Category Archives: Endocannabinoid System

The bright side of psychoactive substances: cannabinoid-based drugs in motor diseases.

Posted on by

“Psychoactive substances are associated with the idea of drugs with high addictive liability, affecting mental states, cognition, emotion and motor behavior. However these substances can modify synaptic transmission and help to disclose some mechanisms underlying alterations in brain processing and pathophysiology of motor disease. Hence, the “bright side” of cannabinoid-based drugs must be thoroughly examined to be identified within the latter framework.

We will analyze the preclinical and clinical evidence of cannabinoid-based drugs, discussing their therapeutic value in basal ganglia motor disorders such as Parkinson’s disease and Huntington disease.

Expert commentary: despite the knowledge acquired in the last years, the therapeutic potential of cannabinoid-based drugs should be further tested by novel routes of investigation. This should be focused on the role of cannabinoid signaling system in mitochondrial function as well as on the physical and functional interaction with other key receptorial targets belonging to this network.”

http://www.ncbi.nlm.nih.gov/pubmed/27373318

Medical Marijuana for Epilepsy?

Posted on by

“Treatment-refractory epilepsy remains an important clinical problem. There is considerable recent interest by the public and physicians in using medical marijuana or its derivatives to treat seizures. The endocannabinoid system has a role in neuronal balance and ictal control. There is clinical evidence of success in diminishing seizure frequencies with cannabis derivatives, but also documentation about exacerbating epilepsy or of no discernible effect. There are lay indications and anecdotal reports of success in attenuating the severity of epilepsy, but without solid investigational corroboration. Marijuana remains largely illegal, and may induce adverse consequences. Clinical applications are not approved, thus are restricted and only recommended in selected treatment unresponsive cases, with appropriate monitoring.”

http://www.ncbi.nlm.nih.gov/pubmed/27354925

Cannabinoid receptors in the kidney.

Posted on by

“The endocannabinoid system modulates cell signaling targets that are essential for energy homeostasis. Endocannabinoids bind to G protein-coupled receptors in the central nervous system and periphery, including the kidney. Modulation of cannabinoid receptor 1 (CB1) and CB2 activity in the kidney in diabetes and obesity has been identified as potential therapeutic target to reduce albuminuria and renal fibrosis.

CB1 and CB2 have been reported to play key roles in renal function and dysfunction. Recent studies have determined that antagonism of CB1 and agonism of CB2 in diabetic nephropathy and obesity associated kidney disease can reduce albuminuria, potentially by acting on both the glomeruli and tubules. Emerging studies have also identified a role for CB1 in renal diseases associated with fibrosis, with CB1 upregulated in multiple models of human nephropathies.

Emerging studies using isolated cells, rodent models, and human studies have identified a critical role for the endocannabinoid system in renal function and disease. Thus, therapeutics that modulate the activity of CB1 and CB2 in renal disease could become clinically relevant.”

http://www.ncbi.nlm.nih.gov/pubmed/27367912

 

Endocannabionoid System in Neurological Disorders.

Posted on by

“Several studies support the evidence that the endocannabinoid system and cannabimimetic drugs might have therapeutic potential in numerous pathologies. These pathologies range from neurological disorders, atherosclerosis, stroke, cancer to obesity/metabolic syndrome and others.

In this paper we review the endocannabinoid system signaling and its alteration in neurodegenerative disorders like multiple sclerosis, Alzheimer’s disease, Parkinson’s disease and Huntington’s disease and discuss the main findings about the use of cannabinoids in the therapy of these pathologies.

Despite different etiologies, neurodegenerative disorders exhibit similar mechanisms like neuro-inflammation, excitotoxicity, deregulation of intercellular communication, mitochondrial dysfunction and disruption of brain tissue homeostasis.

Current treatments ameliorate the symptoms but are not curative.

Interfering with the endocannabinoid signaling might be a valid therapeutic option in neuro-degeneration.

