Editorial: The CB2 Cannabinoid System: A New Strategy in Neurodegenerative Disorder and Neuroinflammation

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“The cannabinoid receptors subtype 2 (CB2R) are emerging as novel targets for the development of new therapeutic approaches and PET probes useful to early diagnose neuroinflammation as first step in several neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson disease (PD).

This Research Topic is mainly focused on the involvment of CB2R in neurodegenerative disorders and on the usefulness of CB2R ligands in the therapy and early diagnosis of neuroinflammation as onset of neurodegeneration.

In the reviews of Aso and Ferrer and Cassano et al. an interesting and exaustive overview of the endogenous cannabinoid signaling and its role in neuroinflammation and neurogenesis is reported. The potential of CB2R as therapeutic target in AD is argued by several evidences derived by robust experimental models and the effects modulated by CB2R agonists on different pathways involved in the pathogenesis of AD are discussed; indeed, these ligands are able to reduce inflammation, Aβ production and deposition, tau protein hyper-phosphorylation and oxidative stress damage caused by Aβ peptides. CB2R agonists are also able to induce Aβ clearance leading to cognitive improvement in AD models.

In conclusion, considering that neuroinflammation has been widely reported as indicator and modulator of neurodegeneration, the reduction of the neuroinflammatory responses could be considered as a new therapeutic strategy in these diseases. Moreover, the selective CB2R overexpression on the activated-microglial cells provides also a highly specialized target useful to an early diagnosis of the neurodegenerative diseases.”

http://journal.frontiersin.org/article/10.3389/fnins.2017.00196/full

Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome

“Fragile X syndrome, the most commonly known genetic cause of autism, is due to loss of the fragile X mental retardation protein, which regulates signal transduction at metabotropic glutamate receptor-5 in the brain.

The results identify the endocannabinoid signalosome as a molecular substrate for fragile X syndrome, which might be targeted by therapy.”  http://www.nature.com/articles/ncomms2045

“Cannabis-like chemical combats chief genetic cause of autism” http://www.belfasttelegraph.co.uk/news/health/cannabislike-chemical-combats-chief-genetic-cause-of-autism-28867862.html#ixzz2DRLsbjJO

A natural product from Cannabis sativa subsp. sativa inhibits homeodomain-interacting protein kinase 2 (HIPK2), attenuating MPP+-induced apoptosis in human neuroblastoma SH-SY5Y cells.

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“Homeodomain-interacting protein kinase 2 (HIPK2) is a conserved serine/threonine kinase, which regulate transcription, cell differentiation, proliferation and apoptosis. Previous evidences indicated that HIPK2 could be involved in the pathogenesis of neurodegenerative diseases, suggesting as a novel target for Parkinson’s disease (PD) therapeutic development.

Herein, gene microarray analysis was performed to verify the key regulatory function of HIPK2 in PD. (Z)-methylp-hydroxycinnamate (ZMHC, 7) with other eighteen compounds were isolated from Cannabis sativa subsp. sativa, growing in Bama Yao Autonomous County, one of the five largest longevity regions of the world.

Intriguingly, ZMHC was identified to bind HIPK2 with high affinity through molecular modeling and molecular dynamics (MD) simulations. Moreover, cell morphology, flow cytometry and western blot assay suggested that ZMHC inhibited HIPK2, which attenuated MPP+-induced apoptosis in SH-SY5Y cells.

In conclusion, these findings discovered a natural product that inhibited HIPK2, and highlighted that ZMHC could be a potential precursor agent for future PD therapy.”

https://www.ncbi.nlm.nih.gov/pubmed/28366826

It’s Oral, Head & Neck Cancer Awareness Month. Please Be Aware.

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“Oral, Head & Neck Cancer Awareness Month. While smoking and tobacco use are still major risk factors, the fastest growing segment of oral cancer patients is young, healthy, nonsmoking individuals due to the connection to the HPV virus. We cannot stop this virus from spreading; our only hope to save lives is with professional involvement and public awareness.”  http://oralcancerfoundation.org/events/oral-head-neck-cancer-awareness-month/

“Oral Sex Linked to Rise in Oral Cancers”  https://www.roswellpark.org/cancertalk/201304/oral-sex-linked-rise-oral-cancers

“Role of human papilloma virus in the oral carcinogenesis”  https://www.ncbi.nlm.nih.gov/pubmed/19542661                                                           “A causal role for human papillomavirus in head and neck cancer.”  https://www.ncbi.nlm.nih.gov/pubmed/15135592/

