Tag Archives: CB(1) and CB(2) receptors

Endocannabionoid System in Neurological Disorders.

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“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.

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“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

Effects of activation of endocannabinoid system on myocardial metabolism.

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“Endocannabinoids exert their effect on the regulation of energy homeostasis via activation of specific receptors. They control food intake, secretion of insulin, lipids and glucose metabolism, lipid storage. Long chain fatty acids are the main myocardial energy substrate. However, the heart exerts enormous metabolic flexibility emphasized by its ability to utilzation not only fatty acids, but also glucose, lactate and ketone bodies. Endocannabinoids can directly act on the cardiomyocytes through the CB1 and CB2 receptors present in cardiomyocytes. It appears that direct activation of CB1 receptors promotes increased lipogenesis, pericardial steatosis and bioelectrical dysfunction of the heart. In contrast, stimulation of CB2 receptors exhibits cardioprotective properties, helping to maintain appropriate amount of ATP in cardiomyocytes. Furthermore, the effects of endocannabinoids at both the central nervous system and peripheral tissues, such as liver, pancreas, or adipose tissue, resulting indirectly in plasma availability of energy substrates and affects myocardial metabolism. To date, there is little evidence that describes effects of activation of the endocannabinoid system in the cardiovascular system under physiological conditions. In the present paper the impact of metabolic diseases, i. e. obesity and diabetes, as well as the cardiovascular diseases – hypertension, myocardial ischemia and myocardial infarction on the deregulation of the endocannabinoid system and its effect on the metabolism are described.”

http://www.ncbi.nlm.nih.gov/pubmed/27333924

Harnessing the Endocannabinoid 2-Arachidonoylglycerol to Lower Intraocular Pressure in a Murine Model.

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“Cannabinoids, such as Δ9-THC, act through an endogenous signaling system in the vertebrate eye that reduces IOP via CB1 receptors.

Endogenous cannabinoid (eCB) ligand, 2-arachidonoyl glycerol (2-AG), likewise activates CB1 and is metabolized by monoacylglycerol lipase (MAGL). We investigated ocular 2-AG and its regulation by MAGL and the therapeutic potential of harnessing eCBs to lower IOP.

Our data confirm a central role for MAGL in metabolism of ocular 2-AG and related lipid species, and that endogenous 2-AG can be harnessed to reduce IOP. The MAGL blocker KML29 has promise as a therapeutic agent, while JZL184 may have difficulty crossing the cornea.

These data, combined with the relative specificity of MAGL for ocular monoacylglycerols and the lack of desensitization in MAGL-/- mice, suggest that the development of an optimized MAGL blocker offers therapeutic potential for treatment of elevated IOP.”

http://www.ncbi.nlm.nih.gov/pubmed/27333182

Activation of cannabinoid CB1 receptors suppresses the ROS-induced hypersensitivity of rat vagal lung C-fiber afferents.

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“Reactive oxygen species (ROS), including H2O2, have been shown to induce hypersensitivity of vagal lung C-fibers (VLCFs) mainly through receptor potential ankyrin 1 (TRPA1) and P2X receptors.

Cannabinoids (CBs) exert antinociceptive effects by binding to specific CB receptors, designated CB1 and CB2 (type 2) for type 1 and type 2, respectively.

We investigated whether activation of CB receptors can suppress ROS-mediated VLCF hypersensitivity and, if so, what type(s) of CB receptors are involved.

:Our results suggest that activation of CB1 receptors may suppress the ROS-mediated VLCF hypersensitivity through a mechanism that is at least partly distinct from the function of TRPA1 and P2X receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27328978

The multiplicity of spinal AA-5-HT anti-nociceptive action in a rat model of neuropathic pain.

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“There is considerable evidence to support the role of anandamide (AEA), an endogenous ligand of cannabinoid receptors, in neuropathic pain modulation. AEA also produces effects mediated by other biological targets, of which the transient receptor potential vanilloid type 1 (TRPV1) has been the most investigated. Both, inhibition of AEA breakdown by fatty acid amide hydrolase (FAAH) and blockage of TRPV1 have been shown to produce anti-nociceptive effects.

Recent research suggests the usefulness of dual-action compounds, which may afford greater anti-allodynic efficacy. Therefore, in the present study, we examined the effect of N-arachidonoyl-serotonin (AA-5-HT), a blocker of FAAH and TRPV1, in a rat model of neuropathic pain after intrathecal administration.

We found that treatment with AA-5-HT increased the pain threshold to mechanical and thermal stimuli, with highest effect at the dose of 500nM, which was most strongly attenuated by AM-630, CB2 antagonist, administration. The single action blockers PF-3845 (1000nM, for FAAH) and I-RTX (1nM, for TRPV1) showed lower efficacy than AA-5-HT. Moreover AA-5-HT (500nM) elevated AEA and palmitoylethanolamide (PEA) levels.

Among the possible targets of these mediators, only the mRNA levels of CB2, GPR18 and GPR55, which are believed to be novel cannabinoid receptors, were upregulated in the spinal cord and/or DRG of CCI rats. It was previously reported that AA-5-HT acts in CB1 and TRPV1-dependent manner after systemic administration, but here for the first time we show that AA-5-HT action at the spinal level involves CB2, with potential contributions from GRP18 and/or GPR55 receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27326920

The cannabinoid WIN 55,212-2 prevents neuroendocrine differentiation of LNCaP prostate cancer cells.

