脑出血后血-脑屏障破坏与血肿周围水肿形成

脑出血后血肿周围水肿的形成是继发性脑组织损害的表现形式之一。普遍认为血肿周围水肿的形成是由于脑出血后血-脑屏障破坏,进而引发血管源性水肿。目前定量评价血-脑屏障通透性的方法包括影像学和生物学标志物,二者均可以作为研究血-脑屏障与血肿周围水肿关系的重要方法。研究血-脑屏障破坏与血肿周围水肿之间关系的最终目的是探寻到可以阻止血-脑屏障破坏、减少血肿周围水肿的治疗方法。     

高胆固醇血症对神经功能和脑血管病影响的研究进展

胆固醇对维持脑组织正常生理功能十分重要,其表达水平的精准调控通过神经血管单元三要素(神经元、神经胶质细胞和血-脑屏障)的密切协同得以实现.高胆固醇血症通常伴随血-脑屏障通透性增加,激活的星形胶质细胞上调一系列胆固醇相关基因的转录,引起胆固醇跨膜转运蛋白高表达,破坏神经胶质细胞-神经元之间信号转导的稳定,连同小胶质细胞共...     

脑小血管病相关免疫炎症机制研究进展

脑小血管病是以反复发作的脑卒中和神经退行性变为特征的颅内小血管病变,发病机制尚不清楚,血-脑屏障通透性破坏、慢性炎症反应和白细胞浸润等免疫炎症机制在脑小血管病的发生与发展中发挥重要作用.目前除控制危险因素外,尚无预防与治疗的有效方法.本文综述脑小血管病相关免疫炎症机制进展.     

富马酸二甲酯对缺血性卒中的神经保护作用及其机制

缺血性卒中(ischemic stroke, IS)发病机制复杂。近年来越来越多的研究证实，富马酸二甲酯(dimethyl fumarate, DMF)可通过减轻IS后氧化应激和炎性反应发挥神经保护作用，促进血-脑屏障修复和神经功能转归，改善预后。现就DMF对IS的神经保护作用及相关机制研究进展进行综述。     

神经炎症与血脑屏障的相关性研究进展

神经炎症是一种发生在大脑中的炎症过程,参与许多神经系统疾病的发生和发展,这一炎症反应伴随着血-脑屏障的改变,同时血-脑屏障也是临床治疗中枢神经系统疾病干预的目标,致力于改善其通透性、降低药物无效运输以提高生物利用度仍是神经治疗学发展中的一大挑战。本文综述了神经炎症与血脑屏障的相关性研究,以期对中枢神经系统疾病的诊断和治疗提供帮助。     

糖尿病对血-脑屏障的损害及其机制

血-脑屏障是中枢神经系统特有的重要结构.血-脑屏障损害与多种中枢神经系统疾病的发生与发展有关.糖尿病所致血-脑屏障病理学改变、屏障功能损害、转运功能障碍和脑微血管紧密连接性质改变,是糖尿病引起中枢神经系统并发症的重要原因之一.     

黄芪甲苷对大鼠脑缺血再灌注后血-脑屏障的保护作用及ZO-1蛋白表达的影响

目的探讨黄芪甲苷对大鼠脑缺血再灌注后血-脑屏障的保护作用及其相关蛋白ZO-1表达的影响。方法SD大鼠72只,随机分为假手术组、模型组和黄芪甲苷治疗A组(10mg/kg)、黄芪甲苷治疗B组(20mg/kg)。分别采用伊文思蓝及干湿法测定大鼠血-脑屏障的通透性,使用免疫组化与医学图像分析相结合的方法检测血-脑屏障上ZO-1蛋白的表达。结果与模型组相比,两黄芪甲苷治疗组大鼠脑组织中伊文思蓝含量及含水量显著降低,ZO-1蛋白表达增加(均P<0.05);两黄芪甲苷治疗组间相比,差异无统计学意义。结论黄芪甲苷可通过抑制脑缺血再灌注后血-脑屏障通透性的增高而发挥脑保护作用,其保护血-脑屏障的机制可能与上调ZO-1蛋白的表达有关。     

