Arizona Health Sciences

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

TitleHypoxia/reoxygenation stress signals an increase in organic anion transporting polypeptide 1a4 (Oatp1a4) at the blood-brain barrier: relevance to CNS drug delivery.
Publication TypeJournal Article
Year of Publication2014
AuthorsThompson BJ, Sanchez-Covarrubias L, Slosky LM, Zhang Y, Laracuente M-L, Ronaldson PT
JournalJ Cereb Blood Flow Metab
Volume34
Issue4
Pagination699-707
Date Published2014 Apr
ISSN1559-7016
KeywordsAnimals, Atorvastatin Calcium, Biological Transport, Blood Gas Analysis, Blood-Brain Barrier, Blotting, Western, Carbon Dioxide, Drug Delivery Systems, Electrolytes, Female, Heptanoic Acids, Hypoxia, Brain, Microvessels, Neuroprotective Agents, Organic Anion Transporters, Oxygen, Pyrroles, Rats, Rats, Sprague-Dawley, Reperfusion Injury
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.

DOI10.1038/jcbfm.2014.4
Alternate JournalJ. Cereb. Blood Flow Metab.
PubMed ID24473481
PubMed Central IDPMC3982098
Faculty Member Reference: 
Patrick T Ronaldson, Ph.D.