Mediators of inflammation · 2015
Kaurenoic Acid Possesses Leishmanicidal Activity by Triggering a NLRP12/IL-1β/cNOS/NO Pathway.
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Miranda Milena Menegazzo, Panis Carolina, da Silva Suelen Santos, Macri Juliana Aparecida, Kawakami Natalia Yoshie, Hayashida Thiago Hideki, Madeira Tiago Bervelieri, Acquaro Vinicius Ricardo, Nixdorf Suzana Lucy, Pizzatti Luciana, Ambrósio Sérgio Ricardo, Cecchini Rubens, Arakawa Nilton Syogo, Verri Waldiceu Aparecido, Costa Ivete Conchon, Pavanelli Wander Rogério
Аннотация
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.