当前位置： SCI文献检索 > PHARMACEUTICAL RESEARCH期刊下所有文献 > In Vivo and In Vitro Evidence for Brain Uptake of 4-Phenylbutyrate by the Monocarboxylate Transporter 1 (MCT1).

In Vivo and In Vitro Evidence for Brain Uptake of 4-Phenylbutyrate by the Monocarboxylate Transporter 1 (MCT1).

Abstract：

PURPOSE:4-Phenylbutyrate (4-PBA) is expected to be a potential therapeutic for several neurodegenerative diseases. These activities require 4-PBA transport into the brain across the blood-brain barrier (BBB). The objective of the present study was to characterize the brain transport mechanism of 4-PBA through the BBB. METHODS:The brain transport of 4-PBA across the BBB was investigated following intravenous (IV) injection and internal carotid artery perfusion (ICAP) in vivo. The mechanism of transport was examined using TR-BBB cells, an in vitro model of the BBB. RESULTS:The volume of distribution (VD) of 4-PBA by rat brain was about 7-fold greater than that of sucrose, a BBB impermeable vascular space marker, suggesting the blood-to-brain transport of 4-PBA through the BBB in the physiological state. [(14)C]4-PBA uptake by TR-BBB cells showed time-, pH- and concentration-dependence with a K m of 13.4 mM at pH 7.4 and 3.22 mM at pH 6.0. The uptake was Na(+) independent, and was significantly inhibited by alpha-cyano-4-hydroxycinnamate (a typical inhibitor for monocarboxylate transport), endogenous monocarboxylate compounds and monocarboxylic drugs. Lactate and valproate competitively inhibited [(14)C]4-PBA uptake with K i value of 13.5 mM and 7.47 mM, respectively. These results indicate the role of monocarboxylate transporters (MCTs) in 4-PBA transport into the brain at the BBB. TR-BBB cells expressed mRNA of rMCT1, 2, and 4, especially, rMCT1 showed high mRNA expression level. In addition, [(14)C]4-PBA uptake was inhibited by rMCT1 specific small interfering RNA. CONCLUSION:The transport mechanism of 4-PBA from blood to brain across the BBB likely involves MCT1.

journal_name

Pharm Res

journal_title

Pharmaceutical research

authors

Lee NY,Kang YS

doi

10.1007/s11095-016-1912-6

subject

Has Abstract

pub_date

2016-07-01 00:00:00

pages

1711-22

issue

7

eissn

0724-8741

issn

1573-904X

pii

10.1007/s11095-016-1912-6

journal_volume

33

pub_type

杂志文章

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