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Extensive frontal focused ultrasound Check for updates mediated blood-brain barrier opening for the treatment of Alzheimer's disease:a proof-of-concept study

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Translational Neurodegeneration 2021年第4期10卷 573-583页

作者： So Hee Park Kyoungwon Baik Seun Jeon Won Seok Chang Byoung Seok Ye Jin Woo Chang brain Research Institute Department of NeurosurgeryYonsei University College of MedicineSeoulKorea Department of Neurology Yonsei University College of MedicineSeoulKorea

Background:Focused ultrasound(FUS)-mediated blood-brain barrier(BBB)opening has shown efficacy in removal of amyloid plaque and improvement of cognitive functions in preclinical studies,but this is rarely reported in clinical studies.This study was conducted to evaluate the safety,feasibility and potential benefits of repeated extensive BBB opening.Methods:In this open-label,prospective study,six patients with Alzheimer's disease(AD)were enrolled at Severance Hospital in Korea between August 2020 and September 2020.Five of them completed the study.FUS-mediated BBB opening,targeting the bilateral frontal lobe regions over 20 cm^(3),was performed twice at three-month intervals.Magnetic resonance imaging,^(18)F-Florbetaben(FBB)positron emission tomography,Caregiver-Administered Neuropsychiatric Inventory(CGA-NPI)and comprehensive neuropsychological tests were performed before and after the procedures.Results:FUS targeted a mean volume of 21.1±2.7 cm^(3)and BBB opening was confirmed at 95.7%±9.4%of the targeted volume.The frontal-to-other cortical region FBB standardized uptake value ratio at 3 months after the procedure showed a slight decrease,which was statistically significant,compared to the pre-procedure value(-1.6%,0.986 vs 1.002,P=0.043).The CGA-NPI score at 2 weeks after the second procedure significantly decreased compared to baseline(2.2±3.0 vs 8.6±6.0,P=0.042),but recovered after 3 months(5.2±5.8 vs 8.6±6.0,P=0.89).No adverse effects were observed.Conclusions:The repeated and extensive BBB opening in the frontal lobe is safe and feasible for patients with AD.In addition,the BBB opening is potentially beneficial for amyloid removal in AD patients.

关键词： Alzheimer disease Focused ultrasound blood-brain barrier Amyloid beta-peptides

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Research Progresses in the Inhibitory Effect of Bone Mesenchymal Stem Cell-Derived Exosome on blood-brain barrier Disruption following Intracerebral Hemorrhage in Rats

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Journal of Biosciences and Medicines 2021年第9期9卷 125-137页

作者： Gang Yang Zhanwei Ruan Chenbing Wang Chao Gu Junjie Lv Shaojun Yang Lulu Weng Feng Ding Long Ai Donghai Yuan Fei Chen Jiangli Chen Gaofeng Shao Department of Neurosurgery Zhuji Affiliated Hospital of Shaoxing University Shaoxing China Department of Emergency The Third Affiliated Hospital Wenzhou Medical University Wenzhou China

Mesenchymal Stem Cells (MSCs) are a type of non-hematopoietic progenitor cells which have self-replication capacity and multilineage differentiation. They have widely applied in studies of various diseases due to their effects in damaged tissue repair, neuroprotection and immunoregulation. MSCs can secret exosomes through multiple ways in the physiological or pathological state. Many researches’ results on MSC-Exo show that it possesses many functions similar to MSCs, such as immunoregulation and regeneration promotion of damaged tissues. Hence, MSC-Exo is believed to have considerable research potentials in regenerative medicines. This study reviewed the research progresses on biological characteristics and functions of MSC-Exo.

关键词： Bone Mesenchymal Stem Cell-Derived Exosome blood-brain barrier Intracerebral Hemorrhage

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Decreased Cortical Perfusion in Areas with blood-brain barrier Dysfunction in Moyamoya disease

Decreased Cortical Perfusion in Areas with Blood-Brain Barri...

