Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis

Abstract

Doxorubicin (DOX) is a widely used, potent chemotherapeutic agent; however, its clinical application is limited because of its dose-dependent cardiotoxicity. DOX's cardiotoxicity involves increased oxidative/nitrative stress, impaired mitochondrial function in cardiomyocytes/endothelial cells and cell death. Cannabidiol (CBD) is a nonpsychotropic constituent of marijuana, which is well tolerated in humans, with antioxidant, antiinflammatory and recently discovered antitumor properties. We aimed to explore the effects of CBD in a well-established mouse model of DOX-induced cardiomyopathy. DOX-induced cardiomyopathy was characterized by increased myocardial injury (elevated serum creatine kinase and lactate dehydrogenase levels), myocardial oxidative and nitrative stress (decreased total glutathione content and glutathione peroxidase 1 activity, increased lipid peroxidation, 3-nitrotyrosine formation and expression of inducible nitric oxide synthase mRNA), myocardial cell death (apoptotic and poly[ADP]-ribose polymerase 1 [PARP]-dependent) and cardiac dysfunction (decline in ejection fraction and left ventricular fractional shortening). DOX also impaired myocardial mitochondrial biogenesis (decreased mitochondrial copy number, mRNA expression of peroxisome proliferator-activated receptor γ coactivator 1-alpha, peroxisome proliferator-activated receptor alpha, estrogen-related receptor alpha), reduced mitochondrial function (attenuated complex I and II activities) and decreased myocardial expression of uncoupling protein 2 and 3 and medium-chain acyl-CoA dehydrogenase mRNA. Treatment with CBD markedly improved DOX-induced cardiac dysfunction, oxidative/nitrative stress and cell death. CBD also enhanced the DOX-induced impaired cardiac mitochondrial function and biogenesis. These data suggest that CBD may represent a novel cardioprotective strategy against DOX-induced cardiotoxicity, and the above-described effects on mitochondrial function and biogenesis may contribute to its beneficial properties described in numerous other models of tissue injury.

Role of the endocannabinoid system in diabetes and diabetic complications

“…In these studies, the beneficial effects of cannabidiol were largely attributed to its antioxidant, anti‐inflammatory and tissue protective effects (Horvath and Pacher, 2012). A recent study also demonstrated that cannabidiol improved mitochondrial function and biogenesis in a myocardial injury model (Hao et al ., ), which could also contribute to its beneficial properties observed in diabetes and diabetic complications. In light of these preclinical data and recent orphan drug approval of cannabidiol by the FDA for the treatment of refractory childhood epilepsy and glioblastoma, there is a strong rationale to explore its therapeutic potential in human diabetes and diabetic complications.…”

Cannabidiol attenuates OGD/R-induced damage by enhancing mitochondrial bioenergetics and modulating glucose metabolism via pentose-phosphate pathway in hippocampal neurons

“…CBD has recently been approved in the United Kingdom and several other European countries as an important component of an oromucosal spray that is used as a complementary treatment for multiple sclerosis [11]. It has also received orphan drug approval by the U.S. Food and Drug Administration (FDA) to treat refractory childhood epilepsy [12]. To explore the positive effects of CBD on cerebral IRI, we used the immortalized mouse hippocampal neuronal cell line, HT22, and a model of oxygen–glucose deprivation/reperfusion (OGD/R) to mimic the conditions for IRI in vitro .…”

Cannabidiol: an alternative therapeutic agent for oral mucositis?

“…It is known that limitations to the therapeutic use of THC stems from its capacity to cause psychoactive effects mediated through receptors in the central nervous system (CNS). CBD is totally devoid of psychoactive properties, due to the low affinity of these receptors for CBD, thus offering greater safety in clinical use …”

“…CBD is totally devoid of psychoactive properties, due to the low affinity of these receptors for CBD, thus offering greater safety in clinical use. 12,32 Cannabinoid receptors were identified in the 1980s and named by order of discovery, that is CB1 and CB2. 14 They are involved in the modulation of neuronal functions and inflammatory processes and in the aetiology of some diseases.…”