Institute of Biomedical Sciences, Federal University of Alfenas, Alfenas 37130-001, Minas Gerais, Brazil; Department of Structural Biology, Federal University of Alfenas, Alfenas 37130-001, Minas Gerais, Brazil.
Institute of Biomedical Sciences, Federal University of Alfenas, Alfenas 37130-001, Minas Gerais, Brazil; Department of Pathology and Parasitology, Federal University of Alfenas, Alfenas 37130-001, Minas Gerais, Brazil.
Int Immunopharmacol. 2020 Aug;85:106611. doi: 10.1016/j.intimp.2020.106611. Epub 2020 May 21.
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 < 0.05). All parameters were markedly attenuated in animals receiving Bz alone (P < 0.05). However, the co-administration of Tio impaired the response to Bz chemotherapy, causing a decrease in parasitological control (parasitemia and parasite load), skeletal muscle and liver inflammation, and increased microstructural damage, when compared to the group receiving Bz alone (P < 0.05). Altogether, our findings indicated that Tio aggravates systemic inflammation, skeletal myositis and hepatic inflammatory damage in T. cruzi-infected mice. By antagonizing the antiparasitic potential of Bz, Tio limits the anti-inflammatory, myoprotectant and hepatoprotective effects of the reference chemotherapy, aggravating the pathological remodeling of both organs. As the interaction of T. cruzi infection, Bz and Tio is potentially toxic to the liver, inducing inflammation and microvesicular steatosis; this drug combination represents a worrying pharmacological risk factor in Chagas disease.
虽然噻氯匹定（Tio）抑制了克氏锥虫的抗氧化防御能力，但金标准抗锥虫药物苯硝唑（Bz）具有强大的抗炎和促氧化特性。这两种药物的联合应用从未被测试过，以确定其对克氏锥虫感染的影响。因此，我们比较了 Tio 和 Bz 单独和联合使用对克氏锥虫感染小鼠骨骼肌肌炎和肝脏炎症发展的影响。瑞士小鼠被随机分为六组：未感染未治疗组、感染未治疗组、单独用 Tio（80mg/kg）治疗组、单独用 Bz（50 或 100mg/kg）治疗组或 Tio 和 Bz 联合治疗组。感染动物用强毒克氏锥虫株（Y）接种，并通过灌胃治疗 20 天。未治疗或单独用 Tio 治疗的感染小鼠发生最严重的寄生虫血症、最高寄生虫载量、升高的白细胞介素-10（IL-10）、白细胞介素-17（IL-17）、干扰素-γ（IFN-γ）和肿瘤坏死因子-α（TNF-α）血浆水平，肝和骨骼肌中 N-乙酰氨基葡萄糖苷酶和髓过氧化物酶活性增加，以及严重的肌炎和肝脏炎症（P<0.05）。单独使用 Bz 的动物所有参数均明显减弱（P<0.05）。然而，与单独使用 Bz 的组相比，Tio 的联合给药会削弱对 Bz 化疗的反应，导致寄生虫学控制（寄生虫血症和寄生虫载量）、骨骼肌和肝脏炎症以及微结构损伤恶化（P<0.05）。总之，我们的研究结果表明，Tio 加重了克氏锥虫感染小鼠的全身炎症、骨骼肌肌炎和肝炎症性损伤。通过拮抗 Bz 的抗寄生虫潜力，Tio 限制了参考化疗的抗炎、肌肉保护和肝保护作用，加剧了两个器官的病理重塑。由于 T. cruzi 感染、Bz 和 Tio 的相互作用对肝脏有潜在毒性，可诱导炎症和微泡性脂肪变性；这种药物联合使用在恰加斯病中代表了一个令人担忧的药理危险因素。
