Mood stabilizers regulate cytoprotective and mRNA-binding proteins in the brain: long-term effects on cell survival and transcript stability

Abstract

Manic depressive illness (MDI) is a common, severe, chronic and often life-threatening illness. Despite wellestablished genetic diatheses and extensive research, the biochemical abnormalities underlying the predisposition to, and the pathophysiology of, these disorders remain to be clearly established. Despite formidable obstacles in our attempts to understand the underlying neurobiology of this illness, there is currently considerable excitement about the progress that is being made using novel strategies to identify changes in gene expression that may have therapeutic relevance in the long-term treatment of MDI. In this paper, we describe our recent research endeavours utilizing newer technologies, including a concerted series of mRNA RT-PCR studies, which has led to the identification of novel, hitherto completely unexpected targets for the long-term actions of mood stabilizers -the major cytoprotective protein bcl-2, a human mRNA binding (and stabilizing) protein, AUH, and a Rho kinase. These results add to the growing body of data suggesting that mood stabilizers may bring about some of their long-term benefits by enhancing neuroplasticity and cellular resilience. These results are noteworthy since recent morphometric brain imaging and post-mortem studies have demonstrated that MDI is associated with the atrophy and\or loss of neurons and glia. The development of novel treatments which more directly target molecules involved in critical CNS cell survival and cell death pathways have the potential to enhance neuroplasticity and cellular resilience, and thereby modulate the long-term course and trajectory of these devastating illnesses.

Pharmacogenetics of antidepressant and mood-stabilizing drugs: a review of candidate-gene studies and future research directions

“…A number of potentially important outcomes of this work have recently been reviewed (see Chen et al, 2001 ;Wang et al, 2001). One intriguing direction was noted in the preceding section.…”

“…One intriguing direction was noted in the preceding section. Using differential display, Manji and colleagues identified a number of genes whose expression is markedly increased by lithium and valproate (reviewed in Chen et al, 2001 ;Manji et al, 2001). One of these was the human transcription factor polyomavirus enhancer-binding protein 2β gene (PEP2β).…”

Support of Retinal Ganglion Cell Survival and Axon Regeneration by Lithium through a Bcl-2-Dependent Mechanism

“…Although it is known that Li ϩ directly inhibits inositol monophosphatases and GSK-3␤, [11][12][13] it is likely that the long-term changes in gene expression mediated by Li ϩ are responsible for its therapeutic efficacy. 35,36 In this context, recent evidence demonstrating that Li ϩ robustly upregulates Bcl-2, promotes cell survival, and enhances hippocampal neurogenesis has generated considerable excitement within the clinical neuroscience community. 37,38 Although it is still unclear how Li ϩ induces the expression of Bcl-2 in neurons, emerging evidence suggests three possibilities.…”

Gene expression differences in bipolar disorder revealed by cDNA array analysis of post‐mortem frontal cortex

“…Of potential relevance in the treatment of these disorders, studies also suggest that TGF-b1 may be a target system for the action of certain mood stabilizers. While the mode of action for these compounds remains to a large extent unde®ned, evidence has accrued suggesting a neuroprotective or neurotrophic role for both lithium and valproic acid (VPA) in BD Chen et al 2001). Chronic lithium treatment has been shown to protect rat cerebellar granule cells from NMDA-mediated excitotoxicity (Nonaka et al 1998), while suppressing the expression of the proapoptotic genes, p53 and Bax, and increasing the expression of the anti-apoptotic gene bcl-2 (Chen and Chuang 1999;.…”