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<!DOCTYPE html> <html lang="en" class="no-js"> <head> <meta charset="UTF-8"> <meta http-equiv="X-UA-Compatible" content="IE=edge"> <meta name="applicable-device" content="pc,mobile"> <meta name="viewport" content="width=device-width, initial-scale=1"> <title>Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis | Molecular Medicine | Full Text</title> <meta name="citation_abstract" content="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."/> <meta name="journal_id" content="10020"/> <meta name="dc.title" content="Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis"/> <meta name="dc.source" content="Molecular Medicine 2015 21:1"/> <meta name="dc.format" content="text/html"/> <meta name="dc.publisher" content="BioMed Central"/> <meta name="dc.date" content="2015-01-06"/> <meta name="dc.type" content="OriginalPaper"/> <meta name="dc.language" content="En"/> <meta name="dc.copyright" content="2015 The Author(s)"/> <meta name="dc.rights" content="2015 The Author(s)"/> <meta name="dc.rightsAgent" content="reprints@biomedcentral.com"/> <meta name="dc.description" content="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."/> <meta name="prism.issn" content="1528-3658"/> <meta name="prism.publicationName" content="Molecular Medicine"/> <meta name="prism.publicationDate" content="2015-01-06"/> <meta name="prism.volume" content="21"/> <meta name="prism.number" content="1"/> <meta name="prism.section" content="OriginalPaper"/> <meta name="prism.startingPage" content="38"/> <meta name="prism.endingPage" content="45"/> <meta name="prism.copyright" content="2015 The Author(s)"/> <meta name="prism.rightsAgent" content="reprints@biomedcentral.com"/> <meta name="prism.url" content="https://molmed.biomedcentral.com/articles/10.2119/molmed.2014.00261"/> <meta name="prism.doi" content="doi:10.2119/molmed.2014.00261"/> <meta name="citation_pdf_url" content="https://molmed.biomedcentral.com/counter/pdf/10.2119/molmed.2014.00261"/> <meta name="citation_fulltext_html_url" content="https://molmed.biomedcentral.com/articles/10.2119/molmed.2014.00261"/> <meta name="citation_journal_title" content="Molecular Medicine"/> <meta name="citation_journal_abbrev" content="Mol Med"/> <meta name="citation_publisher" content="BioMed Central"/> <meta name="citation_issn" content="1528-3658"/> <meta name="citation_title" content="Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis"/> <meta name="citation_volume" content="21"/> <meta name="citation_issue" content="1"/> <meta name="citation_publication_date" content="2015/01"/> <meta name="citation_online_date" content="2015/01/06"/> <meta name="citation_firstpage" content="38"/> <meta name="citation_lastpage" content="45"/> <meta name="citation_article_type" content="Research Article"/> <meta name="citation_fulltext_world_readable" content=""/> <meta name="citation_language" content="en"/> <meta name="dc.identifier" content="doi:10.2119/molmed.2014.00261"/> <meta name="DOI" content="10.2119/molmed.2014.00261"/> <meta name="size" content="123407"/> <meta name="citation_doi" content="10.2119/molmed.2014.00261"/> <meta name="citation_springer_api_url" content="http://api.springer.com/xmldata/jats?q=doi:10.2119/molmed.2014.00261&api_key="/> <meta name="description" content="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."/> <meta name="dc.creator" content="Hao, Enkui"/> <meta name="dc.creator" content="Mukhopadhyay, Partha"/> <meta name="dc.creator" content="Cao, Zongxian"/> <meta name="dc.creator" content="Erdélyi, Katalin"/> <meta name="dc.creator" content="Holovac, Eileen"/> <meta name="dc.creator" content="Liaudet, Lucas"/> <meta name="dc.creator" content="Lee, Wen-Shin"/> <meta name="dc.creator" content="Haskó, György"/> <meta name="dc.creator" content="Mechoulam, Raphael"/> <meta name="dc.creator" content="Pacher, Pál"/> <meta name="dc.subject" content="Molecular Medicine"/> <meta name="citation_reference" content="citation_journal_title=Med. Res. 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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."/> <meta property="og:image" content="https://static-content.springer.com/image/art%3A10.2119%2Fmolmed.2014.00261/MediaObjects/10020_2015_2101038_Fig1.jpg"/> <script type="application/ld+json">{"mainEntity":{"headline":"Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis","description":"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. 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xlink:href="#icon-download"/></svg> </a> </div> </div> </div> <article lang="en"> <div class="c-article-header"> <ul class="c-article-identifiers" data-test="article-identifier"> <li class="c-article-identifiers__item" data-test="article-category">Research Article</li> <li class="c-article-identifiers__item"> <a href="https://www.springernature.com/gp/open-research/about/the-fundamentals-of-open-access-and-open-research" data-track="click" data-track-action="open access" data-track-label="link" class="u-color-open-access" data-test="open-access">Open access</a> </li> <li class="c-article-identifiers__item">Published: <time datetime="2015-01-06">06 January 2015</time></li> </ul> <h1 class="c-article-title" data-test="article-title" data-article-title="">Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis</h1> <ul class="c-article-author-list c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Enkui-Hao-Aff1-Aff2" data-author-popup="auth-Enkui-Hao-Aff1-Aff2" data-author-search="Hao, Enkui">Enkui Hao</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Partha-Mukhopadhyay-Aff1" data-author-popup="auth-Partha-Mukhopadhyay-Aff1" data-author-search="Mukhopadhyay, Partha">Partha Mukhopadhyay</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Zongxian-Cao-Aff1" 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data-author-popup="auth-Gy_rgy-Hask_-Aff5" data-author-search="Haskó, György">György Haskó</a><sup class="u-js-hide"><a href="#Aff5">5</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Raphael-Mechoulam-Aff6" data-author-popup="auth-Raphael-Mechoulam-Aff6" data-author-search="Mechoulam, Raphael">Raphael Mechoulam</a><sup class="u-js-hide"><a href="#Aff6">6</a></sup> & </li><li class="c-article-author-list__show-more" aria-label="Show all 10 authors for this article" title="Show all 10 authors for this article">…</li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-P_l-Pacher-Aff1-Aff7" data-author-popup="auth-P_l-Pacher-Aff1-Aff7" data-author-search="Pacher, Pál" data-corresp-id="c1">Pál Pacher<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff7">7</a></sup> </li></ul><button aria-expanded="false" class="c-article-author-list__button"><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-down-medium"></use></svg><span>Show authors</span></button> <p class="c-article-info-details" data-container-section="info"> <a data-test="journal-link" href="/" data-track="click" data-track-action="journal homepage" data-track-category="article body" data-track-label="link"><i data-test="journal-title">Molecular Medicine</i></a> <b data-test="journal-volume"><span class="u-visually-hidden">volume</span> 21</b>, <span class="u-visually-hidden">pages </span>38–45 (<span data-test="article-publication-year">2015</span>)<a href="#citeas" class="c-article-info-details__cite-as u-hide-print" data-track="click" data-track-action="cite this article" data-track-label="link">Cite this article</a> </p> <div class="c-article-metrics-bar__wrapper u-clear-both"> <ul class="c-article-metrics-bar u-list-reset"> <li class=" c-article-metrics-bar__item" data-test="access-count"> <p class="c-article-metrics-bar__count">2706 <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="citation-count"> <p class="c-article-metrics-bar__count">115 <span class="c-article-metrics-bar__label">Citations</span></p> </li> <li class="c-article-metrics-bar__item" data-test="altmetric-score"> <p class="c-article-metrics-bar__count">28 <span class="c-article-metrics-bar__label">Altmetric</span></p> </li> <li class="c-article-metrics-bar__item"> <p class="c-article-metrics-bar__details"><a href="/articles/10.2119/molmed.2014.00261/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics <span class="u-visually-hidden">details</span></a></p> </li> </ul> </div> </div> <section aria-labelledby="Abs1" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Abstract</h2><div class="c-article-section__content" id="Abs1-content"><p>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.</p></div></div></section> <section data-title="Introduction"><div class="c-article-section" id="Sec1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec1">Introduction</h2><div class="c-article-section__content" id="Sec1-content"><p>Doxorubicin (DOX) is one of the most commonly used broad-spectrum chemotherapeutic drugs; however, its clinical application is limited because of its dose-dependent cardiotoxicity, which may lead to the development of irreversible cardiomyopathy and/or heart failure (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Carvalho FS, et al. (2014) Doxorubicin-induced cardiotoxicity: from bioenergetic failure and cell death to cardiomyopathy. Med. Res. Rev. 34:106–35." href="/articles/10.2119/molmed.2014.00261#ref-CR1" id="ref-link-section-d132987092e552">1</a>). The mechanism of DOX’s cardiotoxicity is complex and may involve oxidative (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Rajagopalan S, Politi PM, Sinha BK, Myers CE. (1988) Adriamycin-induced free radical formation in the perfused rat heart: implications for cardiotoxicity. Cancer Res. 48:4766–9." href="/articles/10.2119/molmed.2014.00261#ref-CR2" id="ref-link-section-d132987092e555">2</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Sterba M, et al. (2013) Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection. Antioxid. Redox. Signal. 