4.2 Article

Preferential accumulation of the active S-( plus ) isomer in murine retina highlights novel mechanisms of vigabatrin-associated retinal toxicity

Journal

EPILEPSY RESEARCH
Volume 170, Issue -, Pages -

Publisher

ELSEVIER
DOI: 10.1016/j.eplepsyres.2020.106536

Keywords

GABA; Vigabatrin; Retina; Isomers; 2-aminoadipic acid

Funding

  1. National Eye Institute, National Institutes of Health [R01EY027476]

Ask authors/readers for more resources

The study investigated the distribution of vigabatrin in different tissues of mice, with a focus on the preferential accumulation of the active isomer (S)-(+) VGB in the retina. This finding suggests the involvement of a stereospecific transporter in the partitioning of vigabatrin to the retina, which could potentially lead to new therapeutic approaches for mitigating its well-known retinal toxicity and expanding its clinical utility.
((S)-(+)/(R)-(-)) vigabatrin (Sabril(R); gamma-vinyl GABA), an antiepileptic irreversibly inactivating GABA-transaminase, was administered to male C57Bl6 J mice via continuous infusion (0, 40, 80 mg/kg/d) for 12 days. Our study design pooled retina, eye (minus retina), whole brain and plasma from n = 24 animals for each dose to provide n = 8 triplicates per treatment group. Hypothesizing that (S)-(+) VGB (active isomer) would preferentially accumulate in retina, we determined VGB isomers, comprehensive amino acids, and pharmacokinetic parameters. In brain, eye and plasma, the ((S)-(+)/(R)-(-)) ratio varied from 0.73 to 1.29 and 13.3 in retina, accompanied by a partition coefficient (tissue/plasma, ((S)-(+);(R)-(-))) of 5.8;0.34, 0.63;0.49, and 0.51;0.34 in retina, eye and brain, respectively. Racemic VGB (nmol/g; plasma, nmol/mL, range of means for dose) content was: retina, 25-36; eye (minus retina), 4.8-8.0; brain, 3.1-6.8 and plasma, 8.7-14.9. GABA tissue content (nmol/g) was 1246-3335, 18-64 and 2615-3200 as a function of VGB dose for retina, eye (minus retina) and brain, respectively. The retinal glial cell toxin 2-aminoadipic acid also increased with VGB dose (76-96 nmol/g). Partitioning of active (S)-(+) VGB to retina suggests the involvement of a stereospecific transporter, the identification of which could reveal new therapeutic paradigms that might mitigate VGB's wellknown retinal toxicity and expand its clinical utility.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.2
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available