Anti-leishmanial, immunomodulatory and additive potential effect of Piperine on Leishmania major: The in silico and in vitro study of Piperine and its combination

Fatemeh Sharifi; Neda Mohamadi; Ali Afgar; Razieh Tavakoli Oliaee

doi:10.1016/j.exppara.2023.108607

Anti-leishmanial, immunomodulatory and additive potential effect of Piperine on Leishmania major: The in silico and in vitro study of Piperine and its combination

Exp Parasitol. 2023 Nov:254:108607. doi: 10.1016/j.exppara.2023.108607. Epub 2023 Sep 2.

Authors

Fatemeh Sharifi¹, Neda Mohamadi², Ali Afgar³, Razieh Tavakoli Oliaee⁴

Affiliations

¹ Research Center of Tropical and Infectious Diseases, Kerman University of Medical Sciences, Kerman, Iran.
² Herbal and Traditional Medicines Research Center, Kerman University of Medical Sciences, Kerman, Iran. Electronic address: mohamadineda15@gmail.com.
³ Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman, Iran.
⁴ Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address: razieh.tavakoly@yahoo.com.

PMID: 37666407
DOI: 10.1016/j.exppara.2023.108607

Abstract

Background: Piperine (Pn), an indole alkaloid compound found in pepper, is an effective compound with anti-leishmanial medications that administered alone or in combination. This study aimed to use Pn for possible biochemical targets and to assess mechanisms of anti-leishmanial action and immunomodulatory roles.

Methods: The ability of Pn to bind to interleukin-12P40 (IL-12P40) and interferon-γ (IFN-γ) was investigated using molecular docking. The leishmanicidal effect of Pn, meglumine antimoniate (Glucantime®; MA), and Pn plus MA was assessed on Leishmania major promastigotes and amastigotes. A real-time PCR was applied to quantify cytokines gene expression in drug-treated murine macrophages.

Results: The molecular docking findings indicated that Pn could bind to IL-12P40/IFN-γ. In silico analyses showed an affinity of Pn to IL-12P40/IFN-γ, with the MolDock score of -236.91 and -64.87 kcal/mol, respectively. Pn plus MA reduced the proliferation rate of promastigote and amastigote forms of L. major compared to each drug alone (IC₅₀ = 43.22 and 19.41 μg/mL, respectively). Moreover, the combination drug demonstrated no cytotoxicity as the selectivity index (SI) was 14.81. Also, Th1-related cytokines were upregulated, while Th2-related cytokines were downregulated in Pn combination-treated murine macrophages.

Conclusions: The superior effectiveness of combination therapy on L. major warrants further investigations on the clinical potential of this combination in the treatment of leishmaniasis.

Keywords: Additive effect; Anti-leishmanial effect; Cytokines gene expression; Molecular docking; Piperine.