Drug Transporters in the Central Nervous System

Stieger, Bruno; Gao, Bo

doi:10.1007/s40262-015-0241-y

Cited by 46 publications

(54 citation statements)

References 209 publications

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“…Expression and localization of Mrp isoforms at the BBB is species-dependent and remains highly controversial [48, 49]. Localization of Mrp1 is thought to be at the abluminal plasma membrane in brain microvascular endothelial cells in rodents, but at the luminal membrane in humans [50, 51].…”

Section: Discussionmentioning

confidence: 99%

Nrf2 signaling increases expression of ATP-binding cassette subfamily C mRNA transcripts at the blood–brain barrier following hypoxia-reoxygenation stress

Ibbotson

Yell

Ronaldson

2017

Fluids Barriers CNS

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BackgroundStrategies to maintain BBB integrity in diseases with a hypoxia/reoxygenation (H/R) component involve preventing glutathione (GSH) loss from endothelial cells. GSH efflux transporters include multidrug resistance proteins (Mrps). Therefore, characterization of Mrp regulation at the BBB during H/R is required to advance these transporters as therapeutic targets. Our goal was to investigate, in vivo, regulation of Abcc1, Abcc2, and Abcc4 mRNA expression (i.e., genes encoding Mrp isoforms that transport GSH) by nuclear factor E2-related factor (Nrf2) using a well-established H/R model.MethodsFemale Sprague–Dawley rats (200–250 g) were subjected to normoxia (Nx, 21% O2, 60 min), hypoxia (Hx, 6% O2, 60 min) or H/R (6% O2, 60 min followed by 21% O2, 10 min, 30 min, or 1 h) or were treated with the Nrf2 activator sulforaphane (25 mg/kg, i.p.) for 3 h. Abcc mRNA expression in brain microvessels was determined using quantitative real-time PCR. Nrf2 signaling activation was examined using an electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) respectively. Data were expressed as mean ± SD and analyzed via ANOVA followed by the post hoc Bonferroni t test.ResultsWe observed increased microvascular expression of Abcc1, Abcc2, and Abcc4 mRNA following H/R treatment with reoxygenation times of 10 min, 30 min, and 1 h and in animals treated with sulforaphane. Using a biotinylated Nrf2 probe, we observed an upward band shift in brain microvessels isolated from H/R animals or animals administered sulforaphane. ChIP studies showed increased Nrf2 binding to antioxidant response elements on Abcc1, Abcc2, and Abcc4 promoters following H/R or sulforaphane treatment, suggesting a role for Nrf2 signaling in Abcc gene regulation.ConclusionsOur data show increased Abcc1, Abcc2, and Abcc4 mRNA expression at the BBB in response to H/R stress and that Abcc gene expression is regulated by Nrf2 signaling. Since these Mrp isoforms transport GSH, these results may point to endogenous transporters that can be targeted for BBB protection during H/R stress. Experiments are ongoing to examine functional implications of Nrf2-mediated increases in Abcc transcript expression. Such studies will determine utility of targeting Mrp isoforms for BBB protection in diseases with an H/R component.

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Section: Discussionmentioning

confidence: 99%

Nrf2 signaling increases expression of ATP-binding cassette subfamily C mRNA transcripts at the blood–brain barrier following hypoxia-reoxygenation stress

Ibbotson

Yell

Ronaldson

2017

Fluids Barriers CNS

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“…It is thus expressed at the luminal pole of brain capillary endothelial cells and prevents the entry of drugs into brain by actively expelling them into the blood stream [40]. In this way, P-gp contributes to the blood–brain barrier in a major way [41]. Multidrug resistance-associated protein (MRP) 1 ( ABCC1 ) is another ABC transporter implicated in cancer multidrug resistance.…”

Section: The Drug Transportomementioning

confidence: 99%

Protein Kinases C-Mediated Regulations of Drug Transporter Activity, Localization and Expression

