ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

Posted on April 19, 2016 by David

Image result for Curr Clin Pharmacol.

“Cannabis sativa is also popularly known as marijuana. It is being cultivated and used by man for recreational and medicinal purposes from many centuries.

Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries.

The research of drugs acting on endocannabinoid system has seen many ups and down in recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve “protective role” in many medical conditions.

Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and Tourette’s syndrome could possibly be treated by drugs modulating endocannabinoid system.

Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008.

Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite of some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish the therapeutic targets for both cannabinoid receptor agonists and antagonists.

One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that acts selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted.

Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids.

In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as “protective” and “disease inducing substance”, time-dependent changes in the expression of cannabinoid receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27086601

The endocannabinoid system: novel pathway for cardiometabolic Risk-factor reduction.

Posted on February 20, 2016 by David

“Although rimonabant has been approved for use in several countries, the Food and Drug Administration has expressed concern about the potential for adverse neurologic and psychiatric effects, considering the widespread distribution of CB1 receptors in the brain. While more research is clearly needed, the clinical evidence shows that CB1-receptor blockade with rimonabant improves multiple cardiovascular and metabolic variables, including body weight and waist circumference, HDL-C, triglycerides, and glucose metabolism. Furthermore, these effects, which are probably mediated by both peripheral and central actions in the ECS, appear to be greater than the improvements that would be expected from weight loss alone. There are multiple ongoing and planned studies with rimonabant as well as several other CB-receptor blockers (e.g., taranabant, CP-945,598). While diet and exercise are the cornerstones of cardiometabolic risk-factor reduction, improved pharmacotherapies are urgently needed. The ECS has provided us with new insights and a promising new avenue for the management of obesity and its associated cardiometabolic risk factors.”

http://www.ncbi.nlm.nih.gov/pubmed/18047036

The endocannabinoid system: potential for reducing cardiometabolic risk.

Posted on February 20, 2016 by David

“The endocannabinoid system (ECS) affects multiple metabolic pathways in the brain and other organs. The transmembrane CB receptors were cloned in the early 1990s, followed shortly thereafter by the discovery of endogenous ligands, now known as endocannabinoids.

Three general types of cannabimimetic compounds have been described: herbal CBs, which occur uniquely in the cannabis plant (Cannabis sativa); endogenous CBs (or endocannabinoids), which are produced in the brain and peripheral tissues; and synthetic CBs, which are functionally similar compounds synthesized in the laboratory.

Obesity is associated with increased risk for insulin resistance, type 2 diabetes, nonalcoholic fatty liver disease, atherogenic dyslipidemia, and cardiovascular disease. Recent studies indicate that the body protects itself from weight loss by lowering energy expenditure. Both energy consumption and energy expenditure are regulated by hormones from a number of organs that act on the brain, as well as neural signals emanating from the brain itself.

Lifestyle modification is the initial intervention for obesity, with emphasis on reducing calorie intake and increasing physical activity; pharmacotherapy may be indicated for certain cardiovascular and metabolic risk factors.

This review focuses on the link between the biology of the cannabinoid receptor type 1 (CB₁ receptor) system and body-weight regulation, as well as clinical data from studies of the first CB₁ receptor antagonist…”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2905146/

The endocannabinoid system: a new approach to control cardiovascular disease.

Posted on February 20, 2016 by David

“The endocannabinoid (EC) system consists of 2 types of G-protein-coupled cannabinoid receptors–cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2)–and their natural ligands.

The EC system plays a key role in the regulation of food intake and fat accumulation, as well as glucose and lipid metabolism.

When overactivated, the EC system triggers dyslipidemia, thrombotic and inflammatory states, and insulin resistance.

Blocking CB1 receptors centrally and peripherally in adipose tissue can help normalize an overactivated EC system. CB1 blockade helps regulate food intake and adipose tissue metabolism, contributing to improved insulin sensitivity and other features of the metabolic syndrome.

