Melatonin Regulates the Viability and Differentiation of Rat Midbrain Neural Stem Cells

Abstract

(1) Neurogenesis driven by neural stem cells (NSCs) is regulated by physiological and pathological factors. Melatonin (MT) has profound neurotrophic and neuroprotective effects. Hence, we studied the role of MT in regulating the viability and differentiation of NSCs derived from rat ventral midbrain. (2) NSCs were isolated from the rat ventral midbrain. The viability of NSCs was determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-ulfophenyl)-2H-tetrazolium assay. The differentiation of NSCs was examined by analyzing the expression of the neural markers, MT receptors, brain derived neurotropic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) with semi-quantitative RT-PCR, immunofluorescence cytochemistry, and Western blot. (3) Our results showed that MT could promote the viability of NSCs. In addition, MT could significantly elevate the mRNA and protein levels of tyroxine hydroxylase (TH), a marker of dopaminergic neurons, and decrease the expression of the astrocytes maker glial fibrillary acidic protein (GFAP). MT also increased the production of BDNF and GDNF in the cultured NSCs. Meanwhile, we first found that two subtypes of MT receptors, MT1 and MT2, were expressed in the ventral midbrain NSCs. (4) These results demonstrated that MT could induce NSCs to differentiate into dopaminergic neurons and decrease astrocyte production. These findings also suggest that MT could offer a beneficial tool in guiding directional differentiation of NSCs.

Mechanisms Contributing to the Phase-Dependent Regulation of Neurogenesis by the Novel Antidepressant, Agomelatine, in the Adult Rat Hippocampus

“…The implication of melatonin agonist properties of agomelatine in this process is consistent with recent data showing a melatonin-induced increase of new granule cell maturation and survival in mice (Ramirez-Rodriguez et al, 2009). This neurotrophic role of melatonin was also suggested by in vitro data on viability and differentiation of neural stem cells (NSCs), which was associated to an increase in BDNF expression (Kong et al, 2008), even if in our experimental conditions melatonin alone does not modify cell survival. Indeed, we also found an increase in hippocampal BDNF level in agomelatine-and melatonin-treated rats, but for melatonin the increase is less pronounced.…”

“…These changes led to similar increases in newly formed neurons or astrocytes, as shown by the confocal microscopy analyses revealing no effect of agomelatine on the respective percentages of BrdU-NeuN-vs BrdU-GFAP-labeled cells neither in the DH nor in the VH (Table 1). As melatonin has been implicated in hippocampal cell survival (Kong et al, 2008;Quiros et al, 2008;Manda et al, 2009;Ramirez-Rodriguez et al, 2009), we tried to show a possible implication of melatonin agonist properties in the effect of agomelatine by adding a melatonin inhibitor together with agomelatine. We found that the daily pretreatment with the …”

Melatonin Modulates Cell Survival of New Neurons in the Hippocampus of Adult Mice

“…In addition, we observed that in melatonin-treated cell cultures, new neurons established contacts with surrounding cells and formed a network. Recently, another in vitro study has reported that 10 À6 mM melatonin modulated rat midbrain neural stem cells viability (Kong et al, 2008). Our data suggest that 10 À6 -10 À4 mM of melatonin caused a 28 and 26% increase in the number of surviving progenitor cells undergoing differentiationFpossibly through an antiapoptotic effect (Reiter, 1998b).…”

“…Melatonin has been previously found by others to enhance neurogenesis in vitro but no data on adult neural precursor cells from the hippocampus were available (Kong et al, 2008;Moriya et al, 2007). The published findings were difficult to extrapolate to adult neurogenesis because embryonic and adult neural stem cells have distinct properties, the details of which are poorly understood.…”

“…Melatonin modulated proliferative activity in the dentate gyrus in early postnatal rats (Kim et al, 2004) and influenced proliferation and differentiation of embryonic neural stem cells (Moriya et al, 2007). In addition, melatonin increased differentiation of rat midbrain neural stem cells (Kong et al, 2008).…”