“Bogarting that joint might decrease oral hpv among cannabis users. The development of oral cancer is not a result of smoking cannabis per se; rather, it is hypothesized to be a result of contracting hpv through various forms of sharing and passing joints and other smoking apparatuses. Therefore, it is hypothesized that bogarting (and not passing) joints might decrease oral hpv among cannabis smokers.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2794675/

“Additive found in toothpaste and food products could cause cancer, say scientists” http://www.independent.co.uk/news/science/toothpaste-additive-e171-titanium-dioxide-food-products-cancer-cause-scientists-a7541956.html

“Mouthwash And Poor Dental Hygiene May Up The Risk Of Oral Cancer”  http://www.npr.org/sections/health-shots/2014/04/08/300257396/mouthwash-and-poor-dental-hygiene-may-up-the-risk-of-oral-cancer

“Gum Disease Linked to Risk of Oral Cancer Causing Virus”  https://www.bloomberg.com/news/articles/2013-08-21/gum-disease-linked-to-risk-of-oral-cancer-causing-virus

“ROUGH TEETH AND RUBBING DENTURES MAY BE LINKED TO ORAL CANCER” http://www.managedhealthcareconnect.com/content/rough-teeth-and-rubbing-dentures-may-be-linked-oral-cancer

“Unhealthy lifestyles blamed for sharp rise in mouth cancer cases”  http://www.itv.com/news/2016-11-25/bad-habits-linked-to-soaring-rates-of-mouth-cancer/

“Type of food and risk of oral cancer. To reduce the risk of oral and pharyngeal cancer, especially squamous cell carcinoma, the most common oral cancer, diet must be optimized, primarily to reduce calorie intake, monounsaturated fat, and red or processed meat. Consumption of fruits, vegetables, and cereals, which are the major source of vitamins and fiber, should be adequate in the daily diet. Optimal levels of daily allowance of micronutrients like vitamin C, E, antioxidants, zinc, beta-carotene, and folate are effective in prevention of oral cancer. Consumption of fried or broiled foods and employment of microwave cooking, because of formation of heterocyclic amines, must be avoided because of increasing risks of oral cancer including the salivary gland tumors.”  https://www.ncbi.nlm.nih.gov/pubmed/17367228

“Coffee consumption associated with reduced risk of oral cancer: a meta-analysis”  http://www.sciencedirect.com/science/article/pii/S2212440315013656

“Tobacco and alcohol use are among the strongest risk factors for oral cavity and oropharyngeal cancers.” https://www.cancer.org/cancer/oral-cavity-and-oropharyngeal-cancer/causes-risks-prevention/risk-factors.html

“Marijuana use on its own does not merit definitive oral cancer development, according to research. In fact, cannabis also contains cannabinoids, such as THC, which contain anticancer properties. Some of these anticancer properties include the slowing of the inflammatory arm of the immune system designed to slow free-radical growths. Some researchers link medicinal marijuana to these anticancer properties.” http://www.dentistryiq.com/articles/2014/04/should-marijuana-users-be-worried-that-smoking-causes-oral-cancer.html

“Marijuana has been used in herbal remedies for centuries. More recently, scientists reported that THC and other cannabinoids such as CBD slow growth and/or cause death in certain types of cancer cells.” http://www.cancer.org/treatment/treatmentsandsideeffects/physicalsideeffects/chemotherapyeffects/marijuana-and-cancer

“Cannabis has been shown to kill cancer cells in the laboratory. Cannabinoids appear to kill tumor cells but do not affect their nontransformed counterparts and may even protect them from cell death.” http://www.cancer.gov/about-cancer/treatment/cam/patient/cannabis-pdq#section/all

“Marijuana Kills Cancer Cells, Admits The U.S. National Cancer Institute” http://naturalsociety.com/marijuana-kills-cancer-cells-admits-the-u-s-national-cancer-institute/

“US government says cannabis kills cancer cells”  http://www.telegraph.co.uk/news/worldnews/northamerica/usa/11820620/US-government-says-cannabis-kills-cancer-cells.html

“US government finally admits that cannabis kills cancer cells”  http://www.mirror.co.uk/news/world-news/government-finally-admits-cannabis-kills-6303176

“Review of Various Herbal Supplements as Complementary Treatments for Oral Cancer. Diet changes, supplementation with antioxidants, high-dose vitamin C therapy, and cannabinoid use have been suggested to decrease cancer cell replication and increase chance of remission.”  https://www.ncbi.nlm.nih.gov/pubmed/26863913

