Does modulation of the endocannabinoid system have potential therapeutic utility in cerebellar ataxia?

Posted on March 13, 2016 by David

“Cerebellar ataxias represent a spectrum of disorders which are, however, linked by common symptoms of motor incoordination and are typically associated with deficient in Purkinje cell firing activity and, often, degeneration. Cerebellar ataxias currently lack a curative agent.

The endocannabinoid (eCB) system includes eCB compounds and their associated metabolic enzymes, together with cannabinoid receptors, predominantly the cannabinoid CB₁ receptor (CB₁ R) in the cerebellum; activation of this system in the cerebellar cortex is associated with deficits in motor coordination characteristic of ataxia, effects which can be prevented by CB₁ R antagonists.

Of further interest are various findings that CB₁ R deficits may also induce a progressive ataxic phenotype.

Together these studies suggest that motor coordination is reliant on maintaining the correct balance in eCB system signalling.

Recent work also demonstrates deficient cannabinoid signalling in the mouse ‘ducky^2J ‘ model of ataxia.

In light of these points, the potential mechanisms whereby cannabinoids may modulate the eCB system to ameliorate dysfunction associated with cerebellar ataxias are considered.”

http://www.ncbi.nlm.nih.gov/pubmed/26970080

Endocannabinoids and Endocannabinoid-Related Mediators: Targets, Metabolism and Role In Neurological Disorders.

Posted on March 12, 2016 by David

“The endocannabinoid system (ECS) is composed of two G protein-coupled receptors (GPCRs), the cannabinoid CB1 and CB2 receptors, and the two main endogenous lipid ligands of such receptors (also known as the “endocannabinoids”), anandamide and 2-arachidonoyl-glycerol. The ECS is a pleiotropic signalling systems involved in all aspects of mammalian physiology and pathology, and for this reason it represents a potential target for the design and development of new therapeutic drugs. However, the endocannabinoids as well as some of their congeners also interact with a much wider range of receptors, including members of the Transient Receptor Potential (TRP) channels, Peroxisome Proliferator-Activated Receptors (PPARs), and other GPCRs. Indeed, following the discovery of the endocannabinoids, endocannabinoid-related lipid mediators, which often share the same metabolic pathways of the endocannabinoids, have also been identified or rediscovered. In this review article, we discuss the role of endocannabinoids and related lipids during physiological functions, as well as their involvement is some of the most common neurological disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26965148

Cannabinoid receptors are involved in the protective effect of a novel curcumin derivative C66 against CCl4-induced liver fibrosis.

Posted on March 12, 2016 by David

“Liver fibrosis is one of the major causes of morbidity and mortality worldwide and lacks efficient therapy. Recent studies suggest the curcumin protects liver from fibrosis. However, curcumin itself is in low bioavailable concentration when administered orally, and the protective mechanism remains poorly understood. The current study aimed to investigate whether a more stable derivative of curcumin, C66, protects against CCl₄-inudced liver fibrosis and examine the underlying mechanism involving cannabinoid receptor (CB receptor). At a dose lower than curcumin itself, C66 displayed a superior anti-fibrotic effect. C66 significantly reduced collagen deposition, pro-inflammatory cytokine expression, and liver enzyme activities. Mechanistic study revealed that C66 treatment decreased CCl₄-induced cannabinoid receptor 1 (CB₁ receptor) expression and increased cannabinoidreceptor 2 (CB₂ receptor) expression, along with an inhibition of JNK/NF-κB-mediated inflammatory signaling. In conclusion, this curcumin derivative attenuates liver fibrosis likely involving a CB/JNK/NF-κB-mediated pathway.”

http://www.ncbi.nlm.nih.gov/pubmed/26945822

Plant-derived, synthetic and endogenous cannabinoids as neuroprotective agents. Non-psychoactive cannabinoids, ‘entourage’ compounds and inhibitors of N-acyl ethanolamine breakdown as therapeutic strategies to avoid pyschotropic effects.

Posted on February 23, 2016 by David

“There is good evidence that plant-derived and synthetic cannabinoids possess neuroprotective properties.

These compounds, as a result of effects upon CB(1) cannabinoid receptors, reduce the release of glutamate, and in addition reduce the influx of calcium following NMDA receptor activation.

The major obstacle to the therapeutic utilization of such compounds are their psychotropic effects, which are also brought about by actions on CB(1) receptors. However, synthesis of the endogenous cannabinoids anandamide and 2-arachidonoylglycerol, which also have neuroprotective properties, are increased under conditions of severe inflammation and ischemia, raising the possibility that compounds that prevent their metabolism may be of therapeutic utility without having the drawback of producing psychotropic effects.

In this review, the evidence indicating neuroprotective actions of plant-derived, synthetic and endogenous cannabinoids is presented. In addition, the pharmacological properties of endogenous anandamide-related compounds that are not active upon cannabinoid receptors, but which are also produced during conditions of severe inflammation and ischemia and may contribute to a neuroprotective action are reviewed.”

http://www.ncbi.nlm.nih.gov/pubmed/12505646

Endocannabinoid system in the brain…and elsewhere.

Posted on February 20, 2016 by David

“The endocannabinoid system is a complex system with endogenous ligands, synthesis and transport processes, specific receptors (CB1 and CB2) and intracellular degrading enzymes.

It is widely distributed in the central nervous system, but also in peripheral organs.

In the brain, endocannabinoids and CB1 receptors are almost ubiquitous and play a role in synaptic plasticity: they modulate, through an inhibitory retrograde action, the release of classical neurotransmitters such as amines, acetylcholine or amino acids.

They may exert a neuroprotective effect, but are also involved in appetite and alcohol/drug dependence.

At the periphery, they are present (and overexpressed in case of abdominal obesity) in various organs involved in energy control and metabolic regulation.

Furthermore, CB2 receptors are also present in the brain, although less numerous than CB1 receptors.

They could attenuate pain and also be neuroprotective.

Selective agonists, antagonists and inverse agonists of CB1 and CB2 receptors are currently developed and open new interesting therapeutic perspectives.”

http://www.ncbi.nlm.nih.gov/pubmed/18669206

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/

Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain.

Posted on February 19, 2016 by David

“We report the discovery of compound 4a, a potent β-lactam-based monoacylglycerol lipase (MGL) inhibitor characterized by an irreversible and stereoselective mechanism of action, high membrane permeability, high brain penetration evaluated using a human in vitro blood brain barrier model, high selectivity in binding and affinity-based proteomic profiling assays, and low in vitro toxicity.

Mode-of-action studies demonstrate that 4a, by blocking MGL, increases 2-arachidonoylglycerol, and behaves as cannabinoid (CB1/CB2) receptor indirect agonist.

Administration of 4a in mice suffering from experimental autoimmune encephalitis ameliorates the severity of the clinical symptoms in a CB1/CB2-dependent manner. Moreover, 4a produced analgesic effects in a rodent model of acute inflammatory pain, which was antagonized by CB1 and CB2 receptor antagonists/inverse agonists. 4a also relieves the neuropathic hypersensitivity induced by oxaliplatin.

Given these evidences, 4a, as MGL selective inhibitor, could represent a valuable lead for the future development of therapeutic options for multiple sclerosis and chronic pain.”

http://www.ncbi.nlm.nih.gov/pubmed/26888301

Cannabinoid receptor signaling regulates liver development and metabolism.

Posted on February 19, 2016 by David

“Endocannabinoid (EC) signaling mediates psychotropic effects and regulates appetite.

By contrast, potential roles in organ development and embryonic energy consumption remain unknown. Here, we demonstrate that genetic or chemical inhibition of cannabinoid receptor (Cnr) activity disrupts liver development and metabolic function in zebrafish (Danio rerio), impacting hepatic differentiation, but not endodermal specification: loss of cannabinoid receptor 1 (cnr1) and cnr2 activity leads to smaller livers with fewer hepatocytes, reduced liver-specific gene expression and proliferation.

Our work describes a novel developmental role for EC signaling, whereby Cnr-mediated regulation of Srebfs and methionine metabolism impacts liver development and function.”

http://www.ncbi.nlm.nih.gov/pubmed/26884397

Effects of chronic exercise on the endocannabinoid system in Wistar rats with high-fat diet-induced obesity.

Posted on February 18, 2016 by David

“The endocannabinoid system is dysregulated during obesity in tissues involved in the control of food intake and energy metabolism.

We examined the effect of chronic exercise on the tissue levels of endocannabinoids (eCBs) and on the expression of genes coding for cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) (Cnr1 and Cnr2, respectively) in the subcutaneous (SAT) and visceral adipose tissues and in the soleus and extensor digitorim longus (EDL) muscles, in rats fed with standard or high-fat diet…

The levels of eCBs and Cnr1 expression are altered in a tissue-specific manner following a high-fat diet, and chronic exercise reverses some of these alterations.”

http://www.ncbi.nlm.nih.gov/pubmed/26880264

Functions of the CB1 and CB 2 receptors in neuroprotection at the level of the blood-brain barrier.

Posted on February 17, 2016 by David

“The cannabinoid (CB) receptors are the main targets of the cannabinoids, which include plant cannabinoids, endocannabinoids and synthetic cannabinoids. Over the last few years, accumulated evidence has suggested a role of the CB receptors in neuroprotection.

The blood-brain barrier (BBB) is an important brain structure that is essential for neuroprotection. A link between the CB receptors and the BBB is thus likely, but this possible connection has only recently gained attention.

Cannabinoids and the BBB share the same mechanisms of neuroprotection and both protect against excitotoxicity (CB1), cell death (CB1), inflammation (CB2) and oxidative stress (possibly CB independent)-all processes that also damage the BBB.

Several examples of CB-mediated protection of the BBB have been found, such as inhibition of leukocyte influx and induction of amyloid beta efflux across the BBB.

Moreover, the CB receptors were shown to improve BBB integrity, particularly by restoring the tightness of the tight junctions. This review demonstrated that both CB receptors are able to restore the BBB and neuroprotection, but much uncertainty about the underlying signaling cascades still exists and further investigation is needed.”

http://www.ncbi.nlm.nih.gov/pubmed/24929655