Mahanine exerts in vitro and in vivo antileishmanial activity by modulation of redox homeostasis

Abstract

Leishmania is an obligatory intracellular protozoan parasite responsible for the development of a spectrum of disease manifestation ranging from cutaneous to the more destructive visceral form 1 . Visceral leishmaniasis (VL) is a neglected tropical disease, mainly caused by the species L. donovani, which is prevalent in the Indian subcontinent with 40,000 cases registered each year and 147 million people under the risk 2 . Macrophages are the primary host for the parasite to survive and multiply in the mammalian system. Development of antileishmanial immunity depends on the Th1 type immune response generated by IL-12 secretion by antigen presenting cells (APCs) which in turn induce IFNγ secretion by T cells. This secreted IFNγ further induce macrophages for generation of nitric oxide (NO) and reactive oxygen species (ROS), which are the major antileishmanial defense molecules 3 . Uncoupling protein (UCP) is a mitochondrial membrane transporter which takes part in the regulation of mitochondrial ROS generation in macrophages 4 . Leishmania developed several strategies to dodge the host immune response to the establishment of successful infection in the hostile environment. This parasite induces the expression of negative regulatory protein UCP2 in macrophages as well as utilizes their own cascade of antioxidant enzymes like ascorbate peroxidase (APX), glutathione synthetase, tryparedoxin peroxidase for the suppression of ROS generation thereby neutralizing oxidative stress in host for their survival [5][6][7][8] . Due to unavailability of effective vaccines, treatment solely relies on chemotherapy. Although pentavalent antimonials were the mainstream therapy for past 70 years, a large percentage of patients are resistant to this drug. Currently, amphotericin B (conventional deoxycholate or liposomal formulations) has emerged as the first line of treatment. Miltefosine is the only oral drug. However, emerging resistance to miltefosine is particularly worrying. Alongside, most of these synthetic antileishmanial drugs are highly expensive and suffer from various side effects, long treatment regimen and acute toxicity, thus pose a real challenge for the management and elimination

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Host-Directed Drug Therapies for Neglected Tropical Diseases Caused by Protozoan Parasites

“…Mahanine is a carbazole alkaloid isolated from a medicinal plant native to the Indian subcontinent. In vivo studies have shown that mahanine induces apoptosis of both antimony sensitive and resistant L. donovani ( Roy et al, 2017 ). Mahanine augments NO and ROS generation, thereby causing parasitic apoptosis due to oxidative stress.…”

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“…Additionally, it showed a good synergistic effect with clinically approved drugs both in colon and cervical cancers. It also exhibited antileishmanial activity through immunomodulation [9].…”