Thioridazine aggravates skeletal myositis, systemic and liver inflammation in Trypanosoma cruzi-infected and benznidazole-treated mice

• Published in: International immunopharmacology 2020-08, Vol.85, p.106611, Article 106611
• Main Authors: Mendonça, Andréa A.S., Gonçalves-Santos, Elda, Souza-Silva, Thaiany G., González-Lozano, Kelly J., Caldas, Ivo S., Gonçalves, Reggiani V., Diniz, Lívia F., Novaes, Rômulo D.
• Format: Article
• Language: English
• Subjects: Acetylglucosaminidase - metabolism; Animals; Antioxidants; Antiparasitic agents; Antiparasitic chemotherapy; Benznidazole; Chagas disease; Chagas Disease - blood; Chagas Disease - drug therapy; Chagas Disease - immunology; Chemotherapy; Cytokines - blood; Damage; Disease Models, Animal; Drug Combinations; Experimental pathology; Female; Glycogen - metabolism; Health risks; Hepatitis; Hepatitis - metabolism; Hepatitis - pathology; Infections; Inflammation; Interleukin 10; Interleukin 17; Liver; Mice; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscle, Skeletal - ultrastructure; Muscles; Musculoskeletal system; Myositis; Myositis - drug therapy; Myositis - pathology; N-Acetylglucosaminidase; NADH, NADPH Oxidoreductases - antagonists & inhibitors; Nitroimidazoles - pharmacology; Nitroimidazoles - therapeutic use; Organs; Oxidants; Oxidizing agents; Parasite Load; Parasitemia; Parasitemia - drug therapy; Parasites; Peroxidase; Peroxidase - metabolism; Plasma levels; Protozoa; Risk analysis; Risk factors; Skeletal muscle; Steatosis; Thioridazine; Thioridazine - therapeutic use; Thioridazine - toxicity; Transaminases - metabolism; Trypanocidal Agents - pharmacology; Trypanocidal Agents - therapeutic use; Trypanosoma cruzi; Trypanosoma cruzi - drug effects; Trypanosoma cruzi - growth & development; Tumor necrosis factor-α; Vector-borne diseases; γ-Interferon
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2020.106611

•Thioridazine (Tio) and benznidazole (Bz) were tested against T. cruzi infection.•Bz attenuated skeletal myositis, liver and systemic inflammation in infected mice.•Tio increased skeletal myositis, liver and systemic inflammation in infected mice.•Tio attenuated the antiparasitic and anti-inflammatory potential of Bz.•Tio represented a pharmacological risk factor in T. cruzi infection. While thioridazine (Tio) inhibits the antioxidant defenses of Trypanosoma cruzi, the gold standard antitrypanosomal drug benznidazole (Bz) has potent anti-inflammatory and pro-oxidant properties. The combination of these drugs has never been tested to determine the effect on T. cruzi infection. Thus, we compared the impact of Tio and Bz, administered alone and in combination, on the development of skeletal myositis and liver inflammation in T. cruzi-infected mice. Swiss mice were randomized into six groups: uninfected untreated, infected untreated, treated with Tio (80 mg/kg) alone, Bz (50 or 100 mg/kg) alone, or a combination of Tio and Bz. Infected animals were inoculated with a virulent T. cruzi strain (Y) and treated by gavage for 20 days. Mice untreated or treated with Tio alone developed the most intense parasitemia, highest parasitic load, elevated IL-10, IL-17, IFN-γ, and TNF-α plasma levels, increased N-acetylglucosaminidase and myeloperoxidase activity in the liver and skeletal muscle, as well as severe myositis and liver inflammation (P