Hypoxia/Reoxygenation (H/R) Stress Increases Organic Anion Transporting Polypeptide 1a4 (Oatp1a4)‐mediated Transcellular Transport at the Blood‐Brain Barrier (BBB): Relevance to CNS Drug Delivery

Abstract

Our objective was to investigate effects of H/R stress, a component of ischemic stroke, on Oatp1a4‐mediated transcellular transport at the BBB. Rats (200–250 g) were subjected to normoxia (Nx, 21% O2, 60 min), hypoxia (Hx, 6% O2, 60 min) or H/R (6% O2, 60 min followed by 21% O2, 10 min). In rat brain microvessels, Oatp1a4 expression was increased following H/R but was unchanged by Nx or Hx. Uptake of Oatp1a4 substrates (i.e., taurocholate, atorvastatin) were increased following H/R. Oatp1a4 inhibitors (i.e., fexofenadine, estrone‐3‐sulfate) blocked taurocholate and atorvastatin brain uptake in H/R animals, further implicating Oatp1a4 in BBB transcellular transport of these drugs. Additionally, H/R reduced serum levels of transforming growth factor‐β1 (TGF‐β1) and decreased microvascular expression of TGF‐β receptor activin receptor‐like kinase (ALK)‐5. Pretreatment with SB431542, an ALK5 inhibitor, increased Oatp1a4 functional expression both in H/R and Nx animals. These novel data demonstrate that targeting an endogenous BBB transporter may be a viable approach for delivering drugs to the brain during cerebral ischemia. Our study also identifies a BBB signaling mechanism (i.e., TGF‐β/ALK5 pathway) that can be exploited to control expression of Oatp1a4 during H/R and, therefore, optimize CNS drug delivery. This work was supported by NIH R01 grant DA‐11271 and an AAPS New Investigator Grant.