The Efficacy of Fluvoxamine in Preventing the Aging Process of Mouse Neural Stem Cells in a Di-galactose-Induced Model in a Culture Medium

Background & aim: Cellular senescence is an irreversible process in cells that is affected by various factors such as oxidative stress and inflammation, and the importance of this issue rises in its effect on neural stem cells. Fluvoxamine at appropriate concentrations provides proliferation and differentiation of neural stem cells into glial and neurons and modulates inflammatory factors. Therefore, considering the mechanism of the aging process on neural stem cells, the present study investigated the effects of fluvoxamine in culture. Methods: The present experimental study was conducted in 2023. Neural stem cells were isolated from the subventricular zone of the adult male mouse brain and cultured using a standard method to generate neurospheres. Cell viability, number of neurospheres and cells in the control group, the D-galactose treatment group (20 mg/cc), the fluvoxamine treatment groups with different concentrations, and the D-galactose and fluvoxamine combined groups were measured using the MTT method. The number of neurospheres, the number of proliferating cells and senescent cells were also counted. The collected data were analyzed using the one-way analysis of variance statistical test. Results: The survival of neural stem cells in the low-dose fluvoxamine group was higher than in the control group but significantly decreased with increasing doses (p<0.001). In contrast, the D-galactose group indicated a significant decrease compared to the control (p<0.01). Low-dose fluvoxamine combined with D-galactose significantly increased survival compared to the D-galactose group (p<0.001) but decreased in the high-dose groups. The number of neurospheres in the D-galactose group was significantly lower than in the control group (p<0.001), while the combination treatment with 50 nM fluvoxamine showed a significant increase compared to D-galactose alone (p<0.01). The average number of BrdU-positive cells in the 100 fluvoxamine group increased significantly compared to the control (p<0.001), whereas in the D-galactose group, it was significantly reduced (p<0.01). D-galactose and low-dose fluvoxamine treatment increased BrdU-positive cells compared to D-galactose treatment alone. The average number of neural stem cells in the D-galactose groups dropped significantly compared to the control, but the combination with 50 nM fluvoxamine led to a significant increase (p<0.001). The average number of senescent cells rose significantly with higher fluvoxamine doses compared to the control, and treatment with D-galactose also elevated senescent cell counts. However, combining D-galactose with low concentrations of fluvoxamine resulted in a significant decrease in senescent cells compared to D-galactose alone (p<0.0001). Conclusion: The results of the present study indicated that fluvoxamine, prescribed for the treatment of major depression and obsessive-compulsive disorders, while increasing the survival and viability of cells at low doses, demonstrated significant toxicity at higher doses in a dose-dependent manner. Furthermore, it elevated aging-related factors and induced aging in neural stem cells under ex vivo conditions. In other words, it reduced the survival of neural stem cells, the number of neurospheres, and the number of cells derived from each neurosphere, while simultaneously it increased the number of aged cells. These findings necessitate further investigations in both in vivo and in vitro environments.