Fluoxetine suppresses inflammatory reaction in microglia under OGD/R challenge via modulation of NF-κB signaling

Abstract

We aimed to investigate the anti-inflammatory role of fluoxetine, a selective serotonin reuptake inhibitor, in microglia (MG) and the mechanisms under oxygen glucose deprivation/reoxygenation (OGD/R). An OGD/R model on BV-2 cells was used for the study of microglia under ischemia/reperfusion injury in ischemic stroke. Lentiviral transfection was applied to knock down IκB-α. Enzyme-linked immunosorbent assay (ELISA) was used for detecting levels of TNF-α, IL-1β, and IL-6, and real-time PCR was used to assess the expression of IκB-α protein. Western blotting was applied to analyze NF-κB-signaling related proteins and Cell Counting Kit-8 (CCK-8) was used for assessing cell viability. Molecular docking and drug affinity responsive target stability (DARTS) assay were used for the detection of the interaction between IκB-α and fluoxetine. We found that fluoxetine decreased the levels of TNF-α, IL-1β, and IL-6 in supernatant as well as NF-κB subunits p65 and p50 in BV-2 cells under OGD/R. Fluoxetine significantly increased the level of IκB-α through the inhibition of IκB-α ubiquitylation and promoted the bonding of IκB-α and fluoxetine in BV-2 cells under OGD/R. Knocking down IκB-α attenuated the decreasing effect of TNF-α, IL-1β, and IL-6 as well as p65 and p50 in BV-2 cells under OGD/R led to by fluoxetine. In conclusion, our present study demonstrated the anti-inflammatory role of fluoxetine and its mechanisms related to the modulation of NF-κB-related signaling in MG under ischemia/reperfusion challenge.

Nonerythropoietic Erythropoietin Mimetic Peptide ARA290 Ameliorates Chronic Stress-Induced Depression-Like Behavior and Inflammation in Mice

“…Even though both fluoxetine and ARA290 inhibited chronic stress-induced peripheral inflammation and microglia activation, the two drugs showed different effects on the expression of inflammatory cytokines, suggesting that the two drugs inhibit inflammation through different mechanisms. It has been reported that fluoxetine inhibits NF-κB activation in microglia/macrophages ( Tian et al, 2019 ) and works as a direct NLRP3 inhibitor to limit inflammasome activation ( Ambati et al, 2021 ). On the other hand, several studies have revealed that EPO induces microglia/macrophage polarization toward M2 whereas such a role was not found for fluoxetine ( Wang et al, 2017 ; Wei et al, 2017 ; Gu et al, 2021 ; Wang et al, 2021 ).…”

Systemic exosomal miR-193b-3p delivery attenuates neuroinflammation in early brain injury after subarachnoid hemorrhage in mice

“…Inhibition of HDAC3 activity following miR-193b-3p treatment reduced expression levels of these inflammatory cytokines in vivo. NF-κB should be a transcription factor of inflammatory mediators that plays a key role in neuroinflammation [46,47]. MiR-193b-3p significantly increased NF-κB p65 acetylation and reduced its transcriptional activity after SAH, suggesting that miR-193b-3p exerts neuroprotective effects.…”

Post Stroke Depression to be Expected

“…in experimental studies [227]. Furthermore, Fluoxetine injections in rat models enhanced neurogenesis and prevented a pathological increase in stem cell recruitment in the hippocampus [228].…”