Mayati

Moreau

Vée

et al. 2017

IJMS

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Drug transporters are now recognized as major actors in pharmacokinetics, involved notably in drug–drug interactions and drug adverse effects. Factors that govern their activity, localization and expression are therefore important to consider. In the present review, the implications of protein kinases C (PKCs) in transporter regulations are summarized and discussed. Both solute carrier (SLC) and ATP-binding cassette (ABC) drug transporters can be regulated by PKCs-related signaling pathways. PKCs thus target activity, membrane localization and/or expression level of major influx and efflux drug transporters, in various normal and pathological types of cells and tissues, often in a PKC isoform-specific manner. PKCs are notably implicated in membrane insertion of bile acid transporters in liver and, in this way, are thought to contribute to cholestatic or choleretic effects of endogenous compounds or drugs. The exact clinical relevance of PKCs-related regulation of drug transporters in terms of drug resistance, pharmacokinetics, drug–drug interactions and drug toxicity remains however to be precisely determined. This issue is likely important to consider in the context of the development of new drugs targeting PKCs-mediated signaling pathways, for treating notably cancers, diabetes or psychiatric disorders.

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“…Of these, members of the SCLO (i.e., OATPs/Oatps) and SLC22 (OCT/Oct; OAT/ Oat) family are expressed at the BBB (48). Reviews of OAT and OCT transporters have been published elsewhere (12,49,50). …”

Section: Organic Anion Transporting Polypeptides (Oatps/oatps)mentioning

confidence: 99%

“…Of these, Oatp1a4 (previously designated Oatp2 and a known drug transporting isoform) is expressed in the brain capillaries, liver, intestine, kidney, retina, and choroid plexus (2,50–52). Oatp1a4 was originally isolated from the rat brain with an apparent molecular weight of 92 kDa (48).…”

Section: Organic Anion Transporting Polypeptides (Oatps/oatps)mentioning

confidence: 99%

Functional Expression of P-glycoprotein and Organic Anion Transporting Polypeptides at the Blood-Brain Barrier: Understanding Transport Mechanisms for Improved CNS Drug Delivery?

Abdullahi

Davis

Ronaldson

2017

AAPS J

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Drug delivery to the central nervous system (CNS) is greatly limited by the blood-brain barrier (BBB). Physical and biochemical properties of the BBB have rendered treatment of CNS diseases, including those with a hypoxia/reoxygenation (H/R) component, extremely difficult. Targeting endogenous BBB transporters from the ATP-binding cassette (ABC) superfamily (i.e., P-glycoprotein (P-gp)) or from the solute carrier (SLC) family (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents)) has been suggested as a strategy that can improve delivery of drugs to the brain. With respect to P-gp, direct pharmacological inhibition using small molecules or selective regulation by targeting intracellular signaling pathways has been explored. These approaches have been largely unsuccessful due to toxicity issues and unpredictable pharmacokinetics. Therefore, our laboratory has proposed that optimization of CNS drug delivery, particularly for treatment of diseases with an H/R component, can be achieved by targeting Oatp isoforms at the BBB. As the major drug transporting Oatp isoform, Oatp1a4 has demonstrated blood-to-brain transport of substrate drugs with neuroprotective properties. Furthermore, our laboratory has shown that targeting Oatp1a4 regulation (i.e., TGF-β signaling mediated via the ALK-1 and ALK-5 transmembrane receptors) represents an opportunity to control Oatp1a4 functional expression for the purpose of delivering therapeutics to the CNS. In this review, we will discuss limitations of targeting P-gp-mediated transport activity and the advantages of targeting Oatp-mediated transport. Through this discussion, we will also provide critical information on novel approaches to improve CNS drug delivery by targeting endogenous uptake transporters expressed at the BBB.

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Drug Transporters in the Central Nervous System

Cited by 46 publications

References 209 publications

Nrf2 signaling increases expression of ATP-binding cassette subfamily C mRNA transcripts at the blood–brain barrier following hypoxia-reoxygenation stress

Nrf2 signaling increases expression of ATP-binding cassette subfamily C mRNA transcripts at the blood–brain barrier following hypoxia-reoxygenation stress

Protein Kinases C-Mediated Regulations of Drug Transporter Activity, Localization and Expression

Functional Expression of P-glycoprotein and Organic Anion Transporting Polypeptides at the Blood-Brain Barrier: Understanding Transport Mechanisms for Improved CNS Drug Delivery?

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