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.
Highlights
Astrocytes play vital roles in maintaining housekeeping functions of the nervous system (CNS), including homeostasis of the extracellular environment, neuronal metabolism, shaping of the brain microarchitecture, and regulation of neurotransmitters, such as glutamate [1]
Treatment with sertraline and paroxetine increased the intracellular calcium concentration, and the calcium continued to rise in astrocytes at 3 and 6 h; only a slight increment in calcium levels was detected after citalopram treatment (Figure 2A)
We found that sertraline and paroxetine, two selective serotonin reuptake inhibitors (SSRIs), reduced CTX TNA2 astrocyte viability but not the other nine commonly used antidepressants, which include three SSRIs, one serotonin-norepinephrine reuptake inhibitors (SNRIs), two TCAs, one tetracyclic antidepressant (TeCA), one monoamine oxidase inhibitors (MAOIs), and one serotonin antagonist and reuptake inhibitors (SARIs)
Summary
Astrocytes play vital roles in maintaining housekeeping functions of the nervous system (CNS), including homeostasis of the extracellular environment, neuronal metabolism, shaping of the brain microarchitecture, and regulation of neurotransmitters, such as glutamate [1]. Antidepressants elevate the transmission of one or more of the monoamines: serotonin, nor-adrenaline, or dopamine [14] They are classified according to their mechanism of action: tricyclic and tetracyclic antidepressants (TCAs and TeCAs), SSRIs, serotonin antagonist and reuptake inhibitors (SARIs), monoamine oxidase inhibitors (MAOIs), and SNRIs. Antidepressants have been proved to improve cognitive functions [15,16,17] but there is a large-scale clinical trial which determined no cognitive improvements in antidepressant users [18]. We obtained consistent results of antidepressant medication being associated with an increased risk of dementia in our previous study [26]. According to those studies and integrating the idea of an astroglio-centric perspective of neurodegenerative diseases [6], we proposed to determine the effects of antidepressant on astrocytes in this study
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