Oxidative stress and antioxidant defenses: a target for the treatment of diseases caused by parasitic protozoa

Turrens, Julio F.

doi:10.1016/j.mam.2004.02.021

Cited by 172 publications

(160 citation statements)

References 42 publications

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“…Trypanothione reductase has been reported to catalyze the reduction of quinones (5,13,30) and could facilitate the initiation of single-electron redox cycling. Hydrogen peroxide and hydroxyl radical formed as a consequence of superoxide production (15,33,34) together with superoxide would lead to T. brucei parasite cell death.…”

Section: Discussionmentioning

confidence: 99%

Induction of Oxidative Stress in Trypanosoma brucei by the Antitrypanosomal Dihydroquinoline OSU-40

Dayton

Kuppusamy

et al. 2012

Antimicrob Agents Chemother

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In the present study, we sought to provide further support for the hypothesis that OSU-40 kills trypanosomes through oxidative stress. Inducible RNA interference (RNAi) was applied to downregulate key enzymes in parasite antioxidant defense, including T. brucei trypanothione synthetase (TbTryS) and superoxide dismutase B (TbSODB). Both TbTryS RNAi-induced and TbSODB RNAi-induced cells showed impaired growth and increased sensitivity toward OSU-40 by 2.4-fold and 3.4-fold, respectively. Decreased expression of key parasite antioxidant enzymes was thus associated with increased sensitivity to OSU-40, consistent with the hypothesis that OSU-40 acts through oxidative stress. Finally, the dose-dependent formation of free radicals was observed after incubation of T. brucei with OSU-40 utilizing electron spin resonance (ESR) spectroscopy. These data support the notion that the mode of antitrypanosomal action for this class of compounds is to induce oxidative stress. H uman African trypanosomiasis (HAT) is a vector-borne parasitic disease caused by the Trypanosoma brucei subspecies T. b. rhodesiense and T. b. gambiense.The trypanosome proliferates in the host's hemolymphatic system during the first stage of HAT and invades the central nervous system in the second stage. Transmitted by the tsetse fly, the disease mainly affects rural populations in sub-Saharan Africa and is fatal if untreated. Although according to the World Health Organization the number of new cases has dropped to just over 7,000 during 2010 (39), very few drugs are available to treat HAT (2, 4, 42). Pentamidine and suramin, both developed in the first half of the 20th century, are used against first-stage disease, while melarsoprol and eflornithine are used to treat second-stage disease. These drugs are far from satisfactory due to limitations such as severe toxicity, poor efficacy, acquired resistance, rising failure rates, and lack of availability (2, 4, 42). With high efficacy and a good safety profile, nifurtimox-eflornithine combination therapy (NECT) was introduced as a first-line treatment for second-stage HAT caused by T. b. gambiense in 2009 (4, 22, 42). However, administration of NECT is relatively complicated, and its efficacy toward T. b. rhodesiense is still questionable (4, 42). Thus, new drugs are needed against HAT that are safe, affordable, easy to administer, active against first-and second-stage disease, and effective against both subspecies of T. brucei (4, 42).From a previous synthetic medicinal chemistry study, we discovered several N1-substituted 1,2-dihydroquinoline-6-ols displaying nanomolar 50% inhibitory concentrations (IC 50 s) in vitro against T. b. rhodesiense and selectivity indexes (SI) up to Ͼ18,000 (11). OSU-40 (1-benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate) (Fig. 1) showed a potency (IC 50 , 0.014 M; SI, 1,700) close to that of melarsoprol (IC 50 , 0.008 M; SI, 1,000) against T. b. rhodesiense STIB900 in vitro. In an early treatment mouse model of acute African trypanosomiasis, OSU-40 prolonged the life s...

