Endocannabinoids and the Cardiovascular System in Health and Disease.

Posted on September 27, 2015 by David

“The endocannabinoid system is widely distributed throughout the cardiovascular system.

Endocannabinoids play a minimal role in the regulation of cardiovascular function in normal conditions, but are altered in most cardiovascular disorders.

In shock, endocannabinoids released within blood mediate the associated hypotension through CB1 activation. In hypertension, there is evidence for changes in the expression of CB1, and CB1 antagonism reduces blood pressure in obese hypertensive and diabetic patients.

The endocannabinoid system is also upregulated in cardiac pathologies.

This is likely to be cardioprotective, via CB2 and CB1 (lesser extent).

In the vasculature, endocannabinoids cause vasorelaxation through activation of multiple target sites, inhibition of calcium channels, activation of potassium channels, NO production and the release of vasoactive substances. Changes in the expression or function of any of these pathways alter the vascular effect of endocannabinoids.

Endocannabinoids have positive (CB2) and negative effects (CB1) on the progression of atherosclerosis. However, any negative effects of CB1 may not be consequential, as chronic CB1 antagonism in large scale human trials was not associated with significant reductions in atheroma.

In neurovascular disorders such as stroke, endocannabinoids are upregulated and protective, involving activation of CB1, CB2, TRPV1 and PPARα.

Although most of this evidence is from preclinical studies, it seems likely that cannabinoid-based therapies could be beneficial in a range of cardiovascular disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26408169

Endocannabinoids and Metabolic Disorders.

Posted on September 27, 2015 by David

“The endocannabinoid system (ECS) is known to exert regulatory control on essentially every aspect related to the search for, and the intake, metabolism and storage of calories, and consequently it represents a potential pharmacotherapeutic target for obesity, diabetes and eating disorders.

While the clinical use of the first generation of cannabinoid type 1 (CB1) receptor blockers has been halted due to the psychiatric side effects that their use occasioned, recent research in animals and humans has provided new knowledge on the mechanisms of actions of the ECS in the regulation of eating behavior, energy balance, and metabolism.

In this review, we discuss these recent advances and how they may allow targeting the ECS in a more specific and selective manner for the future development of therapies against obesity, metabolic syndrome, and eating disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26408168

Endocannabinoids and the Endocrine System in Health and Disease.

Posted on September 27, 2015 by David

“Some of the earliest reports of the effects of cannabis consumption on humans were related to endocrine system changes. In this review, the effects of cannabinoids and the role of the CB1 cannabinoid receptor in the regulation of the following endocrine systems are discussed: the hypothalamic-pituitary-gonadal axis, prolactin and oxytocin, thyroid hormone and growth hormone, and the hypothalamic-pituitary-adrenal axis. Preclinical and human study results are presented.”

http://www.ncbi.nlm.nih.gov/pubmed/26408166

Cannabis and Endocannabinoid Signaling in Epilepsy.

Posted on September 27, 2015 by David

“The antiepileptic potential of Cannabis sativa preparations has been historically recognized.

Recent changes in legal restrictions and new well-documented cases reporting remarkably strong beneficial effects have triggered an upsurge in exploiting medical marijuana in patients with refractory epilepsy.

Parallel research efforts in the last decade have uncovered the fundamental role of the endogenous cannabinoid system in controlling neuronal network excitability raising hopes for cannabinoid-based therapeutic approaches.

However, emerging data show that patient responsiveness varies substantially, and that cannabis administration may sometimes even exacerbate seizures. Qualitative and quantitative chemical variability in cannabis products and personal differences in the etiology of seizures, or in the pathological reorganization of epileptic networks, can all contribute to divergent patient responses.

Thus, the consensus view in the neurologist community is that drugs modifying the activity of the endocannabinoid system should first be tested in clinical trials to establish efficacy, safety, dosing, and proper indication in specific forms of epilepsies.

To support translation from anecdote-based practice to evidence-based therapy, the present review first introduces current preclinical and clinical efforts for cannabinoid- or endocannabinoid-based epilepsy treatments.

Next, recent advances in our knowledge of how endocannabinoid signaling limits abnormal network activity as a central component of the synaptic circuit-breaker system will be reviewed to provide a framework for the underlying neurobiological mechanisms of the beneficial and adverse effects.

Finally, accumulating evidence demonstrating robust synapse-specific pathophysiological plasticity of endocannabinoid signaling in epileptic networks will be summarized to gain better understanding of how and when pharmacological interventions may have therapeutic relevance.”

http://www.ncbi.nlm.nih.gov/pubmed/26408165

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

Endocannabinoids and Mental Disorders.

Posted on September 27, 2015 by David

“Preclinical and clinical data fully support the involvement of the endocannabinoid system in the etiopathogenesis of several mental diseases.

In this review we will briefly summarize the most common alterations in the endocannabinoid system, in terms of cannabinoid receptors and endocannabinoid levels, present in mood disorders (anxiety, posttraumatic stress disorder, depression, bipolar disorder, and suicidality) as well as psychosis (schizophrenia) and autism.