血脑屏障--解剖与生理

由血液运载的物质在进入脑组织的途中需通过一道屏障,人们对它的认识至少已经过一个世纪。Lewandowsky和Goldman观察到只有将酸性活体染剂注入到蛛网膜下腔才能使脑组织染色,而注入到血流中却不能,于是人们找到了血脑屏障(blood-brainbarrier,BBB)存在的证据。实际上,广义上的血脑屏障包括三部分:血-脑屏障,血-脑脊液屏障(blood-cerebrospinalfluidbarrier,BLB)和脑脊液-脑屏障(brain-CSFbarrier,LBB),其中血-脑屏障和血-脑脊液屏障解剖结构有类似之处,生理和病理意义重大。我们这里主要回顾具有典型意义的血-脑屏障(图1)。脑是人体最…     

肿瘤脑转移血-脑屏障功能改变的基础与临床

脑转移瘤是临床上常见的成人脑肿瘤,肿瘤发生脑转移后严重影响病人的生存期及生活质量。肿瘤细胞随血循环到达大脑后接触到的第一个脑部结构就是血-脑屏障,血-脑屏障在脑转移瘤形成及治疗中均扮演着重要角色。肿瘤细胞与血-脑屏障的相互作用过程决定肿瘤细胞是否能在脑部存活、迁移、增殖并最终形成转移性病灶,化疗药物需透过血-脑屏障才能作用于肿瘤。研究肿瘤脑转移过程中血-脑屏障变化,对脑转移瘤的预防及治疗具有重要意义。本文对相关研究进行综述。     

血脑屏障的研究进展

本文参阅最近文献,对血—脑屏障的研究进展作了较全面的介绍。特别在血—脑屏障的形态特征、功能特点、效能机制、影响因素和研究方法等方面作了重点描述。以期对血—脑屏障有进一步的了解。     

Impact of stress and mast cells on brain metastases

Metastases continue to be the chief cause of morbidity and mortality for many tumors, including brain metastases of lung and mammary adenocarcinoma. Stress appears to increase metastases, but the mechanism is not understood. Recent evidence suggests that local inflammation is conducive for cancer growth and a unique immune cell, the mast cell, accumulates in the stroma surrounding tumors and is critically located at the blood-brain-barrier (BBB). Mast cells express receptors for and can be stimulated by corticotropin-releasing hormone (CRH), secreted under stress, to release mediators such as histamine, IL-8, tryptase and vascular endothelial growth factor (VEGF), which disrupt the BBB permitting metastases. Stress and mast cells could serve as new targets for drug development to prevent brain metastases, especially since CRH receptor antagonists and brain mast cell inhibitors have recently been developed.     

Quantifying blood-brain barrier leakage in small vessel disease: Review and consensus recommendations

Cerebral small vessel disease (cSVD) comprises pathological processes of the small vessels in the brain that may manifest clinically as stroke, cognitive impairment, dementia, or gait disturbance. It is generally accepted that endothelial dysfunction, including blood-brain barrier (BBB) failure, is pivotal in the pathophysiology. Recent years have seen increasing use of imaging, primarily dynamic contrast-enhanced magnetic resonance imaging, to assess BBB leakage, but there is considerable variability in the approaches and findings reported in the literature. Although dynamic contrast-enhanced magnetic resonance imaging is well established, challenges emerge in cSVD because of the subtle nature of BBB impairment. The purpose of this work, authored by members of the HARNESS Initiative, is to provide an in-depth review and position statement on magnetic resonance imaging measurement of subtle BBB leakage in clinical research studies, with aspects requiring further research identified. We further aim to provide information and consensus recommendations for new investigators wishing to study BBB failure in cSVD and dementia.     

