Fluoxetine and Paroxetine: Repositioning as a Therapeutic Alternative in the Treatment of Various Diseases

Foletto, Vitória Segabinazzi; Serafin, Marissa Bolson; Rosa, Taciéli Fagundes da; Bottega, Angelita; Coelho, Silvana Silveira; Machado, Catrine de Souza; Hörner, Rosmari

doi:10.1097/mjt.0000000000001011

Cited by 6 publications

(3 citation statements)

References 40 publications

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“…Thus, it is not surprising that it has already been recommended to treat various diseases and pathological conditions outside of its current indication as an antidepressant. 30,31,44,45 Hence, within the confines of this study, we aimed to further investigate its putative beneficial actions by using human epidermal keratinocytes.…”

Section: Discussionmentioning

confidence: 99%

“…It possesses a remarkable safety profile, 42,43 and it was also shown to exert anti‐inflammatory, 23–26 anti‐pruritic, 27,28 pro‐wound healing, 30,31 and anti‐AD 32 effects. Thus, it is not surprising that it has already been recommended to treat various diseases and pathological conditions outside of its current indication as an antidepressant 30,31,44,45 . Hence, within the confines of this study, we aimed to further investigate its putative beneficial actions by using human epidermal keratinocytes.…”

Section: Discussionmentioning

confidence: 99%

“…[38][39][40][41] Considering the remarkable safety profile of FX 42,43 as well as the aforementioned growing body of evidence supporting its additional beneficial biological effects, it is not surprising that repositioning it to treat various diseases and pathological conditions has already been suggested. 30,31,44,45 Thus, in the current study, we aimed to further explore its putative beneficial effects on human epidermal keratinocytes.…”

Section: Introductionmentioning

confidence: 99%

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Fluoxetine exerts anti‐inflammatory effects on human epidermal keratinocytes and suppresses their endothelin release

Tóth,

Ádám,

Arany

et al. 2023

Experimental Dermatology

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Fluoxetine is a safe antidepressant with remarkable anti‐inflammatory actions; therefore, we aimed to investigate its effects on immortalized (HaCaT) as well as primary human epidermal keratinocytes in a polyinosinic‐polycytidylic acid (p(I:C))‐induced inflammatory model. We found that a non‐cytotoxic concentration (MTT‐assay, CyQUANT‐assay) of fluoxetine significantly suppressed p(I:C)‐induced expression and release of several pro‐inflammatory cytokines (Q‐PCR, cytokine array, ELISA), and it decreased the release of the itch mediator endothelins (ELISA). These effects were not mediated by the inhibition of the NF‐κB or p38 MAPK pathways (western blot), or by the suppression of the p(I:C)‐induced elevation of mitochondrial ROS production (MitoSOX Red labeling). Instead, unbiased activity profiling revealed that they were most likely mediated via the inhibition of the phosphoinositide 3‐kinase (PI3K) pathway. Importantly, the PI3K‐inhibitor GDC0941 fully mimicked the effects of fluoxetine (Q‐PCR, ELISA). Although fluoxetine was able to occupy the binding site of GDC0941 (in silico molecular docking), and exerted direct inhibitory effect on PI3K (cell‐free PI3K activity assay), it exhibited much lower potency and efficacy as compared to GDC0941. Finally, RNA‐Seq analysis revealed that fluoxetine deeply influenced the transcriptional alterations induced by p(I:C)‐treatment, and exerted an overall anti‐inflammatory activity. Collectively, our findings demonstrate that fluoxetine exerts potent anti‐inflammatory effects, and suppresses the release of the endogenous itch mediator endothelins in human keratinocytes, most likely via interfering with the PI3K pathway. Thus, clinical studies are encouraged to explore whether the currently reported beneficial effects translate in vivo following its topical administration in inflammatory and pruritic dermatoses.

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Section: Discussionmentioning

confidence: 99%