Oxidative stress mediated anti-leishmanial activity of endoperoxides represent a new therapeutic strategy in Leishmaniasis

Abstract

Endoperoxides kill malaria parasites via cleavage of their endoperoxide bridge by heme or iron, leading to generation of cytotoxic oxygen-centered radicals. In view of the impaired anti-oxidant defense and high iron content of Leishmania parasites, the effectiveness of two endoperoxides, artemisinin and ascaridole was evaluated. Both demonstrated parasiticidal activity (in Leishmania donovani, LD and Leishmania tarentolae, LtP), along with lower cytotoxicity in macrophages. In LtP, carbon-centered radicals were identified in the presence of both endoperoxides by ESR spin-trapping and downstream formation of reactive oxygen species confirmed by flow cytometry. We explored whether leishmanial mitochondria are a target for this secondary oxygen radical formation. Both endoperoxides minimally impaired the electron transport chain, but impaired mitochondrial coupling upon prolonged exposure. Additionally, artemisinin depleted ATP levels, increased ATPase activity and enhanced Ca2+ release which collectively translated into a caspase-independent apoptotic-like cell death. Collectively, the endoperoxide-mediated radical formation was the initial step for their antileishmanial activity and represents a promising therapeutic strategy worthy of pharmacological consideration.