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African sleeping sickness is a parasitic disease in humans and livestock caused by Trypanosoma brucei throughout sub-Saharan Africa. Absence of appropriate vaccines and prevalence of drug resistance proclaim that a new way of therapeutic interventions is essential against African trypanosomiasis. In the present study, we have looked into the effect of andrographolide (andro), a diterpenoid lactone from Andrographis paiculata on Trypanosoma brucei PRA 380. Although andro has been recognized as a promosing anti-cancer drug, its usefulness against Trypanosoma spp remained unexplored. Andro showed promising anti-trypanosomal activity with an IC 50 value of 8.3 μM assessed through SYBR Green cell viability assay and also showed no cytotoxicity towards normal murine macrophages. Cell cycle analysis revealed that andro could induce sub-G 0 /G 1 phase arrest. Flow cytometric analysis also revealed that incubation with andro caused exposure of phosphatidyl serine to the outer leaflet of plasma membrane in T. brucei PCF. This event was preceded by andro-induced depolarization of mitochondrial membrane potential (Δym) and elevation of cytosolic calcium. Andro also caused elevation of intracellular reactive oxygen species (ROS) as well as lipid peroxidation level, and depletion in reduced thiol levels. Taken together, these data indicate that andro has promising antitrypanosomal activity mediated by promoting oxidative stress and depolarizing the mitochondrial membrane potential and thereby triggering an apoptosis-like programmed cell death. Therefore, this study merits further investigation to the therapeutic possibility of using andro for the treatment of African trypanosomiasis. [ABSTRACT FROM AUTHOR]