The Hematoencephalic Barrier

King, Lester S.

doi:10.1001/archneurpsyc.1939.02270130061003

Cited by 62 publications

(4 citation statements)

References 26 publications

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“…The important paper of Wislocki ( 1920 ), discussed above and illustrated in Figure 1A , was rarely cited in most of the literature of the 20th Century, perhaps because it did not fit with the prevailing belief in immaturity of the blood-brain barrier. Even King ( 1939 ), who published with Wislocki, does not mention the seminal 1920 paper preferring instead to cite Behnsen ( 1927 ) as evidence of barrier immaturity; the deficiencies of the latter study are discussed next. These are perhaps the most cited in support of immaturity or leakiness of the blood-brain barrier (Behnsen, 1926 , 1927 ) particularly his 1927 paper (e.g., Spatz, 1934 ; King, 1939 ; Friedemann, 1942 ; Davson, 1967 ).…”

Section: Early Dye Studies In Immature Animalsmentioning

confidence: 99%

“…Even King ( 1939 ), who published with Wislocki, does not mention the seminal 1920 paper preferring instead to cite Behnsen ( 1927 ) as evidence of barrier immaturity; the deficiencies of the latter study are discussed next. These are perhaps the most cited in support of immaturity or leakiness of the blood-brain barrier (Behnsen, 1926 , 1927 ) particularly his 1927 paper (e.g., Spatz, 1934 ; King, 1939 ; Friedemann, 1942 ; Davson, 1967 ). In the 1926 paper Behnsen refers to sealing (“Abdichtung”) of the barrier in the postnatal animals, and writes in the summary on page 1146 that the blood brain barrier is considerably more leaky (original: “erheblich durchlässiger”) than in adult mice as staining with trypan blue appears in young animals more intense generally and also in different places of the CNS compared to the staining pattern of adults.…”

Section: Early Dye Studies In Immature Animalsmentioning

confidence: 99%

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The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history

et al. 2014

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Careful examination of relevant literature shows that many of the most cherished concepts of the blood-brain barrier are incorrect. These include an almost mythological belief in its immaturity that is unfortunately often equated with absence or at least leakiness in the embryo and fetus. The original concept of a blood-brain barrier is often attributed to Ehrlich; however, he did not accept that permeability of cerebral vessels was different from other organs. Goldmann is often credited with the first experiments showing dye (trypan blue) exclusion from the brain when injected systemically, but not when injected directly into it. Rarely cited are earlier experiments of Bouffard and of Franke who showed methylene blue and trypan red stained all tissues except the brain. The term “blood-brain barrier” “Blut-Hirnschranke” is often attributed to Lewandowsky, but it does not appear in his papers. The first person to use this term seems to be Stern in the early 1920s. Studies in embryos by Stern and colleagues, Weed and Wislocki showed results similar to those in adult animals. These were well-conducted experiments made a century ago, thus the persistence of a belief in barrier immaturity is puzzling. As discussed in this review, evidence for this belief, is of poor experimental quality, often misinterpreted and often not properly cited. The functional state of blood-brain barrier mechanisms in the fetus is an important biological phenomenon with implications for normal brain development. It is also important for clinicians to have proper evidence on which to advise pregnant women who may need to take medications for serious medical conditions. Beliefs in immaturity of the blood-brain barrier have held the field back for decades. Their history illustrates the importance of taking account of all the evidence and assessing its quality, rather than selecting papers that supports a preconceived notion or intuitive belief. This review attempts to right the wrongs. Based on careful translation of original papers, some published a century ago, as well as providing discussion of studies claiming to show barrier immaturity, we hope that readers will have evidence on which to base their own conclusions.

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Section: Early Dye Studies In Immature Animalsmentioning

confidence: 99%

Section: Early Dye Studies In Immature Animalsmentioning

confidence: 99%

The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history

et al. 2014

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“…It was noticed many years ago that anionic dyes were retained in the blood, whereas cationic dyes and neutral hydrophobic colored compounds entered the CNS. The dyes that most clearly defined the blood-brain barrier were colored anions with quite large molecules, notably trypan blue (Goldmann, 1913;King, 1939). In aqueous media the molecules of these dyes form colloidal particles, and they can also bind strongly, though noncovalently, to macromolecules, including proteins (Giles, 1975;Gordon and Gregory, 1983;Lillie, 1977).…”

Section: The Blood-brain and Blood-cerebrospinal Fluid Barriersmentioning

confidence: 99%

Vascular permeability in the peripheral autonomic and somatic nervous systems: Controversial aspects and comparisons with the blood-brain barrier

Kiernan

1996

Microsc. Res. Tech.