18:899–929." href="/articles/10.2119/molmed.2014.00261#ref-CR3" id="ref-link-section-d132987092e558">3</a>), nitrosative and nitrative stress (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Pacher P, et al. (2003) Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction. Circulation. 107:896–904." href="/articles/10.2119/molmed.2014.00261#ref-CR4" id="ref-link-section-d132987092e561">4</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Mukhopadhyay P, et al. (2009) Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro. Am. J. Physiol. Heart Circ. Physiol. 296:H1466–83." href="/articles/10.2119/molmed.2014.00261#ref-CR5" id="ref-link-section-d132987092e564">5</a>), mitochondrial dysfunction/toxicity (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Carvalho FS, et al. (2014) Doxorubicin-induced cardiotoxicity: from bioenergetic failure and cell death to cardiomyopathy. Med. Res. Rev. 34:106–35." href="/articles/10.2119/molmed.2014.00261#ref-CR1" id="ref-link-section-d132987092e568">1</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Doroshow JH, Davies KJ. (1986) Redox cycling of anthracyclines by cardiac mitochondria. II. Formation of superoxide anion, hydrogen peroxide, and hydroxyl radical. J. Biol. Chem. 261:3068–74." href="/articles/10.2119/molmed.2014.00261#ref-CR6" id="ref-link-section-d132987092e571">6</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Ichikawa Y, et al. (2014) Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J. Clin. Invest. 124:617–30." href="/articles/10.2119/molmed.2014.00261#ref-CR8" id="ref-link-section-d132987092e574">8</a>), dysregulation of various metabolic (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Tokarska-Schlattner M, Zaugg M, Zuppinger C, Wallimann T, Schlattner U. (2006) New insights into doxorubicin-induced cardiotoxicity: The critical role of cellular energetics. J. Mol. Cell Cardiol. 41:389–405." href="/articles/10.2119/molmed.2014.00261#ref-CR9" id="ref-link-section-d132987092e577">9</a>) and lipid signaling pathways (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Mukhopadhyay P, et al. (2007) Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity. J. Am. Coll. Cardiol. 50:528–36." href="/articles/10.2119/molmed.2014.00261#ref-CR10" id="ref-link-section-d132987092e580">10</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Mukhopadhyay P, et al. (2011) Fatty acid amide hydrolase is a key regulator of endocannabinoid-induced myocardial tissue injury. Free Radic. Biol. Med. 50:179–95." href="/articles/10.2119/molmed.2014.00261#ref-CR12" id="ref-link-section-d132987092e583">12</a>), activation of various stress kinases and cell death mechanisms (both apoptotic and necrotic) (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="Pacher P, et al. (2002) Activation of poly(ADP-ribose) polymerase contributes to development of doxorubicin-induced heart failure. J. Pharmacol. Exp. Ther. 300:862–7." href="/articles/10.2119/molmed.2014.00261#ref-CR13" id="ref-link-section-d132987092e587">13</a>), triggering of secondary inflammation and remodeling (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Bai P, et al. (2004) Matrix metalloproteinase activation is an early event in doxorubicin-induced cardiotoxicity. Oncol. Rep. 11:505–8." href="/articles/10.2119/molmed.2014.00261#ref-CR14" id="ref-link-section-d132987092e590">14</a>), eventually culminating in cardiac dysfunction and heart failure (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Carvalho FS, et al. (2014) Doxorubicin-induced cardiotoxicity: from bioenergetic failure and cell death to cardiomyopathy. Med. Res. Rev. 34:106–35." href="/articles/10.2119/molmed.2014.00261#ref-CR1" id="ref-link-section-d132987092e593">1</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 15" title="Azuma J, et al. (1981) Adriamycin cardiotoxicity: possible pathogenic mechanisms. J. Mol. Cell. Cardiol. 13:381–397." href="/articles/10.2119/molmed.2014.00261#ref-CR15" id="ref-link-section-d132987092e596">15</a>).</p><p>Cannabidiol (CBD) is the most abundant nonpsychoactive constituent of marijuana (<i>Cannabis Sativa</i>), which was considered initially to be biologically inactive (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" title="Pacher P, Batkai S, Kunos G. (2006) The endo-cannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 58:389–462." href="/articles/10.2119/molmed.2014.00261#ref-CR16" id="ref-link-section-d132987092e605">16</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. (2009) Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol. Sci. 30:515–27." href="/articles/10.2119/molmed.2014.00261#ref-CR17" id="ref-link-section-d132987092e608">17</a>). It has a negligible effect on conventional cannabinoid 1 and 2 receptors (CB1/2) <i>in vivo</i> (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" title="Pacher P, Batkai S, Kunos G. (2006) The endo-cannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 58:389–462." href="/articles/10.2119/molmed.2014.00261#ref-CR16" id="ref-link-section-d132987092e614">16</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. (2009) Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol. Sci. 30:515–27." href="/articles/10.2119/molmed.2014.00261#ref-CR17" id="ref-link-section-d132987092e618">17</a>) and is very safe in humans (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Cunha JM, et al. (1980) Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology. 21:175–185." href="/articles/10.2119/molmed.2014.00261#ref-CR18" id="ref-link-section-d132987092e621">18</a>). A pioneering study by J Axelrod and D Wink in 1998 (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Hampson AJ, Grimaldi M, Axelrod J, Wink D. (1998) Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc. Natl. Acad. Sci. U. S. A. 95:8268–73." href="/articles/10.2119/molmed.2014.00261#ref-CR19" id="ref-link-section-d132987092e624">19</a>) demonstrated that CBD was a potent neuroprotective antioxidant. They found that it was more protective against glutamate-induced neurotoxicity than either ascorbate or α-tocopherol, suggesting that it has potential therapeutic utility in neurodegenerative disorders associated with oxidative stress (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Hampson AJ, Grimaldi M, Axelrod J, Wink D. (1998) Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc. Natl. Acad. Sci. U. S. A. 95:8268–73." href="/articles/10.2119/molmed.2014.00261#ref-CR19" id="ref-link-section-d132987092e627">19</a>). Later, large numbers of preclinical studies also confirmed potent antioxidant and antiinflammatory effects of CBD in preclinical models of colitis, ischemic reperfusion injury, various neurodegenerative and cardiovascular disorders, diabetes and diabetic complications (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Rajesh M, et al. (2010) Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J. Am. Coll. Cardiol. 56:2115–25." href="/articles/10.2119/molmed.2014.00261#ref-CR20" id="ref-link-section-d132987092e630">20</a>), among others (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. (2009) Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol. Sci. 30:515–27." href="/articles/10.2119/molmed.2014.00261#ref-CR17" id="ref-link-section-d132987092e633">17</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Stanley CP, Hind WH, O’Sullivan SE. (2013) Is the cardiovascular system a therapeutic target for cannabidiol? Br. J. Clin. Pharmacol. 75:313–22." href="/articles/10.2119/molmed.2014.00261#ref-CR21" id="ref-link-section-d132987092e637">21</a>). 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 (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Pacher P, Kunos G. (2013) Modulating the endocannabinoid system in human health and disease—successes and failures. FEBS J. 280:1918–43." href="/articles/10.2119/molmed.2014.00261#ref-CR22" id="ref-link-section-d132987092e640">22</a>), and CBD recently received orphan drug approval by FDA for the treatment of refractory childhood epilepsy.</p><p>In this study, we aimed to explore the effects of CBD in a well-established, clinically relevant mouse model of DOX-induced cardiomyopathy (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Pacher P, et al. (2003) Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction. Circulation. 107:896–904." href="/articles/10.2119/molmed.2014.00261#ref-CR4" id="ref-link-section-d132987092e646">4</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Mukhopadhyay P, et al. (2009) Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro. Am. J. Physiol. Heart Circ. Physiol. 296:H1466–83." href="/articles/10.2119/molmed.2014.00261#ref-CR5" id="ref-link-section-d132987092e649">5</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Mukhopadhyay P, et al. (2007) Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity. J. Am. Coll. Cardiol. 50:528–36." href="/articles/10.2119/molmed.2014.00261#ref-CR23" id="ref-link-section-d132987092e652">23</a>), particularly focusing on oxidative and nitrative stress and mitochondrial dysfunction/biogenesis. Our results may also provide a novel mechanistic insight on the protective effects of CBD in various models of tissue injury and a promising tool for the prevention of devastating cardiovascular complications of DOX chemotherapy.