Visceral adipose tissue is most closely associated with the metabolic syndrome, which is a constellation of conditions that place people at high risk for coronary artery disease.

Targeting the EC system represents a new approach to treating visceral obesity and reducing cardiovascular risk factors.”

http://www.ncbi.nlm.nih.gov/pubmed/16473257

http://www.thctotalhealthcare.com/category/cardiovascular-disease/

Hempseed as a nutritional resource: An overview

Posted on January 19, 2016 by David

“The seed of Cannabis sativa L. has been an important source of nutrition for thousands of years in Old World cultures. Technically a nut, hempseed typically contains over 30% oil and about 25% protein, with considerable amounts of dietary fiber, vitamins and minerals. Hempseed oil is over 80% in polyunsaturated fatty acids (PUFAs), and is an exceptionally rich source of the two essential fatty acids (EFAs) linoleic acid (18:2 omega-6) and alpha-linolenic acid (18:3 omega-3). The omega-6 to omega-3 ratio (n6/n3) in hempseed oil is normally between 2:1 and 3:1, which is considered to be optimal for human health. Hempseed has been used to treat various disorders for thousands of years in traditional oriental medicine.” http://link.springer.com/article/10.1007%2Fs10681-004-4811-6

The cardiac and haemostatic effects of dietary hempseed

Posted on January 19, 2016 by David

“Cannabis sativa L. is an annual plant in the Cannabaceae family. It has been an important source of food, fiber, medicine and psychoactive/religious drug since prehistoric times. Hemp has a botanical relationship to drug/medicinal varieties of Cannabis. However, hempseed no longer contains psychotropic action and instead may provide significant health benefits. Hempseed has an excellent content of omega-3 and omega-6 fatty acids. These compounds have beneficial effects on our cardiovascular health.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2868018/

Cannabidiol limits Tcell-mediated chronic autoimmune myocarditis: implications to autoimmune disorders and organ transplantation.

Posted on January 17, 2016 by David

“Myocarditis is a major cause of heart failure and sudden cardiac death in young adults and adolescents. Many cases of myocarditis are associated with autoimmune processes in which cardiac myosin is a major autoantigen.

Conventional immunosuppressive therapies often provide unsatisfactory results and are associated with adverse toxicities during the treatment of autoimmune myocarditis.

Cannabidiol (CBD) is a non-psychoactive constituent of Marijuana which exerts antiinflammatory effects independent from classical cannabinoid receptors.

Recently 80 clinical trials have been reported investigating the effects of CBD in various diseases from inflammatory bowel disease to graft-versus-host disease.

CBD-based formulations are used for the management of multiple sclerosis in numerous countries, and CBD also received FDA approval for the treatment of refractory childhood epilepsy and glioblastoma multiforme.

Herein, using a well-established mouse model of experimental autoimmune myocarditis (EAM) induced by immunization with cardiac myosin emmulsified in adjuvant resulting in T cell-mediated inflammation, cardiomyocyte cell death, fibrosis and myocardial dysfunction, we studied the potential beneficial effects of CBD…

CBD may represent a promising novel treatment for management of autoimmune myocarditis and possibly other autoimmune disorders, and organ transplantation.”

http://www.ncbi.nlm.nih.gov/pubmed/26772776

Abrupt Quitting of Long-term Heavy Recreational Cannabis Use is Not Followed by Significant Changes in Blood Pressure and Heart Rate.

Posted on January 14, 2016 by David

“To shed more light on the role of heart rate and blood pressure during cannabis withdrawal.

Abrupt cessation of recreational long-term daily cannabis use was not followed by significant changes in heart rate, blood and pulse pressure.

Also, these measures were not significantly correlated with the severity of the cannabis withdrawal syndrome.

The cohort’s risk for CVD was moderate (all tobacco using, overweight in 9 of 35 patients and elevation of serum C-reactive protein in many patients).

