Proteomic analysis of protein changes developing in rat hippocampus after chronic antidepressant treatment: Implications for depressive disorders and future therapies

Abstract

It is recognized that monoamine reuptake inhibitors (MARIs) exert beneficial effects in the treatment of major depression and general anxiety disorder. The aim of this study was to identify proteins regulated by this class of antidepressant using a proteome differential profiling approach. Either venlafaxine or fluoxetine was administered systemically to adult rats for 2 weeks, and protein patterns from rat hippocampal cytosolic extracts were compared by two-dimensional gel electrophoresis. Silver-stained protein spots displaying differential expression were identified by mass spectrometry. Thirty-three protein spots were modulated by both drug treatments compared to controls. The classification of several proteins that were sorted by function suggested convergent pathway activities for both MARIs at the post-receptor level. These included proteins associated with neurogenesis (insulin like growth factor 1 (IGF-1), glia maturation factor [GMF]-beta), outgrowth/maintenance of neuronal processes (hippocampal cholinergic neurostimulating peptide [HCNP], PCTAIRE-3), and with neural regeneration/axonal guidance collapsin response mediator protein (CRMP-2) systems. Other modulated proteins indicated an increase in neuronal vesicular cell trafficking and synaptic plasticity (Ras-related protein 4a (Rab4a), Ras-related protein 1b (Rab1b), heat shock protein 10 [HSP10]), as well as neurosteroidogenic (hydroxysteroid sulfotransferase A) and possible anti-apoptotic (dimethylargininase-1 L-N,N-dimethylarginine dimethylaminohydrolase-1 [DDAH-1], pyruvate dehydrogenase-E1 [PDH-E1], antioxidant protein-2 [AOP-2]) pathway-mediated regulatory events. Parallel studies to investigate further the effects of venlafaxine and fluoxetine on adult hippocampal neurogenesis in vivo by quantitative bromodeoxyuridine immunolabeling revealed a significant drug-induced increase in the proliferation rate and long-term survivability of progenitor stem cells located in the subgranular zone. These data suggest that MARIs share wide-ranging proteome changes within the hippocampal formation, beyond 5-HT/NE neurotransmission. This may reflect long-term functional adaptations required for antidepressant activity.

Genetic Regulation of Behavioral and Neuronal Responses to Fluoxetine

“…Not surprisingly, a significant majority of upregulated genes were associated with neurogenesis and/or synaptogenesis: these include factors known to promote the proliferation of neuronal progenitor cells (Npy, Edg3, Lgals1, Serpinf1/Pedf, Hspb1), growth factor-associated genes involved in survival and differentiation of adult neuronal cells (Bdnf, Inhba, Acvr1c, c-Ret), and downstream immediate early genes (IEGs) and transcription factors (c-fos, Sox11, Egr3, S100a6). Among the downregulated genes were Calb1, a marker of mature granule neurons, Prdm5, which has growth-suppressive (Khawaja et al, 2004) and amitriptyline, moclobemide, and clorgyline (Drigues et al, 2003). The present microarray results support the hypothesis that BDNF and other growth factors play an important role in antidepressant activity.…”

Interaction of FGF-2 with IGF-1 and BDNF in stimulating Akt, ERK, and neuronal survival in hippocampal cultures

“…Yet, a number of medications and drugs have been shown to increase the expression of multiple growth factors. Antidepressants for example, have been shown to increase the expression of IGF-1, BDNF, and FGF-2 (Duman et al, 1997;Mallei et al, 2002;Khawaja et. al., 2004;Maragoli et al, 2004).…”

“…It has been hypothesized that these changes may be mediated by antidepressant-induced increases in growth factor expression. In fact, chronic antidepressant treatment has been shown to increase the level of brain-derived neurotrophic factor (BDNF) message (Duman et al, 1997) and IGF-1 protein expression (Khawaja et. al., 2004) in the hippocampus.…”

Mechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways

“…These studies suggest that treatment with antidepressants leads to adaptive changes such as neurogenesis over a period of weeks which may account for the delayed therapeutic effect of these drugs. In rats that were given the antidepressants venlafaxine or fluoxetine, 33 proteins were modulated by drug treatment including proteins involved in neurogenesis, outgrowth, maintenance of neuronal process, and neural regeneration/axonal guidance systems [101]. Very little information is available about signal transduction cascades involved in adult neurogenesis, although some studies have implicated the cAMP-CREB cascade in this process [93].…”