Targeted drug delivery to treat pain and cerebral hypoxia

Abstract

Limited drug penetration is an obstacle that is often encountered in treatment of central nervous system (CNS) diseases including pain and cerebral hypoxia. Over the past several years, biochemical characteristics of the brain (i.e., tight junction protein complexes at brain barrier sites, expression of influx and efflux transporters) have been shown to be directly involved in determining CNS permeation of therapeutic agents; however, the vast majority of these studies have focused on understanding those mechanisms that prevent drugs from entering the CNS. Recently, this paradigm has shifted toward identifying and characterizing brain targets that facilitate CNS drug delivery. Such targets include the organic anion-transporting polypeptides (OATPs in humans; Oatps in rodents), a family of sodium-independent transporters that are endogenously expressed in the brain and are involved in drug uptake. OATP/Oatp substrates include drugs that are efficacious in treatment of pain and/or cerebral hypoxia (i.e., opioid analgesic peptides, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors). This clearly suggests that OATP/Oatp isoforms are viable transporter targets that can be exploited for optimization of drug delivery to the brain and, therefore, improved treatment of CNS diseases. This review summarizes recent knowledge in this area and emphasizes the potential that therapeutic targeting of OATP/Oatp isoforms may have in facilitating CNS drug delivery and distribution. Additionally, information presented in this review will point to novel strategies that can be used for treatment of pain and cerebral hypoxia.

Fig. 1.

Basic membrane topology of a prototypical OATP/Oatp transporter. OATP/Oatp family members are predicted to follow a 12-transmembrane domain topology where the OATP superfamily signature sequence is depicted at the junction between the third extracellular loop and transmembrane domain 6. Conserved cysteine residues are localized to the fifth extracellular loop. Additionally, three predicted glycosylation sites (Y) are demarcated on extracellular loops 2 and 5.

Fig. 2.

Localization of OATP/Oatp transporters at the brain barriers and in brain parenchyma cellular compartments (i.e., astrocytes, neurons). AP, apical; BL, basolateral.

Fig. 3.

Evidence for blood-to-brain drug transport mediated by Oatp1a4 at the BBB. Previous in vivo studies have shown that CNS uptake of drugs such as opioid peptide analgesics (e.g., DPDPE) and HMG-CoA reductase inhibitors (e.g., pitavastatin, rosuvastatin) is determined by functional expression of Oatp1a4 at the luminal and abluminal plasma membrane of the brain microvascular endothelium. AP, apical; BL, basolateral.

Fig. 4.

TGF-β signaling modulates Oatp1a4 functional expression at the BBB. (A) The TGF-β signaling pathway. Intracellular signaling molecules associated with TGF-β signaling at the BBB. Signals elicited by the TGF-β pathway involve two cell surface receptors at the brain microvascular endothelium, which are designated ALK1 and ALK5. ALK1 transduces signals via phosphorylation of Smad proteins 1, 5, and 8, while ALK5 signals by phosphorylation of Smad2 and Smad3. Once phosphorylated, these Smad proteins bind to the common Smad (i.e., Smad4), thereby forming a protein complex that can translocate to the nucleus and affect transcription. (B) Effect of SB431542, a selective pharmacological inhibitor of TGF-β/ALK5 signaling, on Oatp1a4 protein expression. Relative levels of Oatp1a4 protein in brain microvessels isolated from rats treated with saline or λ-carrageenan in the presence and absence of SB431542. Results are expressed as mean ± S.D. of three separate experiments. **P < 0.01 vs. control. (C) Uptake of taurocholate into rat brain following 3 hours of λ-carrageenan-induced inflammatory pain in the presence and absence of SB431542. Graph shows the concentration of taurocholate detected in rat brain tissue for the four treatment groups after injection of 3% λ-carrageenan or 0.9% saline into the plantar surface of the right hind paw. SB431542 (1.5 mg/kg) was injected 30 minutes before footpad injection. Results are expressed as mean ± S.D. of six animals per treatment group. **P < 0.01 vs. control. Adapted from Ronaldson et al. (2011).

Fig. 5.

Opportunities for targeting OATP/Oatp isoforms to optimize CNS drug delivery. Results from our recent studies demonstrate that targeting Oatp transporters during pathophysiological stress can modify CNS drug delivery. Oatp1a4 facilitates brain delivery of drugs that may exhibit efficacy in treatment of peripheral inflammatory pain or cerebral hypoxia, such as statins and opioid peptide analgesics. The TGF-β signaling pathway enables control of Oatp isoforms by targeting TGF-β receptors (i.e., ALK5) with small-molecule therapeutics such as SB431542. Additionally, nuclear receptors (e.g., PXR, CAR) offer another potential opportunity to control Oatp-mediated drug delivery by the use of a small-molecule therapeutic such as dexamethasone or acetaminophen. In this scenario, a PXR or CAR ligand binds to the nuclear receptor in the cytoplasm, triggers movement of the nuclear receptor–ligand complex to the nucleus, and thereby increases Oatp expression by enhancing transcription of an Slco gene. Although P-gp is also a critical determinant of CNS drug delivery, caution must be exercised when targeting this transporter to enable greater uptake of therapeutic agents into brain parenchyma. This warning arises from evidence obtained from several laboratories, including our own, that has shown that enhanced brain delivery of drugs can lead to CNS toxicity and unexpected adverse drug reactions.