Date of Award
Doctor of Philosophy (PhD)
Professor L.T. Young
Bipolar disorder, or manic-depressive illness, is a common psychiatric illness affecting 1.5% of the population. It is a chronic illness that requires long-term (often lifetime) pharmacotherapy. The need for lifetime treatment with mood stabilizers (i.e. lithium, valproate and carbmazepine) and high relapse rates suggests that changes in gene expression may be involved in the mechanism of action of these drugs. Using differential display, we identified the 78-kilodalton glucose-regulated protein, GRP78, as being at valporate-regulated gene in both rat brain and cultured cells. GRP78 belongs to a family of resident endoplasmic reticulum proteins, referred to as teh ER stress proteins, which includes GRP94 and calreticulin. These proteins act as both calcium binding proteins and molecular chapterones within the endoplasmic reticulum and when overexpressed protect the cell against cytotoxic insults. In addition to GRP78, we were able to show that GRP94 and calreticulun are also upregulated in a concentration-and-time-dependent manner in response to valporate. This effect was shown to be either drug-or drug class-specific, as treatment with other psychotropic drugs did not elicit a similar response. In patient samples, all three ER stress proteins were increased in postportem temporal cortex from depressed subjects to who died by suicide. These results suggest a possible cytoprotective role for mood stabilizers, since studies have shown that valporate as well as lithium can regulate the expression of proteins with known cytoprotective properties. Indeed, when rat hippocampal neurons were treated for 7 days with the mood stabilizers, lithium, valporate and carbamzepine, a significant reduction in NMDA-mediated cytoplasmic vacuolization could be quantified using transmission electron microscopy. In conclusion, the results of this thesis contribute to a growing number of studies that propose neuroprotective for mood stabilizing drugs, and suggest that valporate might act in part by regulating ER stress proteins.
Brown, Christopher D., "The Neuroprotective Properties of Mood Stabilizers: from Gene Regulation to Ultrastructural Characterization" (2002). Open Access Dissertations and Theses. Paper 1392.