Eric K. Long

Date of Award

7-15-2010

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmacology, Physiology and Therapeutics

First Advisor

Matthew J., Sr. Picklo

Abstract

Lipid peroxidation is a free radical-mediated process characterized by addition of molecular oxygen to polyunsaturated fatty acids (PUFA). Lipid peroxidation occurs basally, resulting in products that participate in normal signaling. One product is trans-4-hydroxy-2-nonenal (HNE). HNE is a product of lipid peroxidation of n-6 PUFA, such as arachidonic acid, and has the ability to mofify proteins, deplete glutathione, and induce apoptosis. Brain is a tissue that consumes large amounts of oxygen and contains an abundance of PUFA, which suggests a high degree of susceptibility of lipid peroxidation. Lipid peroxidation is known to increase in brain in diseases such as Alzheimer's disease and Parkinson's disease, resulting in increased HNE. However, n-3 PUFA, such as DHA, are present in similar abundance to n-6 PUFA in brain. Lipid peroxidation of n-3 PUFA leads to formation of trans-4-hydroxy-2-hexenal (HHE), which is the n-3 analog of HNE. Despite the potential formation of HHE, this molecule has been studied far less than HNE. Based on the structural similarity between HHE and HNE, and the potential for production of HHE from DHA in brain, I hypothesized that HHE is the major α,β-unsaturated aldehyde product of in vitro lipid peroxidation of DHA. In addition, our lab showed that HHE is equitoxic to HNE, depletes glutathione, and modifies proteins in neuronal cell culture. Finally, using a model of ethanol withdrawal, I hypothesized that levels of HHE would increased during withdrawal, resulting in increased levels of the phase II metabolite gluthionyl-HHE (GSHHE). My work showed that HHE is the major 4-hydroxylated α,β-unsaturated aldehyde product of in vitro lipid peroxidation of DHA. In addition, I showed that ethanol withdrawal leads to increased production of HHE in cerebral cortex, resulting in increased levels of GSHHE. I also showed that lipid peroxidation of n-3 PUFA occurs more readily in brain than n-6 PUFA lipid peroxidation, and that n-3 PUFA are selectively susceptible to ethanol withdrawal-induced increases in lipid peroxidation. Finally, I demonstrated that HHE is a better substrate for overall GST activity than HNE in cerebral cortex and hippocampus.

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