Pristimerin protects against doxorubicin-induced cardiotoxicity and fibrosis through modulation of Nrf2 and MAPK/NF-kB signaling pathways.

Abstract

Background/purposePristimerin (Pris) is triterpenoid compound with many biological effects. Until now, nothing is known about its effect on doxorubicin (DOX)-induced cardiotoxicity. Hence, this study investigated the impact of Pris on DOX-induced cardiotoxic effects.Materials and methodsRats were treated with Pris 1 week before and 2 weeks contaminant with repeated DOX injection. Afterwards, electrocardiography (ECG), biochemical, histopathological, PCR, and Western blot assessments were performed.ResultsPris effectively alleviated DOX-induced deleterious cardiac damage. It inhibited DOX-induced ECG abnormities as well as DOX-induced elevation of serum indices of cardiotoxicity. The histopathological cardiac lesions and fibrosis were remarkably improved in Pris-treated animals. Pris reduced hydroxyproline content and attenuated the mRNA and protein expression of the pro-fibrogenic genes. The antioxidant activity of Pris was prominent through the amelioration of oxidative stress parameters and enhancement of antioxidants. Furthermore, Pris enhanced the activation of nuclear factor-erythroid 2 related factor 2 (Nrf2) signaling pathway as it increased the mRNA and protein expression of Nrf2 and Nrf2-dependent antioxidant genes (GCL, NQO1, HO-1). Additionally, the anti-inflammatory effect of Pris was obvious through the inhibition of mitogen activated protein kinase (MAPK)/nuclear factor kappa-B (NF-kB) signaling and subsequent inhibition of inflammatory mediators.ConclusionThis study provides evidence of the cardioprotective activity of Pris which is related to the modulation of Nrf2 and MAPK/NF-kB signaling pathways.