To this aim, pharmacological intervention to modulate the endocannabinoid system and the use of natural and synthetic cannabimimetic drugs have been assessed. CB1 and CB2 receptor signaling contributes to the control of Ca2+ homeostasis, trophic support, mitochondrial activity, and inflammatory conditions.

Several studies and patents suggest that the endocannabinoid system has neuro-protective properties and might be a target in neurodegenerative diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/27364363

Expression of the endocannabinoid receptors in human fascial tissue.

Posted on by

“Cannabinoid receptors have been localized in the central and peripheral nervous system as well as on cells of the immune system, but recent studies on animal tissue gave evidence for the presence of cannabinoid receptors in different types of tissues.

Their presence was supposed also in myofascial tissue, suggesting that the endocannabinoid system may help resolve myofascial trigger points and relieve symptoms of fibromyalgia.

However, until now the expression of CB1 (cannabinoid receptor 1) and CB2 (cannabinoid receptor 2) in fasciae has not yet been established.

Small samples of fascia were collected from volunteers patients during orthopedic surgery. For each sample were done a cell isolation, immunohistochemical investigation (CB1 and CB2 antibodies) and real time RT-PCR to detect the expression of CB1 and CB2.

Both cannabinoid receptors are expressed in human fascia and in human fascial fibroblasts culture cells, although to a lesser extent than the control gene. We can assume that the expression of mRNA and protein of CB1 and CB2 receptors in fascial tissue are concentrated into the fibroblasts.

This is the first demonstration that the fibroblasts of the muscular fasciae express CB1 and CB2. The presence of these receptors could help to provide a description of cannabinoid receptors distribution and to better explain the role of fasciae as pain generator and the efficacy of some fascial treatments.

Indeed the endocannabinoid receptors of fascial fibroblasts can contribute to modulate the fascial fibrosis and inflammation.”

http://www.ncbi.nlm.nih.gov/pubmed/27349320

The Cannabinoid Receptor 2 Protects Against Alcoholic Liver Disease Via a Macrophage Autophagy-Dependent Pathway.

Posted on by

“Kupffer cells, the resident macrophages of the liver, play a major role in the pathogenesis of alcoholic liver disease. We have previously demonstrated that CB2 receptor protects against alcoholic liver disease by inhibiting alcohol-induced inflammation and steatosis via the regulation of Kupffer cell activation.

Here, we explored the mechanism underlying these effects and hypothesized that the anti-inflammatory properties of CB2 receptor in Kupffer cells rely on activation of autophagy.

Altogether these results demonstrate that CB2 receptor activation in macrophages protects from alcohol-induced steatosis by inhibiting hepatic inflammation through an autophagy-dependent pathway.”

http://www.ncbi.nlm.nih.gov/pubmed/27346657

Fatty Acid Amide Hydrolase Binding in Brain of Cannabis Users: Imaging With the Novel Radiotracer [11C]CURB.

Posted on by

“One of the major mechanisms for terminating the actions of the endocannabinoid anandamide is hydrolysis by fatty acid amide hydrolase (FAAH), and inhibitors of the enzyme were suggested as potential treatment for human cannabis dependence.

In cannabis users, FAAH binding was significantly lower by 14%-20% across the brain regions examined than in matched control subjects.

Lower FAAH binding levels in the brain may be a consequence of chronic and recent cannabis exposure and could contribute to cannabis withdrawal. This effect should be considered in the development of novel treatment strategies for cannabis use disorder that target FAAH and endocannabinoids.”

http://www.ncbi.nlm.nih.gov/pubmed/27345297

Dissecting the signaling pathways involved in the crosstalk between mGlu5 and CB1 receptors.

