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Neural Regeneration Research 2015年第12期10卷 2011-2017页

作者： Yan Wang Ning Wang Biao Cai Guang-yun Wang Jing Li Xing-xing Piao Key Laboratory of Xin’an Medicine Ministry of Education Institute for Pharmacodynamics and Safety Evaluation of Chinese Medicine Anhui Academy of Chinese College of Pharmacy Anhui University of Chinese Medicine

Drugs for the treatment and prevention of nervous system diseases must permeate the bloodbrain barrier to take effect.In vitro models of the blood-brain barrier are therefore important in the investigation of drug permeation mechanisms.However,to date,no unified method has been described for establishing a blood-brain barrier model.Here,we modified an in vitro model of the blood-brain barrier by seeding brain microvascular endothelial cells and astrocytes from newborn rats on a polyester Transwell cell culture membrane with 0.4-μm pores,and conducted transepithelial electrical resistance measurements,leakage tests and assays for specific bloodbrain barrier enzymes.We show that the permeability of our model is as low as that of the bloodbrain barrier in vivo.Our model will be a valuable tool in the study of the mechanisms of action of neuroprotective drugs.

关键词： nerve regeneration blood-brain barrier astrocytes brain microvascular endothelial cells permeability co-culture Transwell chamber neural regeneration

Electroacupuncture reduces injury to the blood-brain barrier following cerebral ischemia/reperfusion injury

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Neural Regeneration Research 2012年第36期7卷 2901-2906页

作者： Yongjun Peng Hesheng Wang Jianhua Sun Li Chen Meijuan Xu Jihong Chu Department of Acupuncture and Rehabilitation Affiliated Hospital of Nanjing University of Chinese Medicine

This study used electroacupuncture at Renzhong （DU26） and Baihui （DU20） in a rat model of cerebral ischemia/reperfusion injury. Neurological deficit scores, western blotting, and reverse transcription-PCR results demonstrated that electroacupuncture markedly reduced neurological deficits, decreased corpus striatum aquaporin-4 protein and mRNA expression, and relieved damage to the blood-brain barrier in a rat model of cerebral ischemia/reperfusion injury. These results suggest that electroacupuncture most likely protects the blood-brain barrier by regulating aquaporin-4 expression following cerebral ischemia/reperfusion injury.

关键词： electroacupuncture cerebral ischemia/reperfusion blood-brain barrier aquaporin-4 brain edema rat Renzhong （DU26） Baihui （DU20） brain injury regeneration neural regeneration

Impact of migraine attacks on the blood-brain barrier

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Chinese Medical Journal 2010年第18期123卷 2559-2561页

作者： GAO Hong-mei LI Le ZHANG Ke-ling CHEN Xu-hui TIAN Shu-qing ZHANG Zhong-ling Department of Neurology the First Affiliated Hospital Harbin Medical University Harbin 150001 China

Background Cortical spreading depression can cause migraine attack, and up-regulate matrix metalloproteinase-9 （MMP-9） expression in animal. This study aimed to determine the impact on the structure and function of the blood-brain barrier by measuring plasma MMP-9 levels in patients at the acute and late stages of migraine attacks in order to elucidate the pathological mechanisms involved. Methods We recruited a case-control cohort of 38 adult migraine patients and 20 age- and gender-matched healthy control subjects. Five milliliter blood samples were collected at the acute and late stages of migraine （days 1-7）, and also from the control subjects. Solid phase double antibody sandwich enzyme-linked immunosorbent assay was used to determine plasma MMP-9 levels. Statistical analysis was performed using the SAS version 9.1. Results Initial plasma MMP-9 levels of migraine patients were significantly higher than those of controls （（12.612±0.016） μg/L vs. （6.069±0.023）μg/L, respectively, P 〈0.05）. High MMP-9 expression was observed during days 1-6 of migraine attacks, with highest expression occurring on day 3 （（17.524±0.035） μg/L）. During attacks, MMP-9 levels were similar in migraine patients with and without aura （P 〉0.05）; in addition, levels were not correlated with degree of headache pain （P 〉0.05）. Conclusions We hypothesize that migraine could lead to increased plasma MMP-9 levels resulting in blood-brain barrier damage. MMP-9 levels increase during days 1-6 of migraine attacks, peaking on day 3. Therefore, MMP-9 could be used as a biological marker to guide treatment of migraine attacks.

