Oncotarget

Research Papers:

Antidepressants, sertraline and paroxetine, increase calcium influx and induce mitochondrial damage-mediated apoptosis of astrocytes

Chee-Kin Then, Kao-Hui Liu, Ming-Hsuan Liao, Kuo-Hsuan Chung, Jia-Yi Wang and Shing-Chuan Shen _

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Oncotarget. 2017; 8:115490-115502. https://doi.org/10.18632/oncotarget.23302

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Abstract

Chee-Kin Then1,2, Kao-Hui Liu3,4, Ming-Hsuan Liao1, Kuo-Hsuan Chung5,6, Jia-Yi Wang1,7 and Shing-Chuan Shen1,8,9

1Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan

2School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

3Department of Dermatology, Taipei Medical University Shuang Ho Hospital, New Taipei City, Taiwan

4Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan

5Department of Psychiatry and Psychiatric Research Center, Taipei Medical University Hospital, Taipei, Taiwan

6Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

7Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

8Department of Dermatology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

9International Master/Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

Correspondence to:

Shing-Chuan Shen, email: scshen@tmu.edu.tw

Keywords: antidepressants; calcium overload; mitochondrial damage; astrocyte apoptosis

Received: October 19, 2017     Accepted: December 04, 2017     Published: December 14, 2017

ABSTRACT

The impacts of antidepressants on the pathogenesis of dementia remain unclear despite depression and dementia are closely related. Antidepressants have been reported may impair serotonin-regulated adaptive processes, increase neurological side-effects and cytotoxicity. An ‘astroglio-centric’ perspective of neurodegenerative diseases proposes astrocyte dysfunction is involved in the impairment of proper central nervous system functioning. Thus, defining whether antidepressants are harmful to astrocytes is an intriguing issue. We used an astrocyte cell line, primary cultured astrocytes and neuron cells, to identify the effects of 11 antidepressants which included selective serotonin reuptake inhibitors, a serotonin-norepinephrine reuptake inhibitor, tricyclic antidepressants, a tetracyclic antidepressant, a monoamine oxide inhibitor, and a serotonin antagonist and reuptake inhibitor. We found that treatment with 10 μM sertraline and 20 μM paroxetine significantly reduced cell viability. We further explored the underlying mechanisms and found induction of the [Ca2+]i level in astrocytes. We also revealed that sertraline and paroxetine induced mitochondrial damage, ROS generation, and astrocyte apoptosis with elevation of cleaved-caspase 3 and cleaved-PARP levels. Ultimately, we validated these mechanisms in primary cultured astrocytes and neuron cells and obtained consistent results. These results suggest that sertraline and paroxetine cause astrocyte dysfunction, and this impairment may be involved in the pathogenesis of neurodegenerative diseases.


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