Posted on by

“The metabotropic glutamate (mGlu) receptor 5 and the cannabinoid type 1 (CB1) receptor are G-protein-coupled receptors (GPCR) that are widely expressed in the central nervous system (CNS). mGlu5 receptors, present at the postsynaptic site, are coupled to Gαq/11 proteins and display an excitatory response upon activation, while the CB1 receptor, mainly present at presynaptic terminals, is coupled to the Gi/o protein and triggers an inhibitory response. Recent studies suggest that the glutamatergic and endocannabinoid systems exhibit a functional interaction to modulate several neural processes. In this review we discuss possible mechanisms involved in this crosstalk and its relationship with physiological and pathological conditions, including nociception, addiction and fragil X syndrome.”

http://www.ncbi.nlm.nih.gov/pubmed/27338080

Anatomical characterization of the cannabinoid cb1 receptor in cell type-specific mutant mouse rescue models.

Posted on by

“Type-1 cannabinoid (CB1 ) receptors are widely distributed in the brain. Their physiological roles depend on their distribution pattern that differs remarkably among cell types. Hence, subcellular compartments with little but functional relevant CB1 receptors can be overlooked, fostering an incomplete mapping. To overcome this, knock-in mice with cell-type specific rescue of CB1 receptors have emerged as excellent tools to investigate its cell type-specific localization and sufficient functional role with no bias.

However, to know whether these rescue mice maintain endogenous CB1 receptor expression level, detailed anatomical studies are called for. The subcellular distribution of hippocampal CB1 receptors of rescue mice that express the gene exclusively in dorsal telencephalic glutamatergic neurons (Glu-CB1 -RS) or GABAergic neurons (GABA-CB1 -RS) was studied by immunoelectron microscopy. Results were compared with conditional CB1 receptor knock-out lines.

As expected, CB1immunoparticles appeared at presynaptic plasmalemma making asymmetric and symmetric synapses. In the hippocampal CA1 stratum radiatum, the values of the CB1 receptor immunopositive excitatory and inhibitory synapses were: Glu-CB1 -RS: 21.89% (glutamatergic terminals); 2.38% (GABAergic terminals); GABA-CB1 -RS: 1.92% (glutamatergic terminals); 77.92% (GABAergic terminals). The proportion of CB1 receptor immunopositive excitatory and inhibitory synapses in the inner third of the dentate molecular layer was: Glu-CB1 -RS: 53.19% (glutamatergic terminals); 2.30% (GABAergic terminals); GABA-CB1 -RS: 3.19% (glutamatergic terminals); 85.07% (GABAergic terminals).

Taken together, Glu-CB1 -RS and GABA-CB1 -RS mice show the usual CB1 receptor distribution and expression in hippocampal cell types with specific rescue of the receptor, being therefore ideal for in-depth anatomical and functional investigations of the endocannabinoid system.”

http://www.ncbi.nlm.nih.gov/pubmed/27339436

The multiple waves of cannabinoid 1 receptor signaling.

Posted on by

“The cannabinoid 1 receptor (CB1R) is one of the most abundant G protein-coupled receptor (GPCR) in the CNS with key roles during neurotransmitter release and synaptic plasticity. Upon ligand activation, CB1Rs may signal in three different spatiotemporal waves.

The first wave is transient (<10 minutes) and is initiated by heterotrimeric G proteins followed by a second wave (>10 minutes) mediated by beta-arrestins. A final third wave occurs at intracellular compartments and could be elicited by G proteins or beta-arrestins.

This functional complexity presents multiple challenges, from the correct classification of receptor ligands to the identification of the signaling pathways regulated by each wave and their underlying molecular mechanisms and physiological impact.

Simultaneously, it provides new opportunities to harness the therapeutic potential of the cannabinoid system.

Over the last several years, we have significantly expanded our understanding of the mechanisms and pathways downstream from CB1R. The identification of mutations in the receptor that can bias signaling to specific pathways and the use of siRNA technology in combination with toxins have been key tools to identify which signaling cascades are controlled by G proteins or beta-arrestins.

Here, we review our current knowledge of the multiple waves of CB1R signaling with particular emphasis on the mechanisms and cascades mediated by beta-arrestins downstream from the CB1R.”

http://www.ncbi.nlm.nih.gov/pubmed/27338082