Targeting GPCRs Against Cardiotoxicity Induced by Anticancer Treatments.

Image result for frontiers in cardiovascular medicine“Novel anticancer medicines, including targeted therapies and immune checkpoint inhibitors, have greatly improved the management of cancers. However, both conventional and new anticancer treatments induce cardiac adverse effects, which remain a critical issue in clinic.

Cardiotoxicity induced by anti-cancer treatments compromise vasospastic and thromboembolic ischemia, dysrhythmia, hypertension, myocarditis, and cardiac dysfunction that can result in heart failure. Importantly, none of the strategies to prevent cardiotoxicity from anticancer therapies is completely safe and satisfactory.

Certain clinically used cardioprotective drugs can even contribute to cancer induction. Since G protein coupled receptors (GPCRs) are target of forty percent of clinically used drugs, here we discuss the newly identified cardioprotective agents that bind GPCRs of adrenalin, adenosine, melatonin, ghrelin, galanin, apelin, prokineticin and cannabidiol.

We hope to provoke further drug development studies considering these GPCRs as potential targets to be translated to treatment of human heart failure induced by anticancer drugs.”

https://www.ncbi.nlm.nih.gov/pubmed/32039239

https://www.frontiersin.org/articles/10.3389/fcvm.2019.00194/full

“Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis.”  https://www.ncbi.nlm.nih.gov/pubmed/25569804

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Activation of Cannabinoid Receptors Attenuates Endothelin-1-induced Mitochondrial Dysfunction in Rat Ventricular Myocytes.

Image result for Journal of Cardiovascular Pharmacology.“Evidence suggests that activation of the endocannabinoid system offers cardioprotection.

Aberrant energy production by impaired mitochondria purportedly contributes to various aspects of cardiovascular disease. We investigated whether cannabinoid (CB) receptor activation would attenuate mitochondrial dysfunction induced by endothelin-1 (ET1).

Acute exposure to ET1 (4 h) in the presence of palmitate as primary energy substrate induced mitochondrial membrane depolarization, and decreased mitochondrial bioenergetics and expression of genes related to fatty acid oxidation (i.e. peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α, a driver of mitochondrial biogenesis, and carnitine palmitoyltransferase (CPT)-1β, facilitator of fatty acid uptake).

A CB1/CB2 dual agonist with limited brain penetration, CB-13, corrected these parameters. AMP-activated protein kinase (AMPK), an important regulator of energy homeostasis, mediated the ability of CB-13 to rescue mitochondrial function. In fact, the ability of CB-13 to rescue fatty acid oxidation-related bioenergetics, as well as expression of PGC-1α and CPT-1β, was abolished by pharmacological inhibition of AMPK using compound C and shRNA knockdown of AMPKα1/α2, respectively.

Interventions that target CB/AMPK signaling might represent a novel therapeutic approach to address the multi-factorial problem of cardiovascular disease.”

https://www.ncbi.nlm.nih.gov/pubmed/31815823

https://insights.ovid.com/crossref?an=00005344-900000000-98463

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The effect of high maternal linoleic acid on endocannabinoid signalling in rodent hearts.

Image result for journal of developmental origins of health and disease “The endocannabinoid system (ECS), modulated by metabolites of linoleic acid (LA), is important in regulating cardiovascular function.

In pregnancy, LA is vital for foetal development.

Data indicate that a high LA diet alters cell viability and CB2 expression, potentially influencing cardiac function during pregnancy and development of the offspring’s heart.”

https://www.ncbi.nlm.nih.gov/pubmed/31814560

https://www.cambridge.org/core/journals/journal-of-developmental-origins-of-health-and-disease/article/effect-of-high-maternal-linoleic-acid-on-endocannabinoid-signalling-in-rodent-hearts/C92E2C1126249B7CF9D8A929F0E52FA2

“A number of previous studies have shown that polyunsaturated fatty acids (PUFAs) and phytosterols are critically important for human health. Hempseed is a rich source of plant oil, which contains more than 80% PUFAs. The fatty acids in hempseed oil include a variety of essential fatty acids, including linoleic acid ”

https://link.springer.com/article/10.1007%2Fs10059-011-0042-6

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The protective mechanism of cannabidiol in cardiac injury: A systematic review of non-clinical studies.

“Cardiac disease is accounted as the leading cause of worldwide morbidity and mortality, mainly in association with induction of inflammation and oxidative stress. The disease is characterized by the overproduction of reactive oxygen and/or nitrogen species (ROS/RNS), and reduced antioxidant capacity.

Cannabidiol (CBD) is a non-psychoactive ingredient of marijuana that reported to be safe and well tolerated in patients. Due to its pleiotropic effect, CBD has been shown to exert cytoprotective effects. This study intended to clarify the mechanisms and the potential role of CBD regarding cardiac injuries treatment.

