Tag Archives: endocannabinoid system

Dual therapy targeting the endocannabinoid system prevents experimental diabetic nephropathy.

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“The endocannabinoid system has been implicated in the pathogenesis of diabetic nephropathy (DN). We investigated the effect of combined therapy with AM6545, a ‘peripherally’ restricted cannabinoid receptor type 1 (CB1R) neutral antagonist, and AM1241, a cannabinoid receptor type 2 (CB2R) agonist, in experimental DN.

RESULTS.:

Single treatment with either AM6545 or AM1241 alone reduced diabetes-induced albuminuria and prevented nephrin loss both in vivo and in vitro in podocytes exposed to glycated albumin. Dual therapy performed better than monotherapies, as it abolished albuminuria, inflammation, tubular injury and markedly reduced renal fibrosis. Converging anti-inflammatory mechanisms provide an explanation for this greater efficacy as dual therapy abolished diabetes-induced renal monocyte infiltration and M1/M2 macrophage imbalance in vivo and abrogated the profibrotic effect of M1 macrophage-conditioned media on cultured mesangial cells.

CONCLUSION.:

‘Peripheral’ CB1R blockade is beneficial in experimental DN and this effect is synergically magnified by CB2R activation.”

https://www.ncbi.nlm.nih.gov/pubmed/28387811

Metabolic Syndrome Induced Bladder Cannabinoid Receptor Changes in the Fructose-Fed Rats.

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“To investigate the effect of metabolic syndrome on the bladder cannabinoid receptors 1 and 2 (CB1/CB2) expression and function in the fructose-fed rats (FR).

CONCLUSION:

CB1/CB2 receptors mediate rat bladder relaxation through the PKA and KATP pathway. The CB1 receptor may play a more prominent role. The response is decreased in the FR bladder due to reduced expressions of the cannabinoid receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/28386998

Monoglyceride lipase deficiency affects hepatic cholesterol metabolism and lipid-dependent gut transit in ApoE-/- mice.

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 Image result for Oncotarget“Monoglyceride lipase (MGL) hydrolyzes monoglycerides (MGs) to glycerol and fatty acids. Among various MG species MGL also degrades 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid and potent activator of cannabinoid receptors (CBR) 1 and 2. MGL-knockout (-/-) mice exhibit pronounced 2-AG accumulation, but lack central cannabimimetic effects due to CB1R desensitization. We have previously shown that MGL affects plaque stability in apolipoprotein E (ApoE)-/- mice, an established animal model for dyslipidemia and atherosclerosis. In the current study, we investigated functional consequences of MGL deficiency on lipid and energy metabolism in ApoE/MGL double knockout (DKO) mice. MGL deficiency affected hepatic cholesterol metabolism by causing increased cholesterol elimination via the biliary pathway. Moreover, DKO mice exhibit lipid-triggered delay in gastric emptying without major effects on overall triglyceride and cholesterol absorption. The observed phenotype of DKO mice is likely not a consequence of potentiated CB1R signaling but rather dependent on the activation of alternative signaling pathways. We conclude that MGL deficiency causes complex metabolic changes including cholesterol metabolism and regulation of gut transit independent of the endocannabinoid system.”

https://www.ncbi.nlm.nih.gov/pubmed/28380440

Metabolic side effects induced by olanzapine treatment are neutralized by CB1 receptor antagonist compounds co-administration in female rats.

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“Weight gain is an important side effect of most atypical antipsychotic drugs such as olanzapine. Moreover, although many animal models with metabolic side effects have been well defined, the interaction with other pathways has to be considered.

The endocannabinoid system and the CB1 receptor (CB1R) are among the most promising central and peripheral targets involved in weight and energy balance.

In this study we developed a rat model based 15-days treatment with olanzapine that shows weight gain and an alteration of the blood parameters involved in the regulation of energy balance and glucose metabolism. Consequently, we analysed whether, and by which mechanism, a co-treatment with the novel CB1R neutral antagonist NESS06SM, could attenuate the adverse metabolic effects of olanzapine compared to the reference CB1R inverse agonist rimonabant.

Our results showed alterations of the cannabinoid markers in the nucleus accumbens and of orexigenic/anorexigenic markers in the hypothalamus of female rats treated with olanzapine. These molecular modifications could explain the excessive food intake and the resulting weight gain. Moreover, we confirmed that a co-treatment with CB1R antagonist/inverse agonist compounds decreased food intake and weight increment and restored all blood parameters, without altering the positive effects of olanzapine on behaviour. Furthermore, rimonabant and NESS06SM restored the metabolic enzymes in the liver and fat tissue altered by olanzapine.

Therefore, CB1 receptor antagonist/inverse agonist compounds could be good candidate agents for the treatment of weight gain induced by olanzapine.”

https://www.ncbi.nlm.nih.gov/pubmed/28377074

Antihyperalgesic Activities of Endocannabinoids in a Mouse Model of Antiretroviral-Induced Neuropathic Pain.

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“Nucleoside reverse transcriptase inhibitors (NRTIs) are the cornerstone of the antiretroviral therapy for human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS). However, their use is sometimes limited by the development of a painful sensory neuropathy, which does not respond well to drugs.

Smoked cannabis has been reported in clinical trials to have efficacy in relieving painful HIV-associated sensory neuropathy.

