β-Caryophyllene, a Dietary Phytocannabinoid, Alleviates Diabetic Cardiomyopathy in Mice by Inhibiting Oxidative Stress and Inflammation Activating Cannabinoid Type-2 Receptors

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“Diabetes mellitus (DM) and its associated complications are considered one of the major health risks globally. Among numerous complications, diabetic cardiomyopathy (DCM) is characterized by increased accumulation of lipids and reduced glucose utilization following abnormal lipid metabolism in the myocardium along with oxidative stress, myocardial fibrosis, and inflammation that eventually result in cardiac dysfunction. The abnormal metabolism of lipids plays a fundamental role in cardiac lipotoxicity following the occurrence and development of DCM. Recently, it has been revealed that cannabinoid type-2 (CB2) receptors, an essential component of the endocannabinoid system, play a crucial role in the pathogenesis of obesity, hyperlipidemia, and DM. Provided the role of CB2R in regulating the glucolipid metabolic dysfunction and its antioxidant as well as anti-inflammatory activities, we carried out the current study to investigate the protective effects of a selective CB2R agonist, β-caryophyllene (BCP), a natural dietary cannabinoid in the murine model of DCM and elucidated the underlying pharmacological and molecular mechanisms. Mice were fed a high-fat diet for 4 weeks followed by a single intraperitoneal injection of streptozotocin (100 mg/kg) to induce the model of DCM. BCP (50 mg/kg body weight) was given orally for 12 weeks. AM630, a CB2R antagonist, was given 30 min before BCP treatment to demonstrate the CB2R-dependent mechanism of BCP. DCM mice exhibited hyperglycemia, increased serum lactate dehydrogenase, impaired cardiac function, and hypertrophy. In addition, DCM mice showed alternations in serum lipids and increased oxidative stress concomitant to reduced antioxidant defenses and enhanced cardiac lipid accumulation in the diabetic heart. DCM mice also exhibited activation of TLR4/NF-κB/MAPK signaling and triggered the production of inflammatory cytokines and inflammatory enzyme mediators. However, treatment with BCP exerted remarkable protective effects by favorable modulation of the biochemical and molecular parameters, which were altered in DCM mice. Interestingly, pretreatment with AM630 abrogated the protective effects of BCP in DCM mice. Taken together, the findings of the present study demonstrate that BCP possesses the capability to mitigate the progression of DCM by inhibition of lipotoxicity-mediated cardiac oxidative stress and inflammation and favorable modulation of TLR4/NF-κB/MAPK signaling pathways mediating the CB2R-dependent mechanism.”



Therapeutic effect of cannabidiol on myocardial arachidonic acid content in various lipid fractions in a rat model of obesity

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“The study explored the potential protective influence of cannabidiol (CBD) on myocardial inflammation state, with a special focus on arachidonic acid (AA), and oxidative balance in lipid overload conditions.

The 7-week experiment was conducted on male Wistar rats receiving standard or high-fat diet (HFD) with intraperitoneal CBD injections for the last 14 days. The n-3 and n-6 polyunsaturated fatty acids (PUFAs) activities and AA concentration in selected fractions were evaluated by gas-liquid chromatography (GLC). The expression of proteins was determined by Western blot and the concentration of different parameters by ELISA, colorimetric, or multiplex assay kits.

Our results revealed that CBD increased n-3 PUFAs activity in phospholipid and triacylglycerol fractions, and decreased AA content in the HFD group, especially in the phospholipid pool. Simultaneously, CBD decreased the expression of nuclear factor kappa B, cyclooxygenase-1, and -2, resulting in the reduction of prostaglandin E2 and the increment of prostaglandin I2.

CBD appears to be relatively safe for the treatment of obesity-induced heart disease, as it has anti-inflammatory and partially antioxidative properties.”



The role of cannabidiol in aging

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“Aging is usually considered a key risk factor associated with multiple diseases, such as neurodegenerative diseases, cardiovascular diseases and cancer. Furthermore, the burden of age-related diseases has become a global challenge. It is of great significance to search for drugs to extend lifespan and healthspan. Cannabidiol (CBD), a natural nontoxic phytocannabinoid, has been regarded as a potential candidate drug for antiaging. An increasing number of studies have suggested that CBD could benefit healthy longevity. Herein, we summarized the effect of CBD on aging and analyzed the possible mechanism. All these conclusions may provide a perspective for further study of CBD on aging.”