“Cannabinoids Offer Some Hope for Oral Cancer Pain”  https://www.practicalpainmanagement.com/meeting-summary/cannabinoids-offer-some-hope-oral-cancer-pain

“Cannabinoids Attenuate Cancer Pain and Proliferation in a Mouse Model.  Our results suggest that systemic administration of cannabinoids decease oral cancer pain. Our findings suggest a direct role for cannabinoid mechanisms in oral cancer pain and proliferation. The systemic administration of cannabinoid receptor agonists may have important therapeutic implications wherein cannabinoid receptor agonists may reduce morbidity and mortality of oral cancer. The present findings suggest that cannabinoid treatment may be a promising alternative therapy for oral cancer pain management.”  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3099480/

“Cannabinoids Inhibit Cellular Respiration of Human Oral Cancer Cells. The primary cannabinoids, Δ9-tetrahydrocannabinol (Δ9-THC) and Δ8-tetrahydrocannabinol (Δ8-THC) are known to disturb the mitochondrial function and possess antitumor activities. These observations prompted us to investigate their effects on the mitochondrial O2 consumption in human oral cancer cells (Tu183). This epithelial cell line overexpresses bcl-2 and is highly resistant to anticancer drugs. A rapid decline in the rate of respiration was observed when Δ9-THC or Δ8-THC was added to the cells. These results show the cannabinoids are potent inhibitors of Tu183 cellular respiration and are toxic to this highly malignant tumor.” https://www.karger.com/Article/Abstract/312686

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“CANNABINOIDS INHIBIT ORAL CANCER CELLS”  https://pharmotech.ch/cannabinoids-inhibit-oral-cancer-cells/

“Evaluation of cannabinoid CB1 and CB2 receptors expression in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients’ survival. The present study provides evidence that CB1R and CB2R may play a role in the pathophysiological aspects of the mobile tongue squamous cell carcinoma (SCC) and even each molecule may constitute a potential target for the development of novel anti-cancer drugs for this type of malignancy.” https://www.ncbi.nlm.nih.gov/pubmed/26459312

“Review: cannabidiol may be beneficial for oral mucositis. The researchers found evidence that oxidative stress control could prevent and relieve oral mucositis. Cannabidiol was found to be safe to use and demonstrated antioxidant, anti-inflammatory, and analgesic properties,” https://medicalxpress.com/news/2017-02-cannabidiol-beneficial-oral-mucositis.html

“Salivary bacteria linked to oral cancers”  http://middleeast.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70266-7/abstract

“Antibacterial Cannabinoids from Cannabis sativa: A Structure−Activity Study”  http://pubs.acs.org/doi/abs/10.1021/np8002673

“Targeting Id1 reduces proliferation and invasion in aggressive human salivary gland cancer cells.  Id1 suppression could represent a novel and effective approach for the treatment of salivary gland cancer.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639030/

“Suppression of invasion and metastasis in aggressive salivary cancer cells through targeted inhibition of ID1 gene expression.”  https://www.ncbi.nlm.nih.gov/pubmed/27087608

“Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells. CBD represents the first nontoxic exogenous agent that can significantly decrease Id-1 expression in metastatic breast cancer cells.  Moreover, reducing Id-1 expression with cannabinoids could also provide a therapeutic strategy for the treatment of additional aggressive cancers because Id-1 expression was found to be up-regulated during the progression of almost all types”  http://mct.aacrjournals.org/content/6/11/2921.long

“Anticancer effects of anandamide on head and neck squamous cell carcinoma cells via the production of receptor-independent reactive oxygen species.”  https://www.ncbi.nlm.nih.gov/pubmed/24797795

“The endocannabinoid system and cancer: therapeutic implication. Many in vitro and in vivo studies have shown that cannabinoids are efficacious in reducing cancer progression (i.e. inhibition of tumour growth and metastases as well as induction of apoptosis and other anti-cancer properties) in breast, prostate and bone cancer. Although this review focuses on these three types of cancer, activation of the endocannabinoid signalling system produces anti-cancer effects in other types of cancer.” http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2011.01327.x/full

“Medical marijuana use in head and neck squamous cell carcinoma patients treated with radiotherapy. The purpose of the study was to better understand why patients with history of head and neck cancer (HNC) treated with radiotherapy are using medical marijuana (MM). HNC patients report MM use to help with long-term side effects of radiotherapy.” http://www.ncbi.nlm.nih.gov/pubmed/27005465

