Dissertation
OCULAR AND SYSTEMIC METABOLOMIC/GENOMIC DYSREGULATION IN THE VIGABATRIN INDUCED HYPERGABAERGIC STATE
Washington State University
Doctor of Philosophy (PhD), Washington State University
01/2022
DOI:
https://doi.org/10.7273/000004409
Handle:
https://hdl.handle.net/2376/122327
Abstract
The antiepileptic agent vigabatrin (VGB; SabrilR) is effective in treating infantile spasms and focal-onset seizures. VGB directly targets the metabolic pathway of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), via irreversible inhibition of GABA-transaminase (GABA-T) and ensuant increase of CNS GABA. VGB is administered as a racemic mixture of the R-(-) and S-(+) isomers; only the S-(+) enantiomer is active. Unfortunately, VGB carries a significant risk of use-limiting ocular toxicity, manifesting as permanent peripheral visual field constriction (pVFC) in a subpopulation of patients. Here we demonstrate that adult VGB-treated mice accumulate the active isomer preferentially in the retina and visual cortex. This accumulation is accompanied by altered amino acid profiles, including retinal GABA and 2-aminoadipic acid (AADA), the latter a glial toxin. Brain amino acid alterations during VGB administration included elevated GABA, β-alanine, carnosine, ornithine, and AADA (the latter in the visual cortex). VGB-induced metabolic abnormalities were compared to those found in the autopsied brain of a patient with succinic semialdehyde dehydrogenase deficiency (SSADHD), which is the enzyme directly following GABA-T and responsible for the final conversion of the GABA carbon skeleton to succinate. Retinal transcriptome analysis in VGB-treated animals revealed dysregulation of signaling, including the pathway of phototransduction. This work provides a tissue-specific platform from which to further evaluate VGB’s mechanism of action for adverse retinal toxicity, and the potential for drug development to mitigate this side effect.
Metrics
4 File views/ downloads
24 Record Views
Details
- Title
- OCULAR AND SYSTEMIC METABOLOMIC/GENOMIC DYSREGULATION IN THE VIGABATRIN INDUCED HYPERGABAERGIC STATE
- Creators
- Dana Christopher Walters
- Contributors
- Kenneth M Gibson (Advisor)Jean-Baptiste Roullet (Committee Member)Senthil Natesan (Committee Member)Nancy Potter (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Pharmacy and Pharmaceutical Sciences, College of
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 234
- Identifiers
- OCLC#: 1363848340; 99900883238201842
- Language
- English
- Resource Type
- Dissertation