“CBD is a potential antiaging candidate. CBD possesses antioxidant, anti-inflammatory and autophagy-inducing properties. CBD has potentially beneficial therapeutic effects for several age-related diseases.”


Delta 9-tetrahydrocannabinol conserves cardiovascular functions in a rat model of endotoxemia: Involvement of endothelial molecular mechanisms and oxidative-nitrative stress

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“In endotoxemic models, the inflammatory parameters are altered to a favorable direction as a response to activation of cannabinoid receptors 1 and 2. The phytocannabinoid Δ9-tetrahydrocannabinol (THC) is an agonist/partial antagonist of both cannabinoid receptors. This report targets the effects of THC on the cardiovascular system of endotoxemic rats. In our 24-hour endotoxemic rat model (E. coli derived lipopolysaccharide, LPS i.v. 5mg/kg) with THC treatment (LPS+THC 10 mg/kg i.p.), we investigated cardiac function by echocariography and endothelium-dependent relaxation of the thoracic aorta by isometric force measurement compared to vehicle controls. To evaluate the molecular mechanism, we measured endothelial NOS and COX-2 density by immunohistochemistry; and determined the levels of cGMP, the oxidative stress marker 4-hydroxynonenal, the nitrative stress marker 3-nitrotyrosine, and poly(ADP-ribose) polymers. A decrease in end-systolic and end-diastolic ventricular volumes in the LPS group was observed, which was absent in LPS+THC animals. Endothelium-dependent relaxation was worsened by LPS but not in the LPS+THC group. LPS administration decreased the abundance of cannabinoid receptors. Oxidative-nitrative stress markers showed an increment, and cGMP, eNOS staining showed a decrement in response to LPS. THC only decreased the oxidative-nitrative stress but had no effect on cGMP and eNOS density. COX-2 staining was reduced by THC. We hypothesize that the reduced diastolic filling in the LPS group is a consequence of vascular dysfunction, preventable by THC. The mechanism of action of THC is not based on its local effect on aortic NO homeostasis. The reduced oxidative-nitrative stress and the COX-2 suggest the activation of an anti-inflammatory pathway.”


“The presented results support the notion that a non-selective CB1/2R agonist–partial antagonist may have therapeutic potential in the treatment of sepsis. In our model, the decrement of cardiac filling and the consequential decline of the cardiac output was prevented by THC treatment, due to the maintained endothelial function. One possible mechanism of the more pronounced endothelium-mediated vasodilation is the decreased thromboxane A2 release due to the lessened inducible cyclooxygenase expression, the other salvaging mechanism is the dampened oxidative-nitrative stress. The activation of endocannabinoid system in inflammation and endotoxemia was earlier described; however, the diminished abundance of both cannabinoid receptors in endotoxemia was not detected. The decreased oxidative-nitrative stress and DNA damage are potentially beneficial in a systemic inflammation, and the reduced inflammatory response may help in the prevention to a quick and robust pro-inflammatory cytokine release (cytokine storm).”


Cannabidiol alleviates right ventricular fibrosis by inhibiting the transforming growth factor β pathway in monocrotaline-induced pulmonary hypertension in rats

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

“Cannabidiol (CBD) is a non-intoxicating compound of Cannabis with anti-fibrotic properties. Pulmonary hypertension (PH) is a disease that can lead to right ventricular (RV) failure and premature death. There is evidence that CBD reduces monocrotaline (MCT)-induced PH, including reducing right ventricular systolic pressure (RVSP), vasorelaxant effect on pulmonary arteries, and decreasing expression of profibrotic markers in the lungs. The aim of our study was to investigate the effect of chronic administration of CBD (10 mg/kg daily for 21 days) on profibrotic parameters in the RVs of MCT-induced PH rats. In MCT-induced PH, we found an increase in profibrotic parameters and parameters related to RV dysfunction, i.e. plasma pro-B-type natriuretic peptide (NT-proBNP), cardiomyocyte width, interstitial and perivascular fibrosis area, amount of fibroblasts and fibronectin, as well as overexpression of the transforming growth of factor β1 (TGF-β1), galectin-3 (Gal-3), suppressor of mothers against decapentaplegic 2 (SMAD2), phosphorylated SMAD2 (pSMAD2) and alpha-smooth muscle actin (α-SMA). In contrast, vascular endothelial cadherin (VE-cadherin) levels were decreased in the RVs of MCT-induced PH rats. Administration of CBD reduced the amount of plasma NT-proBNP, the width of cardiomyocytes, the amount of fibrosis area, fibronectin and fibroblast expression, as well as decreased the expression of TGF-β1, Gal-3, SMAD2, pSMAD2, and increased the level of VE-cadherin. Overall, CBD has been found to have the anti-fibrotic potential in MCT-induced PH. As such, CBD may act as an adjuvant therapy for PH, however, further detailed investigations are recommended to confirm our promising results.”


