Tag Archives: cannabinoid receptors

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

Cannabinoid CB2 receptors are involved in the protection of RAW264.7 macrophages against the oxidative stress: an in vitro study.

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“Research in the last decades has widely investigated the anti-oxidant properties of natural products as a therapeutic approach for the prevention and the treatment of oxidative-stress related disorders.

In this context, several studies were aimed to evaluate the therapeutic potential of phytocannabinoids, the bioactive compounds of Cannabis sativa.

Here, we examined the anti-oxidant ability of Cannabigerol (CBG), a non-psychotropic cannabinoid, still little known, into counteracting the hydrogen peroxide (H2O2)-induced oxidative stress in murine RAW264.7 macrophages. In addition, we tested selective receptor antagonists for cannabinoid receptors and specifically CB1R (SR141716A) and CB2R (AM630) in order to investigate through which CBG may exert its action.

Taken together, our in vitro results showed that CBG is able to counteract oxidative stress by activation of CB2 receptors.

Based on its antioxidant activities, CBG may hold great promise as an anti-oxidant agent and therefore used in clinical practice as a new approach in oxidative-stress related disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/28348416

Endocannabinoid signalling modulates susceptibility to traumatic stress exposure.

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“Stress is a ubiquitous risk factor for the exacerbation and development of affective disorders including major depression and posttraumatic stress disorder. Understanding the neurobiological mechanisms conferring resilience to the adverse consequences of stress could have broad implications for the treatment and prevention of mood and anxiety disorders. We utilize laboratory mice and their innate inter-individual differences in stress-susceptibility to demonstrate a critical role for the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) in stress-resilience. Specifically, systemic 2-AG augmentation is associated with a stress-resilient phenotype and enhances resilience in previously susceptible mice, while systemic 2-AG depletion or CB1 receptor blockade increases susceptibility in previously resilient mice. Moreover, stress-resilience is associated with increased phasic 2-AG-mediated synaptic suppression at ventral hippocampal-amygdala glutamatergic synapses and amygdala-specific 2-AG depletion impairs successful adaptation to repeated stress. These data indicate amygdala 2-AG signalling mechanisms promote resilience to adverse effects of acute traumatic stress and facilitate adaptation to repeated stress exposure.” https://www.ncbi.nlm.nih.gov/pubmed/28348378

“Natural cannabinoid found to play key role in anxiety. Stress-related mood and anxiety disorders affect millions of people in the United States. A new study examines the neurobiology behind these illnesses and finds that controlling a molecule that activates cannabinoid receptors can reduce the symptoms of anxiety.” http://www.medicalnewstoday.com/articles/316682.php

“Natural chemical helps brain adapt to stress”  https://www.sciencedaily.com/releases/2017/03/170329140945.htm

Loss of Cannabinoid CB 1 Receptors Induces Cortical Migration Malformations and Increases Seizure Susceptibility.

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“Neuronal migration is a fundamental process of brain development, and its disruption underlies devastating neurodevelopmental disorders. The transcriptional programs governing this process are relatively well characterized. However, how environmental cues instruct neuronal migration remains poorly understood. Here, we demonstrate that the cannabinoid CB 1 receptor is strictly required for appropriate pyramidal neuron migration in the developing cortex. Acute silencing of the CB 1 receptor alters neuronal morphology and impairs radial migration. Consequently, CB 1 siRNA-electroporated mice display cortical malformations mimicking subcortical band heterotopias and increased seizure susceptibility in adulthood. Importantly, rescuing the CB 1 deficiency-induced radial migration arrest by knockdown of the GTPase protein RhoA restored the hyperexcitable neuronal network and seizure susceptibility. Our findings show that CB 1 receptor/RhoA signaling regulates pyramidal neuron migration, and that deficient CB 1 receptor signaling may contribute to cortical development malformations leading to refractory epilepsy independently of its canonical neuromodulatory role in the adult brain.”

https://www.ncbi.nlm.nih.gov/pubmed/28334226

Neuroprotective effect of WIN55,212-2 against 3-nitropropionic acid-induced toxicity in the rat brain: involvement of CB1 and NMDA receptors.

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“The endocannabinoid system (ECS), and agonists acting on cannabinoid receptors (CBr), are known to regulate several physiological events in the brain, including modulatory actions on excitatory events probably through N-methyl-D-aspartate receptor (NMDAr) activity.

Actually, CBr agonists can be neuroprotective.

Our results demonstrate a protective role of WIN55,212-2 on the 3-NP-induced striatal neurotoxicity that could be partially related to the ECS stimulation and induction of NMDAr hypofunction, representing an effective therapeutic strategy at the experimental level for further studies.”

https://www.ncbi.nlm.nih.gov/pubmed/28337258

The CB1 Receptor as the Cornerstone of Exostasis.

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“The type-1 cannabinoid receptor (CB1) is the main effector of the endocannabinoid system (ECS), which is involved in most brain and body functions. In this Perspective, we provide evidence indicating that CB1 receptor functions are key determinants of bodily coordinated exostatic processes. First, we will introduce the concepts of endostasis and exostasis as compensation or accumulation for immediate or future energy needs and discuss how exostasis has been necessary for the survival of species during evolution. Then, we will argue how different specific biological functions of the CB1 receptor in the body converge to provide physiological exostatic processes. Finally, we will introduce the concept of proactive evolution-induced diseases (PEIDs), which helps explain the seeming paradox that an evolutionary-selected physiological function can become the cause of epidemic pathological conditions, such as obesity. We propose here a possible unifying theory of CB1 receptor functions that can be tested by future experimental studies.”

https://www.ncbi.nlm.nih.gov/pubmed/28334603

Effects of JWH015 in cytokine secretion in primary human keratinocytes and fibroblasts and its suitability for topical/transdermal delivery.