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第十六届中国医师协会神经外科医师年会

作者： Xiaocheng Lu Yabo Huang Peng Zhou Pinjing Hui Zhong Wang Department of Neurosurgery & brain and Nerve Research Laboratory The First Affiliated Hospital of Soochow University

Background:Recently,several studies have focused on the relationship between blood-brain barrier(BBB) impairment and the etiology of Moyamoya disease(MMD).However,in vivo studies investigating about BBB impairment and cortical perfusion in MMD patients were really rare.Methods:This study included 16 patients diagnosed with MMD and 9 patients with atherosclerotic cerebrovascular disease(ACVD),all of who were treated with superficial temporal artery–middle cerebral artery(STA-MCA) bypass.Cortical perfusion was assessed using intraoperative indocyanine green(ICG) videoangiography by calculating the blood flow index(BFI).In addition,we used sodium fluorescein(NaFl) to evaluate the permeability of BBB in vivo during operation Results:The results showed that BBB impairment in MMD patients was more significant than that in ACVD patients,whereas,the cortical perfusion was comparable between two groups.BFI was significantly improved after STA-MCA bypass both in MMD group(post-operation vs pre-operation:109.2±67.7 vs 64.3±35.0,p=0.004) and ACVD group(post-operation vs pre-operation:137.6±89.6 vs 90.8±58.3,p=0.015).Moreover,BFI was significantly decreased in the cortex with BBB impairment as compared with that in the cortex with intact BBB(impaired BBB vs intact BBB:55.7±26.5 vs 87.6±55.1,p=0.025).Following bypass,the cortical perfusion significantly improved in the area of BBB impairment(post-operation vs pre-operation:93.8±75.2 vs 55.7±26.5,p=0.004),which was not observed in the BBB intact area(post-operation vs pre-operation:92.4±50.4 vs 87.6±55.1,p=0.58).Conclusion:In summary,we observed that BBB impairment in MMD patients was more significant than that in ACVD patients.This study also demonstrated for the first time that cortical perfusion was significantly decreased in the cortex with BBB impairment as compared with that in the cortex with intact BBB in MMD patients.We also observed that After STA-MCA bypass,the cortical perfusion was significantly improved in the cortex with BBB impairment.These results may provide a

关键词： blood-brain barrier cortical perfusion Moyamoya disease atherosclerotic cerebrovascular disease

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Super Antibiotics, Part II. Hyperforin, Mass Spectroscopy (MS) and Gas Chromatography-Mass Spectrometry (GC-MS), Evidence of Permeability of the blood-Testis barrier (BTB) and the blood-brain barrier (BBB) to Hyperforin

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International Journal of Analytical Mass Spectrometry and Chromatography 2016年第4期4卷 66-73页

作者： Ilia Brondz Norwegian Drug Control and Drug Discovery Institute (NDCDDI) Ski Norway

In the first article of this series, we presented some evidence of hyperforin as an antibiotic, antiprotozoal, antiviral, anticancer, and immunomodulatory substance. In the present article, evidence of the permeability of the blood-testis barrier (BTB) and blood-brain barrier (BBB) to hyperforin and its distribution in other organs of the domestic pig (Sus scrofa domesticus) are revealed. Seven-month-old male boars with a body mass of 100 kg were fed a diet containing hyperforin. Organs were surgically removed under anesthesia. Organs were suitable prepared and extracted, and then analyzed using gas chromatography-mass spectrometry with supersonic molecular beams (GC-MS with SMB). The presence of hyperforin was recorded in all organs and body fluids. Special attention was paid to the evaluation of the presence of hyperforin in the brain and testes of experimental animals. The presence of hyperforin in the brain and testes of experimental animals was established by GC-MS with SMB. The results are of interest because penicillin and numerous other antibiotics cannot pass through the BTB or BBB if healthy or non-inflamed, which limits their use in patients with meningitis and gonorrhea. The findings are also of interest in cases of penicillin- and multi-antibiotic-resistant bacterial infections.

关键词： Antibiotics Hyperforin Super antibiotic Mass Spectroscopy Gas Chromatography-Mass Spectrometry blood-Testis barrier blood-brain barrier Methicillin-Resistant Staphylococcus aureus (MRSA)

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99mTc complex conjugated to insulin: CNS radiopharmaceuticals design based on principles of blood-brain barrier transport vector

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Science Bulletin 2005年第20期 43-47页

作者： LIU Fei, FAN Caiyun, ZHANG Jinming, WANG Wushang & LIU Boli Department of Chemistry, Beijing Normal University, Beijing 100875, China

