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Parasitology Research

, Volume 113, Issue 6, pp 2161–2168 | Cite as

Ketanserin, an antidepressant, exerts its antileishmanial action via inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) enzyme of Leishmania donovani

  • Sushma SinghEmail author
  • Neeradi Dinesh
  • Preet Kamal Kaur
  • Baigadda Shamiulla
Original Paper

Abstract

Leishmaniasis is one of the major health problems existing globally. The current chemotherapy for leishmaniasis presents several drawbacks like toxicity and increased resistance to existing drugs, and hence, there is a necessity to look out for the novel drug targets and new chemical entities. Current trend in drug discovery arena is the “repurposing” of old drugs for the treatment of diseases. In the present study, an antidepressant, ketanserin, was found lethal to both Leishmania donovani promastigotes and intracellular amastigotes with no apparent toxicity to the cells. Ketanserin killed promastigotes and amastigotes with an IC50 value of 37 μM and 28 μM respectively, in a dose-dependent manner. Ketanserin was found to inhibit L. donovani recombinant 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) enzyme with an IC50 value of 43 μM. Ketanserin treated promastigotes were exogenously supplemented with sterols like ergosterol and cholesterol to rescue cell death. Ergosterol could recover the inhibition partially, whereas cholesterol supplementation completely failed to rescue the inhibited parasites. Further, HMGR-overexpressing parasites were generated by transfecting Leishmania promastigotes with an episomal pspα hygroα-HMGR construct. Wild-type and HMGR overexpressors of L. donovani were used to study the effect and mode of action of this inhibitor. The HMGR overexpressors showed twofold resistance to ketanserin. These observations suggest that the lethal effect of ketanserin is due to inhibition of HMGR, the rate-limiting enzyme of the ergosterol biosynthetic pathway. Since targeting of the sterol biosynthetic pathway enzymes may be useful therapeutically, the present study may have implications in treatment of leishmaniasis.

Keywords

Leishmania Ketanserin HMGR Ergosterol Cholesterol 

Notes

Acknowledgments

The authors are grateful for the financial support provided by the Ministry of Chemicals and Fertilizers, India. Special thanks to the Director of NIPER for the financial support. The authors thank Dr. Peter Edwards, UCLA Laboratory (Los Angeles, CA) for providing anti-rat HMGR antibody and Prof. R. Madhubala, School of Life Sciences, JNU, India for providing the pspα hygroα construct. Special thanks to Mr. Neerupudi Kishor Babu for critical reading of the manuscript.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Sushma Singh
    • 1
    Email author
  • Neeradi Dinesh
    • 1
  • Preet Kamal Kaur
    • 1
  • Baigadda Shamiulla
    • 1
  1. 1.Department of BiotechnologyNational Institute of Pharmaceutical Education and Research, SAS NagarMohaliIndia

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