Comprehensive Evidence of Carrier-Mediated Distribution of Amantadine to the Retina across the Blood-Retinal Barrier in Rats.

Yusuke Shinozaki,Shin-Ichi Akanuma,Yoshiyuki Kubo,Yuika Mori,Ken-Ichi Hosoya

doi:10.3390/pharmaceutics13091339

Abstract

Amantadine, a drug used for the blockage of NMDA receptors, is well-known to exhibit neuroprotective effects. Accordingly, assessment of amantadine transport at retinal barriers could result in the application of amantadine for retinal diseases such as glaucoma. The objective of this study was to elucidate the retinal distribution of amantadine across the inner and outer blood–retinal barrier (BRB). In vivo blood-to-retina [3H]amantadine transport was investigated by using the rat retinal uptake index method, which was significantly reduced by unlabeled amantadine. This result indicated the involvement of carrier-mediated processes in the retinal distribution of amantadine. In addition, in vitro model cells of the inner and outer BRB (TR-iBRB2 and RPE-J cells) exhibited saturable kinetics (Km in TR-iBRB2 cells, 79.4 µM; Km in RPE-J cells, 90.5 and 9830 µM). The inhibition of [3H]amantadine uptake by cationic drugs/compounds indicated a minor contribution of transport systems that accept cationic drugs (e.g., verapamil), as well as solute carrier (SLC) organic cation transporters. Collectively, these outcomes suggest that carrier-mediated transport systems, which differ from reported transporters and mechanisms, play a crucial role in the retinal distribution of amantadine across the inner/outer BRB.

Highlights

Retinal neurogenerative diseases, such as glaucoma and diabetic retinopathy, cause progressive visual deficit [1,2]
We examined the involvement of verapamil-sensitive putative transport systems in the inner blood–retinal barrier (BRB) [20] in amantadine transport
We demonstrated the process of retinal amantadine transport

Summary

Introduction

Retinal neurogenerative diseases, such as glaucoma and diabetic retinopathy, cause progressive visual deficit [1,2]. It is well-known that the progression of the visual deficit involves N-methyl-D-aspartate (NMDA) receptors [3,4]. Previous in vitro and in vivo analyses have indicated the involvement of overactivation of NMDA receptors in the loss of retinal ganglion cells (RGCs) [5,6], which transmit light stimuli from the eye to the brain. There has been an attempt to block NMDA receptors for the treatment of retinal diseases. It has been reported that memantine, which is an adamantane derivative and an inhibitor of NMDA receptors, has been shown to exhibit neuroprotection in the retina of animal models of retinal diseases, both in vitro and in vivo [7,8]. Pharmacotherapy with memantine for glaucoma has reached phase III clinical trials [9]

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