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% O 2 , 60 minutes followed by 21% O 2 , 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-b (TGF-b)/activin receptor-like kinase 5 (ALK5) signaling with the selective inhibitor SB431542 increased Oatp1a4 functional expression, suggesting a role for TGF-b/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.

Targeting transporters: Promoting blood–brain barrier repair in response to oxidative stress injury

“…Transporters involved in transendothelial flux of drugs have also been identified and characterized at the BBB and include ATP-dependent efflux transporters such as P-glycoprotein (P-gp) (Roberts et al 2008; Yousif et al 2008; McCaffrey et al 2012; Ohtsuki et al 2013), Multidrug Resistance Proteins 1–6 (MRP1–6 in humans; Mrp1–6 in rodents) (Dallas et al 2006; Bauer et al 2008; Roberts et al 2008; Cartwright et al 2013), and Breast Cancer Resistance Protein (BCRP in humans; Bcrp in rodents) (Yousif et al 2012; Ohtsuki et al 2013). Transporters that facilitate BBB drug permeation include organic anion transporting polypeptides (OATPs in humans; Oatps in rodents) (Ose et al 2010; Ronaldson et al 2011; Thompson et al 2014), organic anion transporters (Hawkins et al 2007; Ose et al 2009; Miyajima et al 2011), monocarboxylate transporters (Vijay and Morris, 2014), nucleoside transporters (Lepist et al 2013), and peptide transporters (Dogrukol-Ak et al 2009). …”

“…Immunofluorescence staining of human brain frontal cortex demonstrated OATP1A2 localization at the level of the brain microvascular endothelium (Gao et al 2000). In rodent brain, expression of Oatp1a4, Oatp1 c1, and Oatp2a1 has been reported in capillary enriched fractions, capillary endothelial cells and/or isolated brain microvessels (Sugiyama et al 2003; Taogoshi et al 2005; Chu et al 2008; Westholm et al 2009a, b; Ronaldson et al 2011; Thompson et al 2014). Oatp1 c1 is selectively expressed at the BBB (Chu et al 2008) and has relatively narrow substrate specificity and primarily transports thyroxine and conjugated sterols (Westholm et al 2009a, b).…”

“…It has proposed that Oatp1a4, a rodent homologue of OATP1A2, is the primary drug transporting Oatp isoform expressed at the rat BBB (Hagenbuch and Meier, 2004). Recently, our laboratory demonstrated that Oatp1a4 is a BBB transporter that can be effectively targeted for facilitation of effective CNS drug delivery (Ronaldson et al 2011; Ronaldson and Davis, 2013; Thompson et al 2014; Thompson and Ronaldson, 2014). …”

“…Additionally, the sodium-glucose cotransporter-1 (SGLT1) plays a significant role in glucose uptake and edema formation during ischemia (Vemula et al 2009). Recently, our own laboratory discovered that the endogenous BBB transporter Oatp1a4 is upregulated at the BBB following global cerebral hypoxia (Thompson et al 2014) or following peripheral inflammatory pain (Ronaldson et al 2011). This transporter is capable of promoting blood-to-brain transport of therapeutic drugs (Ronaldson et al 2011; Thompson et al 2014).…”

“…Recently, our own laboratory discovered that the endogenous BBB transporter Oatp1a4 is upregulated at the BBB following global cerebral hypoxia (Thompson et al 2014) or following peripheral inflammatory pain (Ronaldson et al 2011). This transporter is capable of promoting blood-to-brain transport of therapeutic drugs (Ronaldson et al 2011; Thompson et al 2014). Increased functional expression of efflux transport systems such as P-gp has also been reported at the BBB in an in vivo model of peripheral inflammatory pain (Seelbach et al 2007; McCaffrey et al 2012; Sanchez-Covarrubias et al 2013).…”