Kaurenoic Acid Possesses Leishmanicidal Activity by Triggering a NLRP12/IL-1β/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, thein vitroantiprotozoal effect and mechanisms of the diterpene kaurenoic acid [ent-kaur-16-en-19-oic acid] (KA) againstL. amazonensiswere investigated. KA exhibited a direct antileishmanial effect onL. amazonensispromastigotes. 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 ofL. amazonensis. Furthermore, KA induced increased production of IL-1βand expression of the inflammasome-activating component NLRP12. These findings demonstrate the leishmanicidal capability of KA againstL. amazonensisin macrophage culture by triggering a NLRP12/IL-1β/cNOS/NO mechanism.