关键词： migraine atrix metalloproteinase 9 blood-brain barrier

Transport of carbamazepine and drug interactions at blood-brain barrier

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Acta Pharmacologica Sinica 2006年第2期27卷 249-253页

作者： jing-jing SUN Lin XIE Xiao-dong LIU~2 Center of Drug Metabolism and Pharmacokinetics,China Pharmaceutical University,Nanjing 210009,China Center of Drug Metabolism and Pharmacokinetics China Pharmaceutical University Nanjing China

Aim:To investigate the characteristics of carbamazepine(CBZ)transport anddrug interactions at the blood-brain barrier.Methods:Cultured rat brain microvas-cular endothelial cells(rBMEC)were used as an in vitro model of the blood-brainbarrier(BBB).When cells became confluent,CBZ uptake over time was recordedby incubation of the cells in a medium containing 10 mg/L CBZ at 37℃.Thesteady-state uptake of CBZ by rBMEC was tested for different CBZ concentra-tions at 37℃.The effects of various agents on the steady-state uptake of CBZand efflux of CBZ from rBMEC were also studied.Results:The uptake of CBZ byrBMEC was time-and concentration-dependent.The steady-state uptake oc-curred at 30 rain for incubation.The steady-state uptake was significantly in-creased(P<0.01)by treatment with dinitrophenol.The co-administration ofcyclosporine A significantly increased the steady-state uptake of CBZ by therBMEC,whereas co-administration of olanzapine significantly decreased the up-take in a concentration-and temperature-dependent manner.The efflux of CBZfrom rBMEC was inhibited by CsA.Conclusion:The transport of CBZ at the BBBis mediated by many transporters.Some specific ABC(ATP-binding cassette,ABC)efflux transporters may be involved in the transport of CBZ.Drugs influ-ence the transport of CBZ at the BBB in different ways.

关键词： carbamazepine blood-brain barrier cyclosporine A olanzapine rat brain microvascular endothelial cells drug interaction

Experimental models for cancer brain metastasis

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Cancer Pathogenesis and Therapy 2024年第1期2卷 15-23页

作者： Zihao Liu Shanshan Dong Mengjie Liu Yuqiang Liu Zhiming Ye Jianhao Zeng Maojin Yao Guangzhou Institute of Respiratory Disease The First Affiliated Hospital of Guangzhou Medical UniversityChina State Key Laboratory of Respiratory DiseaseGuangzhouGuangdong 510182China Department of Medical Genetics and Cell Biology GMU-GIBH Joint School of Life SciencesGuangzhou Medical UniversityGuangzhouGuangdong 511436China Department of Microbiology Immunologyand Cancer BiologyUniversity of Virginia Health SystemCharlottesvilleVA 22908USA

brain metastases are a leading cause of cancer-related mortality.However,progress in their treatment has been limited over the past decade,due to an incomplete understanding of the underlying biological mechanisms.Employing accurate in vitro and in vivo models to recapitulate the complexities of brain metastasis offers the most promising approach to unravel the intricate cellular and physiological processes involved.Here,we present a comprehensive review of the currently accessible models for studying brain metastasis.We introduce a diverse array of in vitro and in vivo models,including cultured cells using the Transwell system,organoids,microfluidic models,syngeneic models,xenograft models,and genetically engineered models.We have also provided a concise summary of the merits and limitations inherent to each model while identifying the optimal contexts for their effective utilization.This review serves as a comprehensive resource,aiding researchers in making well-informed decisions regarding model selection that align with specific research questions.

关键词： brain metastases blood-brain barrier Animal model In vitro model

A matrix metalloproteinase-responsive hydrogel system controls angiogenic peptide release for repair of cerebral ischemia/reperfusion injury

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Neural Regeneration Research 2025年第2期20卷 503-517页

作者： Qi Liu Jianye Xie Runxue Zhou Jin Deng Weihong Nie Shuwei Sun Haiping Wang Chunying Shi Department of Human Anatomy Histology and EmbryologySchool of Basic MedicineQingdao UniversityQingdaoShandong ProvinceChina Department of Neurology The Affiliated Hospital of Qingdao UniversityQingdaoShandong ProvinceChina Department of General Practice The Affiliated Hospital of Qingdao UniversityQingdaoShandong ProvinceChina

Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI(QK)are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases.However,conventional topical drug delivery often results in a burst release of the drug,leading to transient retention(inefficacy)and undesirable diffusion(toxicity)in vivo.Therefore,a drug delivery system that responds to changes in the microenvironment of tissue regeneration and controls vascular endothelial growth factor release is crucial to improve the treatment of ischemic stroke.Matrix metalloproteinase-2(MMP-2)is gradually upregulated after cerebral ischemia.Herein,vascular endothelial growth factor mimic peptide QK was self-assembled with MMP-2-cleaved peptide PLGLAG(TIMP)and customizable peptide amphiphilic(PA)molecules to construct nanofiber hydrogel PA-TIMP-QK.PA-TIMP-QK was found to control the delivery of QK by MMP-2 upregulation after cerebral ischemia/reperfusion and had a similar biological activity with vascular endothelial growth factor in vitro.The results indicated that PA-TIMP-QK promoted neuronal survival,restored local blood circulation,reduced blood-brain barrier permeability,and restored motor function.These findings suggest that the self-assembling nanofiber hydrogel PA-TIMP-QK may provide an intelligent drug delivery system that responds to the microenvironment and promotes regeneration and repair after cerebral ischemia/reperfusion injury.

关键词： angiogenesis biomaterial blood-brain barrier cerebral ischemia/reperfusion injury control release drug delivery inflammation QK peptides matrix metalloproteinase-2 neuroprotection self-assembling nanofiber hydrogel

The enhanced protective effects of salvianic acid A: A functionalized nanoparticles against ischemic stroke through increasing the permeability of the blood-brain barrier

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Nano Research 2020年第10期13卷 2791-2802页

作者： Yaru Li Xiaojie Zhang Zhifeng Qi Xueling Guo Xiaopeng Liu Wenjuan Shi Yang Liu Libo Du State Key Laboratory for Structural Chemistry of Unstable and Stable Species Center for Molecular ScienceInstiute of ChemistryChinese Academy of SciencesBeijing 100190China Graduate School University of Chinese Academy of SciencesBejing 100049China Cerebrovascular Diseases Research Institute Xuanwu Hospital of Captital Medical UniversityBeijing 100053China Department of Neurosurger The Second Hospial of Hebei Medical UniversityShijazhuang 050051China

Ischemic stroke is the leading cause of disability and death worldwide. Currently, the only proven treatment for ischemic stroke is restoring the cerebral blood supply. In addition, some of the tissue is damaged during the subsequent reperfusion because of the overproduction of reactive oxygen species (ROS). Furthermore, antioxidant therapies have shown promise in preclinical studies for the treatment of ischemia-reperfusion injury. However, their therapeutic efficacy has been limited because of their low bioavailability in brain. To resolve this issue, we synthesized ROS-responsive, fan-shaped dendrimer nanoparticles (NPs) and conjugated them with a blood-brain barrier (BBB)-targeting peptide, COG1410, and salvianic acid A (SA), which is an effective antioxidant in ischemic stroke. The BBB targeting peptide acts as a ligand of the nanocarrier system and penetrates the BBB through the endocytosis of the ligand receptor. The results showed that T-SA-NPs not only target and accumulate in the infarct area, they also reduce over 2 times of the infarct area and reverse the behavioral deficits in MCAO mice, which illustrates that these NPs have an effective therapeutic effect on the ischemic stroke. In addition, these NPs had no toxicity in any organs of the body. Importantly, the present study provides an alternative strategy for delivering antioxidants to the brain and achieving targeted therapy of ischemic stroke.