Hydrophilic 99mTc-EC and nonlipophilic 99mTc- MAMA′-BA complexes, owing to the existing of intact blood-brain barrier (BBB) in vivo, cannot cross from blood to brain. Previous studies showed that insulin is selectively transported by receptor-mediated transcytosis through the brain capillary endothelial wall that makes up the BBB. In this paper, based on the characteristic of the insulin receptor enriched in brain capillary, the complexes of hydrophilic 99mTc-EC and nonlipophilic 99mTc-MAMA′-BA are conju- gated to insulin respectively. After purification, the radio- chemical purity of 99mTc-EC-insulin and 99mTc-MAMA′- BA-insulin was > 90% and the stability in vitro was good. Expectation for the special formulation can be internalized and endocytosed into the capillary membrane by the vec- tor-mediated brain delivery system, and transported 99mTc-labeled conjugate through the BBB in vivo, thus en- hancing brain uptake in mice. The biodistribution results of 99mTc-EC-insulin and 99mTc-MAMA′-BA-insulin in mice in- dicated that the brain uptake was higher than 99mTc-EC and 99mTc-MAMA′-BA to some extent. The ratios of brain uptake of 99mTc-EC-insulin to 99mTc-EC, 99mTc-MAMA′-BA-insulin to 99mTc-MAMA′-BA were 4―6 at 2 and 3 h post-injection respectively. In conclusion, the given results have illustrated a new way of brain uptake enhancing for nonlipophilic like complexes that have BBB delivery problems. It has a poten- tial value for the ongoing development of 99mTc-labeled ra- diopharmaceuticals for CNS receptors imaging.

关键词： blood-brain barrier 99mTc labeling insulin brain deliv- ery system.

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Evidence on Invasion of blood,Adipose Tissues,Nervous System and Reproductive System of Mice After a Single Oral Exposure:Nanoplastics versus Microplastics

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Biomedical and Environmental Sciences 2022年第11期35卷 1025-1037页

作者： YANG Zuo Sen BAI Ying Long JIN Cui Hong NA Jun ZHANG Rui GAO Yuan PAN Guo Wei YAN Ling Jun SUN Wei Institute of Preventive Medicine China Medical UniversityShenyang 110122LiaoningChina Institute of Chronic Diseases Liaoning Provincial Center for Disease Control and PreventionShenyang 110000LiaoningChina Department of Maternal and Child Health School of Public HealthChina Medical UniversityShenyang 110122LiaoningChina Department of Toxicology School of Public HealthChina Medical UniversityShenyang 110122LiaoningChina Research Center for Universal Health School of Public HealthChina Medical UniversityShenyang 110122LiaoningChina

Objective This study was designed to provide the evidences on the toxicokinetics of microplastics(MPs)and nanoplastics(NPs)in the bodies of mammals.Methods 100 nm,3μm,and 10μm fluorescent polystyrene(PS)beads were administered to mice once by gavage at a dose of 200 mg/kg body weight.The levels and change of fluorescence intensity in samples of blood,subcutaneous fat,perirenal fat,peritesticular fat,cerebrum,cerebellum,testis,and epididymis were measured at 0.5,1,2,and 4 h after administration using an IVIS Spectrum small-animal imaging system.Histological examination,confocal laser scanning,and transmission electron microscope were performed to corroborate the findings.Results After confirming fluorescent dye leaching and impact of pH value,increased levels of fluorescence intensity in blood,all adipose tissues examined,cerebrum,cerebellum,and testis were measured in the 100 nm group,but not in the 3 and 10μm groups except in the cerebellum and testis at 4 h for the 3μm PS beads.The presence of PS beads was further corroborated.Conclusion After a single oral exposure,NPs are absorbed rapidly in the blood,accumulate in adipose tissues,and penetrate the blood-brain/testis barriers.As expected,the toxicokinetics of MPs is significantly size-dependent in mammals.

