Benefits of Ascorbic Acid in Association with Low-Dose Benznidazole in Treatment of Chagas Disease

Abstract

The acute phase of Chagas disease (CD) is characterized by high parasitic proliferation and intense inflammation, exacerbating the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). These reactive molecules are also increased by the metabolism of the nitroheterocyclic compounds benznidazole (BZ) and nifurtimox, the only drugs available for the treatment of CD. This oxidative environment, associated with the intracellular multiplication of , leads to tissue destruction, triggering the pathogenic process. Both drugs have limited efficacy and serious side effects, which demonstrates the need to seek alternative therapies. Due to the difficulty in developing new drugs, reviewing therapeutic regimens appears advantageous, and the use of BZ in low doses associated with antioxidants, such as ascorbic acid (AA), would be a valid alternative to attenuate oxidative stress. In our studies, mice receiving the combination of 7.14 mg/kg of body weight/day AA and 10 mg/kg/day BZ10 (AA+BZ10) showed a reduction in parasitemia that was more effective than that with those receiving BZ or AA alone. The combined treatment was effective in decreasing intracellular ROS and lipid peroxidation in cardiac tissue. Histological and PCR analyzes showed that AA also reduced the cardiac parasitism. However, the greatest benefit was seen in AA+BZ10 group, since cardiac inflammation was significantly reduced. In addition, the combined therapy prevented the hepatic damage induced by the infection. Our findings suggest that AA combined with a low dose of BZ may improve the trypanocidal activity and attenuate the toxic effects of BZ. The decrease in oxidative damage and inflammation observed in mice treated with AA+BZ10 could result in increased cardioprotection.

Molecular dissection of Chagas induced cardiomyopathy reveals central disease associated and druggable signaling pathways

“…Due to the high structural similarity of retinol and isotretinoin, it seems plausible that increased Rbp1 could also increase intracellular isotretinoin concentrations, acting as a host defense mechanism against T. cruzi or chronic inflammation. Treatment of T. cruzi infections with vitamin C has been shown to have myocardial protective effects [78] and retinol can help defend against many forms of cardiovascular disease [74], however, treatment of T. cruzi infections with either retinol or isotretinoin has not yet been tested.…”

Phenothiazinium Dyes Are Active againstTrypanosoma cruziIn Vitro

“…The infected cells were centrifuged for 10 min, 3000 g, and washed with PBS and suspended in trypsin to separate cells and parasites. The cultures were distributed in 1.5 ml microtubes (~ 1 × 10 6 trypomastigotes/tube) and incubated with 4 × IC 50 of compounds at 37°C, 5% CO 2 for 2 h. Menadione (MN), a classic inducer of cellular oxidative stress [13], was used as the positive control of ROS production as previously described in [14]. After treatment, the cultures were centrifuged for 10 minutes, 3000 g, and washed with PBS and suspended in trypsin.…”

Review on Experimental Treatment Strategies Against Trypanosoma cruzi

“…Combination also reduced cardiac inflammation and hepatic damage. [ 188 ] BNZ/acetyl salicylic acid Aspirin combined with lower dosages of BNZ showed better therapeutic effect in infected mice. [ 193 ] BNZ/clomipramine Clomipramine improved BNZ activity in vitro and in vivo with no cell toxicity and fewer side effects [ 184 , 189 ] BNZ/fenofibrate Fenofibrate plus a low dose of BNZ attenuated cardiac dysfunction and promoted parasite clearance in mice sequentially infected with two strains of different genetic backgrounds.…”