RESUMO
OBJECTIVE: The aim: To evaluate the effect of Necrostatin-1s (Nec-1s), an inhibitor of necroptosis, on acute Dox-induced cardiotoxicity in a mice model. PATIENTS AND METHODS: Materials and methods: Fifteen male mice were used. The animals were allocated into three groups. On the third day of the experiment, a single intraper¬itoneal dose of 20 mg/kg Dox was used to induce cardiotoxicity. Mice in the control group were given vehicle (DMSO) intraperitoneally, whereas mice in the third group were given 5 mg/kg Nec-1s two days before Dox treatment and continued for a total of five days. Animals were euthanized at the conclusion of the research. ELISA was used to assess the following parameters: cTnI, TNF-α, IL-1ß, GPX-4, and Hmox-1. The expression of TNF-R1 and phosphorylated NF-κß p65 was measured using immunohistochemistry. In addition, a histopathologic evaluation of the cardiac lesions was conducted. RESULTS: Results: Our results showed that Dox treatment substantially elevated serum cTnI levels, increased tissue inflammatory biomarkers (TNF-α, IL-1ß, phospho NF-κß p65 and TNF-R1), and reduced tissue antioxidant enzymes (GPX-4, Hmox-1). A histopathological analysis showed pronounced necrosis and vacuolization. These results were drastically changed by pretreatment with Nec-1s, with serum cTnI levels in this group being much lower than in the Dox group. In addition to a significant decrease in inflammatory markers, antioxidant enzymes were partially recovered. Moreover, there was preservation of the cardiac morphology to a level that was roughly normal. CONCLUSION: Conclusions: Our findings demonstrate that pretreatment with Nec-1s protected against acute Dox-induced cardiotoxicity. This cardioprotective effect was mainly due to amelioration of inflammation that reflected by inhibition of NF-κß/TNF-α/TNF-R1 pathway, with partial restoration of antioxidant enzymes, GPX-4 and Hmox1.