RESULTS:

Our findings obviously demonstrate that CBD has multi-functional protective assets to improve cardiac injuries; preliminary through scavenging of free radicals, and reduction of oxidative stress, apoptosis, and inflammation.

CONCLUSION:

CBD can protect against cardiac injuries, mainly through its anti-oxidant, anti-inflammatory, and anti-apoptotic effects on the basis of non-clinical studies.”

https://www.ncbi.nlm.nih.gov/pubmed/31291873

http://www.eurekaselect.com/173374/article

“Cytoprotection is a process by which chemical compounds provide protection to cells against harmful agents.” https://en.wikipedia.org/wiki/Cytoprotection

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β-Caryophyllene, a natural bicyclic sesquiterpene attenuates doxorubicin-induced cardiotoxicity via activation of myocardial cannabinoid type-2 (CB2) receptors in rats.

Chemico-Biological Interactions

“The cannabinoid type 2 receptor (CB2) has recently emerged as an important therapeutic target for cancer as well as cardiovascular diseases. The CB2 receptor downregulation has been reported in solid tumors and cardiovascular diseases, therefore the CB2receptor activation has been considered as a viable strategy for chemotherapy as well as cardioprotection.

In chemotherapy, doxorubicin (DOX) is an important drug that continues to be the mainstay of chemotherapy in solid tumors, leukemia, and lymphoma. However, the use of DOX is often limited due to its lethal cardiotoxicity. Considering the role of CB2 receptors in cardiovascular diseases and cancer, the activation of CB2 receptors may protect against DOX-induced chronic cardiotoxicity in rats.

In the present study, we investigated the cardioprotective effect of a selective CB2 receptor agonist; β-Caryophyllene (BCP), a natural bicyclic sesquiterpene, against DOX-induced chronic cardiotoxicity in rats. AM630, a CB2 receptor antagonist was administered as a pharmacological challenge prior to BCP treatment to demonstrate CB2 receptor mediated cardioprotective mechanism of BCP. DOX (2.5 mg/kg) was injected intraperitoneally once a week for five weeks to induce chronic cardiotoxicity in rats.

BCP was also injected into rats six days a week for a total duration of five weeks. DOX induced a significant decline in cardiac function and oxidative stress evidenced by the depletion of antioxidant enzymes, glutathione, and increased lipid peroxidation. DOX also triggered activation of nuclear factor kappa B (NF-κB) and increased the levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) and expression of the inflammatory mediators (iNOS and COX-2) in the heart.

Furthermore, DOX also upregulated the expression of pro-apoptotic markers such as Bax, p53, cleaved PARP, active caspase-3 and downregulated anti-apoptotic marker Bcl-2 in the myocardium. BCP treatment exerted significant cardioprotective effect by salvaging the heart tissues, improving cardiac function, mitigating oxidative stress, inflammation, and apoptosis. The histological and ultrastructural studies also appear in line with our findings of biochemical and molecular parameters.

The CB2 receptor-mediated cardioprotective mechanism was further confirmed by the abrogation of the beneficial effects of BCP with prior administration of the CB2 receptor antagonist; AM630.

Our study revealed the novel mechanism of BCP in cardioprotection against DOX-induced chronic cardiotoxicity by the activation of CB2 receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/30836069

https://www.sciencedirect.com/science/article/pii/S0009279718316284?via%3Dihub

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934

“Beta-caryophyllene is a dietary cannabinoid.”   https://www.ncbi.nlm.nih.gov/pubmed/18574142

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Selective Activation of Cannabinoid Receptor 2 Attenuates Myocardial Infarction via Suppressing NLRP3 Inflammasome.

“The administration of cannabinoid receptor 2 (CB2R) agonist has been reported to produce a cardioprotective effect against the pathogenesis and progression of myocardial infarction (MI).

Here in this study, we investigated the specific mechanism related to inflammatory suppression. JWH-133 was used for the activation of CB2R.

Taken together, we demonstrated for the first time the cardioprotective effect of CB2R agonist and its NLRP3 inflammasome-related mechanism in MI.”

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Activating Cannabinoid Receptor 2 Protects Against Diabetic Cardiomyopathy Through Autophagy Induction.

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“Cannabinoid receptor 2 (CB2) has been reported to produce a cardio-protective effect in cardiovascular diseases such as myocardial infarction. Here in this study, we investigated the role of CB2 in diabetic cardiomyopathy (DCM) and its underlying mechanisms.

