Tag Archives: cannabinoid receptors

Anti-inflammatory activity of cannabinoid receptor 2 ligands in primary hPDL fibroblasts.

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“Approximately 65 million adults in the US have periodontitis, causing tooth loss and decreased quality of life.

 Cannabinoids modulate immune responses, and endocannabinoids are prevalent during oral cavity inflammation. Targets for intervention in periodontal inflammation are cannabinoid type 1 and 2 receptors (CB1R, CB2R), particularly CB2R because its levels increase during inflammation.

We previously demonstrated that SMM-189 (CB2R inverse agonist) decreased pro-inflammatory cytokine production in primary microglial cells. The hypothesis of this study was that cannabinoids anandamide (AEA), HU-308 (CB2R selective agonist), and SMM-189 decrease pro-inflammatory IL-6 and MCP-1 production by primary human periodontal ligament fibroblasts (hPDLFs) stimulated with P. gingivalis LPS, TNF-α, or IL-1β.

CONCLUSION:

The effective inhibition of LPS, TNF-α, IL-1β stimulated IL-6 and MCP-1 production by CB2R ligands in hPDLFs suggests that targeting the endocannabinoid system may lead to development of novel drugs for periodontal therapy, aiding strategies to improve oral health.”

https://www.ncbi.nlm.nih.gov/pubmed/29274621

Enhancing Endocannabinoid Neurotransmission Augments The Efficacy of Extinction Training and Ameliorates Traumatic Stress-Induced Behavioral Alterations in Rats.

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“Exposure to a traumatic event may result in the development of Post-Traumatic Stress Disorder (PTSD).

Endocannabinoids are crucial modulators of the stress response, interfere with excessive retrieval and facilitate the extinction of traumatic memories. Exposure therapy, combined with pharmacotherapy, represents a promising tool for PTSD treatment.

We investigated whether pharmacological manipulations of the endocannabinoid system during extinction learning ameliorates the behavioral changes induced by trauma exposure.

Our findings suggest that drugs potentiating endocannabinoid neurotransmission may represent promising tools when combined to exposure-based psychotherapies in the treatment of PTSD.”

https://www.ncbi.nlm.nih.gov/pubmed/29265107

https://www.nature.com/articles/npp2017305

Role of the endogenous cannabinoid receptor 1 in brain injury induced by chronic intermittent hypoxia in rats.

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“This study investigated the effect of rimonabant, a cannabinoid receptor type 1 (CB1) antagonist, on calcium/calmodulin dependent protein kinase II (CaMKII) and CB1 in chronic intermittent hypoxia (CIH).

Rimonabant had a protective effect against CIH.” https://www.ncbi.nlm.nih.gov/pubmed/29264962

http://www.tandfonline.com/doi/abs/10.1080/00207454.2017.1420069

 

Activation of cannabinoid receptor type 2 by JWH133 alleviates bleomycin-induced pulmonary fibrosis in mice.

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“Activation of cannabinoid receptor type 2 has been shown to have anti-fibrosis function in skin and heart.

In this research, we aimed to investigate the role of cannabinoid receptor type 2 in pulmonary fibrosis in vitro and in vivo.

Our research indicated that activating cannabinoid receptor type 2 by a pharmacological method might be a potential strategy for pulmonary fibrosis.”  https://www.ncbi.nlm.nih.gov/pubmed/29262578

“In conclusion, we demonstrate that activating cannabinoid receptor type 2 by selective agonist JWH133 is a potential strategy for pulmonary fibrosis. Our researches offer a new choice for this life-threatening disease.” http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=21975&path[]=69664

Discovery of Selective Cannabinoid CB2 Receptor Agonists by High-Throughput Screening.

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“The endocannabinoid system (ECS) plays a diverse role in human physiology ranging from the regulation of mood and appetite to immune modulation and the response to pain.

Drug development that targets the cannabinoid receptors (CB1 and CB2) has been explored; however, success in the clinic has been limited by the psychoactive side effects associated with modulation of the neuronally expressed CB1 that are enriched in the CNS. CB2, however, are expressed in peripheral tissues, primarily in immune cells, and thus development of CB2-selective drugs holds the potential to modulate pain among other indications without eliciting anxiety and other undesirable side effects associated with CB1 activation.

