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| Title: | ADRENOCORTICOSTEROID RECEPTOR EFFECTS ON HIPPOCAMPAL NEURON VIABILITY |
| Authors: | McCullers, Deanna Lynn |
| Keywords: | Mineralocorticoid Receptor
Glucocorticoid Receptor
Messenger RNA
Kainic Acid
Traumatic Brain Injury |
| Date Created: | 2001 |
| Publisher: | University of Kentucky |
| Abstract: | Glucocorticoid activation of two types of adrenocorticosteroid receptors (ACRs), the
mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), influences hippocampal
neuron vulnerability to injury. Excessive activation of GR may compromise hippocampal
neuron survival after several types of challenge including ischemic, metabolic, and excitotoxic
insults. In contrast, MR prevents adrenalectomy-induced loss of granule neurons in the dentate
gyrus. The present thesis addresses the respective roles of MR and GR in modulating neuronal
survival following two forms of neuronal injury, excitotoxicity and traumatic brain injury. Male
Sprague-Dawley rats were pretreated with MR antagonist spironolactone or GR antagonist
mifepristone (RU486) and subsequently injected with kainic acid, an excitotoxic glutamate
analog, or injured with a controlled cortical impact. Twenty-four hours following injury,
hippocampal neuron survival was measured to test the hypotheses that MR blockade would
endanger and GR blockade would protect hippocampal neurons following injury. Messenger
RNA levels of viability-related genes including bcl-2, bax, p53, BDNF, and NT-3 were also
measured to test the hypothesis that ACR regulation of these genes would
correlate with neuronal survival. In addition, ACR mRNA levels were measured following
receptor blockade and injury to test the hypothesis that glucocorticoid signaling is altered
following neuronal injury via regulation of ACR expression.
Mineralocorticoid receptor blockade with spironolactone increased neuronal vulnerability to
excitotoxic insult in hippocampal field CA3, and GR blockade with RU486 prevented neuronal
loss after traumatic brain injury in field CA1. These results are consistent with the hypotheses
that MR protects and GR endangers hippocampal neurons. Adrenocorticosteroid receptor
blockade decreased mRNA levels of the anti-apoptotic gene bcl-2 in select regions of uninjured
hippocampus, yet ACR regulation of bcl-2 did not consistently correspond with measures of
neuronal survival after injury. Kainic acid decreased MR mRNA levels in CA1 and CA3, while
both kainic acid and controlled cortical impact dramatically decreased GR mRNA levels in
dentate gyrus. These data suggest that injury modulation of glucocorticoid signaling through
regulation of ACR expression may influence hippocampal neuron viability following injury. |
| URI: | http://hdl.handle.net/10225/77 |
| Appears in Collections: | Electronic Theses and Dissertations
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| mcculler.pdf | | 2558Kb | Adobe PDF | View/Open |
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