Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation

BackgroundSelective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used new-generation drugs for depression. Depressive symptoms are thought to be closely related to neuroinflammation. In this study, we used up-to-date protocols of culture and stimulation and aimed to understand how astrocytes respond to the antidepressants.MethodsPrimary astrocytes were isolated and cultured using neurobasal-based serum-free medium. The cells were treated with a cytokine mixture comprising complement component 1q, tumor necrosis factor alpha, and interleukin 1 alpha with or without pretreatments of antidepressants. Cell viability, phenotypes, inflammatory responses, and the underlying mechanisms were analyzed.ResultsAll the SSRIs, including paroxetine, fluoxetine, sertraline, citalopram, and fluvoxamine, show a visible cytotoxicity within the range of applied doses, and a paradoxical effect on astrocytic inflammatory responses as manifested by the promotion of inducible nitric oxide synthase (iNOS) and/or nitric oxide (NO) and the inhibition of interleukin 6 (IL-6) and/or interleukin 1 beta (IL-1 beta). The SNRI venlafaxine was the least toxic to astrocytes and inhibited the production of IL-6 and IL-1 beta but with no impact on iNOS and NO. All the drugs had no regulation on the polarization of astrocytic A1 and A2 types. Mechanisms associated with the antidepressants in astrocytic inflammation route via inhibition of JNK1 activation and STAT3 basal activity.ConclusionsThe study demonstrated that the antidepressants possess differential cytotoxicity to astrocytes and function differently, also paradoxically for the SSRIs, to astrocytic inflammation. Our results provide novel pieces into understanding the differential efficacy and tolerability of the antidepressants in treating patients in the context of astrocytes.

Automated summary

The study found that SSRIs have visible cytotoxicity to astrocytes and show a paradoxical effect on astrocytic inflammatory responses. The SNRI venlafaxine has the least toxicity to astrocytes and inhibits the production of certain inflammatory factors. The antidepressants alter astrocytic inflammation through inhibition of specific signaling pathways.