Time-dependent oxidative stress caused by benznidazole

Abstract

Benznidazole (BZN) is a nitroimidazole derivative which has a notable trypanocide activity, and it is the only drug used in Brazil and Argentina for the treatment of Chagas' disease. The drug in current use is thought to act, at least in part, by inducing oxidative stress within the parasite. Imidazolic compounds are involved in the production of reactive oxygen species (ROS). In order to evaluate the effect of BZN on ROS production and on the antioxidant status of the host, male rats were treated for different periods of time (2, 4, 6, 10 and 30 days) with 40 mg BZN/kg body weight. After treatment, biomarkers of oxidative stress such as the activities of catalase (CAT), superoxide dismutase (SOD), glutathione-S-transferase (GST) and glutathione reductase (GR), and also thiobarbituric acid reactive species (TBARS), reduced glutathione (GSH), total glutathione (TG) and oxidized glutathione (GSSG) concentrations, were measured in crude hepatic homogenates. Our results revealed that BZN is able to cause tissue damage as shown by increased TBARS content, inhibition of some antioxidants and induction of other antioxidants in a concentration- and time-dependent manner. The tissue damage measured as TBARS increased up to the 10th day of treatment. GST activity was inhibited during the BZN treatment. On the other hand, CAT and GR showed similar increased activities at the beginning, followed by decreased activities at the end of the treatment. After 30 days of treatment, GR activity remained low while CAT activity was high, compared to controls. The SOD activities remained unchanged throughout the experimental period. GSH showed lower values at the beginning of BZN treatment but the hepatic concentrations were enhanced at the end of the experimental period. Total glutathione showed a similar profile, and oxidized glutathione showed higher values in rats treated with BZN. In conclusion, these results indicate that, at therapeutic doses, BZN treatment elicits an oxidative stress in rat hepatocytes.

Antioxidant therapy attenuates oxidative insult caused by benzonidazole in chronic Chagas' heart disease

“…GPx and GST are able to metabolize hydroperoxides thus counteracting the lipoperoxidation process in cells [52]. In contrast, TBARS levels were increased after BZN therapy in rat liver, together with the GST activity inhibition [17].…”

“…In acute Chagas' disease the immune response has a similar activation and subsequent production of ROS. Moreover, the BZN metabolism generates ROS during the nitroreduction of the drug, and together these mechanisms can elicit a compensatory mechanism in the host promoting an increase in antioxidant enzyme activity [13,17,[40][41][42].…”

“…Accordingly, a previous study carried out by our research group revealed that BZN treatment elicits an oxidative stress in rat hepatocytes [17].…”

In Vitro and In Vivo Trypanocidal Effects of the Cyclopalladated Compound 7a, a Drug Candidate for Treatment of Chagas' Disease

“…The inefficiency of benznidazole with the Y strain infection may be explained by the partial resistance of this strain (16) and was confirmed here, as even a single dose of 400 nmol ⅐ kg Ϫ1 body weight of benznidazole had minimal effect. As it has been proposed that benznidazole toxicity for T. cruzi is due to oxidative stress generated preferentially in the parasite (19), compound 7a could easily circumvent the resistance mechanism.…”

Vitamin C effects in mice experimentally infected with Trypanosoma cruzi QM2 strain

“…The only drug currently available for the treatment of these patients is benznidazole 3 , the pharmacological action of which results in reactive oxygen species (ROS) formation as superoxide anion and hydrogen peroxide, promoting oxidative damage to T. cruzi [4][5][6] . Besides ROS, reactive nitrogen species (RNS), which are formed from the reaction of nitric oxide (NO) with superoxide radical 6,7 , may also lead to oxidative stress, responsible for many pathological conditions such as chagasic cardiomyopathy 8 .…”