title: Metformin induces up-regulation of blood-brain barrier functions by activating AMP-activated protein kinase in rat brain microvascular endothelial cells.
abstract: Blood-brain barrier (BBB) disruption occurs frequently in CNS diseases and injuries. Few drugs have been developed as therapeutic candidates for facilitating BBB functions. Here, we examined whether metformin up-regulates BBB functions using rat brain microvascular endothelial cells (RBECs). Metformin, concentration- and time-dependently increased transendothelial electrical resistance of RBEC monolayers, and decreased RBEC permeability to sodium fluorescein and Evans blue albumin. These effects of metformin were blocked by compound C, an inhibitor of AMP-activated protein kinase (AMPK). AMPK stimulation with an AMPK activator, AICAR, enhanced BBB functions. These findings indicate that metformin induces up-regulation of BBB functions via AMPK activation.
authors.affiliation: Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.
authors.forename: Fuyuko
authors.initials: F
authors.lastname: Takata
authors.forename: Shinya
authors.initials: S
authors.lastname: Dohgu
authors.forename: Junichi
authors.initials: J
authors.lastname: Matsumoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Machida
authors.forename: Shuji
authors.initials: S
authors.lastname: Kaneshima
authors.forename: Mai
authors.initials: M
authors.lastname: Matsuo
authors.forename: Shinya
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takeshige
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamauchi
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kataoka
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation; D019793:Fluorescein / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D047428:Protein Kinase Inhibitors; D008687:Metformin; D000242:Cyclic AMP; D000263:Adenylate Kinase; D019793:Fluorescein