Metformin rescues the myocardium from doxorubicin-induced energy starvation and mitochondrial damage in rats.
Clinical use of doxorubicin (DOX) is limited by its cardiotoxic side effects. Recent studies established that metformin (MET), an oral antidiabetic drug, possesses an antioxidant activity. However, whether it can protect against DOX-induced energy starvation and mitochondrial damage has not been reported. Our results, in a rat model of DOX-induced cardiotoxicity, show that DOX treatment significantly increased serum levels of LDH and CK-MB, indicators of cardiac injury, and induced expression of hypertrophic gene markers. DOX also caused marked decreases in the cardiac levels of glutathione, CoA-SH and ATP, and mRNA expression of catalase and NQO-1. These biochemical changes were associated with myocardial histopathological and ultrastructural deteriorations, as observed by light and electron microscopy, respectively. Cotreatment with MET (500 mg/kg) eliminated all DOX-induced biochemical, histopathological, and ultrastructural changes. These findings demonstrate that MET successfully prevents DOX-induced cardiotoxicity in vivo by inhibiting DOX-induced oxidative stress, energy starvation, and depletion of intramitochondrial CoA-SH.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Abdelkader E
AE
Ashour
Mohamed M
MM
Sayed-Ahmed
Adel R
AR
Abd-Allah
Hesham M
HM
Korashy
Zaid H
ZH
Maayah
Hisham
H
Alkhalidi
Mohammed
M
Mubarak
Abdulqader
A
Alhaider
D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000473:pathology; D003065:Coenzyme A / Q000378:metabolism; D004317:Doxorubicin / Q000009:adverse effects* / Q000633:toxicity; D004734:Energy Metabolism / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology*; D009206:Myocardium / Q000473:pathology* / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D020011:Protective Agents; D004317:Doxorubicin; D008687:Metformin; D005978:Glutathione; D003065:Coenzyme A