The mood stabilizers lithium and valproate are both effective in the treatment of bipolar disorder; however, their therapeutic mechanisms remain unclear. Because of the delayed onset of clinical efficacy (days to weeks), it has been proposed that adaptive changes in gene expression, rather than initial pharmacological actions, may be directly responsible. To investigate the strategic regulation of signaling pathways and gene expression in critical neuronal circuits likely involved in the long term treatment of bipolar disorder, we used microarray methodologies to identify novel targets of therapeutic relevance using the following validating criteria: (1) dose and time frame consistent with clinical therapeutic effects; (2) structurally highly dissimilar but clinically efficacious agents; (3) specific to brain regions implicated in the disorder (4) specific for mood stabilizers (5) validated at a protein level. Using these stringent criteria, our recent microarray studies have revealed a novel target for the long-term actions of the mood stabilizers lithium and valproate. Chronic administration of both agents at therapeutic doses increased the expression of BAG-1 (bcl-2 associated athanogene) in rat hippocampus. Furthermore, these findings were validated in the hippocampus at the protein level, the effects were seen in a time frame consistent with therapeutic effects, and were specific for mood stabilizers. BAG -1 is an important chaperone of bcl-2 (B-cell CLL/lymphoma 2), and enhances bcl-2's anti-apoptotic functions; furthermore, through interaction with raf (v-raf-1 murine leukemia viral oncogene homolog 1), BAG-1 is able to activate ERK(extracellular signal-regulated protein kinase) MAP (mitogen-activated protein) kinases. Consistent with this, we found that lithium and valproate activate ERK MAP kinases and exert anti-apoptotic effects. Bag-1 also inhibits GR (glucocorticoid receptor) activation, which may counteract the deleterious effects of hypercortisolemia seen in bipolar disorder. Anti-GR antibody immunostaining plus double staining with DAPI (4',6-Diamidino-2-phenylindole) showed either lithium or VPA, at therapeutically relevant levels, inhibited dexamethasone induced GR nuclear translocation. In addition, glucocorticoid response element (GRE) transfection assay showed lithium, at therapeutically relevant levels, inhibited GR activity in SH-SY5Y cells. Evaluated through siRNA (short interference RNA) silencing of BAG-1, the inhibition of mood stabilizers to GR nuclear translocation and to GR activity is mediated, at least in part, by BAG-1. The effect that BAG-1 inhibits glucocorticoid activation suggests mood stabilizers may counteract the deleterious effects of hypercortisolemia seen in bipolar disorder by up-regulating BAG-1. Together, the data suggests that BAG-1 may represent a novel, highly therapeutically relevant target in the long-term treatment of bipolar disorder. Complementary human studies have shown that chronic lithium significantly increases gray matter content in a regionally selective manner, suggesting a reversal of illness-related atrophy and an increase in the volume of the neuropil. Interestingly, the gray matter changes are seen in a regionally-specific manner and are only observed in treatment-responders. The growing body of preclinical/clinical data suggests that for many refractory patients, optimal treatment may only be attained by providing both trophic and neurochemical support; the trophic support would be envisioned as enhancing and maintaining normal synaptic connectivity, thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal affective functioning.
