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.
| Identifer | oai:union.ndltd.org:MONTANA/oai:etd.lib.umt.edu:etd-05312007-151334 |
| Date | 24 July 2007 |
| Creators | Rau, Thomas Fredrick |
| Contributors | David Poulsen, PhD, Stephen Black, PhD, Diana Lurie, PhD, Jesse Hay, PhD, Richard Bridges, PhD |
| Publisher | The University of Montana |
| Source Sets | University of Montana Missoula |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lib.umt.edu/theses/available/etd-05312007-151334/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Montana or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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