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Endothelium, choroidal epithelium, and arachnoid exclude plasma proteins from most parts of the mammalian central nervous system (CNS). Nerve roots, in contrast, have permeable capillaries and permeable pia‐arachnoid sheaths. Diffusion of plasma proteins into the cerebrospinal fluid is probably prevented by slow bulk flow along a pressure gradient from the subarachnoid space into the veins of the roots. In nerves, the perineurium prevents diffusion of proteins from the epineurium into the endoneurium. Capillaries within fascicles are permeable to macromolecules, though less so than the microvessels of roots and ganglia. Endoneurial vascular permeability is lowest in rats and mice, but even in these species albumin is normally present in the extracellular spaces around the nerve fibers. The so‐called blood‐nerve barrier is not equivalent to the blood‐brain barrier. Capillaries in sensory and sympathetic ganglia are fully permeable to macromolecules, and extravasated protein is in contact with neuronal cell bodies and neurites. An impenetrable perineurium surrounds each ganglion, but serves no obvious purpose when the vessels inside are as permeable as those outside. The enteric nervous system lacks a perineurium, and the neurons in its avascular ganglia and tracts are exposed to extracellular fluid formed by permeable vessels in adjacent tissues of the gut. The reasons for excluding macromolecules from some parts of the nervous system are obscure. Carrier‐mediated transport, which maintains a constant supply of ions, glucose, and other metabolites to cells in the CNS, would be impossible if larger molecules could diffuse freely. Presumably the metabolic needs of ganglia are adequately met by exchange vessels similar to those of nonnervous tissues. Most of the CNS is protected from exogenous toxic substances that bind to plasma proteins. Peripheral neurons and glial cells are damaged by some such substances because of the lack of blood‐tissue barriers. © 1996 Wiley‐Liss, Inc.

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“…It appears to be locally generated by a brain renin-an giotensin system (RAS) [9,14], since all components neces sary for the ANG II production as well as the effector pep tide itself and specific ANG II receptors could be demon Central dipsogenic and cardiovascular actions of ANG II can also be brought about by blood-borne ANG II [7,10,60] perhaps passing capillary windows within circumventricular organs which seem to be lacking a bloodbrain barrier (BBB) [24,41], The permeability of the BBB for ANG II has been investigated by intravenous infusions of radioactively labelled ANG II and measurement of radioacitivity in brain tissue and/or cerebrospinal fluid (CSF) [22,63]. In these studies, radioactivity was found in brain and CSF, but no satisfactory characterization of the peptide was performed.…”

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Components of the Renin-Angiotensin System in the Cerebrospinal Fluid of Rats and Dogs with Special Consideration of the Origin and the Fate of Angiotensin II

et al. 1980

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From the in vitro and in vivo measurements of the components of the renin-angiotensin system (RAS) in the cerebrospinal fluid (CSF) of rats and dogs, it was concluded that angiotensin II (ANG II) is not generated within the CSF in significant amounts, since renin was found to be unmeasurable in CSF under most circumstances. The specific concentrations of angiotensinogen and of converting enzyme (CE) were high. Angiotensin I (ANG I) concentrations were low in CSF, while ANG II levels were comparable to those measured in plasma under control conditions. Neither ANG I nor ANG II penetrated from the blood into the brain ventricles of rats, provided that no unrealistically high doses of ANG II were administered intravenously. This holds true even if high blood pressure increases were induced by intravenous ANG II infusion in deoxycorticosterone acetate (DOCA) and salt-treated rats. However, increased ANG II concentrations were measured in CSF perfusate, when the blood-brain barrier (BBB) was opened by the intracarotid injection of a hyperosmolar urea solution. The brain ventricular perfusion of increasing concentrations of ANG II revealed constant recovery of less than 40%. CSF did not contain angiotensinase activity, but ANG II degradation was high in some periventricular regions. ANG II, the ANG II antagonist saralasin, and the CE inhibitor captopril, respectively, escaped from CSF into circulation when high doses of these substances were applied intraventricularly. We conclude that ANG II in the CSF does not originate from and is not related to plasma ANG II. It is probably not generated within the CSF. ANG II may be synthetized in the brain tissue and be released into the brain ventricles where its rapid degradation occurs in contact with circumventricular structures.

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The Hematoencephalic Barrier

Cited by 62 publications

References 26 publications

The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history

The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history

Vascular permeability in the peripheral autonomic and somatic nervous systems: Controversial aspects and comparisons with the blood-brain barrier

Components of the Renin-Angiotensin System in the Cerebrospinal Fluid of Rats and Dogs with Special Consideration of the Origin and the Fate of Angiotensin II

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