Expanding the definition of the blood-brain barrier to protein.

Broadwell, Richard D.; Salcman, Michael

doi:10.1073/pnas.78.12.7820

Cited by 114 publications

(39 citation statements)

References 23 publications

(32 reference statements)

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“…These HRP-labeled structures all have counterparts possessing acid hydrolase activity in the same cell types (2). Thus, internalized endothelial surface membrane associated with the bulk-phase endocytosis of native peroxidase from the luminal or abluminal side of cerebral capillaries and arterioles is directed, at least in part and perhaps entirely, to secondary lysosomes.…”

Section: Discussionmentioning

confidence: 96%

“…Specific morphological characteristics of cerebral endothelial cells and enzyme activities within these cells define the mammalian blood-brain barrier (1)(2)(3). The transcellular transport of large molecular weight, blood-borne substances through the endothelium to the brain extracellular space is believed not to occur under normal conditions.…”

mentioning

confidence: 99%

“…Details of the injection procedure have been presented elsewhere (9). Fifteen of the injected mice received 30 ,ul (2)(3) ,ul/min) of a 30% HRP/saline solution and were sacrificed 3, 6, 12, or 24 hr later. The brainstem, cortex, and hypothalamus from each mouse were saved for processing.…”

mentioning

confidence: 99%

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Brain-blood barrier? Yes and no.

Broadwell¹,

Balin²,

Salcman³

et al. 1983

Proc. Natl. Acad. Sci. U.S.A.

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Ventriculo-cisternal perfusion of horseradish peroxidase (HRP) in the mousebrainhas demonstrated thata brainblood barrier exists at the microvascular endothelium in brain parenchyma but not in the median eminence of the hypothalamus. The brain-blood barrier is similar to the blood-brain barrier in that: tight junctions prevent the movement of protein between endothelial cells, HRP taken into the endothelial cells is directed to lysosomal dense bodies, and, contrary to the literature, a vesicular transendothelial transport of HRP from brain to blood does not occur under normal conditions. The endocytosis of ventricular injected HRP from the abluminal side of the endothelium is demonstrably less than the endocytosis of intravenous injected HRP from the luminal side; hence, the cerebral endothelium expresses a degree of polarity regarding the internalization of its cell surface membrane and extracellular protein. The passage of cerebrospinal fluid-borne or blood-borne HRP between some ependymal cells of the median eminence is not precluded by tight junctions. These patent extracellular channels offer a direct pathway for the exchange of substances between cerebrospinal fluid in the third ventricle and fenestrated capillaries in the median eminence.Specific morphological characteristics of cerebral endothelial cells and enzyme activities within these cells define the mammalian blood-brain barrier (1-3). The transcellular transport of large molecular weight, blood-borne substances through the endothelium to the brain extracellular space is believed not to occur under normal conditions. Circumventricular organs (i.e., median eminence, area postrema, etc.) and the choroid plexus possess fenestrated capillaries and lie outside the blood-brain barrier (4, 5); circumferential belts of tight junctions between ependymal cells and between choroid epithelial cells lining the circumventricular organs and choroid plexus, respectively, are considered to provide the physical barrier between the blood and cerebrospinal fluid (CSF) (1, 4, 6). Despite the overwhelming acceptance of a blood-brain barrier, available evidence indicates that the cerebral microvasculature does not manifest a brain-blood barrier. The cerebral endothelium is reported to take up protein from the perivascular space and transport it to the luminal surface where the protein is deposited into the blood (7,8). In this fashion the transendothelial transport of protein from brain to blood could supplement the CSF in the removal of substances from the brain extracellular space.Evidence obtained with horseradish peroxidase (HRP) as a tracer is presented in this paper to suggest that a brain-blood barrier exists at the level of capillaries and arterioles in the brain but not in the median eminence of the hypothalamus. Open junctions observed between some median eminence ependymal cells permit the bidirectional exchange of substances between the median eminence capillaries and the third ventricle CSF.MATERIALS AND METHODS The microvascular endothelium and th...

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

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Brain-blood barrier? Yes and no.