As part of a collaborative effort among industry and academic laboratories, we performed a high-throughput screen designed to discover selective agonists or positive allosteric modulators (PAMs) of CB2. Although no CB2 PAMs were identified, 167 CB2 agonists were discovered here, and further characterization of four select compounds revealed two with high selectivity for CB2 versus CB1.

These results broaden drug discovery efforts aimed at the ECS and may lead to the development of novel therapies for immune modulation and pain management with improved side effect profiles.”

https://www.ncbi.nlm.nih.gov/pubmed/29257918

 

Restoration of osteogenic differentiation by overexpression of cannabinoid receptor 2 in bone marrow mesenchymal stem cells isolated from osteoporotic patients.

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“Cannabinoid receptor 2 (CNR2) has a critical role in osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). CNR2 expression was found to be downregulated in osteoporotic patients.

The present study aimed to investigate the functionality of CNR2 in restoring osteogenic differentiation and mineralization of BMSCs isolated from osteoporotic patients.

The results demonstrated that overexpression of CNR2 in osteoporotic BMSCs increased ALP activity, promoted expression of osteogenic genes and enhanced deposition of mineralized extracellular matrix. In addition, phosphorylation of p38 MAPK was found to be increased by overexpression of CNR2.

In conclusion, the present study indicated that restoration of CNR2 recovered the osteogenic differentiation of BMSCs isolated from osteoporotic patients. This finding may provide a novel strategy for a treatment approach for osteoporosis.”

https://www.ncbi.nlm.nih.gov/pubmed/29250156

https://www.spandidos-publications.com/10.3892/etm.2017.5369

Cannabidiol restores intestinal barrier dysfunction and inhibits the apoptotic process induced by Clostridium difficile toxin A in Caco-2 cells.

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 SAGE Journals

“Clostridium difficile toxin A is responsible for colonic damage observed in infected patients.

Drugs able to restore Clostridium difficile toxin A-induced toxicity have the potential to improve the recovery of infected patients. Cannabidiol is a non-psychotropic component of Cannabis sativa, which has been demonstrated to protect enterocytes against chemical and/or inflammatory damage and to restore intestinal mucosa integrity.

The purpose of this study was to evaluate (a) the anti-apoptotic effect and (b) the mechanisms by which cannabidiol protects mucosal integrity in Caco-2 cells exposed to Clostridium difficile toxin A.

RESULTS:

Clostridium difficile toxin A significantly decreased Caco-2 cells’ viability and reduced transepithelial electrical resistence values and RhoA guanosine triphosphate (GTP), bax, zonula occludens-1 and occludin protein expression, respectively. All these effects were significantly and concentration-dependently inhibited by cannabidiol, whose effects were completely abolished in the presence of the cannabinoid receptor type 1 (CB1) antagonist, AM251.

CONCLUSIONS:

Cannabidiol improved Clostridium difficile toxin A-induced damage in Caco-2 cells, by inhibiting the apoptotic process and restoring the intestinal barrier integrity, through the involvement of the CB1 receptor.”

https://www.ncbi.nlm.nih.gov/pubmed/29238589

“In the last decade, cannabinoids extracted from the marijuana plant (Cannabis sativa) and synthetic cannabinoids have shown numerous beneficial effects on gastrointestinal (GI) functions. Non-psychotropic phytocannabinoid cannabidiol (CBD) is one of the most interesting compounds, since it exerts a wide range of beneficial pharmacological actions on GI functions, ranging from antioxidant to antinflammatory activities. CBD has been shown to act as a non-competitive negative allosteric modulator of CB1 receptors. Notably, CBD is able to restore in vitro intestinal permeability increased by ethylenediaminetetraacetic acid (EDTA) or pro-inflammatory stimuli.

Conclusion

Clostridium difficile infection is the leading cause of hospital-acquired diarrhoea and pseudomembranous colitis. Clostridium difficile-Toxin A significantly affects enterocytes permeability leading to apoptosis and colonic mucosal damage.

In the present study, we showed that Cannabidiol, a non-psychotropic component of Cannabis sativa significantly inhibit the apoptosis rate in TcdA-exposed cells and restores barrier function by a significant RhoA GTP rescue.

