Could phenothiazine-benznidazole combined chemotherapy be effective in controlling heart parasitism and acute infectious myocarditis?
Autor: | Rômulo Dias Novaes, Kelly J. González-Lozano, Ivo Santana Caldas, Andréa A.S. Mendonça, Elda Gonçalves-Santos, Reggiani Vilela Gonçalves, Lívia de Figueiredo Diniz, Thaiany G. Souza-Silva |
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Rok vydání: | 2020 |
Předmět: |
Chagas Cardiomyopathy
0301 basic medicine Myocarditis Trypanosoma cruzi Antiprotozoal Agents Thioridazine Parasitemia Pharmacology Nitric oxide Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Phenothiazines parasitic diseases Animals Medicine Chagas Disease biology business.industry Combination chemotherapy biology.organism_classification medicine.disease Malondialdehyde Trypanocidal Agents 030104 developmental biology chemistry Nitroimidazoles Benznidazole 030220 oncology & carcinogenesis Drug Therapy Combination Female business medicine.drug |
Zdroj: | Pharmacological Research. 158:104907 |
ISSN: | 1043-6618 |
Popis: | Phenothiazines inhibit major antioxidant defense mechanisms in trypanosomatids and exhibit potent cytotoxic effects in vitro. However, the relevance of these drugs in the treatment of Trypanosoma cruzi-induced acute myocarditis is poorly explored, especially in combination with reference trypanocidal drugs. Thus, we compared the antiparasitic and cardioprotective potential of thioridazine (TDZ) and benznidazole (Bz) administered in monotherapy and combined in a murine model of T. cruzi-induced acute myocarditis. Female mice were randomized into six groups: (i) uninfected untreated, (ii) infected untreated, or infected treated with (iii) Bz (100 mg/kg), (iv) TDZ (80 mg/kg), (v) Bz (100 mg/kg) + TDZ (80 mg/kg), or (vi) Bz (50 mg/kg) + TDZ (80 mg/kg). Infected animals were inoculated with 2000 T. cruzi trypomastigotes and treated by gavage for 20 days. Animals that received TDZ alone presented the highest levels of parasitemia, parasitic load and anti-T. cruzi immunoglobulin G titers; cardiac upregulation of N-acetyl-β-D-glucosaminidase activity, nitric oxide, malondialdehyde and cytokines (IFN-γ, TNF-α, IL-10 and IL-17); as well as microstructural damage compared to the other groups (p < 0.05). These parameters were reduced in groups receiving Bz monotherapy compared to the other groups (p < 0.05). The combination of TDZ and Bz attenuated the response to treatment, worsening parasitological control, oxidative heart damage and myocarditis compared to the group treated with Bz alone (p < 0.05). Our results indicate that when administered alone, TDZ potentiated the pathological outcomes in animals infected with T. cruzi. Moreover, TDZ attenuated the antiparasitic effect of Bz when administered together, impairing parasitological control, potentiating inflammation, molecular oxidation and pathological microstructural remodeling of the heart. Thus, our findings indicate that TDZ acts as a pharmacological risk factor and Bz-based monotherapy remains a better cardioprotective drug against Trypanosoma cruzi-induced acute myocarditis. |
Databáze: | OpenAIRE |
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