Affiliation:
1. DEPARTMENT OF PHARMACOLOGY, COLLEGE OF MEDICINE, UNIVERSITY OF BASRAH, BASRAH, IRAQ
2. DEPARTMENT OF PHARMACOLOGY, COLLEGE OF MEDICINE, UNIVERSITY OF KUFA, KUFA, IRAQ
3. DEPARTMENT OF PATHOLOGY, COLLEGE OF MEDICINE, UNIVERSITY OF BASRAH, BASRAH, IRAQ
Abstract
The aim: To evaluate the effect of Necrostatin-1s (Nec-1s), an inhibitor of necroptosis, on acute Dox-induced cardiotoxicity in a mice model.
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-1β, GPX-4, and Hmox-1. The expression of TNF-R1 and phosphorylated NF-κβ p65 was measured using immunohistochemistry. In addition, a histopathologic evaluation of the cardiac lesions was conducted.
Results: Our results showed that Dox treatment substantially elevated serum cTnI levels, increased tissue inflammatory biomarkers (TNF-α, IL-1β, phospho NF-κβ 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.
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-κβ/TNF-α/TNF-R1 pathway, with partial restoration of antioxidant enzymes, GPX-4 and Hmox1.