Hypoxia/reoxygenation stress signals an increase in organic anion transporting polypeptide 1a4 (Oatp1a4) at the blood-brain barrier: Relevance to CNS drug delivery

Brandon J. Thompson, Lucy Sanchez-Covarrubias, Lauren M. Slosky, Yifeng Zhang, Mei Li Laracuente, Patrick T Ronaldson

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)699-707
Number of pages9
JournalJournal of Cerebral Blood Flow and Metabolism
Volume34
Issue number4
DOIs
StatePublished - 2014

Fingerprint

Central Nervous System Agents
Blood-Brain Barrier
Anions
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Peptides
Organic Anion Transporters
Brain
fexofenadine
Growth Factor Receptors
Transforming Growth Factors
Brain Hypoxia
Taurocholic Acid
Poly(ADP-ribose) Polymerases
Microvessels
Pharmaceutical Preparations
Hypoxia
Oxidoreductases
Central Nervous System
Pharmacology
Atorvastatin Calcium

Keywords

  • Blood-brain barrier
  • Drug transport
  • Hypoxia/reoxygenation
  • Oatp1a4
  • Statins
  • TGF-β signaling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Neurology

Cite this

Hypoxia/reoxygenation stress signals an increase in organic anion transporting polypeptide 1a4 (Oatp1a4) at the blood-brain barrier : Relevance to CNS drug delivery. / Thompson, Brandon J.; Sanchez-Covarrubias, Lucy; Slosky, Lauren M.; Zhang, Yifeng; Laracuente, Mei Li; Ronaldson, Patrick T.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 34, No. 4, 2014, p. 699-707.

Research output: Contribution to journalArticle

@article{0f882178cf8f461cb0d115ebf0c69fdb,
title = "Hypoxia/reoxygenation stress signals an increase in organic anion transporting polypeptide 1a4 (Oatp1a4) at the blood-brain barrier: Relevance to CNS drug delivery",
abstract = "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.",
keywords = "Blood-brain barrier, Drug transport, Hypoxia/reoxygenation, Oatp1a4, Statins, TGF-β signaling",
author = "Thompson, {Brandon J.} and Lucy Sanchez-Covarrubias and Slosky, {Lauren M.} and Yifeng Zhang and Laracuente, {Mei Li} and Ronaldson, {Patrick T}",
year = "2014",
doi = "10.1038/jcbfm.2014.4",
language = "English (US)",
volume = "34",
pages = "699--707",
journal = "Journal of Cerebral Blood Flow and Metabolism",
issn = "0271-678X",
publisher = "Nature Publishing Group",
number = "4",

}

TY - JOUR

T1 - Hypoxia/reoxygenation stress signals an increase in organic anion transporting polypeptide 1a4 (Oatp1a4) at the blood-brain barrier

T2 - Relevance to CNS drug delivery

AU - Thompson, Brandon J.

AU - Sanchez-Covarrubias, Lucy

AU - Slosky, Lauren M.

AU - Zhang, Yifeng

AU - Laracuente, Mei Li

AU - Ronaldson, Patrick T

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Blood-brain barrier

KW - Drug transport

KW - Hypoxia/reoxygenation

KW - Oatp1a4

KW - Statins

KW - TGF-β signaling

UR - http://www.scopus.com/inward/record.url?scp=84897570512&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84897570512&partnerID=8YFLogxK

U2 - 10.1038/jcbfm.2014.4

DO - 10.1038/jcbfm.2014.4

M3 - Article

C2 - 24473481

AN - SCOPUS:84897570512

VL - 34

SP - 699

EP - 707

JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

SN - 0271-678X

IS - 4

ER -