion and laceration injury in humans is involved in the formation of brain edema.

关键词： neural regeneration brain injury cerebral contusion and laceration injury aquaporin 4 blood-brain barrier ultrastructure brain edema human early stage photographs-containing paper neuroregeneration

blood-brain barrier penetration of cefepime after neurosurgery

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Chinese Medical Journal 2007年第13期120卷 1176-1178页

作者： WANG Jiang-fei WANG Qiang ZHAO Li-hong SHI Guang-zhi ZHOU Jian-xin Department of Neurosurgery. Beijing Tiantan Hospital Capital Medical University Beijing 100050 China ICU. Beijing Tiantan Hospital Capital Medical University Beijing 100050 China

Background It has been confirmed that the concentration of cefepime in cerebrospinal fluid （CSF） could reach the 10% of its concentration in plasma, exceeding the inhibitory concentration to 90% of organisms （MIC90） for common bacteria. However, the blood-brain barrier （BBB） penetration ability of cefepime is still unclear. The aim of this study was to measure the CSF concentration of cefepime in patients after neurosurgical operations, and to determine the penetration of the drug through an incomplete BBB. Methods Eight patients who received ventricular drainage （VD group） and 5 who underwent lumbar puncture drainage （LPD group） were enrolled into this study. Cefepime （2 g） was injected intravenously in 30 minutes after the neurosurgeries. The concentrations of cefepime in the CSF and plasma were measured by high-pressure liquid chromatography （HPLC） at different time points. Results The CSF concentrations of cefepime at different time points in the VD group were significantly higher than those in the LPD group （P〈0.05）. In the VD group, the concentration of cefepime in CSF reached the peak （（22.54±14.06） pg/ml） at 1 to 2 hours after the injection, while in the LPD group at 4 hours （（5.61±3.73） pg/ml）. In both groups, the peak was higher than the MIC90 of most common bacteria in intensive care unit. The ratio of CSF to plasma cefepime concentrations ranged from 0.30 to 2.14 in the VD group and 0.03 to 1.14 in the LPD group. Conclusion After neurosurgeries, CSF concentration of cefepime can reach a therapeutic level. Thus, the drug could be used to prevent and treat postoperative intracranial infection.

关键词： cefepime blood-brain barrier drug concentration high-pressure liquid chromatography

Development of Human in vitro brain-blood barrier Model from Induced Pluripotent Stem Cell-derived Endothelial Cells to Predict the in vivo Permeability of Drugs

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Neuroscience Bulletin 2019年第6期35卷 996-1010页

作者： Yuan Li Xueying Sun Houfu Liu Liang Huang Guofeng Meng Yu Ding Wenji Su Jiaqi Lu Sophie Gong Georg C.Terstappen Ru Zhang Wandong Zhang Shanghai Key Laboratory of Signaling and Disease Research Laboratory of Receptor-Based Bio-medicineCollaborative Innovation Center for Brain ScienceSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China Platform Technology&Sciences GlaxoSmithKline China R&D CentreShanghai 201203China Neurosciences Therapeutic Area Unit GlaxoSmithKline China R&D CentreShanghai 201203China Human Health Therapeutics Research Centre National Research Council of Canada Faculty of Medicine University of OttawaOttawa K1A0R6Canada

