Ammonium trichloro [1,2-ethanediolato-O,O']-tellurate cures experimental visceral leishmaniasis by redox modulation of Leishmania donovani trypanothione reductase and inhibiting host integrin linked PI3K/Akt pathway.

Abstract

In an endeavor to search for affordable and safer therapeutics against debilitating visceral leishmaniasis, we examined antileishmanial potential of ammonium trichloro [1,2-ethanediolato-O,O']-tellurate (AS101); a tellurium based non toxic immunomodulator. AS101 showed significant in vitro efficacy against both Leishmania donovani promastigotes and amastigotes at sub-micromolar concentrations. AS101 could also completely eliminate organ parasite load from L. donovani infected Balb/c mice along with significant efficacy against infected hamsters (˃93% inhibition). Analyzing mechanistic details revealed that the double edged AS101 could directly induce apoptosis in promastigotes along with indirectly activating host by reversing T-cell anergy to protective Th1 mode, increased ROS generation and anti-leishmanial IgG production. AS101 could inhibit IL-10/STAT3 pathway in L. donovani infected macrophages via blocking α4β7 integrin dependent PI3K/Akt signaling and activate host MAPKs and NF-κB for Th1 response. In silico docking and biochemical assays revealed AS101's affinity to form thiol bond with cysteine residues of trypanothione reductase in Leishmania promastigotes leading to its inactivation and inducing ROS-mediated apoptosis of the parasite via increased Ca2+ level, loss of ATP and mitochondrial membrane potential along with metacaspase activation. Our findings provide the first evidence for the mechanism of action of AS101 with excellent safety profile and suggest its promising therapeutic potential against experimental visceral leishmaniasis.

• Authors: Preeti Vishwakarma, Naveen Parmar, Pragya Chandrakar, Tanuj Sharma, Manoj Kathuria, Pramod K Agnihotri, Mohammad Imran Siddiqi, Kalyan Mitra, Susanta Kar
• Journal: Cellular and molecular life sciences : CMLS (Cell Mol Life Sci) Vol. 75 Issue 3 Pg. 563-588 (02 2018) ISSN: 1420-9071 [Electronic] Switzerland
• PMID: 28900667 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ethylenes
• Integrins
• Phosphoinositide-3 Kinase Inhibitors
• ammonium trichloro(dioxoethylene-O,O'-)tellurate
• NADH, NADPH Oxidoreductases
• trypanothione reductase
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Cells, Cultured
• Cricetinae
• Disease Models, Animal
• Ethylenes (pharmacology, therapeutic use)
• Female
• Host-Parasite Interactions (drug effects)
• Integrins (antagonists & inhibitors, drug effects)
• Leishmania donovani (drug effects, enzymology, metabolism)
• Leishmaniasis, Visceral (drug therapy, metabolism, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• NADH, NADPH Oxidoreductases (drug effects, metabolism)
• Oxidation-Reduction (drug effects)
• Phosphatidylinositol 3-Kinases (drug effects)
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, drug effects)
• Signal Transduction (drug effects)