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

Abstract

Background Selective 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. Methods Primary 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 α, and interleukin 1α with or without pretreatments of antidepressants. Cell viability, phenotypes, inflammatory responses, and the underlying mechanisms were analyzed. Results All 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 1β (IL-1β). The SNRI venlafaxine was the least toxic to astrocytes and inhibited the production of IL-6 and IL-1β 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. Conclusions The 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.

The Neuroprotection of Verbascoside in Alzheimer’s Disease Mediated through Mitigation of Neuroinflammation via Blocking NF-κB-p65 Signaling

“…Due to its extreme instability, NO is quickly and proportionally metabolized to nitrite. Therefore, nitrite has been extensively used as an indicator of NO [ 26 ]. BV2 cells (1.5 × 10 5 per well) were cultured in 6-well plates overnight.…”

Pharmacological Investigations in Glia Culture Model of Inflammation

“…This effect on STAT3 was independently from a previous induction by a cytokine mixture (comprising complement component 1q, TNF-α, IL-1α). Venlafaxine here revealed a low cytotoxicity on astrocytes compared to other antidepressants ( He et al, 2021 ). Additionally, glioma cells pretreated with venlafaxine and isoproterenol revealed an increased p90Rsk phosphorylation compared to isoproterenol alone, indicating further intracellular effects of venlafaxine on neuro-glial pathways ( Khawaja et al, 2004 ).…”

Purinergic receptor ligands: the cytokine storm attenuators, potential therapeutic agents for the treatment of COVID-19

“…The effect of antidepressants on the secretion of various pro-inflammatory markers, including IL-10, IL-4, IL-1β, and TNF-α has been studied [ 139 ]. An investigation about the inflammatory responses of some antidepressants, such as fluoxetine, sertraline, paroxetine, citalopram, mirtazapine, fluvoxamine, and venlafaxine showed that all investigated antidepressants suppressed the IL-6 production so that the most and the least efficient drugs were fluvoxamine and venlafaxine respectively [ 141 , 142 ]. In this regard, except for citalopram, the other drugs prevented IL-1β secretion which the best efficacy was associated with venlafaxine.…”

“…In this regard, except for citalopram, the other drugs prevented IL-1β secretion which the best efficacy was associated with venlafaxine. [ 141 ]. Furthermore, paroxetine downregulates IL‐1β, TNF‐α, and IL‐17, and upregulates IL-10 [ 143 ].…”