Role of l -Type Amino Acid Transporter 1 at the Inner Blood-Retinal Barrier in the Blood-to-Retina Transport of Gabapentin

Shin Ichi Akanuma, Atsuko Yamakoshi, Takeshi Sugouchi, Yoshiyuki Kubo, Anika M.S. Hartz, Björn Bauer, Ken Ichi Hosoya

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Gabapentin is an antiseizure drug that is known to also have beneficial effects on the retinal cells. To use gabapentin in retinal pharmacotherapy, it is critical to understand gabapentin distribution in the retina. The purpose of this study was to clarify the kinetics of gabapentin influx transport across the inner and outer blood-retinal barrier (BRB), which regulates the exchange of compounds/drugs between the circulating blood and the retina. In vivo blood-to-retina gabapentin transfer was evaluated by the rat carotid artery injection technique. In addition, gabapentin transport was examined using in vitro models of the inner (TR-iBRB2 cells) and outer BRB (RPE-J cells). The in vivo [ 3 H]gabapentin transfer to the rat retina across the BRB was significantly reduced in the presence of unlabeled gabapentin, suggesting transporter-mediated blood-to-retina distribution of gabapentin. Substrates of the Na + -independent l-type amino acid transporter 1 (LAT1), such as 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH), also significantly inhibited the in vivo [ 3 H]gabapentin transfer. [ 3 H]Gabapentin uptake in TR-iBRB2 and RPE-J cells exhibited Na + -independent and saturable kinetics with a K m of 735 and 507 μM, respectively. Regarding the effect of various transporter substrates/inhibitors on gabapentin transport in these cells, LAT1 substrates significantly inhibited [ 3 H]gabapentin uptake in TR-iBRB2 and RPE-J cells. In addition, preloaded [ 3 H]gabapentin release from TR-iBRB2 and RPE-J cells was trans-stimulated by LAT1 substrates through the obligatory exchange mechanism as LAT1. Immunoblot analysis indicates the protein expression of LAT1 in TR-iBRB2 and RPE-J cells. These results imply that LAT1 at the inner and outer BRB takes part in gabapentin transport between the circulating blood and retina. Moreover, treatment of LAT1-targeted small interfering RNA to TR-iBRB2 cells significantly reduced both the level of LAT1 protein expression and [ 3 H]gabapentin uptake activities in TR-iBRB2 cells. In conclusion, data from the present study indicate that LAT1 at the inner BRB is involved in retinal gabapentin transfer, and also suggest that LAT1 mediates gabapentin transport in the RPE cells.

Original languageEnglish
Pages (from-to)2327-2337
Number of pages11
JournalMolecular Pharmaceutics
Issue number6
StatePublished - Jun 4 2018

Bibliographical note

Funding Information:
This research was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI [Grants JP16H05110 and JP16K08365]. We thank Y. Kinoshita and Y. Tanno (University Toyama) for technical advice on the in vivo and in vitro studies, respectively.

Publisher Copyright:
© 2018 American Chemical Society.


  • LAT1
  • blood-retinal barrier
  • gabapentin
  • inner blood-retinal barrier
  • l-type amino acid transporter
  • outer blood-retinal barrier

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery


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