</p></div></div></section><section data-title="Materials and Methods"><div class="c-article-section" id="Sec2-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec2">Materials and Methods</h2><div class="c-article-section__content" id="Sec2-content"><h3 class="c-article__sub-heading" id="Sec3">Animals/Drugs</h3><p>All protocols involving the use of animals were approved by the Institutional Animal Care and Use Committees and were performed in line with the <i>Guidelines for the Care and Use of Laboratory Animals</i> adopted by the National Institutes of Health (NIH) (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Committee for the Update of the Guide for the Care and Use of Laboratory Animals, Institute for Laboratory Animal Research, Division on Earth and Life Studies, National Research Council of the National Academies. (2011) Guide for the Care and Use of Laboratory Animals. 8th edition. Washington (DC): National Academies Press." href="/articles/10.2119/molmed.2014.00261#ref-CR24" id="ref-link-section-d132987092e670">24</a>). Male C57BL/6J mice weighing 22–30 g were acutely administered with single high dose (20 mg/kg) of DOX (Sigma-Aldrich, St. Louis, MO, USA) intraperitoneally (IP) freshly dissolved in physiological saline. CBD obtained from Tocris (Ellisville, MO, USA) or isolated as described earlier (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Gaoni Y, Mechoulam R. (1971) The isolation and structure of delta-1-tetrahydrocannabinol and other neutral cannabinoids from hashish. J. Am. Chem. Soc. 93:217–24." href="/articles/10.2119/molmed.2014.00261#ref-CR25" id="ref-link-section-d132987092e673">25</a>) was dissolved in vehicle solution (one drop of Tween-80 in 3 mL 2.5% DMSO in saline). Mice were treated with CBD 10 mg/kg IP, or vehicle started 1.5 h before the DOX injection and once every day. Mice were subjected to hemodynamic measurements at the end of study (5 d). Hearts were excised and snap frozen in liquid nitrogen for biochemical measurements or fixed for histological evaluation as described previously (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Mukhopadhyay P, et al. (2007) Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity. J. Am. Coll. Cardiol. 50:528–36." href="/articles/10.2119/molmed.2014.00261#ref-CR10" id="ref-link-section-d132987092e676">10</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Mukhopadhyay P, et al. (2010) CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes. Cardiovasc. Res. 85:773–84." href="/articles/10.2119/molmed.2014.00261#ref-CR11" id="ref-link-section-d132987092e679">11</a>).</p><h3 class="c-article__sub-heading c-article__sub-heading--divider" id="Sec4">Hemodynamic Measurements in Mice</h3><p>Echocardiography was performed by using the VisualSonics Vevo0770 system (VisualSonics Inc., Toronto, ON, Canada), which is equipped with a 30 MHz mechanical scan probe which can obtain high resolution 2-dimensional images. Animals were anesthetized with isoflurane (2%) inhalation anesthesia. B mode images were obtained in the plane containing aortic and mitral valves. M mode images were obtained from the parasternal short-axis view at the level of papillary muscles. LV end-diastolic diameters, ejection fraction and fractional shortening were calculated by using Vevo Analysis software as described previously. The investigators performing echocardiography were blinded to the treatment status.</p><h3 class="c-article__sub-heading c-article__sub-heading--divider" id="Sec5">Serum Creatine Kinase (CK) and Lactate Dehydrogenase (LDH) Levels</h3><p>The blood samples were collected and the serum was removed immediately for CK and LDH measurements using a clinical chemistry analyzer system (VetTest 8008, IDEXX Laboratories, Westbrook, ME, USA).</p><h3 class="c-article__sub-heading c-article__sub-heading--divider" id="Sec6">Myocardial 3-Nitrotyrosine (NT) Determination</h3><p>Myocardial 3-nitrotyrosine content, a marker of nitrative stress (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Pacher P, Beckman JS, Liaudet L. (2007) Nitric oxide and peroxynitrite in health and disease. Physiol. Rev. 87:315–424." href="/articles/10.2119/molmed.2014.00261#ref-CR26" id="ref-link-section-d132987092e704">26</a>), was determined by nitrotyrosine enzyme-linked immunosorbent assay (ELISA) according to the protocol supplied with the kit (Cell Biolabs, San Diego, CA, USA) as previously described (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Mukhopadhyay P, et al. (2010) CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes. Cardiovasc. Res. 85:773–84." href="/articles/10.2119/molmed.2014.00261#ref-CR11" id="ref-link-section-d132987092e707">11</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Mukhopadhyay P, et al. (2011) Fatty acid amide hydrolase is a key regulator of endocannabinoid-induced myocardial tissue injury. Free Radic. Biol. Med. 50:179–95." href="/articles/10.2119/molmed.2014.00261#ref-CR12" id="ref-link-section-d132987092e710">12</a>).</p><h3 class="c-article__sub-heading c-article__sub-heading--divider" id="Sec7">Determination of Myocardial Caspase 3/7 and Poly(ADP-Ribose) Polymerase (PARP) Activities</h3><p>Caspase 3/7 activity in the heart homogenates was determined using the fluorimetric-based Apo-ONE homogenous assay kit (Promega, Madison, WI, USA) as described (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Mukhopadhyay P, et al. (2010) CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes. Cardiovasc. Res. 85:773–84." href="/articles/10.2119/molmed.2014.00261#ref-CR11" id="ref-link-section-d132987092e722">11</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Mukhopadhyay P, et al. (2011) Fatty acid amide hydrolase is a key regulator of endocannabinoid-induced myocardial tissue injury. Free Radic. Biol. Med. 50:179–95." href="/articles/10.2119/molmed.2014.00261#ref-CR12" id="ref-link-section-d132987092e725">12</a>). Myocardial PARP activity was assayed using a colorimetric kit according to manufacturer’s protocol (Trevigen, Gaithersburg, MD, USA) as described (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Mukhopadhyay P, et al. (2010) CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes. Cardiovasc. Res. 85:773–84." href="/articles/10.2119/molmed.2014.00261#ref-CR11" id="ref-link-section-d132987092e728">11</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Mukhopadhyay P, et al. (2011) Fatty acid amide hydrolase is a key regulator of endocannabinoid-induced myocardial tissue injury. Free Radic. Biol. Med. 50:179–95." href="/articles/10.2119/molmed.2014.00261#ref-CR12" id="ref-link-section-d132987092e731">12</a>).</p><h3 class="c-article__sub-heading c-article__sub-heading--divider" id="Sec8">Myocardial DNA Fragmentation ELISA</h3><p>The quantitative determinations of cytoplasmic histone-associated-DNA-fragmentation (mono and oligonucleo-somes) due to <i>in vivo</i> cell death were measured using ELISA kit (Roche Diagnostics GmbH, Indianapolis, IN, USA) (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Mukhopadhyay P, et al. (2011) Fatty acid amide hydrolase is a key regulator of endocannabinoid-induced myocardial tissue injury. Free Radic. Biol. Med. 50:179–95." href="/articles/10.2119/molmed.2014.00261#ref-CR12" id="ref-link-section-d132987092e745">12</a>).</p><h3 class="c-article__sub-heading c-article__sub-heading--divider" id="Sec9">Determination of Myocardial Glutathione (GSH) Content</h3><p>Myocardial GSH content was determined using kits from Trevigen according to the manufacturer’s protocols, as previously reported (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Mukhopadhyay P, et al. (2011) Fatty acid amide hydrolase is a key regulator of endocannabinoid-induced myocardial tissue injury. Free Radic. Biol. Med. 50:179–95." href="/articles/10.2119/molmed.2014.00261#ref-CR12" id="ref-link-section-d132987092e756">12</a>).</p><h3 class="c-article__sub-heading c-article__sub-heading--divider" id="Sec10">Histological Examination of Heart Sections</h3><p>Heart samples were fixed in 4% buffered formalin. After embedding and cutting 5 µm slices, all sections were stained with nitrotyrosine (Cayman Chemical, Ann Arbor, MI, USA) according to the manufacturer’s protocol and/or as described (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Rajesh M, et al. (2010) Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J. Am. Coll. Cardiol. 56:2115–25." href="/articles/10.2119/molmed.2014.00261#ref-CR20" id="ref-link-section-d132987092e767">20</a>). Nitrotyrosinestained sections were counterstained with hematoxylin. The specific staining was visualized and images were acquired using BX-41 microscope and U-TV1 × 2 camera (Olympus, Tokyo, Japan) with 200 × fold magnification.