2007). There is also evidence of a novel organic cation transporter in RPE cells that has not been characterized at the molecular level (Han et al. 2001). This transport system recognizes verapamil, diphenhydramine, pyrilamine, quinidine, quinacrine, and brimonidine (Zhang et al. 2006), an a2-adrenergic agonist approved for the treatment of open-angle glaucoma. Since systemically administrated brimonidine can reach the back of the eye at concentrations sufficient to activate a2-adrenergic receptors (Acheampong et al. 2002), the novel organic cation transporter in RPE cells regulates the brimonidine concentration in the retina. Uptake of the endogenous organic cation choline by TR-iBRB cells is Na+- independent and potential-dependent, indicating that a specific carrier exists at the inner BRB for the transfer of choline into the retina (Tomi et al. 2007a). The features of this uptake process are distinct from those of choline uptake mediated by other known organic cation transporters although the molecular identity of the transporter remains to be established. Considering that organic cation transporters exhibit broad substrate selectivity, the transport systems responsible for the transfer of organic cations across the BRB hold great potential for delivery of various organic cationic drugs into retina.

4.2.6  Opioid Peptides and Peptidomimetic Drugs

It has been proposed that RPE cells possess two novel oligopeptide transport systems that accept opioid peptides and the peptide fragments of human immunodeficiency

virus HIV-1 Tat (e.g., Tat47–57) and HIV-1 Rev (e.g., Rev34–50) as substrates (Hu et al. 2003; Chothe et al. 2010). Although these transporters have not been characterized at

the molecular level, it has been shown that peptides consisting of up to 25 amino acids interact with these transport systems. The two transport systems are called Na+- coupled oligopeptide transporters SOPT1 and SOPT2, which are distinct from the H+-coupled peptide transporters PEPT1 (SLC15A1) and PEPT2 (SLC15A2). Although there is a marked overlap between SOPT1 and SOPT2 in substrate specificity, dipeptides and tripeptides stimulate the activity of SOPT1 but inhibit the activity of SOPT2 (Chothe et al. 2010; Thakkar et al. 2008). SOPT1 and SOPT2 have potential for the transport of peptide and peptidomimetic drugs into RPE cells.

4.2.7Antioxidants

The retina has an obligate need for antioxidants for protection against light-induced damage to the cells. Indeed, retinal diseases such as diabetic retinopathy and age-related macular degeneration have oxidative insults as a pathological component. Vitamin C, vitamin E, and glutathione are important antioxidants that may have potential in the treatment of these retinal diseases. Understanding the transport characteristics of these antioxidants at the BRB may assist in the design and development of suitable therapy with appropriate antioxidants for treatment of the retinal diseases.

4.2.7.1  Vitamin C

Vitamin C exists in plasma as the oxidized form (dehydroascorbic acid, DHA) as well as the reduced form (ascorbic acid). The concentration of ascorbic acid in plasma is in the range of 50–100 mM whereas DHA is present in the circulation at much lower levels (~10 mM). However, the influx permeability rate of DHA across the BRB is ~40-fold greater than that of the reduced form ascorbic acid (Hosoya et al. 2004). The facilitative glucose transporter GLUT1 (SLC2A1) at the BRB is responsible for DHA transport in the blood-to-retinal direction. GLUT1 is expressed on both the luminal and abluminal membranes of the endothelial cells (Hosoya et al. 2004; Takata et al. 1992). RPE cells also express GLUT1 which is present both at the apical membrane and basolateral membrane (Takata et al. 1992). After entering the retina, DHA is reduced into ascorbic acid for subsequent use in photoreceptors and other retinal cells as an antioxidant. Since the primary function of GLUT1 at the BRB is to transport glucose from blood into retina, the fact that GLUT1 is responsible for the transport of both glucose and DHA to the retina across the inner BRB is very relevant to diabetic retinopathy. The Michaelis constant for GLUT1 for the transport of glucose is 5–8 mM, which is similar to the physiological plasma concentration of glucose (~5 mM). This suggests that GLUT1 is not completely saturated with its physiologic substrate in vivo under physiological conditions. However, the blood-to- retina transfer of DHA via GLUT1 at the BRB may be impaired significantly in diabetes because plasma levels of glucose rise markedly in untreated diabetes. The resultant deficiency of antioxidant machinery may contribute to the pathology of diabetic retinopathy (Minamizono et al. 2006). The reduced form of the vitamin C, known as ascorbic acid, is transported via the Na+-dependent vitamin C transporters SVCT1 (SLC23A1) and SVCT2 (SLC23A2). RPE cells express predominantly SVCT2 (Ganapathy et al. 2008). Functional studies have shown that the Na+-dependent uptake of ascorbic acid by RPE cells occurs predominantly at the apical membrane (Khatami et al. 1986; DiMattio and Streitman 1991; Lam et al. 1993). Thus, ascorbic acid also enters RPE cells from subretinal space via SVCT2 at the apical membrane.

4.2.7.2  Vitamin E

Vitamin E has preventive and therapeutic effects in human retinopathies. Among the members of the vitamin E family, a-tocopherol has the highest biologic activity, and is exclusively associated with high-density lipoprotein (HDL) in the blood (Goti et al. 2001). Uptake of HDL-associated a-tocopherol into TR-iBRB cells is most likely mediated by scavenger receptor class B type I (SR-BI) (Tachikawa et al. 2007). RPE cells express SR-BI and its splice variant SR-BII (Duncan et al. 2009; Tserentsoodol et al. 2006). It is likely that SR-BI at the BRB functions as an efficient pathway for the supply of a-tocopherol from the blood to retina.