TGF-β/ALK1 Signaling Increases Organic Anion Transporting Polypeptide 1a4 (Oatp1a4) Expression at the Blood-Brain Barrier

2016 ◽  
Author(s):  
Wazir Abdullahi
Keyword(s):  
Blood Brain Barrier ◽  
Organic Anion ◽  
Brain Barrier ◽  
Organic Anion Transporting Polypeptide ◽  
Blood Brain

scholarly journals Hypoxia/Reoxygenation Stress Signals an Increase in Organic Anion Transporting polypeptide 1a4 (Oatp1a4) at the Blood–Brain Barrier: Relevance to CNS Drug Delivery

2014 ◽  
Vol 34 (4) ◽  
pp. 699-707 ◽  
Author(s):  
Brandon J Thompson ◽  
Lucy Sanchez-Covarrubias ◽  
Lauren M Slosky ◽  
Yifeng Zhang ◽  
Mei-li Laracuente ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Transforming Growth Factor ◽  
Organic Anion ◽  
Functional Expression ◽  
Brain Barrier ◽  
Parp Cleavage ◽  
Organic Anion Transporting Polypeptide ◽  
Cns Drug Delivery ◽  
Blood Brain

Cerebral hypoxia and subsequent reoxygenation stress (H/R) is a component of several diseases. One approach that may enable neural tissue rescue after H/R is central nervous system (CNS) delivery of drugs with brain protective effects such as 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (i.e., statins). Our present in vivo data show that atorvastatin, a commonly prescribed statin, attenuates poly (ADP-ribose) polymerase (PARP) cleavage in the brain after H/R, suggesting neuroprotective efficacy. However, atorvastatin use as a CNS therapeutic is limited by poor blood–brain barrier (BBB) penetration. Therefore, we examined regulation and functional expression of the known statin transporter organic anion transporting polypeptide 1a4 (Oatp1a4) at the BBB under H/R conditions. In rat brain microvessels, H/R (6% O2, 60 minutes followed by 21% O2, 10 minutes) increased Oatp1a4 expression. Brain uptake of taurocholate (i.e., Oap1a4 probe substrate) and atorvastatin were reduced by Oatp inhibitors (i.e., estrone-3-sulfate and fexofenadine), suggesting involvement of Oatp1a4 in brain drug delivery. Pharmacological inhibition of transforming growth factor- β (TGF- β)/activin receptor-like kinase 5 (ALK5) signaling with the selective inhibitor SB431542 increased Oatp1a4 functional expression, suggesting a role for TGF- β/ALK5 signaling in Oatp1a4 regulation. Taken together, our novel data show that targeting an endogenous BBB drug uptake transporter (i.e., Oatp1a4) may be a viable approach for optimizing CNS drug delivery for treatment of diseases with an H/R component.

scholarly journals Bone morphogenetic protein-9 increases the functional expression of organic anion transporting polypeptide 1a4 at the blood–brain barrier via the activin receptor-like kinase-1 receptor

2017 ◽  
Vol 37 (7) ◽  
pp. 2340-2345 ◽  
Author(s):  
Wazir Abdullahi ◽  
Hrvoje Brzica ◽  
Kathryn Ibbotson ◽  
Thomas P Davis ◽  
Patrick T Ronaldson
Keyword(s):  
Drug Delivery ◽  
Bone Morphogenetic Protein ◽  
Blood Brain Barrier ◽  
Organic Anion ◽  
Brain Barrier ◽  
Activin Receptor ◽  
Organic Anion Transporting Polypeptide ◽  
Blood Brain ◽  
Morphogenetic Protein ◽  
Receptor Like Kinase

Targeting uptake transporters such as organic anion transporting polypeptide 1a4 (Oatp1a4) at the blood–brain barrier (BBB) can facilitate central nervous system (CNS) drug delivery. Effective blood-to-brain drug transport via this strategy requires characterization of mechanisms that modulate BBB transporter expression and/or activity. Here, we show that activation of activin receptor-like kinase (ALK)-1 using bone morphogenetic protein (BMP)-9 increases Oatp1a4 protein expression in rat brain microvessels in vivo. These data indicate that targeting ALK1 signaling with BMP-9 modulates BBB Oatp1a4 expression, presenting a unique opportunity to optimize drug delivery and improve pharmacotherapy for CNS diseases.

scholarly journals Competitive Inhibition of Organic Anion Transporting Polypeptide 1c1-Mediated Thyroxine Transport by the Fenamate Class of Nonsteroidal Antiinflammatory Drugs

