Chrysin mitigates cyclophosphamide-triggered cardiotoxicity.

Chrysin mitigates cyclophosphamide-triggered cardiotoxicity in rats: Insights into cardioprotection via Treg expression modulation and iNOS downregulation.

Dalia O Saleh, Marawan A Elbaset, Kazi Mokim Ahmed, Ahmed A Sedik

Toxicol Rep

May 31, 2025

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Abstract

Cyclophosphamide (CP) is a potent chemotherapeutic agent widely used in cancer treatment; however, its clinical efficacy is limited by severe cardiotoxic side effects. This study aimed to evaluate the cardioprotective effects of chrysin, a natural flavonoid, against CP-induced cardiotoxicity in rats. To achieve this aim, forty male Wistar rats were randomly divided into five groups (n = 8 per group). Chrysin was administered orally at doses of 25, 50, or 100 mg/kg for 7 days before and 7 days after a single intraperitoneal injection of CP (200 mg/kg). Electrocardiography (ECG) was performed in vivo using the ECG PowerLab module to assess cardiac function, measuring the RR interval, heart rate, and corrected QT (QTc) interval. Serum levels of cardiac injury markers-creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH)-were also determined. Flow cytometry was utilized to evaluate the expression of regulatory T cell markers (CD4, CD25, and Foxp3) and apoptotic marker Annexin V. Histopathological assessment of myocardial tissues was conducted using hematoxylin and eosin (H&E) staining. Immunohistochemical analysis of inducible nitric oxide synthase (iNOS) expression was also performed. CP administration significantly elevated serum levels of cardiac injury markers compared with normal controls. ECG revealed that CP significantly altered cardiac function, as evidenced by a reduced RR interval, an increased heart rate, and an elevated QTc interval. In contrast, chrysin coadministration produced dose-dependent improvements; the highest dose (100 mg/kg) most effectively reduced serum CK-MB and LDH levels, improved the RR interval, decreased the heart rate, and partially restored QTc values. Moreover, CP significantly decreased the cardiac expression of regulatory T cell markers (CD4, CD25, and Foxp3) while markedly increasing Annexin V expression. Chrysin treatment reversed these changes in a dose-dependent manner, with the 100 mg/kg dose eliciting the greatest improvement in Treg expression and reducing Annexin V expression toward normal levels. Histopathological examination confirmed that CP induced myocardial congestion, edema, necrosis, and inflammatory cell infiltration, which were progressively ameliorated by chrysin, with the highest dose restoring near-normal myocardial architecture. Additionally, immunohistochemical analysis demonstrated that CP markedly upregulated iNOS expression in cardiac tissue, whereas chrysin dose-dependently downregulated iNOS, achieving complete normalization at the highest dose. Collectively, these findings suggest that chrysin exerts significant cardioprotective effects against CP-induced cardiotoxicity, likely through the modulation of Treg expression, attenuation of apoptosis, and suppression of iNOS-mediated inflammatory responses, underscoring its potential as an adjunctive therapy in chemotherapy-associated cardiac complications.