Clomipramine and Benznidazole Act Synergistically and Ameliorate the Outcome of Experimental Chagas Disease

Abstract

bChagas disease is an important public health problem in Latin America, and its treatment by chemotherapy with benznidazole (BZ) or nifurtimox remains unsatisfactory. In order to design new alternative strategies to improve the current etiological treatments, in the present work, we comprehensively evaluated the in vitro and in vivo anti-Trypanosoma cruzi effects of clomipramine (CMP) (a parasite-trypanothione reductase-specific inhibitor) combined with BZ. In vitro studies, carried out using a checkerboard technique on trypomastigotes (T. cruzi strain Tulahuen), revealed a combination index (CI) of 0.375, indicative of a synergistic effect of the drug combination. This result was correlated with the data obtained in infected BALB/c mice. We observed that during the acute phase (15 days postinfection [dpi]), BZ at 25 mg/kg of body weight/day alone decreased the levels of parasitemia compared with those of the control group, but when BZ was administered with CMP, the drug combination completely suppressed the parasitemia due to the observed synergistic effect. Furthermore, in the chronic phase (90 dpi), mice treated with both drugs showed less heart damage as assessed by the histopathological analysis, index of myocardial inflammation, and levels of heart injury biochemical markers than mice treated with BZ alone at the reference dose (100 mg/kg/day). Collectively, these data support the notion that CMP combined with low doses of BZ diminishes cardiac damage and inflammation during the chronic phase of cardiomyopathy. The synergistic activity of BZ-CMP clearly suggests a potential drug combination for Chagas disease treatment, which would allow a reduction of the effective dose of BZ and an increase in therapeutic safety.

Systematic screening of generic drugs for progressive multiple sclerosis identifies clomipramine as a promising therapeutic

“…Clomipramine has been used previously in mice in different dosages to study conditions such as antinociception (0.5 mg/kg) 40 , Chagas disease (7.5 mg/kg) 41 , and neurotransmitter and histone deacetylase expression (50 mg/kg) 42 . In humans taking clomipramine as an antidepressant, mean serum levels after a mean daily intake of 127 ± 91 mg/d have been reported to be 122 ng/ml (387 nM, considering a molecular weight of 314.9) 17 .…”

Relevance of Trypanothione Reductase Inhibitors on Trypanosoma cruzi Infection: A Systematic Review, Meta-Analysis, and In Silico Integrated Approach

“…There is evidence that damage to β -adrenergic receptors is mediated by autoantibodies produced against T. cruzi antigens that exhibit molecular mimicry to heart molecules [ 84 , 85 ]. It is natural that reduction in receptor density from immunological attack is accompanied by a compensatory increase in the affinity of the remaining receptors [ 25 , 86 ]. This behavior represents an important adaptive and counterregulatory mechanism in the attempt to adjust the cardiac function and to resist organ parasitism [ 38 ].…”

“…More recently, molecular modeling techniques showed that tricyclic drugs, in particular phenothiazine, contained some of the best-fitting probes at the active site of TR and could indeed inhibit the parasite's flavoenzymes [ 115 ]. Although there is evidence of parasitological cure after clomipramine and thioridazine administration in T. cruzi- infected mice [ 26 , 86 ], it is still debatable whether this effect is exclusively mediated by TR inhibition and induction of redox imbalance, or other alternative mechanisms. There is evidence that clomipramine and thioridazine also interact with membranes and their components, intracellular proteins, and dopaminergic receptors; inhibit Mg 2+ -dependent ATPase activity; present a strong anticalmodulin activity; induce condensation of cytoplasm organoids; and disrupt mitochondria as well as kinetoplasts [ 25 , 116 ].…”

Joining forces: Leveraging novel combination therapies to combat infections with eukaryotic pathogens

“…brucei [ 57 ], and T . cruzi [ 58 ]. Trypanothione reductase is a protein that is critical in the antioxidant response of T .…”

“…Trypanothione reductase is a protein that is critical in the antioxidant response of T . cruzi ; thus, oxidative stress, inflicted by benznidazole, may be intensified by an inhibited antioxidant response mediated by clomipramine [ 58 ]. The antipsychotic drug, prochlorperazine [ 59 ], and the antihistamine, chlorpheniramine [ 60 ], both potentiated chloroquine and mefloquine by binding parasite-specific efflux pumps and ATP-binding cassette (ABC) transporters in Plasmodium vivax [ 59 ] or P .…”