Recent studies pioneer the existence of a novel programmed cell death pathway in malaria parasite plasmodium and suggest that it could be helpful in developing new targeted anti-malarial therapies. Considering this fact, we evaluated the underlying action mechanism of this pathway in mefloquine (MQ) treated parasite. Since cysteine proteases play a key role in apoptosis hence we performed preliminary computational simulations to determine binding affinity of MQ with metacaspase protein model. Binding pocket identified using computational studies, was docked with MQ to identify it's potential to bind with the predicted protein model. We further determined apoptotic markers such as mitochondrial dysregulation, activation of cysteine proteases and in situ DNA fragmentation in MQ treated/untreated parasites by cell based assay. Our results showed low mitochondrial membrane potential, enhanced activity of cysteine protease and increased number of fragmented DNA in treated parasites compared to untreated ones. We next tested the involvement of oxidative stress in MQ mediated cell death and found significant increase in reactive oxygen species generation after 24 h of treatment. Therefore we conclude that apart from hemozoin inhibition, MQ is competent to induce apoptosis in plasmodium by activating metacaspase and ROS production.
Although over the last 15 years, prevalence of malaria became reduced by over half but developing resistance against artemisinin derivatives and its combinations, which are only ray of hope to treat resistant malaria set back the control efforts and the key hinderence to achieve the goal of malaria elimination till 2030. In spite these artemisinins are precious antimalarials, their action mechanism is yet to be fully understood. Reactive oxygen species (ROS) produces by cleavage of endoperoxide bridge of artemisinin derivatives are known to be its antimalarial efficacy. Since ROS could induce apoptosis, here we had explored the effect of artemisinin derivatives on apoptotic machinery of malaria parasite, Plasmodium falciparum and its survival. We have studied the effect of a/β arteether, artesunate and a synthetic 1, 2, 4 trioxane on mitochondria, caspase activity and DNA during asexual blood stages of Plasmodium falciparum 3D7. Results have shown that cleavage of peroxide bridge of artemisinin derivatives and 1,2,4 trioxane generate reactive oxygen species which depolarize mitochondrial membrane potential and make it permeable which further followed by activation of caspase like enzyme and DNA fragmentation, which are hallmark of apoptotic cell death. These findings suggest that artemisinin derivatives and synthetic trioxane induce apoptosis like phenomena in erythrocytic stage of malaria parasite; Plasmodium falciparum.
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