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, 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.

Immunomodulatory Effects of Diterpenes and Their Derivatives Through NLRP3 Inflammasome Pathway: A Review

“…Recently, it has been reported that the NLRP12, through its binding to the hematopoiesis cell kinase, may impart an effect on the pathogenesis of acute myeloid leukemia (62). Kaurenoic acid was seen to exert leishmanicidal activity through triggering a NLRP12/IL-1β/cNOS/NO pathway (35).…”

“…On the other hand, sodium tanshinone IIA sulfonate (Compound 4) reduced the overproduction and overexpression of cardiac ROS and thioredoxin-interacting protein (TXNIP), respectively, through diminishing the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3)/insulin signaling/peroxisome proliferator-activated receptor-α (PPAR-α) pathway in Beagle dogs (34). In another study, kaurenoic acid (Compound 7) restored the production of nitric oxide (NO) in a constitutive NO synthase-(cNOS-) dependent fashion, increased the formation of IL-1β, and elevated the expression of NLRP12 in Leishmania amazonensis infected BALB/c mice (35). Phorbol myristate acetate (Compound 8) at 100 nM down-regulated the mRNA expression of CASP1, IL-1β, IL-18, myeloid leukemia cell differentiation protein 1 (MCL1), NLRP3, as well as PYCARD expression in BALB/cMlac mice neutrophil cells (36).…”

Diterpenes as lead molecules against neglected tropical diseases

“…Dolabelladienetriol in Leishmania-infected macrophages was found to diminish the levels of nitric oxide (NO), IL-10, TNF-α, and TGF-β production (Soares et al, 2012). A clerodane diterpene in L. donovani exhibited caspase-3/-7-like protease activity and genomic DNA fragmentation, induced mitochondrial dysfunction, and caused an oxidative stressmediated apoptotic cell death (Kathuria et al, 2014), while kaurenoic acid triggered the NLRP12/IL-1β/ cNOS/NO mechanism in Leishmania amazonensis (Miranda et al, 2015). A number of promising leishmicidal diterpenes have been reported (Sinha et al, 2000;Sairafianpour et al, 2001;Lala et al, 2003;Habtemariam, 2003;González et al, 2005;Fokialakis et al, 2006;Brito et al, 2006;Suryawanshi et al, 2008;Roy et al, 2010;Dos Santos et al, 2011;Mondal et al, 2013;Soares et al, 2013;Santos et al, 2013;Mothana et al, 2014;Moreira et al, 2014;Mokoka et al, 2014;Falodun et al, 2014;Demarchi et al, 2015;da Silva et al, 2015;Mizuno et al, 2015;Lima et al, 2015; Leprosy.…”

“…The current review suggests that a number of diterpenes act through reduction of pathogenic infectionmediated oxidative species and pro-inflammatory and/or inflammatory mediators (Alfaro-Bustamante et al, 1997;Chen et al, 2009;Liou et al, 2008;Soares et al, 2012;Miranda et al, 2015), while augmenting the antiinflammatory and interferon levels (D'Agostino et al, 2004;Montero et al, 2004). The diterpene, 5-epiicetexone, is evident to cause cell death by arresting S/G2 phase in T. cruzi (Lozano et al, 2012a), while taxoid 10-deacetylbaccatin III acts on G2/M phase in Leishmania-infected murine macrophages (Georgopoulou et al, 2007).…”

Leishmanicidal and fungicidal activity of lipases obtained from endophytic fungi extracts

“…American Cutaneous Leishmaniasis is a zoonotic disease caused by protozoans of the genus Leishmania , and has as its main characteristic the formation of painless ulcerated lesions with intense red colored edges. The treatment of cutaneous leishmaniasis is unsatisfactory and has limited efficacy, prolonged treatment, high cost and undesirable side effects to the host, which has prompted the search for new therapeutic strategies and dogs are the main domestic reservoir of the Leishmania parasite [ 1 ]. Another health problem, which compromises domestic animals, are pathogens of the skin, among them Malassezia [ 2 ], Microsporum canis and Trichophyton [ 3 ] represent the most prevalent.…”