Therapeutic drugs modulate ATP-Binding cassette transporter-mediated transport of amyloid beta(1–42) in brain microvascular endothelial cells
Deposition of amyloid-β peptide (Aβ(1–42)) is a hallmark of Alzheimer's disease. Clearance of Aβ(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 ther...
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Veröffentlicht in: | European journal of pharmacology 2020-05, Vol.874, p.173009-173009, Article 173009 |
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description | Deposition of amyloid-β peptide (Aβ(1–42)) is a hallmark of Alzheimer's disease. Clearance of Aβ(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 Aβ(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 Aβ(1–42) was determined using fluorescent Aβ(1–42). The ability of the ABCB1, ABCC5 and ABCG2 inhibitor telmisartan to modify transcellular Aβ(1–42) transport was investigated using PBEC monolayers housed in Transwell® inserts.
Treatment of PBECs with ABC transporter inhibitory drugs (indomethacin, olanzapine, chlorpromazine, telmisartan, pantoprazole, quinidine, sulfasalazine and nefazodone) increased Aβ(1–42) intracellular accumulation. Inhibition of ABCB1, ABCC5 and ABCG2 by telmisartan increased Aβ(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 Aβ(1–42) in BBB endothelial cells. Inhibition of ABC transporters by therapeutic drugs, at plasma concentrations, could decrease Aβ(1–42) clearance from brain, across BBB endothelial cells into blood, and potentially influence levels of the Aβ(1–42) peptide within the brain. |
doi_str_mv | 10.1016/j.ejphar.2020.173009 |
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Treatment of PBECs with ABC transporter inhibitory drugs (indomethacin, olanzapine, chlorpromazine, telmisartan, pantoprazole, quinidine, sulfasalazine and nefazodone) increased Aβ(1–42) intracellular accumulation. Inhibition of ABCB1, ABCC5 and ABCG2 by telmisartan increased Aβ(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 Aβ(1–42) in BBB endothelial cells. Inhibition of ABC transporters by therapeutic drugs, at plasma concentrations, could decrease Aβ(1–42) clearance from brain, across BBB endothelial cells into blood, and potentially influence levels of the Aβ(1–42) peptide within the brain.</description><identifier>ISSN: 0014-2999</identifier><identifier>EISSN: 1879-0712</identifier><identifier>DOI: 10.1016/j.ejphar.2020.173009</identifier><identifier>PMID: 32061744</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>ABCB1 ; ABCC5 ; ABCG2 ; Alzheimer's disease ; Amyloid-beta ; Porcine brain endothelial cells ; Therapeutic drugs</subject><ispartof>European journal of pharmacology, 2020-05, Vol.874, p.173009-173009, Article 173009</ispartof><rights>2020 Elsevier B.V.</rights><rights>Copyright © 2020 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c408t-7be34512899086702f274f4d3c3890ed72435c5a5ab049304264473438e38c393</citedby><cites>FETCH-LOGICAL-c408t-7be34512899086702f274f4d3c3890ed72435c5a5ab049304264473438e38c393</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejphar.2020.173009$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32061744$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shubbar, Maryam H.</creatorcontrib><creatorcontrib>Penny, Jeffrey I.</creatorcontrib><title>Therapeutic drugs modulate ATP-Binding cassette transporter-mediated transport of amyloid beta(1–42) in brain microvascular endothelial cells</title><title>European journal of pharmacology</title><addtitle>Eur J Pharmacol</addtitle><description>Deposition of amyloid-β peptide (Aβ(1–42)) is a hallmark of Alzheimer's disease. Clearance of Aβ(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 Aβ(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 Aβ(1–42) was determined using fluorescent Aβ(1–42). The ability of the ABCB1, ABCC5 and ABCG2 inhibitor telmisartan to modify transcellular Aβ(1–42) transport was investigated using PBEC monolayers housed in Transwell® inserts.
