Desipramine Activated Bcl-2 Expression and Inhibited Lipopolysaccharide-Induced Apoptosis in Hippocampus-Derived Adult Neural Stem Cells

Abstract

Abstract. Desipramine (DP) is a tricyclic antidepressant used for treating depression and numerous other psychiatric disorders. Recent studies have shown that DP can promote neurogenesis and improve the survival rate of hippocampal neurons. However, whether DP induces neuroprotection or promotes the differentiation of neural stem cells (NSCs) needs to be elucidated. In this study, we cultured NSCs derived from the hippocampal tissues of adult rats as an in vitro model to evaluate the modulation effect of DP on NSCs. First, we demonstrated that the expression of Bcl-2 mRNA and nestin in 2 µM DP-treated NSCs were up-regulated and detected by real-time reverse transcriptase polymerase chain reaction (RT-PCR). The results of Western blotting and immunofluorescent study confirmed that Bcl-2 protein expression was significantly increased in Day 3 DP-treated NSCs. Using the Bcl-2 small interfering RNA (siRNA) method, our results further showed that DP protects the lipopolysaccharide (LPS)-induced apoptosis in NSCs, in part by activating the expression of Bcl-2. Furthermore, DP treatment significantly inhibited the induction of proinflammatory factor interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in the culture medium of LPS-treated NSCs mediated by Bcl-2 modulation. The results of high performance liquid chromatography coupled to electrochemical detection further confirmed that DP significantly increased the functional production of serotonin (26 ± 3.5 µM, DP-treated 96 h) and noradrenaline (50 ± 8.9 µM, DP-treated 96 h) in NSCs through activation of the MAPK / ERK pathway and partially mediated by Bcl-2. In conclusion, the present results indicate that DP can increase neuroprotection ability by inhibiting the LPS-induced inflammatory process in NSCs via the modulation of Bcl-2 expression, as confirmed by the siRNA method.

Effects of desipramine on the cell cycle and apoptosis in Ca3/7 mouse skin squamous carcinoma cells

“…These findings suggest that Bcl-xL may play a pivotal role in mediating the anti-apoptotic effects of glucocorticoid in Ca3/7 cells. Huang et al reported that an increase in mRNA expression of Bcl-2, inhibition of caspases and apoptosis were induced by a low concentration of DMI (19). It is possible that the Bcl-2 family may be a key target in DMI-induced cell viability.…”

“…DMI has been shown to induce apoptosis in several cancer cell lines (13)(14)(15)(16)(17)(18)(19). In our previous study, we also examined the effect of DMI on the growth of three murine skin cell lines (3PC, MT1/2 and Ca3/7) representing different stages of skin carcinogenesis.…”

“…Both in vitro and in vivo studies indicate antidepressants are cytotoxic to most malignant cells, particularly colon and breast cancer (10)(11)(12). The induction of apoptosis by DMI has been demonstrated to be significant in colon cancer, glioma and renal tubular cells (13)(14)(15)(16)(17)(18)(19). In these studies, an increase in intracellular calcium and caspase-3 appear to play a pivotal role in the induction of DNA fragmentation.…”

Post-Myocardial Infarction Depression

“…In another study, the same authors suggested that the contribution of cell death may have been underestimated, since antidepressant treatments are now known to be anti-apoptotic (Lucassen et al 2004). Since then, 3 investigations have responded to this comment: a) The antidepressant Desipramine is associated with cultured hippocampal neural stem cell neuroprotection against lipopolysaccharide-induced apoptosis by inhibiting inflammatory processes in vitro (Huang et al 2007); b) Desipramine and Fluoxetine increase Fibroblast Growth Factor-2 activity, a growth factor involved in maturation, synaptic connectivity, neurogenesis and survival of catecholamine neurons in the cortex and hippocampus ; c) Our own data, showing that Sertraline, an antidepressant with selective serotonin reuptake inhibition properties, blocks early post-MI apoptosis in the limbic system (Wann et al 2009). The anti-apoptotic effect of antidepressants was also reported in 2 other recent studies in rats (Huang et al 2007;.…”

“…Since then, 3 investigations have responded to this comment: a) The antidepressant Desipramine is associated with cultured hippocampal neural stem cell neuroprotection against lipopolysaccharide-induced apoptosis by inhibiting inflammatory processes in vitro (Huang et al 2007); b) Desipramine and Fluoxetine increase Fibroblast Growth Factor-2 activity, a growth factor involved in maturation, synaptic connectivity, neurogenesis and survival of catecholamine neurons in the cortex and hippocampus ; c) Our own data, showing that Sertraline, an antidepressant with selective serotonin reuptake inhibition properties, blocks early post-MI apoptosis in the limbic system (Wann et al 2009). The anti-apoptotic effect of antidepressants was also reported in 2 other recent studies in rats (Huang et al 2007;. Although apoptosis is difficult to document in human clinical cases (because patients are usually treated with antidepressants), another set of evidence indicates that the lymphocytes (Ivanova et al 2007) or blood leukocytes (Szuster-Ciesielska et al 2008) of depressed patients manifest a higher proportion of apoptotic elements compared to healthy controls.…”