Endocrinology ◽  
2009 ◽  
Vol 150 (2) ◽  
pp. 1025-1032 ◽  
Author(s):  
Daniel E. Westholm ◽  
David D. Stenehjem ◽  
Jon N. Rumbley ◽  
Lester R. Drewes ◽  
Grant W. Anderson
Keyword(s):  
Indocyanine Green ◽  
Blood Brain Barrier ◽  
Organic Anion ◽  
Brain Barrier ◽  
Dependent Manner ◽  
Human Embryonic Kidney ◽  
Organic Anion Transporting Polypeptide ◽  
Meclofenamic Acid ◽  
Blood Brain ◽  
293 Cells

Organic anion transporting polypeptide (Oatp) 1c1 is a high-affinity T4 transporter with narrow substrate specificity expressed at the blood-brain barrier. A transport model using cells overexpressing Oatp1c1 was created to identify novel Oatp1c1 substrates and inhibitors. Rat Oatp1c1 was cloned and stably expressed in human embryonic kidney 293 cells. Oatp1c1-transfected human embryonic kidney 293 cells transported 125I-labeled T4 in a time-dependent manner that was completely abolished in the presence of excess unlabeled T4. Next, various compounds, including inhibitors of thyroid hormone uptake, were screened for inhibitory effects on Oatp1c1-mediated T4 uptake. Phenytoin (64%), indocyanine green (17%), fenamic acid (68%), diclofenac (51%), and meclofenamic acid (33%) all reduced T4 uptake by Oatp1c1 when assayed at concentrations of 10 μM. Dose-response assays for the fenamic acids, iopanoic acid, indocyanine green, and phenytoin revealed IC50 values for Oatp1c1 T4 uptake below or near the blood plasma levels after therapeutic doses. Further kinetic assays and reciprocal plot analyses demonstrated that the fenamic acid diclofenac inhibited in a competitive manner. Finally, microvessels were isolated from adult rat brain and assessed for T4 uptake. Ten micromolar of fenamate concentrations inhibited T4 microvessel uptake with a similar hierarchical inhibition profile [fenamic acid (43%), diclofenac (78%), and meclofenamic acid (85%)], as observed for Oatp1c1 transfected cells. Oatp1c1 is expressed luminally and abluminally in the blood-brain barrier endothelial cell, and exhibits bidirectional transport capabilities. Together, these data suggest that Oatp1c1 transports fenamates into, and perhaps across, brain barrier cells. The fenamate class of nonsteroidal anti-inflammatory drugs is transported by organic anion transporting polypeptides and competitively inhibits thyroxine transport in brain microvessels.

scholarly journals Parallel Regulation of Thyroid Hormone Transporters OATP1c1 and MCT8 During and After Endotoxemia at the Blood-Brain Barrier of Male Rodents

Endocrinology ◽  
2015 ◽  
Vol 156 (4) ◽  
pp. 1552-1564 ◽  
Author(s):  
Gábor Wittmann ◽  
Judit Szabon ◽  
Petra Mohácsik ◽  
Shira S. Nouriel ◽  
Balázs Gereben ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Blood Brain Barrier ◽  
Organic Anion ◽  
Brain Barrier ◽  
Monocarboxylate Transporter ◽  
Mrna Levels ◽  
Brain Vessels ◽  
Altered Expression ◽  
Protein Levels ◽  
Blood Brain

Abstract There is increasing evidence that local thyroid hormone (TH) availability changes profoundly in inflammatory conditions due to altered expression of deiodinases that metabolize TH. It is largely unknown, however, how inflammation affects TH availability via the expression of TH transporters. In this study we examined the effect of bacterial lipopolysaccharide (LPS) administration on two TH transporters that are critically important for brain TH homeostasis, organic anion-transporting polypeptide 1c1 (OATP1c1), and monocarboxylate transporter 8 (MCT8). MRNA levels were studied by in situ hybridization and qPCR as well as protein levels by immunofluorescence in both the rat and mouse forebrain. The mRNA of both transporters decreased robustly in the first 9 hours after LPS injection, specifically in brain blood vessels; OATP1c1 mRNA in astrocytes and MCT8 mRNA in neurons remained unchanged. At 24 and/or 48 hours after LPS administration, OATP1c1 and MCT8 mRNAs increased markedly above control levels in brain vessels. OATP1c1 protein decreased markedly in vessels by 24 hours whereas MCT8 protein levels did not decrease significantly. These changes were highly similar in mice and rats. The data demonstrate that OATP1c1 and MCT8 expression are regulated in a parallel manner during inflammation at the blood-brain barrier of rodents. Given the indispensable role of both transporters in allowing TH access to the brain, the results suggest reduced brain TH uptake during systemic inflammation.

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