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Section: Discussionmentioning

confidence: 99%

Induction of Oxidative Stress in Trypanosoma brucei by the Antitrypanosomal Dihydroquinoline OSU-40

Dayton

Kuppusamy

et al. 2012

Antimicrob Agents Chemother

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“…Oxidative stress results from increased production of oxidants, reduced level of antioxidants or a combination of both [15]. Several studies have demonstrated that the issue of oxidative stress and antioxidants is involved in the pathogenesis of various parasitic diseases and inflammatory events [25,26]. Malondialdehyde (MDA), a marker of lipid peroxidation; a non-enzymatic antioxidant, glutathione, and enzymatic antioxidants glutathione peroxidase and superoxide dismutase have been determined in patients with hydatid cyst.…”

Section: Discussionmentioning

confidence: 99%

Antioxidant-oxidant status in patients with hydatid cyst

Bakır¹,

Çeliksöz²,

Çelık³

et al. 2012

Turk J Bioch

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“…ROS are produced through the action of specifi c oxidases and oxygenases, the Fenton reaction and are also by-products of the electron transport chain (Turrens 2003(Turrens , 2004. RNS include · NO and its derivatives.…”

Section: Reactive Oxygen Species (Ros) and Reactive Nitrogen Species mentioning

confidence: 99%

An overview of chagasic cardiomyopathy: pathogenic importance of oxidative stress

Zacks

Wen

Vyatkina

et al. 2005

An. Acad. Bras. Ciênc.

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There is growing evidence to suggest that chagasic myocardia are exposed to sustained oxidative stressinduced injuries that may contribute to disease progression. Pathogen invasion-and replication-mediated cellular injuries and immune-mediated cytotoxic reactions are the common source of reactive oxygen species (ROS) in infectious etiologies. However, our understanding of the source and role of oxidative stress in chagasic cardiomyopathy (CCM) remains incomplete. In this review, we discuss the evidence for increased oxidative stress in chagasic disease, with emphasis on mitochondrial abnormalities, electron transport chain dysfunction and its role in sustaining oxidative stress in myocardium. We discuss the literature reporting the consequences of sustained oxidative stress in CCM pathogenesis.Key words: chagasic cardiomyopathy, reactive oxygen species, inflammation, mitochondria, oxidant/antioxidant status, oxidative damage. PARASITE, VECTOR AND TRANSMISSIONTrypanosoma cruzi, a parasitic protozoan of the ancient branch of eukaryotes (Kingdom Eukaryota, Order Kinetoplastida), is the etiological agent of Chagas disease in humans (Miles 2003). Currently, the World Health Organization estimates that 11-18 million individuals are infected worldwide (WHO 2002). Transmission of T. cruzi occurs predominantly via insect vectors of the subfamily Triatoma, family Reduviidae, referred to as " kissing bugs". Residing in the peridomestic habitat of mud-thatch Correspondence to: Nisha Garg Ph.D. E-mail: nigarg@utmb.edu houses in rural areas (Mott et al. 1978), Triatoma infestans in South America, Rhodnius prolixus in Venezuela, Colombia and Central America (Schofi eld and Dias 1999), and Triatoma barberi in Mexico (Guzman 2001), are the most common species responsible for transmission. Improvements in housing conditions and vector control measures instituted by the Southern Cone Initiative in 1991 have contributed to a decline in transmission in endemic countries (Schofi eld and Dias 1999). However, concern remains that reinfestation of homes by secondary sylvatic vectors, e.g. Triatoma sordida, will compromise the long-term effi cacy of vector control measures in Brazil and other Southern American countries (Monteiro et al. 2001, WHO 2002. Blood transfusion and organ transplantation represent further routes of T. cruzi transmission. Although many countries in Latin America screen blood donations for T. cruzi, infection rates ranging from 0.1% to 24.4% are estimated to occur through transfusion (WHO 2002).In the U.S., vector-transmitted human infections have been reported in the southern States (Ochs et al. 1996, Herwaldt et al. 2000. Several studies have shown the presence of the insect vector as well as infection of domestic dogs and wild animals in the US (Meurs et al. 1998, Bradley et al. 2000, Beard et al. 2003, Yabsley and Noblet 2002. Further, due to signifi cant increases in immigration to the USA and Canada from endemic countries and perinatal transmission, it is estimated that ∼ 100, 000 people residing...

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Oxidative stress and antioxidant defenses: a target for the treatment of diseases caused by parasitic protozoa

Cited by 172 publications

References 42 publications

Induction of Oxidative Stress in Trypanosoma brucei by the Antitrypanosomal Dihydroquinoline OSU-40

Induction of Oxidative Stress in Trypanosoma brucei by the Antitrypanosomal Dihydroquinoline OSU-40

Antioxidant-oxidant status in patients with hydatid cyst

An overview of chagasic cardiomyopathy: pathogenic importance of oxidative stress

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