Stimulation of the Retinoid X Receptor Facilitates Beta-Amyloid Clearance Across the Blood–Brain Barrier

Alzheimer’s disease (AD) is a neurodegenerative process characterized, in part, by the accumulation of beta-amyloid proteins (Aβ) in the brain. Evidence now suggests that the excessive Aβ accumulation is the result of impaired clearance from the brain. Recent studies have indicated that retinoid X receptor (RXR) activation stimulates the metabolic clearance of Aβ and rapidly reverses Aβ-induced behavioral deficits, doing so in an apoE-dependent manner. Previously, we reported that soluble apoE (i.e., not bound to Aβ) facilitated Aβ transit across the blood–brain barrier (BBB). As Aβ clearance from the brain involves both metabolic and BBB-mediated processes, the current studies investigated the impact of RXR stimulation on Aβ clearance across the BBB. Treatment with RXR agonists increased Aβ clearance across the BBB both in vitro and in vivo. Moreover, this processes appeared to involve apoE as RXR agonism did not stimulate Aβ BBB clearance when apoE was absent. Thus, RXR activation could mitigate Aβ brain burden by promoting both the metabolic and BBB clearance of Aβ, offering a novel approach to the treatment of AD.     

Image-Guided Synthesis Reveals Potent Blood-Brain Barrier Permeable Histone Deacetylase Inhibitors

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Strategies to target drugs to gliomas and CNS metastases of solid tumors

The treatment for central nervous system metastases of solid tumors and gliomas is limited as the blood–brain barrier (BBB) is an obstacle to systemic therapy. Here, we review the physiochemical properties of the BBB and both current and new drug strategies to penetrate brain tumors. We focus on targeting receptor- or carrier-mediated transport mechanisms over the BBB used by drug conjugates, nanoparticles, polymer-based nanocarriers, siRNA, and antibodies.     

Blood-brain barrier active efflux transporters: ATP-binding cassette gene family

The blood-brain barrier (BBB) contributes to brain homeostasis by protecting the brain from potentially harmful endogenous and exogenous substances. BBB active drug efflux transporters of the ATP-binding cassette (ABC) gene family are increasingly recognized as important determinants of drug distribution to, and elimination from, the CNS. The ABC efflux transporter P-glycoprotein (Pgp) has been demonstrated as a key element of the BBB that can actively transport a huge variety of lipophilic drugs out of the brain capillary endothelial cells that form the BBB. In addition to Pgp, other ABC efflux transporters such as members of the multidrug resistance protein (MRP) family and breast cancer resistance protein (BCRP) seem to contribute to BBB function. Consequences of ABC efflux transporters in the BBB include minimizing or avoiding neurotoxic adverse effects of drugs that otherwise would penetrate into the brain. However, ABC efflux transporters may also limit the central distribution of drugs that are beneficial to treat CNS diseases. Furthermore, neurological disorders such as epilepsy may be associated with overexpression of ABC efflux transporters at the BBB, resulting in pharmacoresistance to therapeutic medication. Therefore, modulation of ABC efflux transporters at the BBB forms a novel strategy to enhance the penetration of drugs into the brain and may yield new therapeutic options for drug-resistant CNS diseases.     

Effects of hypothermia on thrombin-induced brain edema formation

Recent studies have shown that thrombin plays an important role in brain edema formation after intracerebral hemorrhage (ICH). The possible mechanisms of thrombin-induced brain edema formation include blood-brain barrier (BBB) disruption and inflammatory response involving polymorphonuclear (PMN) leukocyte. Animal experiments have revealed that moderate therapeutic hypothermia improves pathological and functional outcome in various models of brain injury. In this study, we examined the effect of hypothermia on thrombin-induced brain edema formation. Effects of hypothermia on BBB permeability and the accumulation of PMN leukocytes were also determined to clarify the protective mechanism of hypothermia in this model. Anesthetized adult rats received an injection of 10 Units of thrombin into the basal ganglia. Animals were separated into the normothermic and hypothermic groups, which were housed in a room maintained at 25 degrees C and in a cold room maintained at 5 degrees C, respectively, for 24 h after the thrombin injection. The brain temperature in rats housed in a cold room reduced temporarily to approximately 30 degrees C and then gradually recovered to 35 degrees C by the end of the observation. Brain water content in the basal ganglia was significantly reduced in rats treated with hypothermia compared to the normothermic rats (84.3+/-0.2 vs. 82.4+/-0.1%; P<0.01). The decrease of brain water content was accompanied with a significant reduction in BBB permeability to Evan's blue dye and in accumulation of PMN leukocytes. This study indicates that hypothermic treatment significantly reduces thrombin-induced brain edema formation in the rat. Inhibition of thrombin-induced BBB breakdown and inflammatory response by hypothermia appear to contribute to brain protection in this model. Hypothermic treatment may provide an approach to potentially reduce ongoing edema after ICH.     

