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Publication Date
12-2024
Date of Final Oral Examination (Defense)
7-23-2024
Type of Culminating Activity
Thesis - Boise State University Access Only
Degree Title
Master of Science in Chemistry
Department
Chemistry and Biochemistry
Supervisory Committee Chair
Kenneth A. Cornell, Ph.D.
Supervisory Committee Member
Xinzhu Pu, Ph.D.
Supervisory Committee Member
Don Warner, Ph.D.
Abstract
Vigabatrin (VGB) is an irreversible inhibitor of GABA-T transaminase and used to treat infantile spasms and refractory complex partial seizures. Unfortunately, VGB causes serious adverse effects including peripheral visual defects in patients of all ages and brain abnormalities on MRI in infants. The mechanism of VGB toxicity is unknown, but several hypotheses have been proposed including GABA excitotoxicity, taurine depletion, hyperornithinemia, α-aminoadipic aciduria, and inhibition of mTOR mitophagy. Our goal in this study was to understand the impact of VGB on metabolism. To do this, 6 neuronal cell types including mouse photoreceptors (661W), rat Müller glial cells (rMC-1), human undifferentiated and differentiated retinal pigment epithelial cells (ARPE-19; dARPE-19), rat pheochromocytoma cells (PC12), and human neuroblastoma cells (SH-SY5Y) were treated with 1 mM VGB for 24 hr. Metabolites were then extracted using 70% MeOH (v/v) and detected using high resolution mass spectrometry. We observed an increase in pipecolic acid with VGB treatment—a known metabolite of the lysine degradation pathway. Unexpectedly, we observed changes with VGB treatment to two folic acid cycle intermediates (5-methyl-THF and 4’-phosphopantheine), several acylcarnitines, and many lysophospholipids. The changes in these unreported metabolites highlight new potential mechanisms for VGB toxicity. Future work will focus on the impact of VGB treatment on the mammalian proteome.
DOI
https://doi.org/10.18122/td.2311.boisestate
Recommended Citation
Leach, Caleb, "Metabolic Consequences of Inhibition of Gaba Transaminase" (2024). Boise State University Theses and Dissertations. 2311.
https://doi.org/10.18122/td.2311.boisestate
Comments
ORCID: 0009-0002-9498-054X