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Parasitology. 2018 Nov 5:1-10. doi: 10.1017/S003118201800183X. [Epub ahead of print]

The leishmanicidal activity of artemisinin is mediated by cleavage of the endoperoxide bridge and mitochondrial dysfunction.

Author information

1
Department of Pharmacology,Institute of Post Graduate Medical Education and Research,Kolkata-700 020,India.
2
Department of Biochemistry,Institute of Post Graduate Medical Education and Research,Kolkata-700 020,India.
3
Department of Biomedical Sciences,Institute of Pharmacology and Toxicology, University of Veterinary Medicine,Vienna,Austria.

Abstract

Endoperoxides kill malaria parasites via cleavage of their endoperoxide bridge by haem or iron, leading to generation of cytotoxic oxygen-centred radicals. In view of the Leishmania parasites having a relatively compromised anti-oxidant defense and high iron content, this study aims to establish the underlying mechanism(s) accounting for the apoptotic-like death of Leishmania promastigotes by artemisinin, an endoperoxide. The formation of reactive oxygen species was confirmed by flow cytometry and was accompanied by inhibition of mitochondrial complexes I-III and II-III. However, this did not translate into a generation of mitochondrial superoxide or decrease in oxygen consumption, indicating minimal impairment of the electron transport chain. Artemisinin caused depolarization of the mitochondrial membrane along with a substantial depletion of adenosine triphosphatase (ATP), but it was not accompanied by enhancement of ATP hydrolysis. Collectively, the endoperoxide-mediated radical formation by artemisinin in Leishmania promastigotes was the key step for triggering its antileishmanial activity, leading secondarily to mitochondrial dysfunction indicating that endoperoxides represent a promising therapeutic strategy against Leishmania worthy of pharmacological consideration.

KEYWORDS:

Artemisinin; Leishmania; endoperoxides; mitochondria; mitochondrial membrane potential; reactive oxygen species (ROS)

PMID:
30392476
DOI:
10.1017/S003118201800183X

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