关键词： Adipose accumulation blood-brain barrier blood-testis barrier blood uptake Microplastics Nanoplastics

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Learning and Memory Impairment and Abnormal blood-brain barrier Function in Rats Induced by Increased blood Pressure Variability

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神经药理学报 2019年第4期 22-23页

作者： JIA Xiao-li WANG Wei ZHOU Yan-meng TAN Rui ZHANG Fang-fang ZHOU Li-jun MIAO Shen JI Wei ZHU De-rong ZHAO Xiao-min ZHANG Han-ting Institute of Pharmacology Shandong First Medical University & Shandong Academy of Medical Sciences

Objective:Clinical reports have shown that increased blood pressure variability can lead to decreased learning and memory,but the mechanism is still unclear. Based on the dysfunction of blood-brain barrier is one of the mechanisms of learning and memory disorder,we hypothesize that the mechanism of learning and memory impairment caused by elevated blood pressure variability is related to abnormal blood-brain barrier function. Method:The rat model of increased blood pressure variability was established by sinoaortic denervation( SAD) in rats. Morris Water Maze was used to evaluate learning and memory ability of rats. Then the blood-brain barrier function was evaluated by the permeability of Evans blue and FITC-dextran. Results:Compared with sham-operated( Sham) rats,the escape latency of Morris Water Maze was significantly extended in rats two,four,eight and sixteen weeks after SAD(Pblood-brain barrier permeability in SAD group was markedly increased than that in Sham group( Pblood pressure variability leads to learning and memory dysfunction in rats and this dysfunction may be associated with the impaired blood-brain barrier function.

关键词： blood pressure variability rat learning and memory blood-brain barrier

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Enhanced Drug Accumulation in the brain Disease via blood-brain barrier Regulating Nano-Platform

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神经药理学报 2019年第Z1期 109-110页

作者： MENG Ling-tong LU Ying-mei HAN Feng College of Pharmacy Nanjing Medical University

Objective:To develop a versatile blood-brain barrier regulating nanoplatform and evaluate the accumulation of therapeutic drugs into the region of brain diseases. Methods:The blood-brain barrier regulating nano-platform is prepared in a one-step ultrasonication method. Taking advantage of the emulsification of transferrin,perfluocarbon of low boiling point can be encapsulated in the hydrophobic region of transferrin. Moreover,the encapsulated adenosine 2 A receptor agonist can regulate the state of tight-junction to open a therapeutic window for drug accumulation. Under the therapeutic ultrasound of low-intensity(0.5 W·cm-2),perfluocarbon is vaporized leading to the instability of structure. Subsequently,adenosine 2 A receptor agonist is immediately released to make brain endothelial cells shrink. As a result,more therapeutic drug can be delivered into brain tissue to enhance the therapeutic efficacy of brain disease treatment,such as glioblastoma. The injection of G422-Luc cells into corpus striatum is used to establish glioblastoma model with micro-injector. Temozolomide,evans blue and dextran-FITC are the selective model molecules. Immumohistochemical staining,high performance liquid chromatography and UV-vis spectrometer are used for the evaluation of blood-brain barrier integrity. Results:The obtained blood-brain barrier regulating nanoplatform is uniform and spherical. The diameter of the nanoparticles is about 180 nm. The nanoplatfrom is stable. The dynamic diameter and polydispersity index keep constant for more than 72 hours. There is no premature release of encapsulated molecules in presence of plasma at 37℃. Meanwhile,under the function of low-intensity ultrasound,the nanoparticles above are broken and adenosine 2 A receptor agonist is released simultaneously. As the application time increases,the percentage of released agonist augments. Orthotopic glioblastoma model is established by the injection of G422-Luc tumor cells into corpus striatum,which is confirmed with IVIS Lumina imaging system. Surprisi

关键词： blood-brain barrier regulating nano-platform drug accumulation brain diseases

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Transport of Cryptotanshinone,a Major Active Triterpenoid in Salvia Miltiorrhiza Bunge Widely Used in the Treatment of Stroke and Alzheimer's Disease,Across the blood-brain barrier

Transport of Cryptotanshinone,a Major Active Triterpenoid in...

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中国(江门)国际中西医结合心血管病学术会议

作者： Balram Chowbay Clinical Pharmacology Laboratory Division of Medical Sciences National Cancer CentreSingapore 169610

