title: In vitro blood-brain barrier models using brain capillary endothelial cells isolated from neonatal and adult rats retain age-related barrier properties.
abstract: The blood-brain barrier (BBB) restricts the entry of circulating drugs and xenobiotics into the brain, and thus its permeability to substances is a critical factor that determines their central effects. The infant brain is vulnerable to neurotoxic substances partly due to the immature BBB. The employment of in vitro BBB models to evaluate permeability of compounds provides higher throughput than that of in vivo animal experiments. However, existing in vitro BBB models have not been able to simulate the intrinsic neonatal BBB. To establish a neonatal BBB model that mimics age-related BBB properties, the neonatal and adult in vitro BBB models were constructed with brain endothelial cells isolated from 2- and 8-week-old rats, respectively. To evaluate BBB functions, transendothelial electrical resistance, permeability of sodium fluorescein and Evans blue-albumin, and transport of rhodamine123 were measured. Radiolabelled drugs were used for BBB permeability studies in the neonatal and adult BBB models (in vitro) and in age-matched rats (in vivo). The neonatal BBB model showed lower barrier and p-glycoprotein (P-gp) functions than the adult BBB model; these were well associated with lower expressions of the barrier-related proteins and P-gp, and a different distribution pattern of immunostained barrier-related proteins. Verapamil (a P-gp inhibitor) significantly increased the influx of rhodamine 123, supporting functional P-gp expression in the neonatal BBB model. Valproic acid, but not nicotine, showed higher BBB permeability in the neonatal BBB model, which was well in accordance with the in vivo BBB property. We established a neonatal BBB model in vitro. This could allow us to assess the age-dependent BBB permeability of drugs.
authors: Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.
authors: Fuyuko
authors: F
authors: Takata
authors: Shinya
authors: S
authors: Dohgu
authors: Atsushi
authors: A
authors: Yamauchi
authors: Junichi
authors: J
authors: Matsumoto
authors: Takashi
authors: T
authors: Machida
authors: Kayoko
authors: K
authors: Fujishita
authors: Keisuke
authors: K
authors: Shibata
authors: Youichi
authors: Y
authors: Shinozaki
authors: Kaoru
authors: K
authors: Sato
authors: Yasufumi
authors: Y
authors: Kataoka
authors: Schuichi
authors: S
authors: Koizumi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000375:Aging / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001812:Blood-Brain Barrier / Q000166:cytology* / Q000378:metabolism*; D002469:Cell Separation; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019108:Tight Junctions / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations
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