</p><h3 class="c-article__sub-heading c-article__sub-heading--divider" id="Sec11">Real-Time PCR Analyses of mRNA</h3><p>Total RNA was isolated from heart homogenate using TRIzol reagents (Invitrogen [Thermo Fisher Scientific Inc., Waltham, MA, USA]) according to manufacturer’s instructions. The isolated RNA was treated with RNase-free DNaseI (Ambion [Thermo Fisher Scientific]) to remove traces of genomic DNA contamination. Each RNA sample (1 µg) was mixed with 2 µL of 5× Genomic DNA Elimination Buffer to remove any residual genomic DNA as supplied with the kit and made up to a final volume of 10 µL. RT cocktail (prepared according to the manufacturer’s instruction) was added to RNA containing Genomic DNA Elimination Mixture and incubated at 42° C for 15 min, followed by heating at 95° C for 5 min. Each 20 µL of cDNA Synthesis Reaction received an addition of 91 µL of sterile water. Real-time PCR was performed using Oxidative Stress and Anti-oxidant Defense RT Profiler PCR array or specific primer sets (SAB Bioscience, Frederick, MD, USA). Relative quantification was calculated using the comparative CT method. The normalizer used for each cDNA sample was housekeeping gene <i>β-actin</i> as described (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Mukhopadhyay P, et al. (2010) CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes. Cardiovasc. Res. 85:773–84." href="/articles/10.2119/molmed.2014.00261#ref-CR11" id="ref-link-section-d132987092e781">11</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Mukhopadhyay P, et al. (2011) Fatty acid amide hydrolase is a key regulator of endocannabinoid-induced myocardial tissue injury. Free Radic. Biol. Med. 50:179–95." href="/articles/10.2119/molmed.2014.00261#ref-CR12" id="ref-link-section-d132987092e784">12</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Rajesh M, et al. (2010) Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J. Am. Coll. Cardiol. 56:2115–25." href="/articles/10.2119/molmed.2014.00261#ref-CR20" id="ref-link-section-d132987092e787">20</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Mukhopadhyay P, et al. (2014) Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis. Hepatology. 59:1998–2009." href="/articles/10.2119/molmed.2014.00261#ref-CR27" id="ref-link-section-d132987092e790">27</a>).</p><h3 class="c-article__sub-heading c-article__sub-heading--divider" id="Sec12">PARP Activity</h3><p>Myocardial PARP activity was assayed using a colorimetric kit according to the manufacturer’s protocol (Trevigen) as described (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Mukhopadhyay P, et al. (2011) Fatty acid amide hydrolase is a key regulator of endocannabinoid-induced myocardial tissue injury. Free Radic. Biol. Med. 50:179–95." href="/articles/10.2119/molmed.2014.00261#ref-CR12" id="ref-link-section-d132987092e801">12</a>).</p><h3 class="c-article__sub-heading c-article__sub-heading--divider" id="Sec13">Myocardial 4-Hydroxy-2-Nonenal (4-HNE) Content</h3><p>Lipid peroxides are unstable indicators of oxidative stress in cells that decompose to form more complex and reactive compounds such as 4-HNE, which has been shown to be capable of binding to proteins and forming stable HNE adducts. HNE in myocardial tissues was determined using a kit (Cell Biolabs). In brief, BSA or Myocardial tissue extracts were adsorbed onto a 96-well plate for overnight at 4° C. HNE adducts present in the sample or standard were probed with anti-HNE antibody, followed by an HRP-conjugated secondary antibody. The HNE protein adduct content in an unknown sample was determined by comparing with a standard curve (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Mukhopadhyay P, et al. (2011) Fatty acid amide hydrolase is a key regulator of endocannabinoid-induced myocardial tissue injury. Free Radic. Biol. Med. 50:179–95." href="/articles/10.2119/molmed.2014.00261#ref-CR12" id="ref-link-section-d132987092e813">12</a>).</p><h3 class="c-article__sub-heading c-article__sub-heading--divider" id="Sec14">Myocardial Glutathione Peroxidase Assay</h3><p>Glutathione peroxidase enzyme activity was assayed using a SpectraMax spectrophotometer (Trevigen) according to the manufacturer’s instructions.</p><h3 class="c-article__sub-heading c-article__sub-heading--divider" id="Sec15">Determination of Myocardial Mitochondrial Complex Activity</h3><p>Microplate assay kits were obtained from MitoSciences (Eugene, OR, USA) and used to determine the activity of mitochondrial complex I, complex II and complex IV according to the manufacturer’s instructions. The complex enzymes were immunocaptured in the microplate and activities were determined in Spectramax M3 (Molecular Devices [Thermo Fisher Scientific]). Complex activities were expressed as percentage activity compared with the heart samples of the vehicle-treated mice similar to that described previously for liver (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Mukhopadhyay P, et al. (2014) Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis. Hepatology. 59:1998–2009." href="/articles/10.2119/molmed.2014.00261#ref-CR27" id="ref-link-section-d132987092e831">27</a>).</p><h3 class="c-article__sub-heading c-article__sub-heading--divider" id="Sec16">Mitochondrial DNA Content</h3><p>Mitochondrial DNA (mtDNA) copy/content determination was performed as described previously (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Mukhopadhyay P, et al. (2014) Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis. Hepatology. 59:1998–2009." href="/articles/10.2119/molmed.2014.00261#ref-CR27" id="ref-link-section-d132987092e842">27</a>).</p><h3 class="c-article__sub-heading c-article__sub-heading--divider" id="Sec17">Analyses of Data</h3><p>Results are expressed as means ± SEM. Statistical significance among groups was determined by paired student <i>t</i> test or ANOVA followed by Tukey <i>post hoc</i> test for multiple comparisons using GraphPad Prism 6 software (San Diego, CA, USA). Probability values of <i>P</i> < 0.05 were considered significant.</p></div></div></section><section data-title="Results"><div class="c-article-section" id="Sec18-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec18">Results</h2><div class="c-article-section__content" id="Sec18-content"><h3 class="c-article__sub-heading" id="Sec19">CBD Attenuates DOX-Induced Cardiac Injury and Cardiac Dysfunction</h3><p>First we investigated if CBD attenuates the DOX-induced increased serum LDH and CK levels (markers of tissue/cardiac injury) and cardiac dysfunction (evaluated by measurement of ejection fraction [EF] and fractional shortening [FS] using echocardiography). DOX-markedly increased serum levels of LDH and CK (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig1">1A</a>) and reduced EF and FS (Figures <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig1">1B</a>, <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig1">C</a>). The DOX-induced tissue injury and cardiac dysfunction were markedly attenuated by CBD treatment (Figures <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig1">1A</a>, <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig1">B</a>). </p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-1" data-title="Figure 1"><figure><figcaption><b id="Fig1" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 1</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/10.2119/molmed.2014.00261/figures/1" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.2119%2Fmolmed.2014.00261/MediaObjects/10020_2015_2101038_Fig1.jpg?as=webp"><img aria-describedby="Fig1" src="//media.springernature.com/lw685/springer-static/image/art%3A10.2119%2Fmolmed.2014.00261/MediaObjects/10020_2015_2101038_Fig1.jpg" alt="figure 1" loading="lazy" width="562" height="444"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-1-desc"><p>CBD treatment attenuates markers of DOX-induced cardiac injury and dysfunction. The effect of DOX and CBD treatment on (A) serum LDH and CK levels and on (B) EF and FS. <i>*P</i> < 0.05 versus vehicle group; <sup>#</sup><i>P</i> < 0.05 versus DOX group; n = 5–9/group</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/10.2119/molmed.2014.00261/figures/1" data-track-dest="link:Figure1 Full size image" aria-label="Full size image figure 1" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><h3 class="c-article__sub-heading" id="Sec20">CBD Attenuates DOX-Induced Myocardial Oxidative Stress</h3><p>Next we explored the effects of CBD on myocardial oxidative stress. DOX induced marked increase in myocardial HNE content (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig2">2A</a>), reduced total glutathione content (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig2">2B</a>), attenuated glutathione peroxidase (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig2">2C</a>) and mitochondrial complex I and II (but not IV) activities (Figures <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig2">2D</a>, <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig2">E</a>) (the unchanged complex IV activity is not shown). DOX also induced a marked increase in the myocardial expression of reactive oxygen species generation NADPH oxidase isoform <i>NOX2</i> (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig2">2F</a>). All markers of DOX-induced oxidative stress were attenuated by CBD treatment (see Figures <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig2">2A</a>–<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig2">F</a>). </p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-2" data-title="Figure 2"><figure><figcaption><b id="Fig2" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 2</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/10.2119/molmed.2014.00261/figures/2" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.2119%2Fmolmed.2014.00261/MediaObjects/10020_2015_2101038_Fig2.jpg?as=webp"><img aria-describedby="Fig2" src="//media.springernature.com/lw685/springer-static/image/art%3A10.2119%2Fmolmed.2014.00261/MediaObjects/10020_2015_2101038_Fig2.jpg" alt="figure 2" loading="lazy" width="661" height="718"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-2-desc"><p>CBD treatment attenuates DOX-induced myocardial oxidative stress and mitochondrial dysfunction. The effect of DOX and CBD treatment on myocardial (A) HNE adducts, (B) total glutathione content, (C) GPX activity, (D,E) mitochondrial complex I and II activities and (F) NOX2 mRNA expression. *<i>P</i> < 0.05 versus vehicle group; <sup>#</sup><i>P</i> < 0.05 versus DOX group; n = 4–6/group.