<i>Seco</i>-limonoid 11<i>α</i>,19<i>β</i>-dihydroxy-7-acetoxy-7- deoxoichangin promotes the resolution of <i>Leishmania panamensis</i> infection

Abstract

The high morbidity generated by the infection caused by parasites of the genus Leishmania, make of this infection into one of the vector-borne infectious diseases most relevant worldwide, which added to the fact that the drugs used for its treatment are far from be optimal and considering that prophylactic approaches (such as the development of a vaccine) still seems far from being achieved, make of the search for new therapeutic alternatives for safe and effective treatment of this disease one of the most accurate approaches to the control of this disease. In this study we evaluated the antileishmanial and immunomodulatory activity of the compound 11α,19β-dihydroxy-7-acetoxy-7-deoxoichangin (a seco-limonid molecule) through: 1) evaluation of its cytotoxicity over promastigotes and axenic amastigotes of L. (V) panamensis, 2) determination of its ability to induce the control of in vitro infection, using infected murine cells (J774.2) and human dendritic cells (hDCs), 3) quantifying the levels of pro-inflammatory cytokines, (iv) evaluating the expression of cell markers associated with hDCs maturation, and (v) determinating the production of nitric oxide free radicals (NO). In this regard, this seco-limonoid exhibited an antileishmanial activity represented in the reduction of in vitro infection in J774.2 cells and hDCs, with a EC 50 of 7.9 µM (4.48 µg/mL) and 25.5 µM (14.39 µg/mL), respectively, and additionally, we observed an increase on the production of IL-12p70, TNF-α and NO, as also, in the number of hDCs HLA-DR-positive in treated infected hDCs. These findings suggest that anti-leishmanial activity of this compound could be associated with the potential "reactivation" of phagocytic cell that is "paralyzed" by the infection, generating an immune phenotype associated with protection.

Seco-limonoid derived from Raputia heptaphylla promotes the control of cutaneous leishmaniasis in hamsters (Mesocricetus auratus)

“…The seco -limonoid compound 11 α ,19 β -dihydroxy-7-acetoxy-7-deoxoichangin has proved to be a promising antileishmanial agent allowing control of the experimental infection with Leishmania promastigotes on murine macrophages (Coy Barrera et al 2011) also it was observed that an immunomodulatory effect of this compound on these antigen presenting cells, leads to the polarization of the immune response to a pro-inflammatory effector phenotype (Granados-Falla et al 2013). Worth mentioning that this seco -limonoid is not the only limonoid compound for which has been described some antileishmanial activity, examples of this being 7-deacetylgedunin and 7-oxo-7-deacetylgedunin compounds (Hay et al 2007).…”

“…Previous studies has shown the in vitro efficacy of the seco -limonoid compound 11 α ,19 β -dihydroxy-7-acetoxy-7-deoxoichangin using the murine macrophage cell line J774·2 as target cell of in vitro infection (Coy Barrera et al 2011), accompanied by an immunomodulatory effect on infected phagocytic cells (murine macrophage and human dendritic cells), which appears to lead to the ‘reactivation’ of the microbicidal capability of infected cells (Granados-Falla et al 2013). In this sense, other studies support the need to confirm the data obtained in in vitro assays by limonoid compounds (as Gedunin, 7-deacetylgedunin and 7-oxo-7-deacetylgedunin) for which over the past years, its potential antiparasitic activity have been assessed against species belonging to the genus Plasmodium, Trypanosoma and Leishmania (Rosas, 2005; Hay et al 2007; Batista et al 2009; Githua et al 2010).…”

An Update on Natural Antileishmanial Treatment Options from Plants, Fungi and Algae

“…[64,65] The seco-limonoid 27 (11α,19β-dihydroxy-7-acetoxy-7-deoxoichangin) from Raputia heptaphylla showed distinct activity against L. panamensis amastigotes (EC 50 = 7.9 μM) accompanied by increased formation of IL-12p70, TNFα and NO. [66] Nor-triterpene 28 (6α,7α,15β,16β,24pentacetoxy-22α-carbomethoxy-21β,22β-epoxy-18βhydroxy-27,30-bisnor-3,4-secofriedela-1,20(29)-dien-3,4R-olide, LLD-3) isolated from Lopanthera lactescens (Malpighiaceae) was also strongly active against L. amazonensis amastigotes (IC 50 = 0.41 μg/mL, 0.16 μM) and had effects on the proliferation of B and T cells as well as on B cell immunoglobulin production. [67] A semi-purified hexane extract (JDHex) of Croton caudatus leaves (Euphorbiaceae) exhibited a higher activity against L. donovani amastigotes (IC 50 = 2.5 μg/mL) than against promastigotes (IC 50 = 10 μg/mL), associated with an increased formation of NO, TNF-α and IL-12 and distinct in vivo activity of the extract, which reduced the spleen and liver parasite burden, accompanied by IFN-γ induction and IL-10 suppression.…”