Andrographolide augments methotrexate's therapeutic potential in psoriasis: comprehensive in vitro and in vivo evaluation.

Abstract

Psoriasis is a persistent autoimmune dermatological condition impacting around 125 million individuals globally. Methotrexate (MTX) is widely used for the treatment of psoriasis. One of the major drawbacks of MTX is dose-dependent hepatotoxicity, resulting in poor compliance with therapy. Andrographolide (AG) is extensively used traditionally in Asia for the treatment of inflammation-related diseases. It possesses both antipsoriatic and hepatoprotective potential. This study was planned to explore the combination of AG with MTX to enhance the efficacy of MTX using in vitro and in vivo models. The anti-inflammatory effects of AG and MTX, individually and in combination, were evaluated in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages by measuring nitric oxide (NO), interleukin (IL)-1β, and IL-6 levels. The combination of AG (40 mg/kg) with subtherapeutic dose of MTX (0.5 mg/kg) was further evaluated in an imiquimod-induced psoriasis mouse model. Co-treatment significantly suppressed the production of NO and pro-inflammatory cytokines in vitro compared to monotherapies. In vivo, the combination significantly alleviated psoriatic symptoms, including erythema, scaling, and epidermal thickening, and improved Baker's histology scores. Additionally, the combination therapy reduced spleen enlargement and modulated cytokine expression in psoriatic skin, with significant downregulation of pro-inflammatory cytokines, along with upregulation of the anti-inflammatory cytokine. These effects were comparable to those achieved with a therapeutic dose of MTX (1 mg/kg). These findings suggest that AG potentiates the antipsoriatic effect of low-dose MTX. This combination approach presents a promising therapeutic strategy for enhancing efficacy and may reduce the MTX-associated hepatotoxicity for the long-term treatment of psoriasis.