Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 874, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ejphar.2020.173009
Keywords
ABCB1; ABCG2; ABCC5; Amyloid-beta; Alzheimer's disease; Therapeutic drugs; Porcine brain endothelial cells
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Funding
- Iraqi Ministry of Higher Education and Scientific Research [1560]
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Deposition of amyloid-beta peptide (A beta((1-42))) is a hallmark of Alzheimer's disease. Clearance of A beta((1-42)), across the blood-brain barrier (BBB), is mediated by ATP-binding Cassette (ABC) efflux transporters. Many therapeutic drugs inhibit ABC transporters, but little is known of the effect of therapeutic drugs on A beta((1-42)) transport across BBB endothelial cells. The effects of selected, widely prescribed, therapeutic drugs on ABCB1, ABCC5 and ABCG2 activities were determined by measuring intracellular levels of calcein, GS-MF, and Hoechst 33342 respectively in primary porcine brain endothelial cells (PBECs). The ability of ABCB1, ABCC5 and ABCG2 to transport A beta((1-42)) was determined using fluorescent A beta((1-42)). The ability of the ABCB1, ABCC5 and ABCG2 inhibitor telmisartan to modify transcellular A beta((1-42)) transport was investigated using PBEC monolayers housed in Transwell (R) inserts. Treatment of PBECs with ABC transporter inhibitory drugs (indomethacin, olanzapine, chlorpromazine, telmisartan, pantoprazole, quinidine, sulfasalazine and nefazodone) increased A beta((1-42)) intracellular accumulation. Inhibition of ABCB1, ABCC5 and ABCG2 by telmisartan increased A beta((1-42)) transport in the apical to basal direction and reduced its transport in basal to apical direction in PBEC monolayers. ABCB1, ABCC5 and ABCG2 mediate the efflux transport of A beta((1-42)) in BBB endothelial cells. Inhibition of ABC transporters by therapeutic drugs, at plasma concentrations, could decrease A beta((1-42))clearance from brain, across BBB endothelial cells into blood, and potentially influence levels of the A beta((1-42) )peptide within the brain.
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