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/10.2119/molmed.2014.00261/figures/2" data-track-dest="link:Figure2 Full size image" aria-label="Full size image figure 2" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><h3 class="c-article__sub-heading" id="Sec21">CBD Attenuates DOX-Induced Myocardial Nitrative Stress</h3><p>We also explored effects of CBD on DOX-induced increased nitrative stress. DOX markedly increased myocardial in-ducible nitric oxide synthase (<i>iNOS</i>) expression (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig3">3A</a>) and 3-nitrotyrosine formation (Figures <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig3">3B</a>, <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig4">4</a>). CBD largely attenuated the DOX-induced increased <i>iNOS</i> expression and nitrotyrosine formation (Figures <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig3">3</a>, <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig4">4</a>). </p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-3" data-title="Figure 3"><figure><figcaption><b id="Fig3" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 3</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/10.2119/molmed.2014.00261/figures/3" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.2119%2Fmolmed.2014.00261/MediaObjects/10020_2015_2101038_Fig3.jpg?as=webp"><img aria-describedby="Fig3" src="//media.springernature.com/lw685/springer-static/image/art%3A10.2119%2Fmolmed.2014.00261/MediaObjects/10020_2015_2101038_Fig3.jpg" alt="figure 3" loading="lazy" width="359" height="522"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-3-desc"><p>CBD treatment attenuates DOX-induced myocardial iNOS expression and 3-nitrotyrosine accumulation. The effect of DOX and CBD treatment on myocardial (A) iNOS mRNA and (B) protein 3-nitrotyrosine content measured by ELISA *<i>P</i> < 0.05 versus vehicle group; <sup>#</sup><i>P</i> < 0.05 versus DOX group; n = 4–6/group.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/10.2119/molmed.2014.00261/figures/3" data-track-dest="link:Figure3 Full size image" aria-label="Full size image figure 3" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div> <div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-4" data-title="Figure 4"><figure><figcaption><b id="Fig4" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 4</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/10.2119/molmed.2014.00261/figures/4" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.2119%2Fmolmed.2014.00261/MediaObjects/10020_2015_2101038_Fig4.jpg?as=webp"><img aria-describedby="Fig4" src="//media.springernature.com/lw685/springer-static/image/art%3A10.2119%2Fmolmed.2014.00261/MediaObjects/10020_2015_2101038_Fig4.jpg" alt="figure 4" loading="lazy" width="455" height="806"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-4-desc"><p>CBD treatment attenuates DOX-induced myocardial 3-nitrotyrosine staining. Representative formalin-fixed myocardial tissue sections from indicated groups immunostained for 3-nitrotyrosine (brown staining) (200× magnification).</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/10.2119/molmed.2014.00261/figures/4" data-track-dest="link:Figure4 Full size image" aria-label="Full size image figure 4" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><h3 class="c-article__sub-heading" id="Sec22">CBD Enhances DOX-Induced Impaired Mitochondrial Biogenesis</h3><p>Since DOX-induced cardiotoxicity is known to be associated with mitochondrial injury and dysfunction (see also Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig2">2</a>), we further explored the effects of CBD on mitochondrial copy number and various markers of mitochondrial biogenesis. DOX decreased the myocardial mitochondrial copy number and attenuated expression of mRNA of various markers of mitochondrial biogenesis such as peroxisome proliferator-activated receptor γ coactivator 1-α (PGC2A), peroxisome proliferator-activated receptor α (<i>PPARA</i>), estrogen-related receptor α (<i>ERRA</i>), uncoupling protein 2 and 3 (<i>UCP2, UCP3</i>) and medium-chain acyl-CoA dehydrogenase (<i>MCAD</i>) (Figures <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig5">5A</a>–<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig5">G</a>). CBD largely prevented the above-mentioned changes (see Figures <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig5">5A</a>–<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig5">G</a>), suggesting that it enhanced mitochondrial biogenesis in damaged hearts. </p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-5" data-title="Figure 5"><figure><figcaption><b id="Fig5" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 5</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/10.2119/molmed.2014.00261/figures/5" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.2119%2Fmolmed.2014.00261/MediaObjects/10020_2015_2101038_Fig5.jpg?as=webp"><img aria-describedby="Fig5" src="//media.springernature.com/lw685/springer-static/image/art%3A10.2119%2Fmolmed.2014.00261/MediaObjects/10020_2015_2101038_Fig5.jpg" alt="figure 5" loading="lazy" width="609" height="938"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-5-desc"><p>CBD attenuates DOX-induced impaired myocardial mitochondrial biogenesis. The effect of DOX and CBD treatment on (A) mitochondrial copy number and expression of (B) <i>PGC1A</i>, (C) <i>PPARA</i>, (D) <i>ERRA</i>, (E,F) <i>UCP2</i> and <i>UCP3</i> and (G) <i>MCAD</i> mRNA levels. Pretreatment with CBD improves DOX-induced decreased expression of mitochondrial biogenesis genes. *<i>P</i> < 0.05 versus vehicle group; <sup>#</sup><i>P</i> < 0.05 versus DOX group; n = 4–6/group.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/10.2119/molmed.2014.00261/figures/5" data-track-dest="link:Figure5 Full size image" aria-label="Full size image figure 5" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><h3 class="c-article__sub-heading" id="Sec23">CBD Attenuates DOX-Induced Myocardial Cell Death and Matrix Metalloproteinases 2 and 9 (<i>MMP2</i> and <i>MMP9</i>) Activation</h3><p>Cell death of cardiomyocytes and endothelial cells, as well as activation of proteolytic MMP enzymes, is a consequence of increased oxidative and nitrative stress and mitochondrial injury. We found that DOX-induced marked increases in myocardial apoptotic and PARP-dependent cell death in the myocardium and in mRNA expression of <i>MMP2</i> and <i>MMP9</i>, which all were largely attenuated by CBD treatment (Figures <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig6">6A</a>–<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig6">E</a>). </p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-6" data-title="Figure 6"><figure><figcaption><b id="Fig6" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 6</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/10.2119/molmed.2014.00261/figures/6" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.2119%2Fmolmed.2014.00261/MediaObjects/10020_2015_2101038_Fig6.jpg?as=webp"><img aria-describedby="Fig6" src="//media.springernature.com/lw685/springer-static/image/art%3A10.2119%2Fmolmed.2014.00261/MediaObjects/10020_2015_2101038_Fig6.jpg" alt="figure 6" loading="lazy" width="685" height="427"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-6-desc"><p>CBD treatment attenuates DOX-induced myocardial cell death and <i>MMP2</i> and <i>MMP9</i> mRNA expression. Effect of DOX and CBD treatment on myocardial (A) caspase 3/7 activity, (B) chromatin fragmentation and (C) PARP activation. (D,E) Expression of <i>MMP2</i> and <i>MMP9</i> mRNA. *<i>P</i> < 0.05 versus vehicle group; <sup>#</sup><i>P</i> < 0.05 versus DOX group; n = 4–6/group.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/10.2119/molmed.2014.00261/figures/6" data-track-dest="link:Figure6 Full size image" aria-label="Full size image figure 6" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><h3 class="c-article__sub-heading" id="Sec24">CBD Attenuates DOX-induced Myocardial inflammation</h3><p>Myocardial injury is known to trigger secondary proinflammatory response. We found that DOX increased myocardial expression of mRNAs of tumor necrosis factor-α (<i>TNFA</i>), interleukin-1β (<i>IL1B</i>) and monocyte chemoattractant protein-1 (<i>MCP-1</i>) (Figures <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig7">7A</a>–<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig7">C</a>). These changes were attenuated by CBD treatment (see Figures <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig7">7A</a>–<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.2119/molmed.2014.00261#Fig7">C</a>). </p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-7" data-title="Figure 7"><figure><figcaption><b id="Fig7" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 7</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/10.2119/molmed.2014.00261/figures/7" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.2119%2Fmolmed.2014.00261/MediaObjects/10020_2015_2101038_Fig7.jpg?as=webp"><img aria-describedby="Fig7" src="//media.springernature.com/lw685/springer-static/image/art%3A10.2119%2Fmolmed.2014.00261/MediaObjects/10020_2015_2101038_Fig7.jpg" alt="figure 7" loading="lazy" width="361" height="797"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-7-desc"><p>CBD attenuates DOX-induced proinflammatory response in the heart. Real-time PCR shows significant increase of (A) <i>TNFA</i>, (B) <i>IL1B</i>, (C) <i>MCP-1</i> mRNA level. Pretreatment with CBD significantly attenuates DOX-induced increased proin-flammatory chemokine levels. *<i>P</i> < 0.05 versus vehicle group; <sup>#</sup><i>P</i> < 0.05 versus DOX group; n = 4–6/group.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/10.2119/molmed.2014.00261/figures/7" data-track-dest="link:Figure7 Full size image" aria-label="Full size image figure 7" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div></div></div></section><section data-title="Discussion"><div class="c-article-section" id="Sec25-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec25">Discussion</h2><div class="c-article-section__content" id="Sec25-content"><p>DOX-induced cardiomyopathy/heart failure is a serious complication of chemotherapy with very limited therapeutic options, mostly including supportive treatment or heart transplantation (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Carvalho FS, et al. (2014) Doxorubicin-induced cardiotoxicity: from bioenergetic failure and cell death to cardiomyopathy. Med. Res. Rev. 34:106–35." href="/articles/10.2119/molmed.2014.00261#ref-CR1" id="ref-link-section-d132987092e1269">1</a>). The currently available preventive strategies are not satisfactory and there is an urgent need for development of novel approaches to prevent this devastating complication of DOX chemotherapy. CBD is a nonpsychoactive constituent of marijuana with potent antioxidant and antiinflammatory effects in preclinical disease models which are independent from classical G-protein coupled cannabinoid 1 and 2 receptors (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" title="Pacher P, Batkai S, Kunos G. (2006) The endo-cannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 58:389–462." href="/articles/10.2119/molmed.2014.00261#ref-CR16" id="ref-link-section-d132987092e1272">16</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. (2009) Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol. Sci. 30:515–27." href="/articles/10.2119/molmed.2014.00261#ref-CR17" id="ref-link-section-d132987092e1275">17</a>).</p><p>Herein, we show that CBD exerts protective effects against DOX-induced cardiotoxicity and cardiac dysfunction by (i) attenuating oxidative and nitrative stress, (ii) improving mitochondrial function, (iii) enhancing mitochondrial biogenesis, (iv) decreasing cell death and expression of MMPs and (v) decreasing myocardial inflammation.</p><p>Consistent with numerous previous reports (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Carvalho FS, et al. (2014) Doxorubicin-induced cardiotoxicity: from bioenergetic failure and cell death to cardiomyopathy. Med. Res. Rev. 34:106–35." href="/articles/10.2119/molmed.2014.00261#ref-CR1" id="ref-link-section-d132987092e1283">1</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Ichikawa Y, et al. (2014) Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J. Clin. Invest. 124:617–30." href="/articles/10.2119/molmed.2014.00261#ref-CR8" id="ref-link-section-d132987092e1286">8</a>) we found that DOX treatment markedly increased oxidative stress and impaired antioxidant defense in the heart. DOX also decreased myocardial mitochondrial complex I and II activities, as well as the activity of the glutathione peroxidase (GPX). This is consistent with studies suggesting a key role for mitochondrial dysfunction and reactive oxygen species generation in triggering the deleterious cascade of the DOX-induced cardiotoxicity (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Pacher P, et al. (2003) Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction. Circulation. 107:896–904." href="/articles/10.2119/molmed.2014.00261#ref-CR4" id="ref-link-section-d132987092e1289">4</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Mukhopadhyay P, et al. (2009) Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro. Am. J. Physiol. Heart Circ. Physiol. 296:H1466–83." href="/articles/10.2119/molmed.2014.00261#ref-CR5" id="ref-link-section-d132987092e1292">5</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Davies KJ, Doroshow JH. (1986) Redox cycling of anthracyclines by cardiac mitochondria. I. Anthracycline radical formation by NADH dehydrogenase. J. Biol. Chem. 261:3060–7." href="/articles/10.2119/molmed.2014.00261#ref-CR28" id="ref-link-section-d132987092e1295">28</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Chandran K, et al. (2009) Doxorubicin inactivates myocardial cytochrome c oxidase in rats: cardioprotection by Mito-Q. Biophys. J. 96:1388–98." href="/articles/10.2119/molmed.2014.00261#ref-CR29" id="ref-link-section-d132987092e1299">29</a>). In addition to mitochondrial, NADPH oxidase-dependent ROS generation (particularly <i>NOX2</i>-dependent) also may contribute to DOX-induced cardiotoxicity (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Pacher P, et al. (2003) Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction. Circulation. 107:896–904." href="/articles/10.2119/molmed.2014.00261#ref-CR4" id="ref-link-section-d132987092e1305">4</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Zhao Y, et al. (2010) Nox2 NADPH oxidase promotes pathologic cardiac remodeling associated with Doxorubicin chemotherapy. Cancer Res. 70:9287–97." href="/articles/10.2119/molmed.2014.00261#ref-CR30" id="ref-link-section-d132987092e1308">30</a>). We also found that DOX increased myocardial expression of iNOS and enhanced 3-nitrotyrosine (3-NT) formation. 3-NT is a marker of peroxynitrite formation, or, more broadly, of nitrative stress (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Pacher P, Beckman JS, Liaudet L. (2007) Nitric oxide and peroxynitrite in health and disease. Physiol. Rev. 87:315–424." href="/articles/10.2119/molmed.2014.00261#ref-CR26" id="ref-link-section-d132987092e1311">26</a>). Peroxynitrite formed from the diffusion limited reaction of superoxide anion and NO recently was implicated as the key downstream effector of promoting DOX-induced cardiotoxicity (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Pacher P, Beckman JS, Liaudet L. (2007) Nitric oxide and peroxynitrite in health and disease. Physiol. Rev. 87:315–424." href="/articles/10.2119/molmed.2014.00261#ref-CR26" id="ref-link-section-d132987092e1314">26</a>). Peroxynitrite may induce lipid peroxidation, nitration of key contractile proteins and/or sarco/endoplasmic reticulum Ca<sup>2+</sup> pump, trigger activation of mitogen-activated protein kinases promoting apoptotic cell death and impair mitochondrial function favoring increased reactive oxygen species generation, eventually culminating in cardiac dysfunction (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Pacher P, Beckman JS, Liaudet L. (2007) Nitric oxide and peroxynitrite in health and disease. Physiol. Rev. 87:315–424." href="/articles/10.2119/molmed.2014.00261#ref-CR26" id="ref-link-section-d132987092e1320">26</a>). In addition, peroxynitrite also can diffuse to the nucleus, inducing DNA breaks and consequent over-activation of the nuclear enzyme PARP-1, which, in turn, leads to energetic crisis and cell necrosis (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Pacher P, Beckman JS, Liaudet L. (2007) Nitric oxide and peroxynitrite in health and disease. Physiol. Rev. 87:315–424." href="/articles/10.2119/molmed.2014.00261#ref-CR26" id="ref-link-section-d132987092e1323">26</a>). Indeed, both neutralization of peroxynitrite by peroxynitrite decomposition catalysts or inhibition of iNOS or PARP is protective against DOX-induced cardiotoxicity in murine models of DOX-induced cardiomyopathies. (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Pacher P, et al. (2003) Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction. Circulation. 107:896–904." href="/articles/10.2119/molmed.2014.00261#ref-CR4" id="ref-link-section-d132987092e1326">4</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Mukhopadhyay P, et al. (2009) Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro. Am. J. Physiol. Heart Circ. Physiol. 296:H1466–83." href="/articles/10.2119/molmed.2014.00261#ref-CR5" id="ref-link-section-d132987092e1329">5</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="Pacher P, et al. (2002) Activation of poly(ADP-ribose) polymerase contributes to development of doxorubicin-induced heart failure. J. Pharmacol. Exp. Ther. 300:862–7." href="/articles/10.2119/molmed.2014.00261#ref-CR13" id="ref-link-section-d132987092e1332">13</a>). DOX via increased generation of reactive oxygen and nitrogen species also leads to activation of MMP enzymes (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Pacher P, Schulz R, Liaudet L, Szabo C. (2005) Nitrosative stress and pharmacological modulation of heart failure. Trends Pharmacol. Sci. 26:302–10." href="/articles/10.2119/molmed.2014.00261#ref-CR31" id="ref-link-section-d132987092e1336">31</a>), which in turn promotes pathological remodeling (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Pacher P, et al. (2003) Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction. Circulation. 