Title | Regulation of Blood-Brain Barrier Transporters by Transforming Growth Factor-/Activin Receptor-Like Kinase 1 Signaling: Relevance to the Brain Disposition of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors (i.e., Statins). |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Betterton RD, Abdullahi W, Williams EI, Lochhead JJ, Brzica H, Stanton J, Reddell E, Ogbonnaya C, Davis TP, Ronaldson PT |
Journal | Drug Metab Dispos |
Volume | 50 |
Issue | 7 |
Pagination | 942-956 |
Date Published | 2022 Jul |
ISSN | 1521-009X |
Keywords | Activin Receptors, Animals, ATP Binding Cassette Transporter, Subfamily B, Member 1, ATP Binding Cassette Transporter, Subfamily G, Member 2, Blood-Brain Barrier, Brain, Coenzyme A, Enzyme Inhibitors, Growth Differentiation Factor 2, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Neoplasm Proteins, Neoplasms, Organic Anion Transporters, Oxidoreductases, Rats, Transforming Growth Factor beta, Transforming Growth Factors |
Abstract | Our laboratory has shown that activation of transforming growth factor- (TGF- )/activin receptor-like kinase 1 (ALK1) signaling can increase protein expression and transport activity of organic anion transporting polypeptide 1a4 (Oatp1a4) at the blood-brain barrier (BBB). These results are relevant to treatment of ischemic stroke because Oatp transport substrates such as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (i.e., statins) improve functional neurologic outcomes in patients. Advancement of our work requires determination if TGF- /ALK1 signaling alters Oatp1a4 functional expression differently across brain regions and if such disparities affect central nervous system (CNS) statin disposition. Therefore, we studied regulation of Oatp1a4 by the TGF- /ALK1 pathway, in vivo, in rat brain microvessels isolated from cerebral cortex, hippocampus, and cerebellum using the ALK1 agonist bone morphogenetic protein-9 (BMP-9) and the ALK1 inhibitor 4-[6-[4-(1-piperazinyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]quinoline dihydrochloride 193189. We showed that Oatp1a4 protein expression and brain distribution of three currently marketed statin drugs (i.e., atorvastatin, pravastatin, and rosuvastatin) were increased in cortex relative to hippocampus and cerebellum. Additionally, BMP-9 treatment enhanced Oatp-mediated statin transport in cortical tissue but not in hippocampus or cerebellum. Although brain drug delivery is also dependent upon efflux transporters, such as P-glycoprotein and/or Breast Cancer Resistance Protein, our data showed that administration of BMP-9 did not alter the relative contribution of these transporters to CNS disposition of statins. Overall, this study provides evidence for differential regulation of Oatp1a4 by TGF- /ALK1 signaling across brain regions, knowledge that is critical for development of therapeutic strategies to target Oatps at the BBB for CNS drug delivery. SIGNIFICANCE STATEMENT: Organic anion transporting polypeptides (Oatps) represent transporter targets for brain drug delivery. We have shown that Oatp1a4 statin uptake is higher in cortex versus hippocampus and cerebellum. Additionally, we report that the transforming growth factor- /activin receptor-like kinase 1 agonist bone morphogenetic protein-9 increases Oatp1a4 functional expression, but not efflux transporters P-glycoprotein and Breast Cancer Resistance Protein, in cortical brain microvessels. Overall, this study provides critical data that will advance treatment for neurological diseases where drug development has been challenging. |
DOI | 10.1124/dmd.121.000781 |
Alternate Journal | Drug Metab Dispos |
PubMed ID | 35504656 |
Grant List | R01 DA051812 / DA / NIDA NIH HHS / United States R01 NS084941 / NS / NINDS NIH HHS / United States |
Regulation of Blood-Brain Barrier Transporters by Transforming Growth Factor-/Activin Receptor-Like Kinase 1 Signaling: Relevance to the Brain Disposition of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors (i.e., Statins).
Faculty Member Reference:
Thomas P Davis, PhD
Jeffrey J. Lochhead, PhD
Patrick T Ronaldson, PhD, FAAPS