Erythropoietin protects the in vitro blood-brain barrier against VEGF-induced permeability

The blood-brain barrier (BBB) ensures the homeostasis of the brain microenvironment, mostly through complex tight junctions between brain endothelial cells that prevent the passage of hydrophilic molecules from blood to brain and vice versa. A recent study has shown in vivo that systemic administration of erythropoietin (Epo) protects against brain injury. Using an in vitro model of the bovine BBB, we observed that the expression of the Epo receptor is modulated by its ligand and hypoxic stimuli such as vascular endothelial growth factor (VEGF) treatment. In addition, Epo protects against the VEGF-induced permeability of the BBB, decreases the levels of endothelial nitric oxide synthase and restores junction proteins. The kinetic transport experiments revealed the capacity of Epo to cross the in vitro BBB in a saturable and specific way. Our results suggest a new mechanism for Epo-induced neuroprotection, in which circulating Epo controls and maintains the BBB through an Epo receptor signalling pathway and the re-establishment of cell junctions.     

Blood-brain barrier integrity in the pathogenesis of Alzheimer’s disease

The blood–brain barrier (BBB) tightly controls the molecular exchange between the brain parenchyma and blood. Accumulated evidence from transgenic animal Alzheimer’s disease (AD) models and human AD patients have demonstrated that BBB dysfunction is a major player in AD pathology. In this review, we discuss the role of the BBB in maintaining brain integrity and how this is mediated by crosstalk between BBB-associated cells within the neurovascular unit (NVU). We then discuss the role of the NVU, in particular its endothelial cell, pericyte, and glial cell constituents, in AD pathogenesis. The effect of substances released by the neuroendocrine system in modulating BBB function and AD pathogenesis is also discussed. We perform a systematic review of currently available AD treatments specifically targeting pericytes and BBB glial cells. In summary, this review provides a comprehensive overview of BBB dysfunction in AD and a new perspective on the development of therapeutics for AD.     

Brain thermo-pooling is the major problem in pediatric influenza encephalitis

The prognosis of pediatric encephalitides, such as infantile influenza encephalitis, is still poor because of the rapid progression, severe brain edema, selective bilateral basal ganglia necrosis, and a poor immune function, the mechanism of which is still unknown. Especially, little is known about virus es in CSF and brain tissue with influenza encephalitis, which hampers successful treatment of this condition. Recently, hypothermia treatment has attracted attention as the management of infantile influenza encephalitis to prevent severe brain edema. Recent clinical studies have revealed brain thermo-pooling (elevation of brain tissue temperature) with damage of blood-brain barrier (BBB). We then studied brain injury mechanism after severe brain injuries, cerebral strokes, reperfusion after shock, and high fever with lower cerebral perfusion pressure in our ICU. The brain thermo-pooling phenomenon results from body temperature higher than 38 degrees C, systolic blood temperature lower than 90-100 mmHg, and cerebral perfusion pressure (CPP) lower than 70 mmHg that hinders washout of brain tissue temperature by cerebral blood flow. We have recorded of brain tissue temperature of 40-44 degrees C in various brain injured patients. Some pathophysiological changes in infantile influenza encephalitis may be explained on the basis of this brain thermo-pooling phenomenon. In systemic infection, it causes severe brain edema by activation of cytokines and destruction of BBB, bilateral basal ganglia necrosis by acute severe brain hypoxia, resulting in poor prognosis without control of brain temperature. In other words, brain thermo-pooling, is the major target of treatment for infantile influenza encephalitis. In this paper, new concepts of the brain injury mechanism and methods of brain hypothermia treatment of pediatric influenza encephalitis are presented.