“Head and neck cancer among marijuana users: A meta-analysis of matched case–control studies. No association between lifetime marijuana use and the development of head and neck cancer was found.”  http://www.aobjournal.com/article/S0003-9969(15)30041-8/abstract

“A Population-based Case-Control Study of Marijuana Use and Head and Neck Squamous Cell Carcinoma. Our study suggests that moderate marijuana use is associated with reduced risk of head and neck cancer (HNSCC). In fact, many of these studies reported non-significant protective estimates of effect, consistent with a possible anticarcinogenic action of cannabinoids.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812803/

“Smoking Marijuana Regularly May Reduce Risk of Some Neck, Head Cancers” http://www.foxnews.com/story/2009/08/26/smoking-marijuana-regularly-may-reduce-risk-some-neck-head-cancers.html

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Delta-9-Tetrahydrocannabinol/Cannabidiol Oromucosal Spray (Sativex®): A Review in Multiple Sclerosis-Related Spasticity.

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“Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (THC/CBD, Sativex®, nabiximols) is available in numerous countries worldwide for the treatment of multiple sclerosis (MS)-related moderate to severe spasticity in patients who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy.

Twelve weeks’ therapy with THC/CBD improved MS-related spasticity in patients with an inadequate response to other anti-spasticity agents who had undergone a successful initial trial of THC/CBD therapy, according to the results of a pivotal phase 3 trial.

Improvements in spasticity were maintained in the longer term with THC/CBD with no evidence of dose tolerance, and results of real-world studies confirm the effectiveness of THC/CBD in everyday clinical practice.

Improvements in health-related quality of life and activities of daily living were also seen with THC/CBD.

THC/CBD is generally well tolerated; adverse effects such as dizziness may occur whilst the THC/CBD dosage is being optimized.

THC/CBD has low abuse potential and a low risk of psychoactive effects.

In conclusion, THC/CBD oromucosal spray is a useful option for the treatment of MS-related spasticity not completely relieved with current anti-spasticity medication.”

https://www.ncbi.nlm.nih.gov/pubmed/28293911

Cannabinoids therapeutic use: what is our current understanding following the introduction of THC, THC:CBD oromucosal spray and others?

 

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“The complexity of the endocannabinoid (eCB) system is becoming better understood and new drivers of eCB signaling are emerging. Modulation of the activities of the eCB system can be therapeutic in a number of diseases.

Research into the eCB system has been paralleled by the development of agents that interact with cannabinoid receptors. In this regard it should be remembered that herbal cannabis contains a myriad of active ingredients, and the individual cannabinoids have quite distinct biological activities requiring independent studies.

This article reviews the most important current data involving the eCB system in relation to human diseases, to reflect the present (based mainly on the most used prescription cannabinoid medicine, THC/CBD oromucosal spray) and potential future uses of cannabinoid-based therapy.

Expert commentary: From the different therapeutic possibilities, THC/CBD oromucosal spray has been in clinical use for approximately five years in numerous countries world-wide for the management of multiple sclerosis (MS)-related moderate to severe resistant spasticity.

Clinical trials have confirmed its efficacy and tolerability.

Other diseases in which different cannabinoids are currently being investigated include various pain states, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and epilepsy. The continued characterization of individual cannabinoids in different diseases remains important.”

https://www.ncbi.nlm.nih.gov/pubmed/28276775

Emerging therapeutic targets in cancer induced bone disease: A focus on the peripheral type 2 cannabinoid receptor.

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“Skeletal complications are a common cause of morbidity in patients with primary bone cancer and bone metastases. The type 2 cannabinoid (Cnr2) receptor is implicated in cancer, bone metabolism and pain perception. Emerging data have uncovered the role of Cnr2 in the regulation of tumour-bone cell interactions and suggest that agents that target Cnr2 in the skeleton have potential efficacy in the reduction of skeletal complications associated with cancer.

This review aims to provide an overview of findings relating to the role of Cnr2 receptor in the regulation of skeletal tumour growth, osteolysis and bone pain, and highlights the many unanswered questions and unmet needs.

This review argues that development and testing of peripherally-acting, tumour-, Cnr2-selective ligands in preclinical models of metastatic cancer will pave the way for future research that will advance our knowledge about the basic mechanism(s) by which the endocannabinoid system regulate cancer metastasis, stimulate the development of a safer cannabis-based therapy for the treatment of cancer and provide policy makers with powerful tools to assess the science and therapeutic potential of cannabinoid-based therapy.

