title: Further evidence of the trypanocidal action of eupomatenoid-5: confirmation of involvement of reactive oxygen species and mitochondria owing to a reduction in trypanothione reductase activity.
abstract: Our group assays natural products that are less toxic and more effective than available nitroheterocycles as promising therapeutic options for patients with Chagas disease. Our previous study reported the trypanocidal activity of eupomatenoid-5, a neolignan isolated from the leaves of Piper regnellii var. pallescens, against the three main parasitic forms of Trypanosoma cruzi. The present study further characterizes the biochemical and morphological alterations induced by this compound to elucidate the mechanisms of action involved in the cell death of T. cruzi. We show that eupomatenoid-5 induced oxidative imbalance in the three parasitic forms, especially trypomastigotes, reflected by a decrease in the activity of trypanothione reductase and increase in the formation of reactive oxygen species (ROS). A reduction of mitochondrial membrane potential was then triggered, further impairing the cell redox system through the production of more ROS and reactive nitrogen species. Altogether, these effects led to oxidative stress, reflected by lipid peroxidation and DNA fragmentation. These alterations are key events in the induction of parasite death through various pathways, including apoptosis, necrosis, and autophagy.
authors: Programa de Pós Graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, 87020-900 Maringá, PR, Brasil.
authors: D
authors: D
authors: Lazarin-Bidóia
authors: V C
authors: VC
authors: Desoti
authors: T
authors: T
authors: Ueda-Nakamura
authors: B P
authors: BP
authors: Dias Filho
authors: C V
authors: CV
authors: Nakamura
authors: S O
authors: SO
authors: Silva
mesh_terms: D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology / Q000473:pathology; D005609:Free Radicals / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D031701:Piper / Q000737:chemistry; D010936:Plant Extracts / Q000737:chemistry; D018515:Plant Leaves / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity
chemical_list: D001572:Benzofurans; D005609:Free Radicals; D010636:Phenols; D010936:Plant Extracts; D017382:Reactive Oxygen Species; C452811:eupomatenoid 5; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase