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Basic Clin Pharmacol Toxicol. 2019 Oct 19. doi: 10.1111/bcpt.13340. [Epub ahead of print]

β-LAPachone ameliorates doxorubicin-induced cardiotoxicity via regulating autophagy and Nrf2 signalling pathways in mice.

Author information

1
Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
2
Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
3
Infectious and Tropical Diseases Research Center, Department of Clinical Biochemistry, Tabriz University of Medical Sciences, Tabriz, Iran.
4
Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Abstract

β-LAPachone (B-LAP) is a naphthoquinone that possesses antioxidant properties. In the present investigation, the protective effect of B-LAP against doxorubicin (DOX)-induced cardiotoxicity was examined in mice. Thirty-five mice were divided into 5 groups; control group, B-LAP (5 mg/kg) group, DOX (15 mg/kg) group, DOX+B-LAP (2.5 mg/kg) group and DOX+B-LAP (5 mg/kg) group. B-LAP was administered orally for 14 days of experimental period. A single dose of DOX (15 mg/kg) was injected intraperitoneally on day 3. Cardiac function, histoarchitecture, indices of oxidative stress, as well as circulating markers of cardiac injury were examined. B-LAP (5 mg/kg) decreased serum levels of lactate dehydrogenase (LDH), creatine kinase MB (CK-MB) and cardiac troponin I (cTnI), and ameliorated cardiac histopathological alterations. In addition to increasing cellular NAD+ /NADH ratio, B-LAP upregulated the cardiac levels of SIRT1, beclin-1, p-LKB1 and p-AMPK, and reduced the cardiac levels of p-mTOR, interleukin (IL)-1β, TNF (tumour necrosis factor)-α and caspase-3. B-LAP also elevated the nuclear accumulation of Nrf2 and simultaneously upregulated the protein levels of heme oxygenase (HO-1) and glutathione S-transferase (GST) in the hearts of DOX mice. While B-LAP reduced malondialdehyde concentrations in heart of DOX-treated mice, it further promoted the activities of cardiac superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT). In accordance with increased cell survival, B-LAP significantly improved the cardiac function of DOX mice. Collectively, these findings underline the protective potential of B-LAP against DOX-induced cardiotoxicity by regulating autophagy and AMPK/Nrf2 signalling pathway in mice.

KEYWORDS:

Cardiotoxicity; Doxorubicin; Mice; Nrf2; β-LAPachone

PMID:
31630478
DOI:
10.1111/bcpt.13340

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