血脑屏障
永生化细胞系
人脑
流出
药理学
化学
细胞培养
体内
P-糖蛋白
细胞生物学
生物
体外
中枢神经系统
抗药性
多重耐药
神经科学
生物化学
生物技术
微生物学
遗传学
作者
Ryo Ito,Kenta Umehara,Shota Suzuki,Kazuko Kitamura,Ken‐ichi Nunoya,Yoshiyuki Yamaura,Haruo Imawaka,Satoshi Izumi,Naomi Wakayama,Takafumi Komori,Naohiko Anzai,Hidetaka Akita,Tomomi Furihata
标识
DOI:10.1021/acs.molpharmaceut.9b00519
摘要
Brain microvascular endothelial cells (BMEC), together with astrocytes and pericytes, form the blood–brain barrier (BBB) that strictly restricts drug penetration into the brain. Therefore, in central nervous system drug development, the establishment of an in vitro human BBB model for use in studies estimating the in vivo human BBB permeability of drug candidates has long been awaited. The current study developed and characterized a human immortalized cell-based BBB triculture model, termed the “hiBBB” model. To set up the hiBBB model, human immortalized BMEC (HBMEC/ci18) were cocultured with human immortalized astrocytes (HASTR/ci35) and brain pericytes (HBPC/ci37) in a transwell system. The trans-endothelial electrical resistance of the hiBBB model was 134.4 ± 5.5 (Ω × cm2), and the efflux ratios of rhodamine123 and dantrolene were 1.72 ± 0.11 and 1.72 ± 0.45, respectively, suggesting that the hiBBB model possesses essential cellular junction and efflux transporter functions. In BBB permeability assays, the mean value of the permeability coefficients (Pe) of BBB permeable compounds (propranolol, pyrilamine, memantine, and diphenhydramine) was 960 × 10–6 cm/s, which was clearly distinguishable from that of BBB nonpermeable compounds (sodium fluorescein and Lucifer yellow, 18 × 10–6 cm/s). Collectively, this study successfully developed the hiBBB model, which exhibits essential BBB functionality. Taking into consideration the high availability of the immortalized cells used in the hiBBB model, our results are expected to become an initial step toward the establishment of a useful human BBB model to investigate drug penetration into the human brain.
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