期刊
JOURNAL OF NEUROCHEMISTRY
卷 121, 期 1, 页码 125-134出版社
WILEY
DOI: 10.1111/j.1471-4159.2012.07669.x
关键词
ammonia; blood-brain barrier; cerebral capillary endothelial cell line; matrix metalloproteinases; oxidative; nitrosative stress
资金
- Ministry of Science and Education [N N401 130839, N N401 037839]
- US National Institute of Environmental Health Sciences [ES R01 07731, ES R01 10563]
Ammonia is responsible for cerebral edema associated with acute liver failure, but the role of the vasogenic mechanism has been a matter of dispute. Here, we tested the hypothesis that ammonia induces changes in bloodbrain barrier (BBB) permeability by a mechanism coupled to oxidative/nitrosative stress (ONS) evoked in the BBB-forming cerebral capillary endothelial cells. Treatment of a rat brain endothelial cell line with ammonia (5 mmol/L, 24 h) caused accumulation of ONS markers: reactive oxygen species, nitric oxide and peroxidation products of phospholipid-bound arachidonic acid, F2-isoprostanes. Concurrently, ammonia increased the activity of extracellular matrix metalloproteinases (MMP-2/MMP-9), increased cell permeability to fluorescein isothiocyanate-dextran (40 kDa), and increased the expression of y+LAT2, a transporter that mediates the uptake to the cells of the nitric oxide precursor, arginine. The increase of cell permeability was ameliorated upon co-treatment with a MMP inhibitor, SB-3CT and with an antioxidant, glutathione diethyl ester, which also reduced F2-isoprostanes. Ammonia-induced ONS was attenuated by cytoprotective agents l-ornithine, phenylbutyrate, and their conjugate l-ornithine phenylbutyrate, an ammonia-trapping drug used to treat hyperammonemia. The results support the concept that ONS and ONS-related activation of MMPs in cerebral capillary endothelial cells contribute to the alterations in BBB permeability and to the vasogenic component of cerebral edema associated with acute liver failure.
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