“CBD may be used in the future as add-on therapy in the treatment of PH.”


Role of Terpenophenolics in Modulating Inflammation and Apoptosis in Cardiovascular Diseases: A Review


“One in every three deaths worldwide is caused by cardiovascular diseases (CVDs), estimating a total of 17.9 million deaths annually. By 2030, it is expected that more than 24 million people will die from CVDs related complications. The most common CVDs are coronary heart disease, myocardial infarction, stroke, and hypertension.

A plethora of studies has shown inflammation causing both short-term and long-term damage to the tissues in many organ systems, including the cardiovascular system. In parallel to inflammation processes, it has been discovered that apoptosis, a mode of programmed cell death, may also contribute to CVD development due to the loss of cardiomyocytes.

Terpenophenolic compounds are comprised of terpenes and natural phenols as secondary metabolites by plants and are commonly found in the genus Humulus and Cannabis. A growing body of evidence has shown that terpenophenolic compounds exhibit protective properties against inflammation and apoptosis within the cardiovascular system.

This review highlights the current evidence elucidating the molecular actions of terpenophenolic compounds in protecting the cardiovascular system, i.e., bakuchiol, ferruginol, carnosic acid, carnosol, carvacrol, thymol and hinokitiol. The potential of these compounds is discussed as the new nutraceutical drugs that may help to decrease the burden of cardiovascular disorders.”


“In this review, we have summarised the evidence on the potential pharmacological activities of terpenophenolic compounds in regulating inflammation and apoptosis associated with CVDs. Treatment of various classes of terpenophenolic compounds has been shown effective in preventing and limiting the progression of heart failure. In addition, all terpenophenolics seem to be potent antioxidants, which are proven to upregulate the Nrf2 pathway and increase the endogenous antioxidant level.”


CBD supplementation reduces arterial blood pressure via modulation of the sympatho-chromaffin system: A substudy from the HYPER-H21-4 trial

Biomedicine & Pharmacotherapy

“Data concerning the effects of cannabidiol (CBD) on blood pressure (BP) is controversial. HYPER-H21-4 was a randomized, placebo-controlled, crossover trial which sought to elucidate if 5-week administration of CBD will reduce BP in hypertensive patients. In the substudy of this trial, we aimed to establish the mechanistic background of CBD-induced BP reduction. Specifically, we explored the dynamic of catestatin, a sympathoinhibitory peptide implicated in the pathophysiology of hypertension. In the present analysis, 54 patients with Grade 1 hypertension were included. 5-week administration of CBD but not placebo reduced serum catestatin concentration in comparison to baseline (13.50 [10.85-19.05] vs. 9.65 [6.37-12.26] ng/mL, p < 0.001). Serum catestatin levels at the start of the treatment period demonstrated a negative correlation with the extent of reduction in mean arterial pressure (r = -0.474, p < 0.001). Moreover, the extent of change in catestatin serum levels showed a strong correlation with the extent of mean arterial pressure reduction (r = 0.712, p < 0.001). Overall, the results of the present study imply that the antihypertensive effects of CBD may be explained by its interaction with the sympatho-chromaffin system, although further research is warranted.”


“CBD supplementation reduces office blood pressure (BP) and serum catestatin levels.”

“Overall, the results of the present study imply that antihypertensive effects of CBD may be explained by its interaction with the sympatho-chromaffin system, although further research is warranted.”


How do phytocannabinoids affect cardiovascular health? An update on the most common cardiovascular diseases

SAGE Journals Home

“Cardiovascular disease (CVD) causes millions of deaths worldwide each year. Despite the great progress in therapies available for patients with CVD, some limitations, including drug complications, still exist. Hence, the endocannabinoid system (ECS) was proposed as a new avenue for CVDs treatment. The ECS components are widely distributed through the body, including the heart and blood vessels, thus the action of its endogenous and exogenous ligands, in particular, phytocannabinoids play a key role in various pathological states. The cardiovascular action of cannabinoids is complex as they affect vasculature and myocardium directly via specific receptors and exert indirect effects through the central and peripheral nervous system. The growing interest in phytocannabinoid studies, however, has extended the knowledge about their molecular targets as well as therapeutical properties; nonetheless, some areas of their actions are not yet fully recognized. Researchers have reported various cannabinoids, especially cannabidiol, as a promising approach to CVDs; hence, the purpose of this review is to summarize and update the cardiovascular actions of the most potent phytocannabinoids and the potential therapeutic role of ECS in CVDs, including ischemic reperfusion injury, arrhythmia, heart failure as well as hypertension.”


