Kaurenoic Acid Possesses Leishmanicidal Activity by Triggering a NLRP12/IL‐1<i>β</i>/cNOS/NO Pathway

Abstract

Leishmania amazonensis ( L. amazonensis ) infection can cause severe local and diffuse injuries in humans, a condition clinically known as American cutaneous leishmaniasis (ACL). Currently, the therapeutic approach for ACL is based on Glucantime, which shows high toxicity and poor effectiveness. Therefore, ACL remains a neglected disease with limited options for treatment. Herein, the in vitro antiprotozoal effect and mechanisms of the diterpene kaurenoic acid [ ent ‐kaur‐16‐en‐19‐oic acid] (KA) against L. amazonensis were investigated. KA exhibited a direct antileishmanial effect on L. amazonensis promastigotes. Importantly, KA also reduced the intracellular number of amastigote forms and percentage of infected peritoneal macrophages of BALB/c mice. Mechanistically, KA treatment reestablished the production of nitric oxide (NO) in a constitutive NO synthase‐ (cNOS‐) dependent manner, subverting the NO‐depleting escape mechanism of L. amazonensis . Furthermore, KA induced increased production of IL‐1 β and expression of the inflammasome‐activating component NLRP12. These findings demonstrate the leishmanicidal capability of KA against L. amazonensis in macrophage culture by triggering a NLRP12/IL‐1 β /cNOS/NO mechanism.