Dapagliflozin and Crocin Ameliorate DOX-Induced Cardiotoxicity in Rats via Activating the Nrf-2/HO-1/NQO1 Pathway: A Comparative Study.
Shaban Anwaar M, Ali Eman A, Khalil Marwa Mohamed Ibrahim, Omar Marwa, Al-Ghalban Yousra Ali Rohem, El-Gizawy Eman I
Abstract
BACKGROUND: Doxorubicin- (DOX-) related cardiotoxicity is a progressive degenerative loss of cardiac muscle mass and strength. This investigation aims to compare the anticipated cardioprotective effects of crocin (Cr) and dapagliflozin (DAPA) against DOX-induced cardiotoxicity, and to assess their effects on apoptosis and the Nrf-2/HO-1/NQO1 pathway. MATERIALS AND METHODS: Forty Wistar male rats were randomly divided into four groups: The control group received distilled water (DW) by oral gavage. The DOX group was given DOX 3 times/week, i.p., 2.5 mg/kg for three weeks. The Cr + DOX-treated group was intraperitoneally injected with Cr daily, concomitantly with DOX, for 12 weeks. The DAPA + DOX-treated group received DAPA daily by oral gavage concomitantly with DOX for 12 weeks. Initial fasting blood glucose (FBG), body weight, vital signs, systolic blood pressure (SBP), and electrocardiography (ECG) were recorded and then repeated monthly throughout the study period. After 12 weeks, biochemical analyses were performed. Moreover, histopathological and immunohistochemical examinations of cardiac tissue were conducteed. RESULTS: DOX significantly affected FBG and increased oxidative stress markers and proinflammatory cytokines, with hypotension, bradycardia, ECG changes, and downregulation of antioxidant genes (Nrf-2/HO-1/NQO1) mRNA. Besides, cardiac biomarkers deteriorated. Administration of either Cr or DAPA resulted in significant improvements in all tested parameters compared with DOX. However, the DAPA + DOX group showed greater improvement, particularly in some parameters. CONCLUSION: DAPA is a promising new cardioprotective medication against DOX-related cardiotoxicity. Cardiotoxicity is better controlled with DAPA than Cr by suppressing oxidative stress, apoptosis, and upregulation of the antioxidant Nrf-2/HO-1/NQO1 genes.
Key Findings
- Doxorubicin induces cardiotoxicity characterized by increased oxidative stress, inflammation, and downregulation of Nrf-2/HO-1/NQO1 antioxidant genes.
- Both crocin and dapagliflozin ameliorate DOX-induced cardiotoxicity by activating the Nrf-2/HO-1/NQO1 pathway and reducing oxidative stress and apoptosis.
- Dapagliflozin shows superior cardioprotective effects compared to crocin in improving biochemical, histopathological, and cardiac function parameters.
Clinical Significance
Dapagliflozin may serve as a promising therapeutic agent to prevent or reduce doxorubicin-induced cardiotoxicity by enhancing antioxidant defenses and mitigating oxidative damage.
Citation
Shaban Anwaar M, Ali Eman A, Khalil Marwa Mohamed Ibrahimet al.. Dapagliflozin and Crocin Ameliorate DOX-Induced Cardiotoxicity in Rats via Activating the Nrf-2/HO-1/NQO1 Pathway: A Comparative Study. Immunopharmacology and immunotoxicology. 2026-Mar-23.