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Keywords
host-directed therapy
macrophage activation
nitric oxide
cytokines
wound healing
natural products
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Abstract
Leishmania braziliensis cutaneous leishmaniasis (CL) remains a major public health challenge due to the toxicity, variable efficacy, and emerging resistance associated with systemic therapies. However, few topical candidates have been successfully developed despite growing guideline support for local treatment in many patients. This study evaluated the antileishmanial, immunomodulatory, and proregenerative effects of a topical formulation combining triterpene saponins from Sapindus saponaria (SS) and a synthetic chroman hydrazone (TC2) using a standardized hamster model of L. braziliensis CL. The antiparasitic and immunomodulatory effects of TC2-SS were examined in human monocytederived macrophages infected with L. braziliensis, assessing intracellular parasite burden, macrophage morphology, nitric oxide (NO) and reactive oxygen species (ROS) production, and cytokine expression by ELISA and RT-qPCR. In vivo efficacy and early wound-healing responses were evaluated in a dorsalskin hamster model treated topically with 4% TC2SS and compared with intralesional meglumine antimoniate, including epidermal growth factor (EGF) and transforming growth factor β1 (TGFβ1) expression. TC2-SS reduced intracellular infection (EC₅₀ 12.83 ± 0.97 µg/mL), decreased parasite burden, and induced macrophage activation-like morphological changes. The formulation preserved infectiondriven NO and ROS and selectively enhanced late NO in infected cells. Cytokine analyses revealed coordinated suppression of IL-1β, TNF-α, IL-4, IL-10, and TGF-β1, preserving MIP-1α. In vivo, TC2-SS achieved cure rates comparable to those of antimonials, with uniform lesion regression, no treatment failures, no systemic toxicity, and an increased ratio of EGF/TGF-β1. Thus, TC2-SS provided dual antileishmanial and host-directed benefits, supporting its advancement as a topical therapeutic candidate for L. braziliensis CL.
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