Hawkins BT, Egleton RDPathophysiology of the blood-brain barrier: animal models and methods. Curr Top Dev Biol 80:277-309

Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Current Topics in Developmental Biology (Impact Factor: 4.68). 02/2008; 80:277-309. DOI: 10.1016/S0070-2153(07)80007-X
Source: PubMed


The specialized cerebral microvascular endothelium interacts with the cellular milieu of the brain and extracellular matrix to form a neurovascular unit, one aspect of which is a regulated interface between the blood and central nervous system (CNS). The concept of this blood-brain barrier (BBB) as a dynamically regulated system rather than a static barrier has wide-ranging implications for pathophysiology of the CNS. While in vitro models of the BBB are useful for screening drugs targeted to the CNS and indispensable for studies of cerebral endothelial cell biology, the complex interactions of the neurovascular unit make animal-based models and methods essential tools for understanding the pathophysiology of the BBB. BBB dysfunction is a complication of neurodegenerative disease and brain injury. Studies on animal models have shown that diseases of the periphery, such as diabetes and inflammatory pain, have deleterious effects on the BBB which may contribute to neurological complications associated with these conditions. Furthermore, genetic and/or epigenetic abnormalities in constituents of the BBB may be significant contributing factors in disease etiology. Research that approaches the BBB as a dynamic system integrated with both the CNS and the periphery is therefore critical to understanding and treating diseases of the CNS. Herein, we review various methodological approaches used to study BBB function in the context of disease. These include measurement of transport between blood and brain, imaging-based technologies, and genomic/proteomic approaches.

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    • "In situ brain perfusion involves the direct infusion of a labeled compound into a carotid artery that has been appropriately ligatured to ensure that all the perfusate reaches the BBB (Dagenais et al., 2000; Hawkins and Egleton, 2008). Briefly, mice were anesthetized by intra-peritoneal injection of a mixture (8/140 mg/kg) of xylazine (Merial, Lyon, France) and ketamine (Bayer, Puteaux, France). "
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    ABSTRACT: We evaluated the integrity and function of the blood-brain barrier in 3xTg-AD mice aged 3-18 months and in APP/PS1 mice aged 8-months to determine the impacts of changes in amyloid and tau proteins on the brain vascular changes. The vascular volume (Vvasc) was sub-normal in 3xTg-AD mice aged from 6 to 18 months, but not in the APP/PS1 mice. The uptakes of [(3)H]-diazepam by the brains of 3xTg-AD, APP/PS1 and their age-matched control mice were similar at all the times studied, suggesting that the simple diffusion of small solutes is unchanged in transgenic animals. The uptake of D-glucose by the brains of 18-month old 3xTg-AD mice, but not by those of 8-month old APP/PS1 mice, was reduced compared to their age-matched controls. Accordingly, the amount of Glut-1 protein was 1.4 times lower in the brain capillaries of 18 month-old 3xTg-AD mice than in those of age-matched control mice. We conclude that the brain vascular volume is reduced early in 3xTg-AD mice, 6 months before the appearance of pathological lesions, and that this reduction persists until they are at least 18 months old. The absence of alterations in the BBB of APP/PS1 mice suggests that hyperphosphorylated tau proteins contribute to the vascular changes that occur in AD.
    Full-text · Article · Mar 2014 · Neuropharmacology
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    • "There are several studies to address BBB permeability in aged animals (reviewed in [35]), in different experimental models, such as reproductive senescent mouse females [36], or senescence-accelerated mice [37]. They all led to the same conclusion that BBB permeability is altered in aged brain. "
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    ABSTRACT: As fundamental research advances, it is becoming increasingly clear that a clinically expressed disease implies a mixture of intertwining molecular disturbances. Oxidative stress is one of such pathogenic pathways involved in virtually all central nervous system pathologies, infectious, inflammatory, or degenerative in nature. Since brain homeostasis largely depends on integrity of blood-brain barrier (BBB), many studies focused lately on BBB alteration in a wide spectrum of brain diseases. The proper two-way molecular transfer through BBB depends on several factors, including the functional status of its tight junction (TJ) complexes of proteins sealing neighbour endothelial cells. Although there is abundant experimental work showing that oxidative stress associates BBB permeability alteration, less is known about its implications, at molecular level, in TJ protein expression or TJ-related cell signalling. In this paper, oxidative stress is presented as a common pathway for different brain pathogenic mechanisms which lead to BBB dysregulation. We revise here oxidative-induced molecular mechanisms of BBB disruption and TJ protein expression alteration, in relation to ageing and neurodegeneration.
    Full-text · Article · Mar 2013 · Oxidative Medicine and Cellular Longevity
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    • "These cells combine with the extracellular basal membrane and microglia to form the support system of the BBB [10, 12, 13]. Together with the surrounding neurons, these components form an intact and functional neurovascular unit [14]. Brain endothelium, the principal and most effective part of the BBB, is formed from abundant exchange vessels, such as capillaries and post-capillary venules, with thin walls and wide surface scales. "
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    ABSTRACT: The blood-brain barrier (BBB), a dynamic and complex barrier formed by endothelial cells, can impede the entry of unwanted substances - pathogens and therapeutic molecules alike - into the central nervous system (CNS) from the blood circulation. Taking into account the fact that CNS-related diseases are the largest and fastest growing unmet medical concern, many potential protein- and nucleic acid-based medicines have been developed for therapeutic purposes. However, due to their poor ability to cross the BBB and the plasma membrane, the above-mentioned bio-macromolecules have limited use in treating neurological diseases. Finding effective, safe, and convenient ways to deliver therapeutic molecules into the CNS is thus urgently required. In recent decades, much effort has been expended in the development of drug delivery technologies, of which cell-penetrating peptides (CPPs) have the most promising potential. The present review covers the latest advances in CPP delivery technology, and provides an update on their use in CNS-targeted drug delivery.
    Full-text · Article · Mar 2013 · Current Neuropharmacology
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