Cannabinoid 2 receptor attenuates inflammation during skin wound healing by inhibiting M1 macrophages rather than activating M2 macrophages.

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“The anti-inflammatory properties of the cannabinoid 2 receptor (CB2R) in injury and inflammatory diseases have been widely substantiated. Specifically, the anti-inflammatory effect of CB2R may be achieved by regulating macrophage polarisation.

Several research findings suggested that the activation of CB2R could attenuate inflammation by reducing pro-inflammatory M1 macrophage polarisation and promoting anti-inflammatory M2 polarisation.

However, considering CB2R inhibits fibrosis and M2 promotes fibrosis, that the activation of CB2R may lead to an increase in M2 macrophages seems contradictory. Therefore, we hypothesised that the activation of CB2R to attenuate inflammation is not achieved by up-regulating M2 macrophages.

In summary, our findings suggested that during incised skin wound healing in mice, increased levels of CB2R may affect inflammation by regulating M1 rather than M2 macrophage subtype polarisation.

These results offer a novel understanding of the molecular mechanisms involved in the inhibition of inflammation by CBR2 that may lead to new treatments for cutaneous inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/30534003

https://journal-inflammation.biomedcentral.com/articles/10.1186/s12950-018-0201-z

Behavioral effects of psychostimulants in mutant mice with cell-type specific deletion of CB2 cannabinoid receptors in dopamine neurons.

Behavioural Brain Research

“Activation of the endocannabinoid system modulate dopaminergic pathways that are involved in the effects of psychostimulants including amphetamine, cocaine, nicotine and other drugs of abuse. Genetic deletion or pharmacological activation of CB2 cannabinoid receptor is involved in the modulation of the effects of psychostimulants and their rewarding properties. Taken together, our data suggest that CB2Rs play a role in the modulation of dopamine-related effects of psychostimulants and could be exploited as therapeutic target in psychostimulant addiction and other psychiatric disorders associated with dopamine dysregulation.”

https://www.ncbi.nlm.nih.gov/pubmed/30508607

https://www.sciencedirect.com/science/article/pii/S0166432818311987?via%3Dihub

Cannabinoid receptor 2 agonist prevents local and systemic inflammatory bone destruction in rheumatoid arthritis.

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“Cannabinoid receptor 2 (CB2) has been implicated as an important clinical regulator of inflammation and malignant osteolysis. Here, we observed that CB2 expression was markedly higher in the collagen-induced arthritis (CIA) mice synovium and bone tissues than in the non-inflamed synovium and bone tissues. We found that JWH133 ameliorates pathologic bone destruction in CIA mice via the inhibition of osteoclastogenesis and modulation of inflammatory responses, thereby highlighting its potential as a treatment for human rheumatoid arthritis.”

https://www.ncbi.nlm.nih.gov/pubmed/30508319

https://onlinelibrary.wiley.com/doi/abs/10.1002/jbmr.3637

Cannabinoid-1 Receptor Antagonism Improves Glycemic Control and Increases Energy Expenditure via Sirt1/mTORC2 and AMPK Signaling.

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“Endocannabinoids promote energy conservation in obesity, whereas cannabinoid-1 receptor (CB1 R) blockade reverses body weight gain and insulin resistance and increases energy expenditure.

Here we investigated the molecular mechanisms of the catabolic effects of CB1 R blockade in the liver.

CONCLUSION: peripheral CB1 R blockade in obese mice improves glycemic control via the hepatic Sirt1/mTORC2/Akt pathway, whereas it increases fatty acid oxidation via LKB1/AMPK signaling.”

https://www.ncbi.nlm.nih.gov/pubmed/30506571

https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.30364

Disordered Peptides Looking for Their Native Environment: Structural Basis of CB1 Endocannabinoid Receptor Binding to Pepcans.

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“Endocannabinoid peptides, or “pepcans,” are endogenous ligands of the CB1 cannabinoid receptor. Depending on their length, they display diverse activity: For instance, the nona-peptide Pepcan-9, also known as hemopressin, is a powerful inhibitor of CB1, whereas the longer variant Pepcan-12, which extends by only three amino acid residues at the N-terminus, acts on both CB1 and CB2 as an allosteric modulator. These findings open the way to structure-driven design of selective peptide modulators of CB1.”

https://www.ncbi.nlm.nih.gov/pubmed/30505835

https://www.frontiersin.org/articles/10.3389/fmolb.2018.00100/full

Cannabinoid receptor type-1 partially mediates metabolic endotoxemia-induced inflammation and insulin resistance.

Physiology & Behavior

“Cannabinoid receptor type-1 partially mediates metabolic endotoxemia-induced inflammation and insulin resistance. Despite no significant differences in body weight among groups, chronic exposure to low-level LPS altered hepatic endocannabinoid signaling, increased inflammation, and impaired insulin sensitivity and insulin clearance. CB1 inhibition significantly attenuated LPS signaling, which attenuated LPS-induced metabolic alterations. Therefore, we concluded that CB1 contributes to LPS-mediated inflammation and insulin resistance, suggesting that blocking CB1 signaling may have therapeutic benefits in reducing inflammation-induced metabolic abnormalities.”

https://www.ncbi.nlm.nih.gov/pubmed/30502357

https://www.sciencedirect.com/science/article/abs/pii/S0031938418304190?via%3Dihub

miR-23b-3p and miR-130a-5p affect cell growth, migration and invasion by targeting CB1R via the Wnt/β-catenin signaling pathway in gastric carcinoma.

