期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 846, 期 -, 页码 119-127出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2019.01.005
关键词
Partial portal vein ligation; Blood-brain barrier; P-glycoprotein; Chronic hyperammonemia; Efflux transporter
资金
- National Natural Science Foundation of China [81872930, 81573490, 81673505]
- Natural Science Foundation of Jiangsu Province [BK20161457]
- 333, Six Talent Peaks and Cyan Blue Project of Jiangsu Province
Liver failure altered P-glycoprotein (P-gp) function and expression at blood-brain barrier (BBB), partly owing to hyperammonemia. We aimed to examine the effects of partial portal vein ligation (PVL) plus chronic hyperammonemia (CHA) on P-gp function and expression at rat BBB. Experimental rats included sham-operation (SH), PVL, CHA and PVL + CHA. The PVL + CHA rats were developed by ammonia-containing diet for 2 weeks after operation. The brain-to-plasma concentration ratios (K-p) and apparent unidirectional influx constants (K-in) of rhodamine123 and sodium fluorescein were measured to assess function of P-gp and BBB integrity, respectively. Human cerebral microvascular endothelial cells (HCMEC/D3) were used to assess effects of ammonia on P-gp expression and function. It was found that PVL + CHA significantly decreased K-p and K-in of rhodamine123 without affecting brain distribution of fluorescein. The P-gp expressions in membrane protein in cortex and hippocampus were significantly increased in CHA and PVL + CHA rats, especially in PVL + CHA rats, while remarkably increased phosphorylated ERK1/2 was only found in PVL + CHA rats. Expressions of tight junction proteins claudin-5 and occluding in rat brain remained unchanged. In vitro data showed that NH4Cl increased reactive oxygen species, membrane expression and function of P-gp as well as phosphorylated ERK1/2 levels in HCMEC/D3. The NH4Cl-induced alterations were reversed by reactive oxygen species scavenger N-acetylcysteine and ERK1/2 inhibitor U0126. In conclusion, PVL + CHA increased function and membrane translocation of P-gp at rat BBB partly via ammonia. Reactive oxygen species/ERK1/2 pathway activation may be one of the reasons that ammonia upregulated P-gp expression and function at BBB.
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