Kaurenoic Acid Possesses Leishmanicidal Activity by Triggering a NLRP12IL-1βcNOSNO Pathway

Abstract EN

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-1β 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-1β/cNOS/NO mechanism.