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“Gastric cancer (GC) is the most common malignancy and third leading cause of cancer mortality worldwide. The identification of a sensitive biomarker as well as effective therapeutic targets for the treatment of GC is of critical importance. microRNAs play significant roles in the development of cancer and may serve as promising therapeutic targets.

RESULTS:

In the present study, it was demonstrated that the cannabinoid receptor 1 (CB1R) was overexpressed, and miR-23b-3p and miR-130a-5p were downregulated, in GC cells. In addition, the results revealed that these effects are associated with malignant biological behaviors exhibited by GC cells. Furthermore, miR-23b-3p and miR-130a-5p may regulate CB1R expression via the Wnt/β-catenin signaling pathway.

CONCLUSION:

Our results suggested dysregulation of CB1R expression is closely related to the malignant biological behavior of gastric cancer cells. miRNA/CB1R-based therapy may represent a promising therapeutic strategy for the clinical treatment of GC patients.”

https://www.ncbi.nlm.nih.gov/pubmed/30498363

https://www.dovepress.com/mir-23b-3p-and-mir-130a-5p-affect-cell-growth-migration-and-invasion-b-peer-reviewed-article-OTT

Peripubertal cannabidiol treatment rescued behavioral and neurochemical abnormalities in MAM model of schizophrenia.

 Neuropharmacology

“In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produced long-lasting behavioral alterations such as social withdrawal and cognitive impairment in the social interaction test and in the novel object recognition test, respectively. At molecular level, an increased cannabinoid receptor type-1 (CB1) mRNA and protein expression which might be due to a reduction in DNA methylation at gene promoter in the prefrontal cortex (PFC), coincided with deficits in the social interaction test and in the novel object recognition test in MAM rats. Both schizophrenia-like phenotype and altered transcriptional regulation of CB1 receptors were reversed by peripubertal treatment (from PND 19 to PND 39) with the non-psychotropic phytocannabinoid cannabidiol (30 mg/kg/day), or, in part, by treatment with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day), but not with haloperidol (0.6 mg/kg/day). These results suggest that early treatment with cannabidiol may prevent both the appearance of schizophrenia-like deficits as well as CB1 alterations in the PFC at adulthood, supporting that peripubertal cannabidiol treatment might be protective against MAM insult.”

https://www.ncbi.nlm.nih.gov/pubmed/30496751

https://www.sciencedirect.com/science/article/pii/S0028390818308761?via%3Dihub

The Role of CB2 Receptor in the Recovery of Mice after Traumatic Brain Injury.

 Journal of Neurotrauma cover image“Cannabis is one of the most widely used plant drugs in the world today. In spite of the large number of scientific reports on medical marijuana there still exists much controversy surrounding its use and the potential for abuse due to the undesirable psychotropic effects. However, recent developments in medicinal chemistry of novel non-psychoactive synthetic cannabinoids have indicated that it is possible to separate some of the therapeutic effects from the psychoactivity. We have previously shown that treatment with the endocannabinoid 2-AG that binds to both CB1 and CB2 receptors 1 hr after traumatic brain injury in mice attenuates neurological deficits, edema formation, infarct volume, blood-brain barrier permeability, neuronal cell loss at the CA3 hippocampal region and neuroinflammation. Recently, we synthesized a set of camphor-resorcinol derivatives, which represent a novel series of CB2 receptor selective ligands. Most of the novel compounds exhibited potent binding and agonistic properties at the CB2 receptors, with very low affinity for the CB1 receptor, and some were highly anti-inflammatory. This selective binding correlated with their intrinsic activities. HU-910 and HU-914 were selected in the present study to evaluate their potential effect in the pathophysiology of traumatic brain injury (TBI). In mice and rats, subjected to closed head injury and treated with these novel compounds, we showed enhanced neurobehavioral recovery, inhibition of TNF-alpha production, increased synaptogenesis and partial recovery of the cortical spinal tract. We propose these CB2 agonists as potential drugs for development of novel therapeutic modality to TBI.”

https://www.ncbi.nlm.nih.gov/pubmed/30489198

https://www.liebertpub.com/doi/10.1089/neu.2018.6063

Cannabinoids, Chemical Senses, and Regulation of Feeding Behavior.

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“The herb Cannabis sativa has been traditionally used in many cultures and all over the world for thousands of years as medicine and recreation.

However, because it was brought to the Western world in the late 19th century, its use has been a source of controversy with respect to its physiological effects as well as the generation of specific behaviors. In this regard, the CB1 receptor represents the most relevant target molecule of cannabinoid components on nervous system and whole-body energy homeostasis.

Thus, the promotion of CB1 signaling can increase appetite and stimulate feeding, whereas blockade of CB1 suppresses hunger and induces hypophagia.

Taste and flavor are sensory experiences involving the oral perception of food-derived chemicals and drive a primal sense of acceptable or unacceptable for what is sampled. Therefore, research within the last decades focused on deciphering the effect of cannabinoids on the chemical senses involved in food perception and consequently in the pattern of feeding.

In this review, we summarize the data on the effect of cannabinoids on chemical senses and their influences on food intake control and feeding behavior.”

https://www.ncbi.nlm.nih.gov/pubmed/30481264