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“Neuroendocrine (NE) differentiation represents a common feature of prostate cancer and is associated with accelerated disease progression and poor clinical outcome. Nowadays, there is no treatment for this aggressive form of prostate cancer.

The aim of this study was to determine the influence of the cannabinoid WIN 55,212-2 (WIN, a non-selective cannabinoid CB1 and CB2 receptor agonist) on the NE differentiation of prostate cancer cells.

Taken together, we demonstrate that PI3K/Akt/AMPK might be an important axis modulating NE differentiation of prostate cancer that is blocked by the cannabinoid WIN, pointing to a therapeutic potential of cannabinoids against NE prostate cancer.”

http://www.ncbi.nlm.nih.gov/pubmed/27324222

Fatty acid amide hydrolase inhibition for the symptomatic relief of Parkinsońs disease.

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“Elements of the endocannabinoid system are strongly expressed in the basal ganglia where they suffer profound rearrangements after dopamine depletion.

Modulation of the levels of the endocannabinoid 2-arachidonoyl glycerol by inhibiting monoacylglycerol lipase alters glial phenotypes and provides neuroprotection in a mouse model of Parkinsońs disease.

In this study, we assessed whether inhibiting fatty acid amide hydrolase could also provide beneficial effects on the time course of this disease.

Together, these results demonstrate an effect of fatty acid amide hydrolase inhibition on the motor symptoms of Parkinsońs disease in two distinct experimental models that is mediated by cannabinoid receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27318096

Cannabinoids in the Brain: New Vistas on an Old Dilemma

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“The use of cannabis as a therapeutic and recreational substance goes back to thousands of years throughout Asia, Middle East, Southern Africa, and South America.

The discovery of Δ-9-tetrahydrocannabinol (Δ9-THC) by Mechoulam and Gaoni in the midsixties as the major psychoactive constituent of cannabis sativa led to another important discovery, namely, its specific binding site that was isolated and cloned in 1990. This first cannabinoid receptor was coined CB1R and triggered a number of investigations on its expression, localization, and function within the body tissue including the brain, in various species. This was followed by the discovery in 1992 of the first endocannabinoid (eCB), anandamide, followed by another cannabinoid receptor CB2R and a second endocannabinoid called 2-arachidonoylglycerol (2-AG). Later on, some of the enzymes responsible for their synthesis (N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD); diacylglycerol lipase (DAGL)) and degradation (fatty acid amide hydrolase (FAAH); monoacylglycerol lipase (MAGL)) were identified.

Studies on the expression and localization of the cannabinoid receptors in the brain have burgeoned in the last decade and have furnished valuable data on their putative involvement in various sensory-motor and cognitive functions in diverse animal species, including Man. These studies have recently received substantial attention from pharmaceutical companies as a potential source for novel treatments. Additionally, the dilemma of legalizing the use of cannabis in some countries makes the investigation on cannabinoid systems more momentous. This special issue is therefore timely and brings historical and groundbreaking novel research on the role of these cannabinoid receptors in the mammalian central nervous system (CNS).

We hope that the collected papers in this special issue will contribute to the understanding of the various mechanisms involved in the functions of the endocannabinoid system and the development of new pharmaceutical tools to treat visual disorders.”

http://www.hindawi.com/journals/np/2016/9146713/

CANNABIS CHEMICALS STOP PROSTATE CANCER GROWTH

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Image result for bjc british journal of cancer

“ACTIVE chemicals in cannabis have been shown to halt prostate cancer cell growth according to research published in the British Journal of Cancer*.

Researchers from the University of Alcala, in Madrid tested the effects of the active chemicals in cannabis called cannabinoids** on three human prostate cancer cell lines – called PC-3, DU-a45 and LNCaP.

The prostate cancer cells carry molecular ‘garages’- called receptors- in which cannabinoids can ‘park’.

The scientists showed for the first time that if cannabinoids ‘park’ on a receptor called CB2, the cancer cells stop multipyling.

“This research suggest that prostate cancer cells might stop growing if they are treated with chemicals found in cannabis but more work needs to be done to explore the potential of the cannabinoids in treatment.”

To confirm the findings the scientists switched off the CB2 receptors – or ‘closed the garage doors’- on the prostate cells. When cannabinoids were then added to cells without the CB2 receptor, the prostate cancer cells carried on dividing and growing. This suggests that cannabinoids connect with the CB2 receptors on prostate cancer cells to stop cell division and spread.

Professor Ines Diaz-Laviada, study author at the University of Alcala said: “Our research shows that there are areas on prostate cancer cells which can recognise and talk to chemicals found in cannabis called cannabinoids. These chemicals can stop the division and growth of prostate cancer cells and could become a target for new research into potential drugs to treat prostate cancer.””

http://www.nature.com/bjc/press_releases/p_r_aug09_6605248.html

https://www.news-medical.net/news/20090821/Cannabis-chemicals-stop-prostate-cancer-growth.aspx