Year of Award

2007

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Neuroscience

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Stephen Black

Committee Co-chair

David Poulsen

Commitee Members

Diana Lurie, Richard Bridges, Jesse Hay

Keywords

hypoxia-ischemia, L-carnitine, mitochondria

Publisher

University of Montana

Abstract

Neonatal hypoxia-ischemia (HI) represents an intractable clinical condition that lacks an effective treatment and results in blindness, cerebral palsy, and cognitive deficits. A primary mechanism of cell death induced by neonatal HI is mitochondrial dysfunction leading to metabolic crisis and apoptosis. L-carnitine (LCAR) is an endogenous compound that transports fatty acids across the mitochondrial membrane for metabolism, buffers endogenous acyl-coA pools and improves the health and efficiency of the mitochondria. In light of the mitochondrial dysfunction observed after HI we hypothesized treatment with LCAR would reduce cell death after HI. Using a novel rat hippocampal slice culture model we observed a decrease in cell death in RHSC treated with 5mM LCAR for 2 hours prior to oxygen glucose deprivation (OGD). Under the same conditions we observed an LCAR induced decrease in both necrosis and mitochondrially-mediated apoptosis. To elucidate the mechanism for these data we studied the effect of LCAR on reactive oxygen species (ROS) before and after OGD. We observed a decrease in superoxide and H2O2 in RHSC treated with LCAR and exposed to OGD. In further experiments we observed LCAR treatment increased the expression and activity of superoxide dismutase 1 (SOD1) and catalase prior to OGD and this effect resulted in decreased cell death after OGD. In addition to increased (ROS) scavenging, we observed an LCAR mediated increase in levels of uncoupling protein 2 (UCP-2). In a series of experiments we observed a correlation between UCP-2 expression, the reversible modulation of mitochondrial membrane potential, and a decrease in cell death after OGD. These observations taken together suggest LCAR decreases cell death in RHSC after OGD by increasing ROS scavenging and UCP-2 expression in the mitochondria prior to OGD.

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© Copyright 2007 Thomas Fredrick Rau