Combining in vitro, in vivo, and in silico approaches to evaluate the effect of serotonergic-based topical therapies on mild to moderate psoriasis

Abstract

Psoriasis, a chronic inflammatory skin disease, poses a significant burden on patients’ quality of life and healthcare systems. While mild-to-moderate cases are treated topically, usually combined with phototherapy, severe cases require systemic treatment with immunosuppressants, retinoids or biologics. However, all available treatments have drawbacks in terms of efficiency and side effects. Drawing from studies linking depression treatment to psoriasis improvement, we investigated whether topical formulations of selective serotonin reuptake inhibitors (SSRIs) could offer a viable therapy for psoriasis.

Five SSRIs (sertraline, fluoxetine, paroxetine, escitalopram, fluvoxamine) were evaluated for their in vitro cytotoxicity, in human keratinocytes and THP-1 monocytes. Their anti-inflammatory action was tested using cell differentiation assays and immunoassays of pro-inflammatory cytokines in THP-1 monocytes. The results obtained with sertraline, escitalopram, and fluvoxamine suggested further evaluation in vivo. Anti-inflammatory effects were evaluated by skin parameter monitoring and histopathology, in an imiquimod-induced psoriasis-like inflammation mice model, and the best results were obtained for fluvoxamine.

These findings were further supported by in silico molecular docking studies of the structural interaction between the serotonergic receptors and the drugs. Future research will focus on developing and characterizing of topical fluvoxamine formulations, like emulsions and penetration-enhancer vesicles, which offer advantages over the gels used herein.

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Materials

Sertraline hydrochloride, escitalopram oxalate, fluvoxamine maleate, fluoxetine hydrochloride and paroxetine hydrochloride were a generous gift from Generis Farmacêutica (Portugal). Dimethyl-β-cyclodextrin was provided by Wacker (Portugal). Transcutol® P (Diethylene Glycol Monoethyl Ether) was a kind gift from Gattefossé (Lyon, France). The parabens Nipagin™ M Sodium (Sodium Methylparaben) and Nipasol M Sodium™ (Sodium Propylparaben) were purchased from Clariant (Muttenz, Switzerland). Hydroxypropylmethylcellulose (HPMC) was obtained from Sigma Aldrich (Germany). The Aldara® cream (5% imiquimod) was obtained from Meda AB (Solna, Sweden) and Dermovate® (0.5 mg/g clobetasol propionate) was obtained from GlaxoSmithKline. Ultrapure water was obtained by inverse osmosis in a MILLI-Q System Elix 3, from EMD Millipore. All other reagents were of analytical grade.

Ana M. Martins, Lídia Gonçalves, Sandra Simões, Patrícia A. Serra, Rita C. Guedes, Helena Ribeiro, Joana Marto,
Combining in vitro, in vivo, and in silico approaches to evaluate the effect of serotonergic-based topical therapies on mild to moderate psoriasis, European Journal of Pharmaceutical Sciences, Volume 206, 2025, 107013, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2025.107013.