title: In Vivo and In Vitro Evidence for Brain Uptake of 4-Phenylbutyrate by the Monocarboxylate Transporter 1 (MCT1).
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  The transport mechanism of 4-PBA from blood to brain across the BBB likely involves MCT1.
authors.affiliation: College of Pharmacy and Research Center for Cell Fate Control, Sookmyung Women's University, 52, Hyochangwon-gil, Yongsan-gu, Seoul, 04310, South Korea.
authors.forename: Na-Young
authors.initials: NY
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Center for Cell Fate Control, Sookmyung Women's University, 52, Hyochangwon-gil, Yongsan-gu, Seoul, 04310, South Korea. yskang@sookmyung.ac.kr.
authors.forename: Young-Sook
authors.initials: YS
authors.lastname: Kang
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D010654:Phenylbutyrates / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters / Q000378:metabolism*; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D019344:Lactic Acid; D027501:Monocarboxylic Acid Transporters; D010654:Phenylbutyrates; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C075773:4-phenylbutyric acid
keywords: 4-Phenylbutyrate (4-PBA); TR-BBB cell; blood-brain barrier; drug transport; internal carotid artery perfusion; intravenous injection; monocarboxylate transporter (MCT)