Retina-to-Blood Transport of 1-Methyl-4-Phenylpyridinium Involves Carrier-Mediated Process at the Blood-Retinal Barrier

1-Methyl-4-phenylpyridinium (MPP+) transport at the blood-retinal barrier (BRB) was investigated. The retinal uptake index estimated for [3H]MPP+ was similar to that of [3H]d-mannitol, and was insensitive to unlabeled MPP+, suggesting no positive evidence to support the involvement of carrier-mediated transport in the blood-to-retina transport of MPP+ at the BRB. A microdialysis investigation showed that the concentration of [3H]MPP+ in the vitreous humor decreased in a biexponential manner, and the rate constant for [3H]MPP+ elimination during the terminal phase was greater than that of [14C]d-mannitol. The inhibition study of [3H]MPP+ elimination showed its substrate specificity, suggesting that the retina-to-blood transport of MPP+ at the BRB involves a carrier-mediated process. The in vitro study with model cells showed the concentration-dependent transport of MPP+, supporting carrier-mediated MPP+ transport at the inner and outer BRB, and suggested membrane potential-sensitive and Na+-, Cl−-, and pH-insensitive MPP+ transport at the BRB. In the in vitro inhibition study, the transport of [3H]MPP+ was significantly inhibited by organic cations, and further reverse transcription PCR analysis and knockdown study suggested that the retina-to-blood transport of MPP+ at the BRB is carried out by an unknown transporter of which transport function is similar to plasma membrane monoamine transporter (PMAT/SLC29A4).