“Accumulating evidence supports the crucial role of ECS in a wide range of physiological and pathophysiological conditions. In the cardiovascular system, ECS is involved in the inflammatory process, hemodynamic homeostasis, or cardiac rhythm control. Thus, it is not surprising that in many CVDs, ECS is highly active. Hence, pharmacological manipulation of the ECS, both by endocannabinoids and pCBs, may offer a novel therapeutic approach to cardiac disorders. Among many components of the Cannabis plant, studies on CBD demonstrate the greatest potential in experimental models of described herein CVDs. Although animal models and in vitro experiments have shown promising outcomes, data from human studies are still extremely limited and only these clinical trials may shed light on the actual therapeutic effect of CBD. Even though some effects of Cannabis compounds on the cardiovascular system are widely known, a thorough examination of their mechanism of action would greatly advance the understanding of pCBs. Molecular targets of Δ9-THC, CBG, CBC, CBN as well as THCV indicate their protective impact on the heart and blood vessels; nonetheless, the lack of in vitro, animal, or human studies creates a huge knowledge gap in this field.”


Cannabidiol Suppresses Cytokine Storm and Protects Against Cardiac and Renal Injury Associated with Sepsis

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“Background: Cytokine release syndrome, also termed “cytokine storm,” is the leading cause of morbidity and mortality among patients with various conditions such as sepsis. While cytokine storm is associated with multiple organ damage, acute cardiac and renal injury represents a hallmark of cytokine storm. Since recent reports have suggested that cannabidiol (CBD) may assist in the treatment of inflammatory diseases, our objective was to examine the effect of CBD on cytokine storm-induced cardiac and renal injury using the lipopolysaccharide (LPS)-induced sepsis mouse model. 

Materials and Methods: At 8 weeks of age, mice were randomly assigned to receive CBD (15 mg/kg) or vehicle one hour before a single injection of either phosphate-buffered saline or LPS (10 mg/kg) for an additional 24 h. 

Results: Our results show that CBD improves cardiac function and reduces renal injury in a mouse model of cytokine storm. Moreover, our data indicate that CBD significantly reduces systemic and renal inflammation to contribute to the improvements observed in a cytokine storm-model of cardiac and renal injury. 

Conclusions: Overall, the findings of this study suggest that CBD could be repurposed to reduce morbidity in patients with cytokine storm particularly in severe infections such as sepsis.”



Treatment with Cannabidiol Results in an Antioxidant and Cardioprotective Effect in Several Pathophysiologies

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“Cannabis sativa has chemically active compounds called cannabinoids, where Δ9- tetrahydrocannabinol (THC) and Cannabidiol (CBD) are the major ones responsible for the various pharmacological effects.

The endocannabinoid system is an endogenous system considered a unique and widespread homeostatic physiological regulator. It is made up of type 1 (CB1) and type 2 (CB2) cannabinoid receptors. CBD, in turn, has a low affinity for CB1 and CB2 receptors, and regulates the effects arising from THC as a CB1 partial agonist, which are tachycardia, anxiety, and sedation. It also acts as a CB2 inverse agonist, resulting in anti-inflammatory effects.

Furthermore, its anticonvulsant, neuroprotective, antipsychotic, antiemetic, anxiolytic, anticancer, and antioxidant effects seem to be linked to other discovered receptors such as GRP55, 5TH1a, TRPV I, TRPV II and the regulation of the intracellular concentration of Ca2+. Regarding oxidative stress, O2- can act as an oxidizing agent, being reduced to hydrogen peroxide (H2O2), or as a reducing agent, donating its extra electron to NO to form peroxynitrite (ONOO-). The ONOO- formed is capable of oxidizing proteins, lipids, and nucleic acids, causing several cell damages.

In this sense, CBD can prevent cardiac oxidative damage in many conditions, such as hypertension, diabetes, or even through the cardiotoxic effects induced by chemotherapy, which makes it a potential target for future clinical use to minimize the deleterious effects of many pathophysiologies.”