Malabaricone C derived from nutmeg inhibits arachidonate 5-lipoxygenase activity and ameliorates psoriasis-like skin inflammation in mice

Abstract

As pro-inflammatory lipid mediators, leukotrienes have pathophysiological activities in several inflammatory diseases, including psoriasis. In the biosynthesis of leukotrienes from arachidonic acid, 5-lipoxygenase catalyzes the first two steps. In the present study, we showed that nutmeg (Myristica fragrans) strongly inhibited the catalytic activity of 5-lipoxygenase. To characterize the bioactive component(s) of nutmeg, we performed 5-lipoxygenase inhibitory activity-guided fractionation of aqueous ethanol extract of nutmeg, resulting in the isolation of malabaricone C having antioxidant activity. Malabaricone C exhibited potent competitive inhibition of 5-lipoxygenase with an IC₅₀ value of 0.2 μM. In mice with imiquimod-induced psoriasis-like skin lesions, topical application of 2 mM malabaricone C significantly ameliorated hyperplasia and inflammatory cell infiltration, and suppressed the expression of the psoriasis-associated genes S100a9, Krt1, Il17a, and Il22. Lipid metabolome analysis of these psoriasis-like skin lesions showed that malabaricone C markedly decreased the level of leukotriene B₄ but did not significantly increase the other pro-inflammatory lipid mediators. These findings suggest that malabaricone C decreases LTB₄ by the 5-lipoxygenase inhibition and ameliorates the symptoms of psoriasis-like skin inflammation.

Keywords: Anti-inflammation; Arachidonate 5-lipoxygenase; Leukotriene B(4); Malabaricone C; Psoriasis.