Eye Metabolomics in Vigabatrin (VGB)-treated Mice: New Clues to VGB Ocular Toxicity

Abstract

Purpose : Vigabatrin (VGB; Sabril^R), an irreversible inhibitor of GABA transaminase (Fig.) can manifest peripheral visual field toxicity of undefined etiology. Earlier studies implicated select amino acids in this toxicity, yet a comprehensive preclinical amino acid characterization is lacking. We tested the hypothesis that chronic treatment with VGB would result in multiple amino acid alterations in eye and visual cortex (VC).

Methods : The study was conducted in male mice (C57/Bl6; age 8-12 weeks) treated for 12 days with VGB using subcutaneous minipumps delivering (per kg and per day) either 0 (vehicle, n=21), 35 (n=8), 70 (n=6) or 140 (n=8) mg of VGB. Amino acids were quantified by UPLC (Waters UPLC® MassTrak™ Amino Acid Analysis (AAA) Solution). VGB was quantified by tandem mass spectrometry. Statistical analysis used GraphPad Prizm 8 with significance set at P < 0.05.

Results : The tissue concentrations of GABA, b-alanine and carnosine (Fig.) paralleled dose-dependent VGB accumulation with frequent plateauing at VGB >70 mg/kg/d (Table). Amino acid (AA) abnormalities occurred primarily at low-dose VGB in eye and intermediate dose in VC. Similar results were observed for basic and acidic AA, although maximal alterations for ornithine occurred at intermediate dose. The glutamate analog, α-aminoadipic acid (α-AADA) accumulated in both eye and VC, whereas the non-AA amines (PEA, EA) accumulated only in eye at low-dose. All other AAs (~30 in total) were unaffected by VGB.

Conclusions : The study demonstrates significant VGB-induced metabolic dysregulation in the eye, all potential contributors to the drug‘s toxicity on the visual system. Like GABA, many dysregulated AAs (glycine, β-alanine, serine, aspartate, glutamate) are neuroactive, potentially inducing excitatory toxicity in eye and VC. Toxic activity in astrocytes and Müller cells has been described for α-AADA, and its increase in eye and VC may be considered a potential contributing factor to VGB-induced toxicity. Last, the effect of VGB on basic AAs (ornithine, citrulline, arginine) suggests disruption of the urea cycle and ammonia handling. Our metabolomic study reveals several novel dose-dependent effects of VGB on intermediary metabolism, and identifies biomarkers potentially implicated in the ocular toxicity of this unique antiepileptic drug.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

 

GABA Metabolism

 

Metabolic Disruptions in Eye and Visual Cortex