Pristimerin protects against doxorubicin-induced cardiotoxicity and fibrosis through modulation of Nrf2 and MAPK/NF-kB signaling pathways
Received 6 September 2018
Accepted for publication 13 November 2018
Published 19 December 2018 Volume 2019:11 Pages 47—61
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Amy Norman
Peer reviewer comments 2
Editor who approved publication: Dr Kenan Onel
Dina S El-Agamy,1,2 Khaled M El-Harbi,3 Saad Khoshhal,3 Nishat Ahmed,1 Mohamed A Elkablawy,4,5 Ahmed A Shaaban,2,6 Hany M Abo-Haded3,7
1Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawwarah 30001, Saudi Arabia; 2Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; 3Cardiogenetic Team, Department of Pediatrics, College of Medicine, Taibah University, Al-Madinah Al-Munawwarah 30001, Saudi Arabia; 4Department of Pathology, Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah 30001, Saudi Arabia; 5Department of Pathology, Faculty of Medicine, Menoufia University, Menoufia 32511, Egypt; 6Department of Pharmacology, Faculty of Pharmacy, Aqaba University of Technology, Aqaba 77110, Jordan; 7Pediatric Cardiology Unit, Department of Pediatrics, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
Background/purpose: Pristimerin (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 methods: Rats 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.
Results: Pris 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.
Conclusion: This study provides evidence of the cardioprotective activity of Pris which is related to the modulation of Nrf2 and MAPK/NF-kB signaling pathways.
Keywords: doxorubicin, pristimerin, cardiotoxicity, Nrf2, MAPK/NF-kB
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