In conclusion, we initially demonstrated that activating CB2 produced a cardio-protective effect in DCM as well as cardiomyocytes under HG challenge through inducing the AMPK-mTOR-p70S6K signaling-mediated autophagy.”

https://www.ncbi.nlm.nih.gov/pubmed/30459625

“Taken together, in this study, we initially showed that activating CB2 produced a cardio-protective effect in DCM as well as cardiomyocytes under HG challenge through the induction of the AMPK-mTOR-p70S6K signaling-mediated autophagy process. We believe that the findings of this study might enhance our knowledge on the understanding of the pathogenesis and progression of DCM and provide a novel insight in the development of therapeutic strategies against DCM.”

https://www.frontiersin.org/articles/10.3389/fphar.2018.01292/full

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A systematic review on the neuroprotective perspectives of beta-caryophyllene.

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“Beta (β)-caryophyllene (BCAR) is a major sesquiterpene of various plant essential oils reported for several important pharmacological activities, including antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, antimicrobial, and immune-modulatory activity. Recent studies suggest that it also possesses neuroprotective effect.

This study reviews published reports pertaining to the neuropharmacological activities of BCAR. Databases such as PubMed, Scopus, MedLine Plus, and Google Scholar with keywords “beta (β)-caryophyllene” and other neurological keywords were searched. Data were extracted by referring to articles with information about the dose or concentration/route of administration, test system, results and discussion, and proposed mechanism of action.

A total of 545 research articles were recorded, and 41 experimental studies were included in this review, after application of exclusion criterion. Search results suggest that BCAR exhibits a protective role in a number of nervous system-related disorders including pain, anxiety, spasm, convulsion, depression, alcoholism, and Alzheimer’s disease.

Additionally, BCAR has local anesthetic-like activity, which could protect the nervous system from oxidative stress and inflammation and can act as an immunomodulatory agent. Most neurological activities of this natural product have been linked with the cannabinoid receptors (CBRs), especially the CB2R. This review suggests a possible application of BCAR as a neuroprotective agent.”

https://www.ncbi.nlm.nih.gov/pubmed/30281175

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.” http://www.ncbi.nlm.nih.gov/pubmed/23138934

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Cannabinoids, the Heart of the Matter

Image result for jaha journal

“Cardiovascular disease (CVD) is a global epidemic representing the leading cause of death in some Western countries. Endocannabinoids and cannabinoid‐related compounds may be a promising approach as therapeutic agents for cardiovascular diseases. This review highlights the potential of cannabinoids and their receptors as targets for intervention.

In summary, the endocannabinoid system is highly active in cardiovascular disease states. Modulation of the ECS, CB1, and TRPV1 antagonism, as well as CB2 agonism, have proven to modulate disease state and severity in CVD. Studies are underway to develop drugs to change the course of cardiovascular diseases.

If therapeutic potential resides in a single molecule component or a derivative, then production and regulation of the therapy are straightforward. If the efficacious agent is a complex mixture that reflects some or all of the secondary metabolome complexity of Cannabis sativa, then safe and consistent production become challenging.”  http://jaha.ahajournals.org/content/7/14/e009099https://www.ncbi.nlm.nih.gov/pubmed/30006489

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Relation of Cannabis Use and Atrial Fibrillation Among Patients Hospitalized for Heart Failure.

 The American Journal of Cardiology

“Left ventricular dysfunction triggers the activation of the sympathetic nervous system, providing inotropic support to the failing heart and concomitantly increasing the risk of atrial fibrillation (AF). The cardiovascular effects of cannabis have been characterized as biphasic on the autonomic nervous system with an increased sympathetic effect at low doses and an inhibitory sympathetic activity at higher doses. It is unknown if the autonomic effect of cannabis impacts the occurrence of AF in patients with heart failure (HF).

We used data from the Healthcare Cost and Utilization Project-National Inpatient Sample for patients admitted with a diagnosis of HF in 2014. The outcome variable was the diagnosis of AF, with the main exposure being cannabis use. We identified a cannabis user group and a 1:1 propensity-matched non-cannabis user group, each having 3,548 patients. We then estimated the odds of AF diagnosis in cannabis users. An estimated 3,950,392 patients were admitted with a diagnosis of HF in the United States in 2014. Among these, there were 17,755 (0.45%) cannabis users. In the matched cohort, cannabis users were less likely to have AF (19.08% vs 21.39%; AOR 0.87 [0.77 to 0.98]).

In conclusion, cannabis users have lower odds of AF when compared with nonusers, which was not explained by co-morbid conditions, age, insurance type, and socioeconomic status.”

https://www.ncbi.nlm.nih.gov/pubmed/29685570

“Surprising Find: Marijuana Linked with Benefits for Heart Failure Patients. Heart failure patients who used marijuana were also less likely to die in the hospital than those who didn’t use the drug, the study found.”  https://www.livescience.com/60988-marijuana-heart-failure.html

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