Antidepressant Administration Modulates Neural Stem Cell Survival and Serotoninergic Differentiation Through Bcl-2

Abstract

The hippocampus has long been associated with learning, memory, and modulation of emotional responses. Previous studies demonstrated that stress-induced loss of hippocampal neurons may contribute to the pathogenesis of depression. The recent observations supported that antidepressant drugs increase the production of serotoninergic neurotransmitter and they play a critical role in the initiation of neurogenesis in the hippocampus. In order to explore the possible new mechanism of the treatment of depression, we cultured neural stem cells (NSCs) derived from the hippocampus of adult rats as an in vitro model to evaluate the capabilities of neuroprotection and neural differentiation in NSCs by fluoxetine (FL) treatment. Our results showed that 20 microM FL treatment can significantly increase the proliferation rate of NSCs (p<0.05), and up-regulate the mRNA and protein expressions of Bcl-2 in Day-7 FL-treated NSCs (p<0.01). Using Bcl-2 gene silencing with small interfering RNA, our data verified that FL can prevent Fas ligand-induced caspase-dependent apoptosis in NSCs through the activation of Bcl-2. The in vitro observation and immunofluorescent study further demonstrated that FL treatment can stimulate the neurite development and serotoninergic differentiation of NSCs through the activation of Bcl-2. Using microdialysis with high performance liquid chromatography- electrochemical detection, the functional release of serotonin in the differentiating NSCs with FL treatment was increased and simultaneously regulated by the Bcl-2 expressions. In sum, the study results indicate that antidepressant administration can increase NSCs survival, promote the neurite development, and facilitate NSCs differentiating into the functional serotoninergic neurons via the modulation of Bcl-2 expression.

Increased cellular turnover in response to fluoxetine in neuronal precursors derived from human embryonic stem cells

“…Our findings differ from previous studies, which argued that cell proliferation occurred after two or three weeks of FLX treatment in vivo or in vitro (Kodama et al, 2004;Malberg and Duman, 2003;Manev et al, 2001;Santarelli et al, 2003). The current study, however, produced results similar to those of Chen et al,2007), who observed cell proliferation under in vitro conditions after seven days, though they used different cell type and culture conditions. It is highly likely that the discrepancies observed are due to differences in the experimental design -i.e., in vivo or in vitro tests.…”

“…This indicates that although induced apoptosis is usually associated with changes in the amount of apoptotic gene transcripts, induced without changes in the transcript level of these genes probably due to posttranscriptional induction/regulation of the pathway. Previous studies examined the effects of FLX on apoptosis with different types of cell, such as adult neurons, hepatocytes, lymphoma cells, and neuroblastoma cells (Chen et al, 2007;Chiou et al, 2006;Koch et al, 2003;Lee et al, 2001;Levkovitz et al, 2005;Nahon et al, 2005;Serafeim et al, 2003). However, these studies used nonhuman CNS cells and animal models.…”

“…Previous reports have shown conflicting evidence regarding the effect of FLX on apoptosis. Some studies showed an increase in apoptotic activity due to FLX in different cell lines using various methods (Koch et al, 2003;Levkovitz et al, 2005;Serafeim et al, 2003), while others found an increase in antiapoptotic activity (Chen et al, 2007;Chiou et al, 2006;Lee et al, 2001;Nahon et al, 2005). These conflicting findings may have resulted from differences in cell lines, FLX concentrations, or the duration of treatment.…”

Ageing abolishes the effects of fluoxetine on neurogenesis

“…42 An strong upregulation of neurogenesis in association with an upregulation of Bcl-2 expression in the dentate gyrus was measured as well in nonhuman primates receiving electroconvulsive therapy (ECT), another potent therapeutic intervention used against depression. 43 Therefore, an increase of Bcl-2 expression levels might be a major component of the antidepressant activity.…”

Harmine stimulates neurogenesis of human neural cells in vitro

“…Fluoxetine, one of the most used selective serotonin reuptake inhibitors, induces proliferation of rat hypothalamic neural progenitors in vitro 7,8 .…”