Abstract
Doxorubicin (DOX) is a widely used, potent chemotherapeutic agent; however, its clinical application is limited because of its dose-dependent cardiotoxicity. DOX's cardiotoxicity involves increased oxidative/nitrative stress, impaired mitochondrial function in cardiomyocytes/endothelial cells and cell death. Cannabidiol (CBD) is a nonpsychotropic constituent of marijuana, which is well tolerated in humans, with antioxidant, antiinflammatory and recently discovered antitumor properties. We aimed to explore the effects of CBD in a well-established mouse model of DOX-induced cardiomyopathy. DOX-induced cardiomyopathy was characterized by increased myocardial injury (elevated serum creatine kinase and lactate dehydrogenase levels), myocardial oxidative and nitrative stress (decreased total glutathione content and glutathione peroxidase 1 activity, increased lipid peroxidation, 3-nitrotyrosine formation and expression of inducible nitric oxide synthase mRNA), myocardial cell death (apoptotic and poly[ADP]-ribose polymerase 1 [PARP]-dependent) and cardiac dysfunction (decline in ejection fraction and left ventricular fractional shortening). DOX also impaired myocardial mitochondrial biogenesis (decreased mitochondrial copy number, mRNA expression of peroxisome proliferator-activated receptor γ coactivator 1-alpha, peroxisome proliferator-activated receptor alpha, estrogen-related receptor alpha), reduced mitochondrial function (attenuated complex I and II activities) and decreased myocardial expression of uncoupling protein 2 and 3 and medium-chain acyl-CoA dehydrogenase mRNA. Treatment with CBD markedly improved DOX-induced cardiac dysfunction, oxidative/nitrative stress and cell death. CBD also enhanced the DOX-induced impaired cardiac mitochondrial function and biogenesis. These data suggest that CBD may represent a novel cardioprotective strategy against DOX-induced cardiotoxicity, and the above-described effects on mitochondrial function and biogenesis may contribute to its beneficial properties described in numerous other models of tissue injury.
Highlights
Doxorubicin (DOX) is one of the most commonly used broad-spectrum chemotherapeutic drugs; its clinical application is limited because of its dose-dependent cardiotoxicity, which may lead to the development of irreversible cardiomyopathy and/or heart failure [1]
We aimed to explore the effects of CBD in a well-established, clinically relevant mouse model of DOX-induced cardiomyopathy [4,5,23], focusing on oxidative and nitrative stress and mitochondrial dysfunction/biogenesis
First we investigated if CBD attenuates the DOX-induced increased serum Lactate Dehydrogenase (LDH) and Creatine Kinase (CK) levels and cardiac dysfunction
Summary
Doxorubicin (DOX) is one of the most commonly used broad-spectrum chemotherapeutic drugs; its clinical application is limited because of its dose-dependent cardiotoxicity, which may lead to the development of irreversible cardiomyopathy and/or heart failure [1]. RESEARCH ARTICLE ijuana (Cannabis Sativa), which was considered initially to be biologically inactive [16,17] It has a negligible effect on conventional cannabinoid 1 and 2 receptors (CB1/2) in vivo [16,17] and is very safe in humans [18]. A pioneering study by J Axelrod and D Wink in 1998 [19] demonstrated that CBD was a potent neuroprotective antioxidant. They found that it was more protective against glutamateinduced neurotoxicity than either ascorbate or α-tocopherol, suggesting that it has potential therapeutic utility in neurodegenerative disorders associated with oxidative stress [19]. An oromucosal spray containing 50% CBD (Sativex) is approved in the United Kingdom, Canada and various other European countries to alleviate pain and spasticity associated with multiple sclerosis [22], and CBD recently received orphan drug approval by FDA for the treatment of refractory childhood epilepsy
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