We also provide evidence that the effects of Cannabidiol are mediated by CB-1 receptor.

Given the absence of any significant toxic effect in humans, cannabidiol may ideally represent an effective adjuvant treatment for Clostridium difficile-associated colitis.”   http://journals.sagepub.com/doi/10.1177/2050640617698622

Bioactive products from singlet oxygen photooxygenation of cannabinoids.

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European Journal of Medicinal Chemistry

“Photooxygenation of Δ8 tetrahydrocannabinol (Δ8-THC), Δ9 tetrahydrocannabinol (Δ9-THC), Δ9 tetrahydrocannabinolic acid (Δ9-THCA) and some derivatives (acetate, tosylate and methyl ether) yielded 24 oxygenated derivatives, 18 of which were new and 6 were previously reported, including allyl alcohols, ethers, quinones, hydroperoxides, and epoxides.

Testing these compounds for their modulatory effect on cannabinoid receptors CB1 and CB2 led to the identification of 7 and 21 as CB1 partial agonists with Ki values of 0.043 μM and 0.048 μM, respectively and 23 as a cannabinoid with high binding affinity for CB2 with Ki value of 0.0095 μM, but much less affinity towards CB1 (Ki 0.467 μM).

The synthesized compounds showed cytotoxic activity against cancer cell lines (SK-MEL, KB, BT-549, and SK-OV-3) with IC50 values ranging from 4.2 to 8.5 μg/mL.

Several of those compounds showed antimicrobial, antimalarial and antileishmanial activities, with compound 14 being the most potent against various pathogens.”

https://www.ncbi.nlm.nih.gov/pubmed/29232588

http://www.sciencedirect.com/science/article/pii/S0223523417309467?via%3Dihub

The endocannabinoid system in cardiovascular function: novel insights and clinical implications.

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Clinical Autonomic Research

“Cardiovascular disease is now recognized as the number one cause of death in the world, and the size of the population at risk continues to increase rapidly. The dysregulation of the endocannabinoid (eCB) system plays a central role in a wide variety of conditions including cardiovascular disorders. Cannabinoid receptors, their endogenous ligands, as well as enzymes conferring their synthesis and degradation, exhibit overlapping distributions in the cardiovascular system. Furthermore, the pharmacological manipulation of the eCB system has effects on blood pressure, cardiac contractility, and endothelial vasomotor control. Growing evidence from animal studies supports the significance of the eCB system in cardiovascular disorders.

RESULTS:

Drugs targeting CB1R, CB2R, TRPV1 and PPARs are proven effective in animal models mimicking cardiovascular disorders such as hypertension, atherosclerosis and myocardial infarction. Despite the setback of two clinical trials that exhibited unexpected harmful side-effects, preclinical studies are accelerating the development of more selective drugs with promising results devoid of adverse effects.

CONCLUSION:

Over the last years, increasing evidence from basic and clinical research supports the role of the eCB system in cardiovascular function. Whereas new discoveries are paving the way for the identification of novel drugs and therapeutic targets, the close cooperation of researchers, clinicians and pharmaceutical companies is needed to achieve successful outcomes.”

https://www.ncbi.nlm.nih.gov/pubmed/29222605

https://link.springer.com/article/10.1007%2Fs10286-017-0488-5

Cannabinoids for epilepsy: What do we know and where do we go?

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Epilepsia

“Over the past decade there has been an increasing interest in using cannabinoids to treat a range of epilepsy syndromes following reports of some remarkable responses in individual patients.

The situation is complicated by the fact that these agents do not appear to work via their attachment to endogenous cannabinoid receptors. Their pharmacokinetics are complex, and bioavailability is variable, resulting in difficulty in developing a suitable formulation for oral delivery. Drug interactions also represent another complication in their everyday use.

Nevertheless, recent randomized, placebo-controlled trials with cannabidiol support its efficacy in Dravet and Lennox-Gastaut syndromes.

Further placebo-controlled studies are underway in adults with focal epilepsy using cannabidivarin. The many unanswered questions in the use of cannabinoids to treat epileptic seizures are briefly summarized in the conclusion.”

https://www.ncbi.nlm.nih.gov/pubmed/29214639

http://onlinelibrary.wiley.com/doi/10.1111/epi.13973/abstract