107:896–904." href="/articles/10.2119/molmed.2014.00261#ref-CR4" id="ref-link-section-d132987092e1339">4</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Bai P, et al. (2004) Matrix metalloproteinase activation is an early event in doxorubicin-induced cardiotoxicity. Oncol. Rep. 11:505–8." href="/articles/10.2119/molmed.2014.00261#ref-CR14" id="ref-link-section-d132987092e1342">14</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="Kizaki K, et al. (2006) Enhanced gene expression of myocardial matrix metalloproteinases 2 and 9 after acute treatment with doxorubicin in mice. Pharmacol. Res. 53:341–6." href="/articles/10.2119/molmed.2014.00261#ref-CR32" id="ref-link-section-d132987092e1345">32</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Spallarossa P, et al. (2006) Matrix metalloproteinase-2 and −9 are induced differently by doxorubicin in H9c2 cells: The role of MAP kinases and NAD(P)H oxidase. Cardiovasc. Res. 69:736–45." href="/articles/10.2119/molmed.2014.00261#ref-CR33" id="ref-link-section-d132987092e1348">33</a>).</p><p>CBD attenuated DOX-induced myocardial lipid peroxidation and the decline in antioxidant glutathione level and in the activity of glutathione peroxidase, which could be the consequence of attenuated formation or enhanced inactivation of reactive oxygen and nitrogen species. CBD also decreased the DOX-induced increased iNOS expression in the myocardium, most likely contributing to the attenuation of DOX-induced myocardial nitrotyrosine formation as a consequence of decreased NO availability for peroxynitrite formation from NO and superoxide anion. In agreement with this, CBD also attenuated nuclear factor-κB (NF-κB) and/or iNOS expression in a model of liver ischemia-reperfusion injury (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 34" title="Mukhopadhyay P, et al. (2011) Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death. Free Radic. Biol. Med. 50:1368–81." href="/articles/10.2119/molmed.2014.00261#ref-CR34" id="ref-link-section-d132987092e1354">34</a>), cisplatin-induced nephropathy (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 35" title="Pan H, et al. (2009) Cannabidiol attenuates cisplatin-induced nephrotoxicity by decreasing oxidative/nitrosative stress, inflammation, and cell death. J. Pharmacol. Exp. Ther. 328:708–14." href="/articles/10.2119/molmed.2014.00261#ref-CR35" id="ref-link-section-d132987092e1357">35</a>), and in diabetic cardiomyopathy (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Rajesh M, et al. (2010) Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J. Am. Coll. Cardiol. 56:2115–25." href="/articles/10.2119/molmed.2014.00261#ref-CR20" id="ref-link-section-d132987092e1360">20</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Rajesh M, et al. (2007) Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption. Am. J. Physiol. Heart Circ. Physiol. 293: H610–9." href="/articles/10.2119/molmed.2014.00261#ref-CR36" id="ref-link-section-d132987092e1363">36</a>). In these models, CBD also attenuated oxidative stress by attenuating mitochondrial dysfunction and reactive oxygen species generation or by decreasing the expression of various reactive oxygen species generating NADPH oxidase isoforms (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Rajesh M, et al. (2010) Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J. Am. Coll. Cardiol. 56:2115–25." href="/articles/10.2119/molmed.2014.00261#ref-CR20" id="ref-link-section-d132987092e1366">20</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 35" title="Pan H, et al. (2009) Cannabidiol attenuates cisplatin-induced nephrotoxicity by decreasing oxidative/nitrosative stress, inflammation, and cell death. J. Pharmacol. Exp. Ther. 328:708–14." href="/articles/10.2119/molmed.2014.00261#ref-CR35" id="ref-link-section-d132987092e1370">35</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Rajesh M, et al. (2007) Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption. Am. J. Physiol. Heart Circ. Physiol. 293: H610–9." href="/articles/10.2119/molmed.2014.00261#ref-CR36" id="ref-link-section-d132987092e1373">36</a>). CBD also attenuated the DOX-induced decreased myocardial mitochondrial complex I activity, in agreement with its effect in a liver ischemia-reperfusion injury model (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 34" title="Mukhopadhyay P, et al. (2011) Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death. Free Radic. Biol. Med. 50:1368–81." href="/articles/10.2119/molmed.2014.00261#ref-CR34" id="ref-link-section-d132987092e1376">34</a>). Furthermore, CBD also reduced the DOX-induced decline in myocardial mitochondrial copy number and enhanced mitochondrial biogenesis in injured hearts. Consistent with previous studies, DOX also induced both apoptotic and PARP-dependent cell death in hearts (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Mukhopadhyay P, et al. (2009) Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro. Am. J. Physiol. Heart Circ. Physiol. 296:H1466–83." href="/articles/10.2119/molmed.2014.00261#ref-CR5" id="ref-link-section-d132987092e1379">5</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Mukhopadhyay P, et al. (2011) Fatty acid amide hydrolase is a key regulator of endocannabinoid-induced myocardial tissue injury. Free Radic. Biol. Med. 50:179–95." href="/articles/10.2119/molmed.2014.00261#ref-CR12" id="ref-link-section-d132987092e1382">12</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Mukhopadhyay P, et al. (2007) Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity. J. Am. Coll. Cardiol. 50:528–36." href="/articles/10.2119/molmed.2014.00261#ref-CR23" id="ref-link-section-d132987092e1385">23</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Pacher P, et al. (2006) Beneficial effects of a novel ultrapotent poly(ADP-ribose) polymerase inhibitor in murine models of heart failure. Int. J. Mol. Med. 17:369–75." href="/articles/10.2119/molmed.2014.00261#ref-CR37" id="ref-link-section-d132987092e1389">37</a>), which could be largely attenuated by CBD. CBD also attenuated the DOX-induced increased myocardial inflammation. These results are in agreement with the attenuation of proinflammatory response by CBD in diabetic hearts (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Rajesh M, et al. (2010) Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J. Am. Coll. Cardiol. 56:2115–25." href="/articles/10.2119/molmed.2014.00261#ref-CR20" id="ref-link-section-d132987092e1392">20</a>) or in human cardiomyocytes (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Rajesh M, et al. (2010) Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J. Am. Coll. Cardiol. 56:2115–25." href="/articles/10.2119/molmed.2014.00261#ref-CR20" id="ref-link-section-d132987092e1395">20</a>) or coronary artery endothelial cells (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Rajesh M, et al. (2007) Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption. Am. J. Physiol. Heart Circ. Physiol. 293: H610–9." href="/articles/10.2119/molmed.2014.00261#ref-CR36" id="ref-link-section-d132987092e1398">36</a>) exposed to high glucose, likewise with beneficial effects of CBD in rodent models of myocardial infarction, primary diabetes and diabetic complications (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. (2009) Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol. Sci. 30:515–27." href="/articles/10.2119/molmed.2014.00261#ref-CR17" id="ref-link-section-d132987092e1401">17</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="Weiss L, et al. (2006) Cannabidiol lowers incidence of diabetes in non-obese diabetic mice. Autoimmunity. 39:143–51." href="/articles/10.2119/molmed.2014.00261#ref-CR38" id="ref-link-section-d132987092e1404">38</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Horvath B, Mukhopadhyay P, Hasko G, Pacher P. (2012) The endocannabinoid system and plant-derived cannabinoids in diabetes and diabetic complications. Am. J. Pathol. 180:432–42." href="/articles/10.2119/molmed.2014.00261#ref-CR40" id="ref-link-section-d132987092e1408">40</a>).</p><p>So far, over 50 metabolites of CBD were identified in the urine, showing considerable variations between different species (including humans), however their biological activity was not evaluated in detail (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="Martin BR, Harvey DJ, Paton WD. (1977) Biotransformation of cannabidiol in mice. Identification of new acid metabolites. Drug Metab. Dispos. 5:259–67." href="/articles/10.2119/molmed.2014.00261#ref-CR41" id="ref-link-section-d132987092e1415">41</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 42" title="Harvey DJ, Samara E, Mechoulam R. (1991) Comparative metabolism of cannabidiol in dog, rat and man. Pharmacol. Biochem. Behav. 40:523–32." href="/articles/10.2119/molmed.2014.00261#ref-CR42" id="ref-link-section-d132987092e1418">42</a>). Substantial evidence from <i>in vitro</i> or <i>in vivo</i> studies suggests that CBD by itself exerts potent antiinflammatory and antioxidant effects, independently from cannabinoid receptors (for example in liver ischemia/reperfusion injury model CBD exerted comparable antiinflammatory effects in both cannabinoid 2 receptor knockout mice and their wild-type littermates). Nevertheless, the potential protective effect of certain CBD metabolites <i>in vivo</i> cannot be excluded either.