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“JWH015 is a cannabinoid (CB) receptor type 2 agonist that produces immunomodulatory effects. Since skin cells play a key role in inflammatory conditions and tissue repair, we investigated the ability of JWH015 to promote an anti-inflammatory and pro-wound healing phenotype in human primary skin cells.

The expression of CB1 and CB2 receptors (mRNA) and the production of pro- and anti-inflammatory factors enhanced in keratinocytes and fibroblasts following lipopolysaccharide stimulation. JWH015 reduced the concentration of major pro-inflammatory factors (IL-6 and MCP-1) and increased the concentration of a major anti-inflammatory factor (TGF-β) in lipopolysaccharide-stimulated cells.

JWH015 induced a faster scratch gap closure. These JWH015’seffects were mainly modulated through both CB1 and CB2 receptors. Topically administered JWH015 was mostly retained in the skin and displayed a sustained and low level of transdermal permeation.

Our findings suggest that targeting keratinocytes and fibroblasts with cannabinoid drugs could represent a therapeutic strategy to resolve peripheral inflammation and promote tissue repair.”

 https://www.ncbi.nlm.nih.gov/pubmed/28326930

Overactivation of the endocannabinoid system alters the anti-lipolytic action of insulin in mouse adipose tissue.

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“Evidence has accumulated that obesity-related metabolic dysregulation is associated with overactivation of the endocannabinoid system (ECS), which involves cannabinoid receptor 1 (CB1R), in peripheral tissues, including adipose tissue (AT).

The functional consequences of CB1R activation on AT metabolism remain unclear. Since excess fat mobilization is considered an important primary event contributing to the onset of insulin resistance, we combined in vivo and in vitro experiments to investigate whether activation of ECS could alter the lipolytic rate.

For this purpose, the appearance of plasma glycerol was measured in wild-type and CB1R-/- mice after acute anandamide administration or inhibition of endocannabinoid degradation by JZL195. Additional experiments were conducted on rat AT explants to evaluate the direct consequences of ECS activation on glycerol release and signaling pathways.

Treatments stimulated glycerol release in mice fasted for 6 h and injected with glucose but not in 24-h fasted mice or in CB1R-/-suggesting that the effect was dependent on plasma insulin levels and mediated by CB1R. We concomitantly observed that Akt cascade activity was decreased, indicating an alteration of the anti-lipolytic action of insulin.

Similar results were obtained with tissue explants exposed to anandamide, thus identifying CB1R of AT as a major target.

This study indicates the existence of a functional interaction between CB1R and lipolysis regulation in AT. Further investigation is needed to test whether the elevation of ECS tone encountered in obesity is associated with excess fat mobilization contributing to ectopic fat deposition and related metabolic disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/28325733

Antidiabetic, antidyslipidemic and toxicity profile of ENV-2: A potent pyrazole derivative against diabetes and related diseases.

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“Diabetes is a major health problem and a predisposition factor for further degenerative complications and, therefore, novel therapies are urgently needed. Currently, cannabinoid receptor 1 (CB1 receptor) antagonists have been considered as promissory entities for metabolic disorders treatment.

Accordingly, the purpose of this work was the evaluation of the sub-acute antidiabetic, anti-hyperglycemic, antidyslipidemic and toxicological profile of ENV-2, a potent hypoglycemic and antioxidant CB1 receptor antagonist.

In this study, ENV-2 showed a pronounced anti-hyperglycemic effect even at a dose of 5mg/kg (P< 0.001) in a glucose tolerance test on normoglycemic rats. Moreover, after administration of ENV-2 (16mg/kg) to diabetic rats, a prominent antidiabetic activity was observed (P< 0.001), which was higher than glibenclamide.

Sub-acute treatment (10 days) of ENV-2 resulted in a significant reduction of plasma glucose (P< 0.001). Also, the levels of peripheral lipids were improved; blood triacylglycerols (TG) and cholesterol (CHOL) were diminished (P< 0.001). In addition, it was found that ENV-2 reduced IL-1β and IL-18 mRNA expression in adipose tissue (P< 0.05). Due to the satisfactory outcomes, we were interested in evaluating the toxicity of ENV-2 in both acute and sub-chronic approaches. Regarding the acute administration, the compound resulted to be non-toxic and was grouped in category 5 according to OECD. It was also found that sub-chronic administration did not increase the size of the studied organs, while no structural damage was observed in heart, lung, liver and kidney tissues. Finally, neither AST nor ALT damage hepatic markers were augmented.”

https://www.ncbi.nlm.nih.gov/pubmed/28322830

Cannabinoid receptor 1 contributes to sprouted innervation in endometrial ectopic growth through mitogen-activated protein kinase activation.

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“The endocannabinoid system regulates neurite outgrowth and neurogenesis during development of the central nervous system.

Cannabinoid receptor 1 (CB1R) is expressed in neurons, including the somata and fibers, that innervate the endometrial ectopic cyst in rats.

 

This finding may provide a new therapeutic target for patients with endometriosis.”

https://www.ncbi.nlm.nih.gov/pubmed/28322749