关键词： ischemic stroke blood-brain barrier salvianic acid A COG1410 reactive oxygen species(ROS)-responsive nanocarrier mitophagy

Special interstitial route can transport nanoparticles to the brain bypassing the blood-brain barrier

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Nano Research 2019年第11期12卷 2760-2765页

作者： Nan Hu Xiaoli Shi Qiang Zhang Wentao Liu Yuting Zhu Yuqing Wang Yi Hou Yinglu Ji Yupeng Cao Qian Zeng Zhuo Ao Quanmei Sun Xiaohan Zhou Xiaochun Wu Dong Han CAS Center for Excellence in Nanoscience National Center for Nanoscience and Technology Beijing 100190China School of Future Technology University of Chinese Academy of SciencesBejjing 100049China Department of Traditional Chinese Medicine Chengde Medical UriversityChengde 066000China Institute of Chemistry Chinese Academy of SciencesBeijing 100190China

Nowadays,nanoparticles(NPs)are considered to be ideal tools for bioimaging and drug delivery.Although increasing research has focused on NP biodistribution,transportation in the interstitial architecture has been neglected.The entire body is connected by the interstitial architecture,which can provide a long-range and direct pathway for NP biodistribution in a nonvascular system.In this study,we report that 10-nm gold NPs injected directly into the interstitial architecture of the tarsal tunnel of rats(intervaginal space injection(ISI))were delivered to the brain without crossing the blood-brain barrier.Furthermore,NaGdF4 nanoparticles were used to explore the transportation route by magnetic resonance imaging.The results demonstrated that,after ISI,the NaGdF4 nanoparticles were transported through the perivascular interstitial space of the carotid arteries and brain vessels to the brain.This is a special nonvascular transportation route like a stream based on the interstitial architecture that provides an alternative pathway for NP biodistribution.

关键词： nanoparticles interstitial stream mass transportation blood-brain barrier magnetic resonance imaging

Effects of Minimally Invasive Puncture and Drainage of Intracranial Hematoma on the blood-brain barrier in Patients with Cerebral Hemorrhage

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2007年第1期27卷 101-103页

作者：黄晓江郭守刚王伟 Department of Neurology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology

The effects of minimally invasive surgery on the blood-brain barrier （BBB） of 30 patients with cerebral hemorrhage were investigated. Difference of the BBB index and serum MBP concentration were assessed in 15 cases of conservative treatment group and 15 cases of minimally invasive surgery group. The BBB index in minimally invasive surgery group was significantly lower than in conservative treatment group （P〈0.05）, and the BBB index in the two treatment groups was significantly higher than in control group （P〈0.01）. Serum MBP concentration in minimally invasive surgery group was significantly lower than in conservative treatment group （P〈0.05）, and that in the two treatment groups was significantly higher than in control group （P〈0.01）. It was suggested the permeability of BBB in patients with cerebral hemorrhage was increased, and BBB index and serum MBP concentration in patients with cerebral hemorrhage were increased. Minimally invasive surgery can reduce the lesion of cytotoxicity to BBB and cerebral edema.

关键词： intracerebral hemorrhage blood-brain barrier BBB index MBP

ATP-binding cassette transporters at the zebrafish blood-brain barrier and the potential utility of the zebrafish as an in vivo model

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Cancer Drug Resistance 2021年第3期4卷 620-633页

作者： Jordan M.Hotz Joanna R.Thomas Emily N.Katz Robert W.Robey Sachi Horibata Michael M.Gottesman Laboratory of Cell Biology Center for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMD 20892USA Zebrafish Core Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesdaMD 20892USA

The brain is protected from toxins by a tightly regulated network of specialized cells,including endothelial cells,pericytes,astrocyes,and neurons,known collectively as the blood-brain barrier(BBB).This selectively permeable barrier permits only the most crucial molecules essential for brain function to enter and employs a number of different mechanisms to prevent the entry of potentially harmful toxins and pathogens.In addition to a physical barrier comprised of endothelial cells that form tight junctions to restrict paracellular transport,there is an active protective mechanism made up of energy-dependent transporters that efflux compounds back into the bloodstream.Two of these ATP-binding cassette(ABC)transporters are highly expressed at the BBB:P-glycoprotein(P-gp,encoded by the ABCB1 gene)and ABCG2(encoded by the ABCG2 gene).Although a number of in vitro and in vivo systems have been developed to examine the role that ABC transporters play in keeping compounds out of the brain,all have inherent advantages and disadvantages.Zebrafish(Danio rerio)have become a model of interest for studies of the BBB due to the similarities between the zebrafish and mammalian BBB systems.In this review,we discuss what is known about ABC transporters in zebrafish and what information is still needed before the zebrafish can be recommended as a model to elucidate the role of ABC transporters at the BBB.

关键词： ABC transporters blood-brain barrier ABCG2 P-glycoprotein zebrafish