Its metabolic risk for CVD was minor considering the mostly normal blood pressure, normal serum lipids and glucose.“

http://www.ncbi.nlm.nih.gov/pubmed/26761126

Oxyradical Stress, Endocannabinoids, and Atherosclerosis.

Posted on December 26, 2015 by David

“Atherosclerosis is responsible for most cardiovascular disease (CVD) and is caused by several factors including hypertension, hypercholesterolemia, and chronic inflammation.

Oxidants and electrophiles have roles in the pathophysiology of atherosclerosis and the concentrations of these reactive molecules are an important factor in disease initiation and progression.

Overactive NADPH oxidase (Nox) produces excess superoxide resulting in oxidized macromolecules, which is an important factor in atherogenesis. Although superoxide and reactive oxygen species (ROS) have obvious toxic properties, they also have fundamental roles in signaling pathways that enable cells to adapt to stress.

In addition to inflammation and ROS, the endocannabinoid system (eCB) is also important in atherogenesis.

Linkages have been postulated between the eCB system, Nox, oxidative stress, and atherosclerosis.

For instance, CB2 receptor-evoked signaling has been shown to upregulate anti-inflammatory and anti-oxidative pathways, whereas CB1 signaling appears to induce opposite effects.

The second messenger lipid molecule diacylglycerol is implicated in the regulation of Nox activity and diacylglycerol lipase β (DAGLβ) is a key biosynthetic enzyme in the biosynthesis eCB ligand 2-arachidonylglycerol (2-AG).

Furthermore, Nrf2 is a vital transcription factor that protects against the cytotoxic effects of both oxidant and electrophile stress.

This review will highlight the role of reactive oxygen species (ROS) in intracellular signaling and the impact of deregulated ROS-mediated signaling in atherogenesis.

In addition, there is also emerging knowledge that the eCB system has an important role in atherogenesis.

We will attempt to integrate oxidative stress and the eCB system into a conceptual framework that provides insights into this pathology.”

http://www.ncbi.nlm.nih.gov/pubmed/26702404

http://www.thctotalhealthcare.com/category/atherosclerosis-2/

Characterization of Lignanamides from Hemp (Cannabis sativa L. ) Seed and their Antioxidant and Acetylcholinesterase Inhibitory Activities.

Posted on November 21, 2015 by David

Image result for J Agric Food Chem.

“Hempseed is known for its content in fatty acids, proteins and fiber, which contribute to its nutritional value.

Here we studied the secondary metabolites of hempseed aiming at identifying bioactive compounds that could contribute to its health benefits.

This investigation led to the isolation of four new lignanamides cannabisin M, 2, cannabisin N, 5, cannabisin O, 8 and 3,3′-demethyl-heliotropamide, 10, together with ten known lignanamides, among which 4 was identified for the first time from hempseed.

Structures were established on the basis of NMR, HR-MS, UV, IR as well as by comparison with the literature data.

Lignanamides 2, 7, 9-14 showed good antioxidant activity among which 7, 10 and 13 also inhibited acetylcholinesterase in vitro.

The new identified compounds in this study added to the diversity of hempseed composition and the bioassays implied that hempseed, with lignanamides as nutrients, may be a good source of bioactive and protective compounds.” http://www.ncbi.nlm.nih.gov/pubmed/26585089

“Alzheimer’s Disease (AD) is the most common single cause of dementia in our ageing society. On full assessment and diagnosis of AD, initiation of an AChe inhibitor is recommended as early as possible, it is important that AChe inhibitor therapy is considered for patients with mild to moderate AD.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014378/

“The Effects of Hempseed Meal Intake and Linoleic Acid on Drosophila Models of Neurodegenerative Diseases and Hypercholesterolemia. Our results indicate that hempseed meal (HSM) and linoleic acid are potential candidates for the treatment of Alzheimer’s disease (AD) and cardiovascular disease. These results show that HSM may prove of great utility as a health food, with potential for the prevention of AD and cardiovascular disease.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933972/