Hypoxia/reoxygenation stress signals an increase in organic anion transporting polypeptide 1a4 (Oatp1a4) at the blood-brain barrier: relevance to CNS drug delivery.
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.
Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona, USA.
Brandon J
BJ
Thompson
Department of Pharmacology, University of Arizona College of Medicine, Tucson, Arizona, USA.
Lucy
L
Sanchez-Covarrubias
Department of Pharmacology, University of Arizona College of Medicine, Tucson, Arizona, USA.
Lauren M
LM
Slosky
Department of Pharmacology, University of Arizona College of Medicine, Tucson, Arizona, USA.
Yifeng
Y
Zhang
Department of Pharmacology, University of Arizona College of Medicine, Tucson, Arizona, USA.
Mei-li
ML
Laracuente
1] Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona, USA [2] Department of Pharmacology, University of Arizona College of Medicine, Tucson, Arizona, USA.
Patrick T
PT
Ronaldson
D000818:Animals; D000069059:Atorvastatin; D001692:Biological Transport; D001784:Blood Gas Analysis; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western; D002245:Carbon Dioxide / Q000097:blood; D016503:Drug Delivery Systems; D004573:Electrolytes / Q000097:blood; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D002534:Hypoxia, Brain / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D055806:Microvessels / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D027361:Organic Anion Transporters / Q000378:metabolism*; D010100:Oxygen / Q000097:blood; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*
D004573:Electrolytes; D006538:Heptanoic Acids; D018696:Neuroprotective Agents; D027361:Organic Anion Transporters; D011758:Pyrroles; C503597:Slco1a4 protein, rat; D002245:Carbon Dioxide; D000069059:Atorvastatin; D010100:Oxygen