</p><p>Another issue which deserves some discussion is whether the above-mentioned antioxidant and antiinflam-matory effects of CBD would interfere with the antitumor activity of DOX. The answer is that it is not likely to do so. For example, mitochondrial-targeted antioxidants appear to have synergistic effects with various chemotherapeutic agents in tumor cell killing (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 43" title="Mukhopadhyay P, et al. (2012) Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy. Free Radic. Biol. Med. 52:497–506." href="/articles/10.2119/molmed.2014.00261#ref-CR43" id="ref-link-section-d132987092e1433">43</a>). Activation of MMPs may be involved in tumor progression and metastasis formation, which is inhibited by CBD, likewise the NF-κB signaling. Furthermore, CBD by itself has been reported to have antitumor effects in a large variety of cancer cell lines, as well as in some explanted tumor models (<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 44" title="Solinas M, et al. (2013) Cannabidiol, a non-psychoactive cannabinoid compound, inhibits proliferation and invasion in U87-MG and T98G glioma cells through a multitarget effect. PloS One 8:e76918." href="/articles/10.2119/molmed.2014.00261#ref-CR44" id="ref-link-section-d132987092e1436">44</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 46" title="Massi P, Solinas M, Cinquina V, Parolaro D. (2013) Cannabidiol as potential anticancer drug. Br. J. Clin. Pharmacol. 75:303–12." href="/articles/10.2119/molmed.2014.00261#ref-CR46" id="ref-link-section-d132987092e1439">46</a>), which would rather predict a synergistic effect with antineoplastic drugs. In fact, Insys Therapeutics just received FDA orphan drug designation for CBD as a potential treatment for glioblastoma multiforme in humans.</p></div></div></section><section data-title="Conclusion"><div class="c-article-section" id="Sec26-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec26">Conclusion</h2><div class="c-article-section__content" id="Sec26-content"><p>In summary, our results indicate that CBD may represent a novel promising approach for the prevention of DOX-induced cardiomyopathy/heart failure by attenuating oxidative/nitrative stress, mitochondrial dysfunction, cell death and inflammation, and by promoting mitochondrial biogenesis. These results, coupled with the excellent safety of CBD in humans, its protective effects against cisplatin-induced nephropathy, its recently reported antineoplastic properties in various malignancies and its orphan drug approval for glioblastoma multiforme and childhood epilepsy, are particularly encouraging from a therapeutic point of view.</p></div></div></section><section data-title="Disclosures"><div class="c-article-section" id="Sec27-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec27">Disclosures</h2><div class="c-article-section__content" id="Sec27-content"><p>The authors declare that they have no competing interests as defined by <i>Molecular Medicine</i>, or other interests that might be perceived to influence the results and discussion reported in this paper.</p></div></div></section> <div id="MagazineFulltextArticleBodySuffix"><section aria-labelledby="Bib1" data-title="References"><div class="c-article-section" id="Bib1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Bib1">References</h2><div class="c-article-section__content" id="Bib1-content"><div data-container-section="references"><ol class="c-article-references" data-track-component="outbound reference" data-track-context="references section"><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="1."><p class="c-article-references__text" id="ref-CR1">Carvalho FS, <i>et al.</i> (2014) Doxorubicin-induced cardiotoxicity: from bioenergetic failure and cell death to cardiomyopathy. <i>Med. 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P Pacher is grateful to George Kunos, Scientific Director of NIAAA, for continuous support, and dedicates this study to collaborator and friend, Itai Bab. The study also was supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism (to P Pacher).</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA</p><p class="c-article-author-affiliation__authors-list">Enkui Hao, Partha Mukhopadhyay, Zongxian Cao, Katalin Erdélyi, Eileen Holovac, Wen-Shin Lee & Pál Pacher</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China</p><p class="c-article-author-affiliation__authors-list">Enkui Hao</p></li><li id="Aff3"><p class="c-article-author-affiliation__address">Department of Intensive Care Medicine, BH 08-621 University Hospital Medical Center, Lausanne, Switzerland</p><p class="c-article-author-affiliation__authors-list">Lucas Liaudet</p></li><li id="Aff4"><p class="c-article-author-affiliation__address">Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taipei, Taiwan</p><p class="c-article-author-affiliation__authors-list">Wen-Shin Lee</p></li><li id="Aff5"><p class="c-article-author-affiliation__address">Departments of Surgery, Rutgers New Jersey Medical School, Newark, New Jersey, USA</p><p class="c-article-author-affiliation__authors-list">György Haskó</p></li><li id="Aff6"><p class="c-article-author-affiliation__address">Department for Medicinal Chemistry and Natural Products, Faculty of Medicine, Hebrew University of Jerusalem, Ein Kerem, Jerusalem, Israel</p><p class="c-article-author-affiliation__authors-list">Raphael Mechoulam</p></li><li id="Aff7"><p class="c-article-author-affiliation__address">Section on Oxidative Stress Tissue Injury, Laboratory of Physiological Studies, National Institutes of Health/NIAAA, 5625 Fishers Lane, MSC-9413, Bethesda, Maryland, 20892-9413, USA</p><p class="c-article-author-affiliation__authors-list">Pál Pacher</p></li></ol><div class="u-js-hide u-hide-print" data-test="author-info"><span class="c-article__sub-heading">Authors</span><ol class="c-article-authors-search u-list-reset"><li id="auth-Enkui-Hao-Aff1-Aff2"><span class="c-article-authors-search__title u-h3 js-search-name">Enkui Hao</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="https://www.biomedcentral.com/search?query=author%23Enkui%20Hao" class="c-article-button" data-track="click" data-track-action="author link - 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id="citeas">Cite this article</h3><p class="c-bibliographic-information__citation">Hao, E., Mukhopadhyay, P., Cao, Z. <i>et al.</i> Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis. <i>Mol Med</i> <b>21</b>, 38–45 (2015). https://doi.org/10.2119/molmed.2014.00261</p><p class="c-bibliographic-information__download-citation u-hide-print"><a data-test="citation-link" data-track="click" data-track-action="download article citation" data-track-label="link" data-track-external="" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.2119/molmed.2014.00261?format=refman&flavour=citation">Download citation<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p><ul class="c-bibliographic-information__list" data-test="publication-history"><li class="c-bibliographic-information__list-item"><p>Received<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2014-12-22">22 December 2014</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Accepted<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2014-12-23">23 December 2014</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Published<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2015-01-06">06 January 2015</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Issue Date<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2015-01">January 2015</time></span></p></li><li class="c-bibliographic-information__list-item c-bibliographic-information__list-item--full-width"><p><abbr title="Digital Object Identifier">DOI</abbr><span class="u-hide">: </span><span class="c-bibliographic-information__value">https://doi.org/10.2119/molmed.2014.00261</span></p></li></ul><div data-component="share-box"><div class="c-article-share-box u-display-none" hidden=""><h3 class="c-article__sub-heading">Share this article</h3><p class="c-article-share-box__description">Anyone you share the following link with will be able to read this content:</p><button class="js-get-share-url c-article-share-box__button" type="button" id="get-share-url" data-track="click" data-track-label="button" data-track-external="" data-track-action="get shareable link">Get shareable link</button><div class="js-no-share-url-container u-display-none" hidden=""><p class="js-c-article-share-box__no-sharelink-info c-article-share-box__no-sharelink-info">Sorry, a shareable link is not currently available for this article.</p></div><div class="js-share-url-container u-display-none" hidden=""><p class="js-share-url c-article-share-box__only-read-input" id="share-url" 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data-track-label="link">Nitrative Stress</a></span></li><li class="c-article-subject-list__subject"><span><a href="/search?query=Estrogen-related%20Receptor%20Alpha&facet-discipline="Biomedicine"" data-track="click" data-track-action="view keyword" data-track-label="link">Estrogen-related Receptor Alpha</a></span></li><li class="c-article-subject-list__subject"><span><a href="/search?query=Mitochondrial%20Copy%20Number&facet-discipline="Biomedicine"" data-track="click" data-track-action="view keyword" data-track-label="link">Mitochondrial Copy Number</a></span></li><li class="c-article-subject-list__subject"><span><a href="/search?query=Poly%20%28ADP-ribose%29%20Polymerase%20%28PARP%29&facet-discipline="Biomedicine"" data-track="click" data-track-action="view keyword" data-track-label="link">Poly (ADP-ribose) Polymerase (PARP)</a></span></li></ul><div data-component="article-info-list"></div></div></div></div></div></section> </article> </main> <div class="c-article-extras u-text-sm 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