Effect of amyloid beta on ATP-binding cassette transporter expression and activity in porcine brain microvascular endothelial cells

Shubbar, Maryam H.; Penny, Jeffrey

doi:10.1016/j.bbagen.2018.07.021

Cited by 19 publications

(21 citation statements)

References 58 publications

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“…brain barrier endothelial cells ABCB1, ABCG2 and ABCC5 functional activities have been demonstrated previously in porcine brain endothelial cells utilized in the present study (Shubbar and Penny 2018).…”

Section: Abcb1 Abcg2 and Abcc5 Reduce Intracellular Accumulation Of Aβ(1-42) In Blood-supporting

confidence: 75%

“…Therefore it is important to obtain a better understanding of the mechanism(s) by which Aβ(1-42) is cleared, across the BBB, from brain to systemic circulation. In the current study we employed a well characterised in vitro model of the BBB (Cantrill et al, 2012;Shubbar and Penny, 2018;Skinner et al, 2009) to investigate the roles of ABCB1, ABCG2 and ABCC5 in Aβ(1-42) clearance.…”

Section: Discussionmentioning

confidence: 99%

“…Functional activity of ABCB1, ABCG2 and ABCC5 was measured as described previously (Cantrill et al 2012;Gutmann et al 1999;Shubbar and Penny 2018).…”

Section: Measurement Of the Effect Of Abcb1 Abcg2 And Abcc5 Inhibition On Intracellular Accumulation Of Aβ(1-42)mentioning

confidence: 99%

“…ATP-binding cassette (ABC) efflux transporters play a fundamental role in determining the permeability characteristics of the BBB and function to restrict penetration of molecules into the brain, whilst also mediating the clearance transport of molecules out of the brain. The ABCB1 (Pglycoprotein), ABCG2 (breast cancer resistance protein) and ABCC5 (multidrug resistanceassociated protein-5) transporters are expressed in BBB endothelial cells (Cantrill et al, 2012;Kubo et al, 2015;Shubbar and Penny, 2018) and limit penetration of numerous therapeutic drugs and endogenous compounds across the BBB (King et al, 2001;Schinkel et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic drugs modulate ATP-Binding cassette transporter-mediated transport of amyloid beta(1–42) in brain microvascular endothelial cells

Shubbar

Penny

2020

European Journal of Pharmacology

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Deposition of amyloid-β peptide ) 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.

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Section: Abcb1 Abcg2 and Abcc5 Reduce Intracellular Accumulation Of Aβ(1-42) In Blood-supporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

“…Functional activity of ABCB1, ABCG2 and ABCC5 was measured as described previously (Cantrill et al 2012;Gutmann et al 1999;Shubbar and Penny 2018).…”

Section: Measurement Of the Effect Of Abcb1 Abcg2 And Abcc5 Inhibition On Intracellular Accumulation Of Aβ(1-42)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Therapeutic drugs modulate ATP-Binding cassette transporter-mediated transport of amyloid beta(1–42) in brain microvascular endothelial cells

Shubbar

Penny

2020

European Journal of Pharmacology

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“…Over 200,000 exonic single-nucleotide variants (SNVs) have been identified, 99.8% of which are present in <1% of analyzed alleles. In the individual genome, there are about 29.7 variants with putative functional effects, and in specific populations, interethnic variability shows over 80% deleterious SLC variants [97].…”

Section: The Pharmacogenomic Machinerymentioning

confidence: 99%

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Cacabelos

2020

IJMS

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Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6–10 drugs/day with the consequent risk for drug–drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.

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Pharmacogenomics of Alzheimer’s Disease: Novel Strategies for Drug Utilization and Development

Cacabelos

Naidoo

Martínez-Iglesias

et al. 2022

Methods in Molecular Biology

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Effect of amyloid beta on ATP-binding cassette transporter expression and activity in porcine brain microvascular endothelial cells

Abstract: Aβ reduces ABC transporter activity and expression in BBB endothelial cells and has the potential to influence BBB permeability characteristics.

Cited by 19 publications

References 58 publications

Therapeutic drugs modulate ATP-Binding cassette transporter-mediated transport of amyloid beta(1–42) in brain microvascular endothelial cells

Therapeutic drugs modulate ATP-Binding cassette transporter-mediated transport of amyloid beta(1–42) in brain microvascular endothelial cells

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Pharmacogenomics of Alzheimer’s Disease: Novel Strategies for Drug Utilization and Development

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