The arising picture for each pathology is not always straightforward; however, both animal and human studies seem to suggest that pharmacological modulation of this system might represent a novel approach for treatment.”

http://www.ncbi.nlm.nih.gov/pubmed/26408164

Endocannabinoids and Neurodegenerative Disorders: Parkinson’s Disease, Huntington’s Chorea, Alzheimer’s Disease, and Others.

Posted on September 27, 2015 by David

“This review focuses on the role of the endocannabinoid signaling system in controlling neuronal survival, an extremely important issue to be considered when developing new therapies for neurodegenerative disorders.

First, we will describe the cellular and molecular mechanisms, and the signaling pathways, underlying these neuroprotective properties, including the control of glutamate homeostasis, calcium influx, the toxicity of reactive oxygen species, glial activation and other inflammatory events; and the induction of autophagy.

We will then concentrate on the preclinical studies and the few clinical trials that have been carried out targeting endocannabinoid signaling in three important chronic progressive neurodegenerative disorders (Parkinson’s disease, Huntington’s chorea, and Alzheimer’s disease), as well as in other less well-studied disorders.

We will end by offering some ideas and proposals for future research that should be carried out to optimize endocannabinoid-based treatments for these disorders.

Such studies will strengthen the possibility that these therapies will be investigated in the clinical scenario and licensed for their use in specific disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26408163

Endocannabinoids and the Immune System in Health and Disease.

Posted on September 27, 2015 by David

“Endocannabinoids are bioactive lipids that have the potential to signal through cannabinoid receptors to modulate the functional activities of a variety of immune cells.

Their activation of these seven-transmembranal, G protein-coupled receptors sets in motion a series of signal transductional events that converge at the transcriptional level to regulate cell migration and the production of cytokines and chemokines.

There is a large body of data that supports a functional relevance for 2-arachidonoylglycerol (2-AG) as acting through the cannabinoid receptor type 2 (CB2R) to inhibit migratory activities for a diverse array of immune cell types.

However, unequivocal data that supports a functional linkage of anandamide (AEA) to a cannabinoid receptor in immune modulation remains to be obtained.

Endocannabinoids, as typical bioactive lipids, have a short half-life and appear to act in an autocrine and paracrine fashion.

Their immediate effective action on immune function may be at localized sites in the periphery and within the central nervous system.

It is speculated that endocannabinoids play an important role in maintaining the overall “fine-tuning” of the immune homeostatic balance within the host.”

http://www.ncbi.nlm.nih.gov/pubmed/26408161

Genetic Manipulation of the Endocannabinoid System.

Posted on September 27, 2015 by David

“The physiological and pathophysiological functions of the endocannabinoid system have been studied extensively using transgenic and targeted knockout mouse models.

The first gene deletions of the cannabinoid CB1 receptor were described in the late 1990s, soon followed by CB2 and FAAH mutations in early 2000.

These mouse models helped to elucidate the fundamental role of endocannabinoids as retrograde transmitters in the CNS and in the discovery of many unexpected endocannabinoid functions, for example, in the skin, bone and liver.

We now have knockout mouse models for almost every receptor and enzyme of the endocannabinoid system.

Conditional mutant mice were mostly developed for the CB1 receptor, which is widely expressed on many different neurons, astrocytes and microglia, as well as on many cells outside the CNS.

These mouse strains include “floxed” CB1 alleles and mice with a conditional re-expression of CB1. The availability of these mice made it possible to decipher the function of CB1 in specific neuronal circuits and cell populations or to discriminate between central and peripheral effects.

Many of the genetic mouse models were also used in combination with viral expression systems.

The purpose of this review is to provide a comprehensive overview of the existing genetic models and to summarize some of the most important discoveries that were made with these animals.”

http://www.ncbi.nlm.nih.gov/pubmed/26408160

Distribution of the Endocannabinoid System in the Central Nervous System.

Posted on September 27, 2015 by David

“The endocannabinoid system consists of endogenous cannabinoids (endocannabinoids), the enzymes that synthesize and degrade endocannabinoids, and the receptors that transduce the effects of endocannabinoids.

Much of what we know about the function of endocannabinoids comes from studies that combine localization of endocannabinoid system components with physiological or behavioral approaches.

This review will focus on the localization of the best-known components of the endocannabinoid system for which the strongest anatomical evidence exists.”

http://www.ncbi.nlm.nih.gov/pubmed/26408158

Biosynthesis and Fate of Endocannabinoids.

Posted on September 27, 2015 by David

“Since the discovery of the two cannabinoid receptors, CB1 and CB2, several molecules, commonly defined as endocannabinoids, able to bind to and functionally activate these receptors, have been discovered and characterized.

Although the general thought was that the endocannabinoids were mainly derivatives of the n-6 fatty acid arachidonic acid, recent data have shown that also derivatives (ethanolamides) of n-3 fatty acids may be classified as endocannabinoids.

Whether the n-3 endocannabinoids follow the same biosynthetic and metabolic routes of the n-6 endocannabinoids is not yet clear and so warrants further investigation.

In this review, we describe the primary biosynthetic and metabolic pathways for the two well-established endocannabinoids, anandamide and 2-arachidonoylglycerol.”

http://www.ncbi.nlm.nih.gov/pubmed/26408157