Cellular and Molecular Life Sciences

, Volume 75, Issue 3, pp 563–588 | Cite as

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

  • Preeti Vishwakarma
  • Naveen Parmar
  • Pragya Chandrakar
  • Tanuj Sharma
  • Manoj Kathuria
  • Pramod K. Agnihotri
  • Mohammad Imran Siddiqi
  • Kalyan Mitra
  • Susanta Kar
Original Article

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.

Keywords

AS101 Visceral leishmaniasis Immunomodulator Reactive oxygen species Integrin Redox modulation Apoptosis 

Abbreviations

α4β7integrin

Alpha-4 Beta-7 integrin

AS101

Ammonium trichloro [1,2-ethanediolato-O,O′]-tellurate

CCCP

Carbonyl cyanide 3-chlorophenylhydrazone

DTNB

5,5-Dithio-bis-(2-nitrobenzoic acid)

EMSA

Electrophoretic mobility shift assay

H2DCFDA

2′,7′-dichlorodihydrofluorescein diacetate

IC50

50% Inhibitory concentration

IFN-γ

Interferon gamma

IL-10

Interlukin 10

i.p

Intra peritoneal

JC-1

5,5′,6,6′-tetra-chloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide

L. donovani

Leishmania donovani

LDU

Leishman donovan unit

MMP

Mitochondrial membrane potential

MTT

3-(4,5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide

PI

Propidium iodide

SbV

Pentavalent antimonials

SLA

Soluble leishmania antigen

TryR

Trypanothione reductase

TeIV

Tellurium with 4 oxidation state

TUNEL

Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling

TNB−2

2-Nitro-5-thiobenzoate

TS2

Trypanothione disulphide

TNF-α

Tumor necrosis factor alpha

TGF-β

Transforming growth factor beta

VL

Visceral leishmaniasis

AST

Aspartate aminotransferase

ALT

Alanine aminotransferase

Notes

Acknowledgements

The authors thank Director, CDRI, Lucknow, for providing the research facilities and encouragement. Authors acknowledge sophisticated analytical instrument facility of CDRI for helping with flow cytometry. Authors also thank Technical Officers, Mr. Anurag Kumar Srivastava and Dr. Kavita Singh, from CDRI for helping in performing liver enzyme assays and confocal microscopy experiments. This work was supported by the Department of Science and Technology (Grant no. SB/FT/LS-310/2012), Council of Scientific and Industrial Research (CSIR NWP BSC0114)—Government of India. P. V., P. C., T. S. and M. K. were supported by the fellowship from Council of Scientific and Industrial Research (CSIR). N. P. was supported by the fellowship from University Grant Commission (UGC) of India. This manuscript has CDRI communication no. 9544.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Preeti Vishwakarma
    • 1
    • 2
  • Naveen Parmar
    • 1
    • 2
  • Pragya Chandrakar
    • 1
    • 2
  • Tanuj Sharma
    • 3
  • Manoj Kathuria
    • 4
  • Pramod K. Agnihotri
    • 5
  • Mohammad Imran Siddiqi
    • 2
    • 3
  • Kalyan Mitra
    • 2
    • 4
  • Susanta Kar
    • 1
    • 2
  1. 1.Division of ParasitologyCSIR-Central Drug Research InstituteLucknowIndia
  2. 2.Academy of Scientific and Innovative ResearchNew DelhiIndia
  3. 3.Molecular and Structural Biology DivisionCSIR-Central Drug Research InstituteLucknowIndia
  4. 4.Electron Microscopy Unit, Sophisticated Analytical Instrument FacilityCSIR-Central Drug Research InstituteLucknowIndia
  5. 5.Division of ToxicologyCSIR-Central Drug Research InstituteLucknowIndia

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