Overlapping molecular pathways between cannabinoid receptors type 1 and 2 and estrogens/androgens on the periphery and their involvement in the pathogenesis of common diseases (Review).

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“The physiological and pathophysiological roles of sex hormones have been well documented and the modulation of their effects is applicable in many current treatments.

On the other hand, the physiological role of endocannabinoids is not yet clearly understood and the endocannabinoid system is considered a relatively new therapeutic target.

The physiological association between sex hormones and cannabinoids has been investigated in several studies; however, its involvement in the pathophysiology of common human diseases has been studied separately.

Herein, we present the first systematic review of molecular pathways that are influenced by both the cannabinoids and sex hormones, including adenylate cyclase and protein kinase A, epidermal growth factor receptor, cyclic adenosine monophosphate response element-binding protein, vascular endothelial growth factor, proto-oncogene serine/threonine-protein kinase, mitogen-activated protein kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, C-Jun N-terminal kinase and extracellular-signal-regulated kinases 1/2.

Most of these influence cell proliferative activity.

Better insight into this association may prove to be beneficial for the development of novel pharmacological treatment strategies for many common diseases, including breast cancer, endometrial cancer, prostate cancer, osteoporosis and atherosclerosis.

The associations between cannabinoids, estrogens and androgens under these conditions are also presented and the molecular interactions are highlighted.”

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N-Oleoylethanolamine Reduces Inflammatory Cytokines and Adhesion Molecules in TNF-α-induced Human Umbilical Vein Endothelial Cells by Activating CB2 and PPAR-α.

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“Inflammation plays a pivotal role in the pathogenesis of atherosclerosis.

Peroxisome proliferator-activated receptor-alpha (PPAR-α) and cannabinoid receptor 2 (CB2) crucially impact the modulation of inflammation.

N-Oleoylethanolamine (OEA), a natural agonist of PPAR-α, can also up-regulate the expression of CB2 in human umbilical vein endothelial cells (HUVECs) and further shows an antiatherosclerotic effect.

Our study was designed to determinate whether OEA could inhibit inflammation in HUVECs induced by tumor necrosis factor-α (TNF-α) and to identify the mechanism of OEA function.

These results suggest that OEA exerts anti-inflammatory and anti-adhesive effects on HUVECs.”

https://www.ncbi.nlm.nih.gov/pubmed/27281236

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Cannabidiol-2′,6′-dimethyl ether as an effective protector of 15-lipoxygenase-mediated low-density lipoprotein oxidation in vitro.

“15-Lipoxygenase (15-LOX) is one of the key enzymes responsible for the formation of oxidized low-density lipoprotein (ox-LDL), a major causal factor for atherosclerosis.

We have recently reported that cannabidiol-2′,6′-dimethyl ether (CBDD) is a selective and potent inhibitor of 15-LOX-catalyzed linoleic acid oxygenation.

The results obtained demonstrate that CBDD is a potent and selective inhibitor of ox-LDL formation generated by the 15-LOX pathway.

These studies establish CBDD as both an important experimental tool for characterizing 15-LOX-mediated ox-LDL formation, and as a potentially useful therapeutic agent for treatment of atherosclerosis.

In sum, these findings suggest that CBDD may be a useful adjuvant in the treatment of atherosclerosis as well as an experimental tool for analyzing the mechanistic details of PUFAs oxygenation by 15-LOX.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012644/

“Cannabidiol-2′,6′-dimethyl ether, a cannabidiol derivative, is a highly potent and selective 15-lipoxygenase inhibitor. Thus, 15-LOX is suggested to be involved in development of atherosclerosis, and CBDD may be a useful prototype for producing medicines for atherosclerosis.”  http://www.ncbi.nlm.nih.gov/pubmed/19406952

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Selective activation of CB2 receptor improves efferocytosis in cultured macrophages.

“Recent evidence indicates that the defective ability to clear apoptotic cells by macrophages (efferocytosis) and the resultant apoptotic cells accumulation in atherosclerotic plaques play an important role during the progression of unstable plaques.

The cannabinoid type 2 receptor (CB2), has recently been emerging as a new target to reduce vulnerability and promote stability of plaques, however, the underlying mechanisms have not been studied in detail. In the present study, we investigated whether selective activation of CB2 improves efferocytosis of macrophages.

SIGNIFICANCE:

The selective activation of CB2 improves efferosytosis of normal-cultured and OxLDL-loaded macrophages, which might provide a novel mechanism on how CB2 activation reduces vulnerability and promotes stability of atherosclerotic plaques.”

http://www.ncbi.nlm.nih.gov/pubmed/27474129

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Cannabis compound benefits blood vessels

This computer rendition shows how fatty deposits can narrow blood vessels.

“Low dose helps combat formation of arterial blockages.

A compound derived from the cannabis plant protects blood vessels from dangerous clogging, a study of mice has shown.

The compound, called delta-9-tetrahydrocannabinol (THC), combats the blood-vessel disease atherosclerosis in mice.

The discovery could lead to new drugs to ward off heart disease and stroke.”

http://www.nature.com/news/2005/050404/full/news050404-7.html

 

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Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption.

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“Cannabinoids, components of the Cannabis sativa (marijuana) plant, are known to exert potent anti-inflammatory, immunomodulatory and analgesic effects through activation of cannabinoid-1 and -2 (CB1 and CB2) receptors located in the central nervous system and immune cells.

