Recent Progress in Blood–Brain Barrier and Blood–CSF Barrier Transport Research: Pharmaceutical Relevance for Drug Delivery to the Brain

Tachikawa, Masanori; Uchida, Yasuo; Ohtsuki, Sumio

doi:10.1007/978-1-4614-9105-7_2

Cited by 14 publications

(10 citation statements)

References 193 publications

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“…; Tachikawa et al . ; Nigam et al . ) and an overlap of substrates and differences in expression between species are becoming apparent.…”

Section: Discussionmentioning

confidence: 99%

“…The OATPs (organic ion transporting polypeptides) and OATs (organic ion transporters) act as bidirectional transporters and may therefore be involved in uptake and/or efflux. New members of these families have recently been identified at the BBB (see Sugiyama et al 2003;Tachikawa et al 2014;Nigam et al 2015) and an overlap of substrates and differences in expression between species are becoming apparent.…”

Section: Discussionmentioning

confidence: 99%

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Uptake and metabolism of sulphated steroids by the blood–brain barrier in the adult male rat

Qaiser

Dolman

Begley

et al. 2017

Journal of Neurochemistry

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Little is known about the origin of the neuroactive steroids dehydroepiandrosterone sulphate (DHEAS) and pregnenolone sulphate (PregS) in the brain or of their subsequent metabolism. Using rat brain perfusion in situ, we have found 3 H-PregS to enter more rapidly than 3 H-DHEAS and both to undergo extensive (> 50%) desulphation within 0.5 min of uptake. Enzyme activity for the steroid sulphatase catalysing this deconjugation was enriched in the capillary fraction of the blood-brain barrier and its mRNA expressed in cultures of rat brain endothelial cells and astrocytes. Although permeability measurements suggested a net efflux, addition of the efflux inhibitors GF120918 and/or MK571 to the perfusate reduced rather than enhanced the uptake of 3 H-DHEAS and 3 H-PregS; a further reduction was seen upon the addition of unlabelled steroid sulphate, suggesting a saturable uptake transporter.Analysis of brain fractions after 0.5 min perfusion with the 3 Hsteroid sulphates showed no further metabolism of PregS beyond the liberation of free steroid pregnenolone. By contrast, DHEAS underwent 17-hydroxylation to form androstenediol in both the steroid sulphate and the free steroid fractions, with some additional formation of androstenedione in the latter. Our results indicate a gain of free steroid from circulating steroid sulphates as hormone precursors at the blood-brain barrier, with implications for ageing, neurogenesis, neuronal survival, learning and memory.

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“…; Tachikawa et al . ; Nigam et al . ) and an overlap of substrates and differences in expression between species are becoming apparent.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Uptake and metabolism of sulphated steroids by the blood–brain barrier in the adult male rat

Qaiser

Dolman

Begley

et al. 2017

Journal of Neurochemistry

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“…The blood–brain barrier (BBB), which is formed by brain capillary endothelial cells linked via tight junctions, serves to separate neural tissue from blood. It possesses vectorial transport systems because of polarized expression of various transporter proteins, and these systems regulate the exchange of endogenous and exogenous compounds between brain and blood . Multidrug resistance 1 (MDR1/P‐gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2), which are representative ATP‐binding cassette (ABC) transporters, are localized at the luminal membrane of the brain capillary endothelial cells in humans and rodents, in accordance with their function to restrict drug entry to the brain .…”

Section: Introductionmentioning

confidence: 99%

“…It possesses vectorial transport systems because of polarized expression of various transporter proteins, and these systems regulate the exchange of endogenous and exogenous compounds between brain and blood. 1,2 Multidrug resistance 1 (MDR1/P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2), which are representative ATP-binding cassette (ABC) transporters, are localized at the luminal membrane of the brain capillary endothelial cells in humans and rodents, in accordance with their function to restrict drug entry to the brain. [3][4][5][6] Amino acid transporter system A2 (ATA2/SLC38A2), a solute carrier (SLC) transporter, is involved in cellular uptake of small neutral amino acids, and is the major subtype of system A at the abluminal membrane in rodents.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Determination of Luminal and Abluminal Membrane Distributions of Transporters in Porcine Brain Capillaries by Plasma Membrane Fractionation and Quantitative Targeted Proteomics

Kubo

Ohtsuki

Uchida

et al. 2015

Journal of Pharmaceutical Sciences

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Abluminal or luminal localization of transporter in plasma membranes at the blood-brain barrier (BBB) is critical for their physiological and pharmacological roles. Therefore, the purpose of this study was to develop a new method to investigate membrane localization of transporters, through quantitative measurement of protein expression levels in fractionated plasma membrane prepared from porcine brain capillaries. Luminal-abluminal distribution ratios were calculated from the results of quantitative targeted absolute proteomics of fractionated membranes, after correction for cross-contamination based on measurements of luminal and abluminal membrane markers. BCRP expression was greater at the luminal membrane than at the abluminal membrane, supporting the usefulness of the distribution ratio as a quantitative indicator of localization. The distribution ratios suggested luminal-dominant localizations of GLUT1 and OATP3A1, and abluminal-dominant localizations of ABCA1 and FATP1. For OATP3A1, ABCA1 and FATP1, these results require reconsideration of their functions at the BBB. Species differences were examined using expression levels normalized to Na(+) /K(+) -ATPase. BCRP expression is dominant over multidrug resistance 1 expression in porcine BBB, as in other primates including humans. This methodology for quantitative measurement of protein localization is expected to improve our understanding of the roles of transporters at the BBB, and should be applicable to other polarized cells.

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“…The blood-brain barrier (BBB), which consists of brain capillary endothelial cells linked by complex tight junctions, strictly regulates transcellular influx and efflux transport of organic ions, including nutrients and xenobiotics, by means of polarized expression of numerous transporters and receptors (Tachikawa et al, 2014). It has been proposed that dysregulation of BBB transport function exacerbates neuronal damage in the acute stage of ischemic stroke.…”

Section: Introductionmentioning

confidence: 99%

Contribution of Pannexin 1 and Connexin 43 Hemichannels to Extracellular Calcium–Dependent Transport Dynamics in Human Blood-Brain Barrier Endothelial Cells

Kaneko

Tachikawa

Akaogi

et al. 2015

J Pharmacol Exp Ther

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Dysregulation of blood-brain barrier (BBB) transport function is thought to exacerbate neuronal damage in acute ischemic stroke. The purpose of this study was to clarify the characteristics of pannexin (Px) and/or connexin (Cx) hemichannel(s)-mediated transport of organic anions and cations in human BBB endothelial cell line hCMEC/D3 and to identify inhibitors of hemichannel opening in hCMEC/D3 cells in the absence of extracellular Ca 21

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Recent Progress in Blood–Brain Barrier and Blood–CSF Barrier Transport Research: Pharmaceutical Relevance for Drug Delivery to the Brain

Cited by 14 publications

References 193 publications

Uptake and metabolism of sulphated steroids by the blood–brain barrier in the adult male rat

Uptake and metabolism of sulphated steroids by the blood–brain barrier in the adult male rat

Quantitative Determination of Luminal and Abluminal Membrane Distributions of Transporters in Porcine Brain Capillaries by Plasma Membrane Fractionation and Quantitative Targeted Proteomics

Contribution of Pannexin 1 and Connexin 43 Hemichannels to Extracellular Calcium–Dependent Transport Dynamics in Human Blood-Brain Barrier Endothelial Cells

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