Abstract
Visceral leishmaniasis (VL) causes fatal life-threatening disease, if left untreated. The current drugs have various limitations; hence, natural products from medicinal plants are being focused in search of new drugs to treat leishmaniasis. The aim of the present study was to evaluate the antileishmanial and immunomodulatory activities of F5 and F6 alcoholic fractions from Withania somnifera leaves and purified withaferin-A in Leishmania donovani-infected peritoneal macrophages and BALB/c mice. We observed that F5 (15 µg/mL), F6 (10 µg/mL), and withaferin-A (1.5 µM) reduce amastigote count in peritoneal macrophages and induce reactive oxygen species and significant decrease in IL-10 mRNA expression compared to control upon treatment. Subsequently, in vivo study mice were treated with F5 (25 and 50 mg/kg b.wt.), F6 (25 and 50 mg/kg b.wt.) orally, and withaferin-A (2 mg/kg b.wt.) intraperitoneally for 10 consecutive days and a drastic reduction in parasite burden in both spleen and liver were observed. The treatment resulted in the reduction in IL-10, IL-4, and TGF-β mRNA expression and a significant increase in IFN-γ/IL-10 expression ratio in the treated group compared to control. The humoral response of these alcoholic fractions and withaferin-A shows increased IgG2a levels when compared with IgG1 in treated mice. Taken together, our result concludes that withanolides in alcoholic fractions demonstrate a potent antileishmanial and immunomodulatory activities in experimental VL.
Highlights
Visceral leishmaniasis (VL) is one of the most severe forms of leishmaniasis, which affects the visceral organs viz. spleen and liver
The results indicated that treatment with F5 decreased the cell survivability of Peritoneal Mouse Macrophages (PMM) by just 40% at the highest concentration of 75 μg/mL, whereas F6 induced the similar effect at 50 μg/mL
Our results suggest that F5, F6, and withaferin-A might exert their antileishmanial activity via reactive oxygen species (ROS) production in peritoneal macrophages compared to their effect on infected PMM as it is one of the mechanisms used by the host in the absence of nitric oxide (NO) production
Summary
Visceral leishmaniasis (VL) is one of the most severe forms of leishmaniasis, which affects the visceral organs viz. spleen and liver. It poses a serious public health problem and is responsible for most of the Leishmania-associated deaths all over the world [1]. Adopted treatment strategies are inadequate due Withanolides Control the Experimental VL to high cost and/or adverse events of the antileishmanial drugs. Growing drug resistance is further affecting the efficacy [5]. The first line of treatment constitutes of pentavalent antimony compounds, in which the resistance is widespread in Bihar, India [6]. Used antileishmanial drugs are liposomal amphotericin-B and an oral drug miltefosine; both have several drawbacks [7]. Major cytokines produced by Th1 cells, include IFN-γ, IL-2, IL-12, and TNF-α, are crucial for disease resistance whereas, IL-4, IL-10, and TGF-β produced by Th2 cells promote disease progression [9]. Activated macrophages play a critical role in innate and adaptive immune response through secretion of toxic molecules such as reactive oxygen species (ROS) and nitric oxide (NO), which show cytotoxic effects against several pathogens [10]
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