The limitation of the therapeutic utility of the major cannabinoid, Δ9-tetrahydrocannabinol, is the development of psychoactive effects through central nervous system CB1 receptor. In contrast, cannabidiol (CBD), one of the most abundant cannabinoids of Cannabis sativa with reported antioxidant, anti-inflammatory, and immunomodulatory effects is well tolerated without side effects when chronically administered to humans and is devoid of psychoactive properties due to a low affinity for the CB1 and CB2 receptors.

A nonpsychoactive cannabinoid cannabidiol (CBD) has been shown to exert potent anti-inflammatory and antioxidant effects and has recently been reported to lower the incidence of diabetes in nonobese diabetic mice and to preserve the blood-retinal barrier in experimental diabetes.

In this study we have investigated the effects of CBD on high glucose (HG)-induced, mitochondrial superoxide generation, NF-κB activation, nitrotyrosine formation, inducible nitric oxide synthase (iNOS) and adhesion molecules ICAM-1 and VCAM-1 expression, monocyte-endothelial adhesion, transendothelial migration of monocytes, and disruption of endothelial barrier function in human coronary artery endothelial cells (HCAECs).

HG markedly increased mitochondrial superoxide generation (measured by flow cytometry using MitoSOX), NF-κB activation, nitrotyrosine formation, upregulation of iNOS and adhesion molecules ICAM-1 and VCAM-1, transendothelial migration of monocytes, and monocyte-endothelial adhesion in HCAECs. HG also decreased endothelial barrier function measured by increased permeability and diminished expression of vascular endothelial cadherin in HCAECs.

Remarkably, all the above mentioned effects of HG were attenuated by CBD pretreatment.

Since a disruption of the endothelial function and integrity by HG is a crucial early event underlying the development of various diabetic complications, our results suggest that CBD, which has recently been approved for the treatment of inflammation, pain, and spasticity associated with multiple sclerosis in humans, may have significant therapeutic benefits against diabetic complications and atherosclerosis.

Collectively, our results suggest that the nonpsychoactive cannabinoid CBD have significant therapeutic benefits against diabetic complications and atherosclerosis by attenuating HG-induced mitochondrial superoxide generation, increased NF-κB activation, upregulation of iNOS and adhesion molecules, 3-NT formation, monocyte-endothelial adhesion, TEM of monocytes, and disruption of the endothelial barrier function.

This is particularly encouraging in light of the excellent safety and tolerability profile of CBD in humans.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2228254/

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Endocannabionoid System in Neurological Disorders.

“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

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Cannabimimetic Drugs: Recent Patents in Central Nervous System Disorders.

“Agents acting via cannabinoid receptors have been widely developed; starting from the chemical structure of phytocannabinoids isolated from cannabis sativa plant, specific and selective compounds of these receptors have been produced ranging from partial to full agonists and /or antagonists endowed with different potency.

The enhanced interest on developing such classes of drugs is due to the beneficial properties widely reported by both anecdotal reports and scientific studies describing the potential medicinal use of cannabinoids and their derivatives in numerous pathological conditions in both in vitro and in vivo models.

The use of these drugs has been found to be of benefit in a wide number of neurological and neuropsychiatric disorders, and in many other diseases ranging from cancer, atherosclerosis, stroke, hypertension, inflammatory related disorders, and autoimmune diseases, just to mention some.

In particular, being the cannabinoid CB1 receptor a central receptor expressed by neurons of the central nervous system, the attention for the treatment of neurological diseases has been mainly focused on compounds acting via this receptor, however some of these compounds has been showed to act by alternative pathways in some cases unrelated to CB1 receptors.

Nonetheless, endocannabinoids are potent regulators of the synaptic function in the central nervous system and their levels are modulated in neurological diseases.

In this study, we focused on endocannabinoid mechanism of action in neuronal signaling and on cannabimimetic drug potential application in neurological disorders.

Finally, novel patents on cannabis-based drugs with applicability in central nervous system disorders are highlighted, to suggest future potential therapeutic utility of derivatives of this ancient plant.”

http://www.ncbi.nlm.nih.gov/pubmed/27334611

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Phytocannabinoids and cannabimimetic drugs: recent patents in central nervous system disorders.

“Starting from the chemical structure of phytocannabinoids, isolated from Cannabis sativa plant, research groups designed numerous cannabimimetic drugs.

These compounds according to their activities can be partial, full agonists and antagonists of cannabinoid receptors.

Anecdotal reports and scientific studies described beneficial properties of cannabinoids and their derivatives in several pathological conditions like neurological and neuropsychiatric disorders, and in many other diseases ranging from cancer, atherosclerosis, stroke, hypertension, inflammatory related disorders, and autoimmune diseases.

The cannabinoid CB1 receptor was considered particularly interesting for therapeutic approaches in neurological diseases, because primarily expressed by neurons of the central nervous system. In many experimental models, these drugs act via this receptor, however, CB1 receptor independent mechanisms have been also described. Furthermore, endogenous ligands of cannabinoid receptors, the endocannabinoids, are potent modulators of the synaptic function in the brain. In neurological diseases, numerous studies reported modulation of the levels of endocannabinoids according to the phase of the disease and its progression.

CONCLUSIONS:

Finally, although the study of the mechanisms of action of these compounds is still unsolved, many reports and patents strongly suggest therapeutic potential of these compounds in neurological diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/27184693

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ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

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“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

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