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.
Kaurenoic acid has been displaying anti-inflammatory effect described in different models. However, the per se immunomodulatory effects of kaurenoic acid remain to be investigated. Thus, the immunomodulatory and antioxidant effects of kaurenoic acid were investigated in vitro on peritoneal macrophages from BALB/c mice. Kaurenoic acid induced per se the production of pro-inflammatory cytokines such as TNFα, IL-1β and IFN-γ while also increased the levels of IL-10. There was also reduction of NO production and induction of anti-oxidant profile. Therefore, in addition to inhibiting inflammation, kaurenoic acid presents immunomodulatory effects per se.
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