The aim of this study was to evaluate whether the expression of endocannabinoid system molecules is altered during NRTI-induced painful neuropathy, and also whether endocannabinoids can attenuate NRTI-induced painful neuropathy.

Conclusion: These data show that ddC induces thermal hyperalgesia, which is associated with dysregulation of the mRNA expression of some endocannabinoid system molecules. The endocannabinoids AEA and 2-AG have antihyperalgesic activity, which is dependent on cannabinoid receptor and GPR55 activation. Thus, agonists of cannabinoid receptors and GPR55 could be useful therapeutic agents for the management of NRTI-induced painful sensory neuropathy.”

https://www.ncbi.nlm.nih.gov/pubmed/28373843

Evaluation of monoacylglycerol lipase as a therapeutic target in a transgenic mouse model of ALS.

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“Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor neuron system with limited therapeutic options. While an increasing number of ALS patients can be linked to a small number of autosomal-dominantly inherited cases, most cases are termed sporadic. Both forms are clinically and histopathologically indistinguishable, raising the prospect that they share key pathogenic steps, including potential therapeutic intervention points.

The endocannabinoid system is emerging as a versatile, druggable therapeutic target in the CNS and its dysregulation is an early hallmark of neurodegeneration. Whether this is a defense mechanism or part of the pathogenesis remains to be determined.

The neuroprotective and anti-inflammatory endocannabinoid 2-arachidonoylglycerol (2-AG), which is degraded by monoacylglycerol lipase (MAGL), accumulates in the spinal cords of transgenic models of ALS. We tested the hypothesis that this 2-AG increase is a protective response in the low-copy SOD1G93A mouse model of ALS.

We show that oral application of the MAGL inhibitor KML29 delays disease onset, progression and survival. Furthermore, we could demonstrate that KML29 reduced proinflammatory cytokines and increased brain-derived neurotrophic factor (BDNF) expression levels in the spinal cord, the major site of neurodegeneration in ALS. Moreover, treatment of primary mouse neurons and primary mousecroglia with 2-AG confirmed the neuroprotective and anti-inflammatory action by increasing BDNF and arginase-1 and decreasing proinflammatory cytokines in vitro.

In summary, we show that elevating 2-AG levels by MAGL inhibition is a therapeutic target in ALS and demonstrate that the endocannabinoid defense mechanisms can be exploited therapeutically in neurodegenerative diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/28373073

[Role of cannabinoid receptor 1-mediated synaptic plasticity in neuropathic pain and associated depression].

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“Neuropathic pain is a class of pain caused by an injury or diseases of the somatosensory system and characterized by spontaneous pain, allodynia, and hyperalgesia. It is well established that central sensitization is one of the key mechanisms underlying the development and maintenance of neuropathic pain. Cannabinoid receptor 1 (CB1R) of endocannabinoid system modulates synaptic transmission, regulates synaptic plasticity, inhibits central sensitization, and thus attenuates neuropathic pain. Recent studies have shown that activation of CB1R also involves in the relief of neuropathic pain-induced depression.” https://www.ncbi.nlm.nih.gov/pubmed/28364110

In vivo TSPO and cannabinoid receptor type 2 availability early in post-stroke neuroinflammation in rats: a positron emission tomography study.

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“Upregulated levels of 18-kDa translocator proteins (TSPO) and type 2 endocannabinoid receptors (CB2) are considered to reflect different aspects of microglia-related neuroinflammatory responses in the brain. Relative to the increase in the TSPO expression that occurs slightly later during neuroinflammation in a proinflammatory fashion, CB2 activation is considered to relate to the neuroprotective responses that occurs predominantly at an early stage of brain disorders. These findings, however, were deduced from studies with different animal samples under different experimental settings. Here, we aimed to examined the differences in TSPO binding and CB2 availability at an early stage of stroke in the same animal using positron emission tomography (PET).

CONCLUSIONS:

The present results provide in vivo evidence of different responses of microglia occurring in the acute state of stroke. The use of the CB2 tracer [11C]NE40 allows us to evaluate the roles played by the neuroprotective aspect of microglia in acute neuroinflammatory processes.” https://www.ncbi.nlm.nih.gov/pubmed/28356120

https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-017-0851-4

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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Anticancer effects of anandamide on head and neck squamous cell carcinoma cells via the production of receptor-independent reactive oxygen species.

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Head & Neck

“The endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), are considered promising potential anticancer agents. In this study, we examined the anticancer effects of AEA and 2-AG in head and neck squamous cell carcinoma (HNSCC) cell lines. Our results showed that AEA effectively inhibited proliferation of HNSCC cells whereas 2-AG did not. The anticancer effect of AEA seemed to be mediated by a receptor-independent mechanism. Inhibitors of AEA intracellular transportation and transfection of HNSCC cells with fatty acid amide hydrolase, a key enzyme in AEA metabolism, reversed AEA-dependent inhibition of cell proliferation. We found that cyclooxygenase-2 (COX-2) did not mediate the anticancer effects of AEA; instead we observed an increase in reactive oxygen species (ROS) production after AEA treatment. Moreover, antioxidants partially reversed AEA-dependent inhibition of cell proliferation. These findings suggest that AEA might have anticancer effects on HNSCC cells by mediating an increase in ROS levels through a receptor-independent mechanism.” https://www.ncbi.nlm.nih.gov/pubmed/24797795

http://onlinelibrary.wiley.com/doi/10.1002/hed.23727/abstract