An in vitro blood-brain barrier(BBB) model is critical for enabling rapid screening of the BBB permeability of the drugs targeting on the central nervous system.Though many models have been developed, their reproducibility and renewability remain a challenge. Furthermore, drug transport data from many of the models do not correlate well with the data for in vivo BBB drug transport.Induced-pluripotent stem cell(i PSC) technology provides reproducible cell resources for in vitro BBB modeling.Here, we generated a human in vitro BBB model by differentiating the human i PSC(hi PSC) line GM25256 into brain endothelial-type cells. The model displayed BBB characteristics including tight junction proteins(ZO-1,claudin-5, and occludin) and endothelial markers(von Willebrand factor and Ulex), as well as high transendothelial electrical resistance(TEER)(1560 X.cm2±230 X.cm2) and c-GTPase activity. Co-culture with primary rat astrocytes significantly increased the TEER of the model(2970 X.cm2 to 4185 X.cm2). RNAseq analysis confirmed the expression of key BBB-related genes in the hi PSC-derived endothelial cells in comparison with primary human brain microvascular endothelial cells,including P-glycoprotein(Pgp) and breast cancer resistant protein(BCRP). Drug transport assays for nine CNS compounds showed that the permeability of non-Pgp/BCRP and Pgp/BCRP substrates across the model was strongly correlated with rodent in situ brain perfusion data for these compounds(R2= 0.982 and R2= 0.9973,respectively), demonstrating the functionality of the drug transporters in the model. Thus, this model may be used to rapidly screen CNS compounds, to predict the in vivo BBB permeability of these compounds and to study the biology of the BBB.

关键词： blood-brain barrier Drug transport Induced pluripotent stem cell Cell differentiation Prediction of in vivo permeability

Evolution of blood-brain barrier in brain diseases and related systemic nanoscale brain-targeting drug delivery strategies

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Acta Pharmaceutica Sinica B 2021年第8期11卷 2306-2325页

作者： Liang Han Chen Jiang Jiangsu Key Laboratory of Neuropsychiatric Diseases Research College of Pharmaceutical SciencesSoochow UniversitySuzhou 215123China Key Laboratory of Smart Drug Delivery Ministry of EducationState Key Laboratory of Medical NeurobiologyDepartment of PharmaceuticsSchool of PharmacyFudan UniversityShanghai 200032China

bloode-brain barrier(BBB)strictly controls matter exchange between blood and brain,and severely limits brain penetration of systemically administered drugs,resulting in ineffective drug therapy of brain diseases.However,during the onset and progression of brain diseases,BBB alterations evolve inevitably.In this review,we focus on nanoscale brain-targeting drug delivery strategies designed based on BBB evolutions and related applications in various brain diseases including Alzheimer’s disease,Parkinson’s disease,epilepsy,stroke,traumatic brain injury and brain tumor.The advances on optimization of small molecules for BBB crossing and non-systemic administration routes(e.g.,intranasal treatment)for BBB bypassing are not included in this review.

关键词： blood-brain barrier brain diseases brain-targeting Drug delivery systems Nanoparticles

Predictive model of blood-brain barrier penetration of organic compounds

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Acta Pharmacologica Sinica 2005年第4期26卷 500-512页

作者： Xiao-lei MA Cheng CHEN Jie YANG~2 State Key Laboratory of Pharmaceutical Biotechnology,School of Life Science,Nanjing University,Nanjing 210093,China State Key Laboratory of Pharmaceutical Biotechnology School of Life Science Nanjing University Nanjing China

Aim:To build up a theoretical model of organic compounds for the prediction ofthe activity of small molecules through the blood-brain barrier(BBB)in drugdesign.Methods:A training set of 37 structurally diverse compounds was used toconstruct quantitative structure-activity relationship(QSAR)models.Intermo-lecular and intramolecular solute descriptors were calculated using molecularmechanics,molecular dynamics simulations,quantum chemistry and so on.TheQSAR models were optimized using multidimensional linear regression fitting andstepwise method.A test set of 8 compounds was evaluated using the models aspart of a validation process.Results:Significant QSAR models(R=0.955,s=0.232)of the BBB penetration of organic compounds were constructed.BBB penetrationwas found to depend upon the polar surface area,the octanol/water partitioncoefficient,Balaban Index,the strength of a small molecule to combine with themembrane-water complex,and the changeability of the structure of a solute-mem-brane-water complex.Conclusion:The QSAR models indicate that the distribu-tion of organic molecules through BBB is not only influenced by organic solutesthemselves,but also relates to the properties of the solute-membrane-water complex,that is,interactions of the molecule with the phospholipid-rich regions of cellularmembranes.

关键词： blood-brain barrier quantitative structureactivity relationship theoretical models