Treatment of PBECs with ABC transporter inhibitory drugs (indomethacin, olanzapine, chlorpromazine, telmisartan, pantoprazole, quinidine, sulfasalazine and nefazodone) increased Aβ(1–42) intracellular accumulation. Inhibition of ABCB1, ABCC5 and ABCG2 by telmisartan increased Aβ(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 Aβ(1–42) in BBB endothelial cells. Inhibition of ABC transporters by therapeutic drugs, at plasma concentrations, could decrease Aβ(1–42) clearance from brain, across BBB endothelial cells into blood, and potentially influence levels of the Aβ(1–42) peptide within the brain.</description><subject>ABCB1</subject><subject>ABCC5</subject><subject>ABCG2</subject><subject>Alzheimer's disease</subject><subject>Amyloid-beta</subject><subject>Porcine brain endothelial cells</subject><subject>Therapeutic drugs</subject><issn>0014-2999</issn><issn>1879-0712</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9kb1uFDEUhS1ERDaBN0DIZShmc_0zP26QkggCUiQoltry2HeyXs0ftidSOt6AgjfkSfBqAnQ0tnT0XZ_rcwh5zWDLgFWXhy0e5r0JWw48S7UAUM_IhjW1KqBm_DnZADBZcKXUKTmL8QAApeLlC3IqOFSslnJDfuz2GMyMS_KWurDcRzpMbulNQnq1-1Jc-9H58Z5aEyOmLKZgxjhPIWEoBnQ-g-6fSKeOmuGxn7yjLSZzwX59_yn5W-pH2gaTz8HbMD2YaLNHoDi6Ke2x96anFvs-viQnnekjvnq6z8nXD-93Nx-Lu8-3n26u7goroUlF3aKQJeONUtBUNfCO17KTTljRKEBXcylKW5rStCCVAMkrKWshRYOisUKJc3KxvjuH6duCMenBx-MGZsRpiZqLsqpYpZoqo3JF8-IxBuz0HPxgwqNmoI9V6INeq9DHKvRaRR578-SwtDmov0N_ss_AuxXA_M8Hj0FH63G0OdSANmk3-f87_Aa4Yp2G</recordid><startdate>20200505</startdate><enddate>20200505</enddate><creator>Shubbar, Maryam H.</creator><creator>Penny, Jeffrey I.</creator><general>Elsevier B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20200505</creationdate><title>Therapeutic drugs modulate ATP-Binding cassette transporter-mediated transport of amyloid beta(1–42) in brain microvascular endothelial cells</title><author>Shubbar, Maryam H. ; Penny, Jeffrey I.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c408t-7be34512899086702f274f4d3c3890ed72435c5a5ab049304264473438e38c393</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>ABCB1</topic><topic>ABCC5</topic><topic>ABCG2</topic><topic>Alzheimer's disease</topic><topic>Amyloid-beta</topic><topic>Porcine brain endothelial cells</topic><topic>Therapeutic drugs</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shubbar, Maryam H.</creatorcontrib><creatorcontrib>Penny, Jeffrey I.</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shubbar, Maryam H.</au><au>Penny, Jeffrey I.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Therapeutic drugs modulate ATP-Binding cassette transporter-mediated transport of amyloid beta(1–42) in brain microvascular endothelial cells</atitle><jtitle>European journal of pharmacology</jtitle><addtitle>Eur J Pharmacol</addtitle><date>2020-05-05</date><risdate>2020</risdate><volume>874</volume><spage>173009</spage><epage>173009</epage><pages>173009-173009</pages><artnum>173009</artnum><issn>0014-2999</issn><eissn>1879-0712</eissn><abstract>Deposition of amyloid-β peptide (Aβ(1–42)) is a hallmark of Alzheimer's disease. Clearance of Aβ(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 Aβ(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 Aβ(1–42) was determined using fluorescent Aβ(1–42). The ability of the ABCB1, ABCC5 and ABCG2 inhibitor telmisartan to modify transcellular Aβ(1–42) transport was investigated using PBEC monolayers housed in Transwell® inserts.
Treatment of PBECs with ABC transporter inhibitory drugs (indomethacin, olanzapine, chlorpromazine, telmisartan, pantoprazole, quinidine, sulfasalazine and nefazodone) increased Aβ(1–42) intracellular accumulation. Inhibition of ABCB1, ABCC5 and ABCG2 by telmisartan increased Aβ(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 Aβ(1–42) in BBB endothelial cells. Inhibition of ABC transporters by therapeutic drugs, at plasma concentrations, could decrease Aβ(1–42) clearance from brain, across BBB endothelial cells into blood, and potentially influence levels of the Aβ(1–42) peptide within the brain.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>32061744</pmid><doi>10.1016/j.ejphar.2020.173009</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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subjects | ABCB1 ABCC5 ABCG2 Alzheimer's disease Amyloid-beta Porcine brain endothelial cells Therapeutic drugs |
title | Therapeutic drugs modulate ATP-Binding cassette transporter-mediated transport of amyloid beta(1–42) in brain microvascular endothelial cells |
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