Fluoxetine promotes gliogenesis during neural differentiation in mouse embryonic stem cells

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for treatment of mood disorders and depression, even during pregnancy and lactation. SSRIs are thought to be much safer than tricyclic antidepressants, with a low risk of embryonic toxicity. Several recent studies, however, have reported that fetal exposure to SSRIs increases the risk of adverse effects during fetal and neonatal development. This is consistent with our previous finding that fluoxetine, a prototypical SSRI, profoundly affected the viability of cultured embryonic stem (ES) cells as well as their ability to differentiate into cardiomyocytes. Furthermore, we found that fluoxetine induced fluctuations in ectodermal marker gene expression during ES cell differentiation, which suggests that fluoxetine may affect neural development. In the present study, we investigated the effects of fluoxetine on the process of differentiation from ES cells into neural cells using the stromal cell-derived inducing activity (SDIA) method. Fluoxetine treatment was found to enhance the expression of glial marker genes following neural differentiation, as observed by immunocytochemical analysis or quantitative RT-PCR. The promoter activity of glial marker genes was also significantly enhanced when cells were treated with fluoxetine, as observed by luciferase reporter assay. The expression of neuronal markers during ES cell differentiation into neural cells, on the other hand, was inhibited by fluoxetine treatment. In addition, FACS analysis revealed an increased population of glial cells in the differentiating ES cells treated with fluoxetine. These results suggest that fluoxetine could facilitate the differentiation of mouse ES cells into glial cell lineage, which may affect fetal neural development.

Comparison of effects of a selective 5-HT reuptake inhibitor versus a 5-HT4 receptor agonist on in vivo neurogenesis at the rectal anastomosis in rats

“…On the other hand, the finding that SSRI treatment induced significant decreases in number of PCNA-, DLX2-, and SR4-positive cells in the implanted GS at the neck may suggest the possibility that SSRI suppresses the mobi- Furthermore, recent studies suggested that a serotonergic depressant, fluoxetine, can reverse the established state of neuronal maturation in the adult hippocampus (8) and promote gliogenesis during neural differentiation in mouse ES cells (11). Therefore, these actions of SSRI may suppress enteric neural differentiation/development as repairing mechanism even in the present adult rat.…”

Fluvoxamine stimulates oligodendrogenesis of cultured neural stem cells and attenuates inflammation and demyelination in an animal model of multiple sclerosis

“…Briefly, dissociated neurosphere derived cells from primary cultures were seeded at a density of 5000 cells in 96-well plates and treated with different concentrations of fluvoxamine (0.1, 1, 5, 50, 100 and 500 nM) for 48 hours and cultured in a humidified atmosphere of 5% CO 2 at 37 °C. Due to lack of similar study, the concentrations of fluvoxamine chose according to other similar studies, which have used fluoxetine with range between 0.1 nM and 50 µM 14, 27, 66 . After the treatment, fluvoxamine -containing medium was removed, wells were gently washed twice with PBS, and then 200 μl of 0.5 mg/ml MTT in PBS was added to each well.…”

“…Recently, in relapsing-remitting MS with depression, Bayas and colleagues used, for the first time, the combination treatment of SSRI and Fingolimod , a confirmed and common therapy for relapsing MS, which showed improvement in depression condition of MS patients while disability remained unchanged 13 . Moreover, fluoxetine was shown to act as a differentiation factor for mouse embryonic stem cells (mESCs) into glial cell lineage 14 . It is worth noting that embryonic neural stem cells (eNSCs) are the more appropriate cells for studying therapeutic and neurotoxic effects in the CNS since they are self-renewing cells which can generate mature cells of all neural lineages, including oligodendrocytes, neurons and astrocytes 15, 16 .…”

The 5-hydroxytryptamine 4 Receptor Agonist-induced Actions and Enteric Neurogenesis in the Gut

“…The effects of an selective serotonin reuptake inhibitor (SSRI) fluoxetine were investigated on the process of differentiation from ES cells into neural cells using the stromal cell-derived inducing activity method 91. Fluoxetine treatment was found to enhance the expression of glial marker genes, as observed by immunocytochemical analysis or qRT-PCR.…”

“…From these results, at least endogenous 5-HT possibly accumulated in myenteric plexus around the anastomosis (not at the anastomosis) was not able to generate new enteric neurons, although the mechanisms for this failure of enteric neurogenesis remain unknown. In addition, considering from literatures reporting the effect of SSRIs in the hippocampus,91-93 it is plausible that SSRIs per se may promote or inhibit neural regeneration in the ENS.…”