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Fluoxetine Induces Apoptotic and Oxidative Neuronal Death Associated with The Influx of Copper Ions in Cultured Neuronal Cells / 전남의대학술지
Chonnam Medical Journal ; : 20-26, 2020.
Article in English | WPRIM | ID: wpr-787278
ABSTRACT
We examined the effect of fluoxetine, a selective serotonin reuptake inhibitor antidepressant, on neuronal viability in mouse cortical near-pure neuronal cultures. Addition of fluoxetine to the media for 24 hours induced neuronal death in a concentration-dependent manner. To delineate the mechanisms of fluoxetine-induced neuronal death, we investigated the effects of trolox, cycloheximide (CHX), BDNF, z-VAD-FMK, and various metal-chelators on fluoxetine-induced neuronal death. Neuronal death was assessed by MTT assay. The addition of 20 µM fluoxetine to the media for 24 hours induced 60–70% neuronal death, which was associated with the hallmarks of apoptosis, chromatin condensation and DNA laddering. Fluoxetine-induced death was significantly attenuated by CHX, BDNF, or z-VAD-FMK. Treatment with antioxidants, trolox and ascorbate, also markedly attenuated fluoxetine-induced death. Interestingly, some divalent cation chelators (EGTA, Ca-EDTA, and Zn-EDTA) also markedly attenuated the neurotoxicity. Fluoxetine-induced reactive oxygen species (ROS) generation was measured using the fluorescent dye 2′,7′-dichlorofluorescin diacetate. Trolox and bathocuproine disulfonic acid (BCPS), a cell membrane impermeable copper ion chelator, markedly attenuated the ROS production and neuronal death. However, deferoxamine, an iron chelator, did not affect ROS generation or neurotoxicity. We examined the changes in intracellular copper concentration using a copper-selective fluorescent dye, Phen Green FL, which is quenched by free copper ions. Fluoxetine quenched the fluorescence in neuronal cells, and the quenching effect of fluoxetine was reversed by co-treatment with BCPS, however, not by deferoxamine. These findings demonstrate that fluoxetine could induce apoptotic and oxidative neuronal death associated with an influx of copper ions.
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Full text: Available Index: WPRIM (Western Pacific) Main subject: DNA / Chromatin / Serotonin / Cell Membrane / Chelating Agents / Fluoxetine / Cell Death / Reactive Oxygen Species / Apoptosis / Brain-Derived Neurotrophic Factor Limits: Animals Language: English Journal: Chonnam Medical Journal Year: 2020 Type: Article

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Full text: Available Index: WPRIM (Western Pacific) Main subject: DNA / Chromatin / Serotonin / Cell Membrane / Chelating Agents / Fluoxetine / Cell Death / Reactive Oxygen Species / Apoptosis / Brain-Derived Neurotrophic Factor Limits: Animals Language: English Journal: Chonnam Medical Journal Year: 2020 Type: Article