Broadwell¹,

Balin²,

Salcman³

et al. 1983

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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“…The study also reported an increased number of capillaries containing pericytes, which the authors interpreted as a protective scaffold to support the weak endothelium which showed junctional leakiness. An interesting view proposed by Broadwell and Salcman [242] is that pericytes could also limit the damage of a leaky BBB by acting as macrophages, degrading extravasated serum proteins in their lysosomes.…”

Section: Microvascular Ultrastructural Alterations In the Ad Brainmentioning

confidence: 99%

Vascular dysfunction in the pathogenesis of Alzheimer's disease — A review of endothelium-mediated mechanisms and ensuing vicious circles

Marco

Venneri

Farkas

et al. 2015

Neurobiology of Disease

231

185

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Article available under the terms of the CC-BY-NC-ND licence (https://creativecommons.org/licenses/by-nc-nd/4.0/) eprints@whiterose.ac.uk https://eprints.whiterose.ac.uk/ Reuse Unless indicated otherwise, fulltext items are protected by copyright with all rights reserved. The copyright exception in section 29 of the Copyright, Designs and Patents Act 1988 allows the making of a single copy solely for the purpose of non-commercial research or private study within the limits of fair dealing. The publisher or other rights-holder may allow further reproduction and re-use of this version -refer to the White Rose Research Online record for this item. Where records identify the publisher as the copyright holder, users can verify any specific terms of use on the publisher's website. TakedownIf you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request.

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“…The BBB is a complex vascular structure composed of a continuous layer of endothelial cells that maintain tight junctions between themselves (10,41). The properties of the BBB suggest that a highly selective exchange system has evolved between the blood and brain to provide a homeostatic environment for the brain in the normal physiological state (41).…”

mentioning

confidence: 99%

Intravenous Infusion of Cereport Increases Uptake and Efficacy of Acyclovir in Herpes Simplex Virus-Infected Rat Brains

Bidanset

Placidi

Rybak

et al. 2001

Antimicrob Agents Chemother

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The outcome of herpes simplex virus (HSV) infections manifesting as encephalitis in healthy or immunocompromised individuals is generally very poor with mortality rates of about 8 to 28% with treatment. The long-term prognosis of survivors is often problematic, posing the need for alternative treatments that may decrease the mortality and morbidity associated with herpes encephalitis. This study addresses one such approach that includes a temporary permeabilization of the blood-brain barrier during treatment with acyclovir (ACV). In these studies we utilized a synthetic bradykinin analog, Cereport (RMP-7), in conjunction with ACV to treat HSV infection of the brain in a rat model. Cereport, infused intravenously via the jugular vein, was shown to increase [ 14 C]ACV uptake in both the HSV-1-infected and -uninfected rat brain by approximately two-to threefold, correlating with enhanced efficacy of ACV in various brain compartments. In another series of experiments to determine efficacy, various doses of unlabeled ACV were administered during infusion with RMP-7. The decrease in viral titers in the temporal regions of the brain after 5 days of treatment suggested that this approach enhanced the efficacy of ACV treatment. These data indicated that Cereport infused with ACV enhances both the penetration and efficacy of this drug in the treatment of an experimental HSV-1 infection of the rat brain.Herpes simplex virus (HSV) infections in humans can manifest as a life-threatening disease with high mortality and significant morbidity in survivors. These infections can be caused by either HSV-1 or HSV-2 (2, 46). In neonates, primary infection that occurs during or shortly after birth is usually symptomatic within 1 month and is frequently lethal (42,43,46). Although treatment with either vidarabine or acyclovir (ACV) significantly reduces the mortality rate, up to 15% of those with encephalitis still do not survive (28,42,43,45). In older individuals, encephalitis caused by primary or recurrent HSV infection results in a 70% mortality rate without treatment and an 8 to 28% mortality rate with treatment depending on when treatment is initiated (32,45,46). This disease is characterized by acute necrotizing focal encephalopathy, inflammation and swelling of the brain tissue, and petechiae or larger hemorrhages in the brain (9,26,39,47). Although therapy with either vidarabine or ACV (42, 44) has proven to be effective in reducing mortality rates of HSV encephalitis, the long-term prognosis of the survivors is less than optimal. A few survivors suffer relapses, but many others have learning and memory abnormalities and impairment of general orientation and perceptive-motor skills (12,14,29). This current state of HSV encephalitis-associated mortality and morbidity suggests that alternative approaches to treatment need to be developed.One possible reason for reduced efficacy in the central nervous system (CNS) may be failure of the drug to penetrate the blood-brain barrier (BBB) and enter the CNS tissues. Inefficient penetra...

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Expanding the definition of the blood-brain barrier to protein.

Cited by 114 publications

References 23 publications

Brain-blood barrier? Yes and no.

Brain-blood barrier? Yes and no.

Vascular dysfunction in the pathogenesis of Alzheimer's disease — A review of endothelium-mediated mechanisms and ensuing vicious circles

Intravenous Infusion of Cereport Increases Uptake and Efficacy of Acyclovir in Herpes Simplex Virus-Infected Rat Brains

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