Thus, offering the prospect of identifying selective Cnr2 ligands, as novel, alternative to cannabis herbal extracts for the treatment of advanced cancer patients.”

https://www.ncbi.nlm.nih.gov/pubmed/28274851

EFFECTS OF CANNABIDIOL IN HUNTINGTON’S DISEASE

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“Cannabidiol (CBD) is a major nonpsychoactive cannabinoid of marijuana.

Based on reports indicating possible efficacy of CBD in dystonic movements, we tried CBD in three patients with Huntington’s disease (HD).

The patients;, aged 30 to 56, had HD of 7 to 12 years’ duration. Their condition has been slowly progressive and unresponsive to prior therapy with neuroleptics. Orally administered CBD was initiated at 300 mg/d and increased 1 week later to 600 mg/d for the next 3 weeks.

Mild improvement ( 5 to 15%) in the choreic movements was documented using the tongueprotrusion test and a chorea severity evaluation scale after the first week. Further improvement (20 to 40%) was noticed after the second week of CBD, and this remained stable for the following 2 weeks.

Except for transient, mild hypotension, no side effects were recorded, and laboratory tests were normal. Withdrawal of CBD after 48 hours resulted in return of choreic movements to the pre-CBD state.”

http://www.druglibrary.org/schaffer/hemp/medical/hunting1.htm

Cannabinoid HU210 Protects Isolated Rat Stomach against Impairment Caused by Serum of Rats with Experimental Acute Pancreatitis

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“Acute pancreatitis (AP), especially severe AP, is a potentially lethal inflammatory disease of pancreas which often leads to extra-pancreatic complications, even multiple systemic organ dysfunctions. It has been reported that 52% of patients with acute pancreatitis develop acute gastrointestinal mucosal lesion (AGML) or stress ulcer.

For centuries, Cannabis plant and its extracts have been used to alleviate symptoms of gastrointestinal inflammatory diseases.

It has been established that D9-tetrahydrocannabinol, the major psychoactive component of Cannabis, exerts its primary cellular actions though two G protein-coupled receptors, cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors.

Since then, these two receptors have been recognized as the major regulators of physiological and pathological processes. Cannabinoids can reduce gastrointestinal secretion, and the activation of CB1 receptor exhibits protective role against stress-induced AGML, but the mechanisms of their action remain elusive.

The results from this study prove that the inflammatory responses and the imbalance of the gastric secretion during the development of AP are responsible for the pathogenesis of AGML, and suggest the therapeutic potential of HU210 for AGML associated with acute pancreatitis.

Therefore, our experimental results suggest a novel mechanism in the onset of AGML and new therapeutic values of cannabinoids as supplement of anti-inflammatory therapy in acute pancreatitis.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532296/

Cannabinoids Ameliorate Pain and Reduce Disease Pathology in Cerulein-Induced Acute Pancreatitis

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“The endocannabinoid system has been identified as a major regulator of physiological and pathological processes, such as pain, inflammation, cell growth, cell death, and as a regulator of diverse gastrointestinal functions, such as intestinal motility and secretion.

Although cannabinoid-induced analgesia was initially primarily attributed to the activation of cannabinoid receptor 1 (CB1) in the nervous system, later studies demonstrated a contribution of cannabinoid receptor 2 (CB2), localized peripherally on immune cells as well as in the nervous system.

A complex interplay between endogenously released cannabinoids, such as anandamide or 2-arachidonoylglycerol, and their receptors both on inflammatory cells and neurons is involved in modulation of inflammatory pain.

In this article, we demonstrate the in vivo significance and therapeutic potential of cannabinoids in inflammation and pain associated with pancreatitis using human specimens and mouse models as test systems.

Our results are more in line with a recent study reporting a protective role for the endogenous cannabinoid system against colonic inflammation in a mouse model of experimental colitis.

Consistent with the above, we now show that acute pancreatitis, a visceral inflammatory disease in humans, is associated with an activation of the endocannabinoid system.

In humans, acute pancreatitis is associated with up-regulation of ligands as well as receptors of the endocannabinoid system in the pancreas. Furthermore, our results suggest a therapeutic potential for cannabinoids in abolishing pain associated with acute pancreatitis and in partially reducing inflammation and disease pathology in the absence of adverse side effects.

Because management of visceral inflammatory diseases should ideally include antinociceptive as well as anti-inflammatory components, our results lay a basis for testing the therapeutic value of cannabinoids as supplements to conventional analgesic therapy.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268094/