Cryptotanshinone(CTS),a major constituent from the roots of Salvia miltiorrhiza(Danshen),is widely used in the treatment of coronary heart disease,stroke and less commonly Alzheimer’s disease.Our recent study indicates that CTS is a substrate for P-glycoprotein (PgP/MDR1/ABCB1).This study has investigated the nature of the brain distribution of CTS across the brain-blood barrier (BBB) using several in vitro and in vivo rodent models.A polarized transport of CTS was found in rat primary microvascular endothelial cell(RBMVEC) monolayers,with facilitated efflux from the abluminal side to luminal side.Addition of a PgP(e.***.verapamil and quinidine) or multi-drug resistance protein 1/2(MRP1/2) inhibitor(e.***.probenecid and MK-571) in both luminal and abluminal sides attenuated the polarized transport.In a bilateral in situ brain perfusion model,the uptake of CTS into the cerebrum increased from 0.52±0.1%at 1min to 11.13±2.36 ml/100 g tissue at 30 min and was significantly greater than that of sucrose.Co-perfusion of a PgP/MDR1(e.***.verapamil) or MRP1/2 inhibitor(e.***.probenecid) significantly increased the brain distribution of CTS by 35.1-163.6%. The brain levels of CTS were only about 21%of those in plasma,and were significantly increased when coadministered with verapamil or probenecid in rats.The brain levels of CTS in rats subjected to middle cerebral artery occlusion and rats treated with quinolinic acid(a neurotoxin) were about 2- to 2.5-fold higher than the control rats.Moreover,the brain levels in mdrla(-/-) and mrpl(-/-) mice were 10.9- and 1.5-fold higher than those in the wild-type mice,respectively.Taken collectively,these findings indicate that PgP and Mrp1 limit the brain penetration of CTS in rodents,suggesting a possible role of PgP and MRP1 in limiting the brain penetration of CTS in patients and causing drug resistance to Danshen therapy and interactions with conventional drugs that are substrates of PgP and MRP1.Further studies are needed to explore the role of other drug transporters in restricting th

关键词： Cryptotanshinone blood-brain barrier P-glycoprotein multidrug resistance associated protein middle cerebral artery occlusion Alzheimer’s disease.

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Effects of captopril on blood-brain barrier permeability and matrix metalloproteinase-9 expression after photothrombotic cerebral ischemia in rats

Effects of captopril on blood-brain barrier permeability and...

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2012第二届国际神经再生高峰论坛

作者： Jianfeng Wang Yingna Wang Li Zhang Ying Zhang Qiong Wu Haiying Chu Department of Neurology Affiliated Dalian Central Hospital of Dalian Medical University Central Laboratory Affiliated Dalian Central Hospital of Dalian Medical University Department of Histology and Embryology Dalian Medical University

Ischemic cerebrovascular disease is a common disease and blood-brain barrier damage is an important pathophysiological basis of cerebral ischemia reperfusion injury. Matrix metalloproteinase （MMP） 9 may cause blood-brain barrier damage. Hypertension is a risk factor for cerebrovascular disease, and captopril is an antihypertensive agent. To investigate the function and mechanism of captopril and expression of MMP-9 and MMP-2 after cerebral ischemia reperfusion injury, we established middle cerebral artery occlusion model by intraluminal suture method, and rats were administrated captopril for 1, 3, 5, 7 and 9 days by oral gavage. After different periods of captopril treatment, there was a significant decrease of neurological score in a time-dependent manner. Evan’s blue extravasation was highest on day 1 and decreased with prolonged drug administration time, but slightly increased from day 7 to day 9 after cerebral ischemia reperfusion. MMP-9 activity peaked 1 day after reperfusion, then gradually decreased 3-7 days after reperfusion by captopril treatment, but slightly increased on day 9 （P ＜ 0.05）. MMP-2 activity peaked on day 3 after reperfusion by captopril treatment, and gradually decreased （P ＜ 0.05）. There was a strong positive correlation between Evan’s blue extravasation and MMP-9 expression （R = 0.981, P = 0.003） but not MMP-2 expression. Evan’s blue extravasation of brain tissues followed the same trend as MMP-9 expression but not MMP-2 expression. Thus, after cerebral ischemia reperfusion, blood-brain barrier permeability correlated with MMP-9 expression. Captopril could reduce MMP activity and cerebral ischemia reperfusion injury, and promote functional recovery of nerves after cerebral ischemia. However, large doses of captopril for more than 7 days enhanced MMP-9 activity and increased blood-brain barrier permeability. This implied that prolonged captopril use inhibited excessive MMP expression, affecting the healing of cerebral ischemia reperfusion and late cellular debris removal, thus aggravatin

关键词： captopril blood-brain barrier permeability matrix metalloproteinase-9 photothrombotic cerebral ischemia rats

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