WIN55,212-2 induces caspase-independent apoptosis on human glioblastoma cells by regulating HSP70, p53 and Cathepsin D.

Toxicology in Vitro

“Despite the standard approaches to treat the highly aggressive and invasive glioblastoma (GBM), it remains incurable.

In this sense, cannabinoids highlight as a promising tool, because this tumor overexpresses CB1 and/or CB2 receptors and being, therefore, can be susceptible to cannabinoids treatment.

Thus, this work investigated the action of the cannabinoid agonist WIN55-212-2 on GBM cell lines and non-malignant cell lines, in vitro and in vivo. WIN was selectively cytotoxic to GBM cells. These presented blebbing and nuclear alterations in addition to cell shrinkage and chromatin condensation. WIN also significantly inhibited the migration of GAMG and U251 cells.

Finally, the data also showed that the antitumor effects of WIN are exerted, at least to some extent, by the expression of p53 and increased cathepsin D in addition to the decreased expression of HSP70.This data can indicate caspase-independent cell death mechanism. In addition, WIN decreased tumoral perimeter as well as caused a reduction the blood vessels in this area, without causing lysis, hemorrhage or blood clotting.

So, the findings herein presented reinforce the usefulness of cannabinoids as a candidate for further evaluation in treatment in glioblastoma treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/30776504

https://www.sciencedirect.com/science/article/pii/S0887233318307537?via%3Dihub

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New Insights in Cannabinoid Receptor Structure and Signaling.

“Cannabinoid has long been used for medicinal purposes. Cannabinoid signaling has been considered the therapeutic targets for treating pain, addiction, obesity, inflammation, and other diseases. Recent studies have suggested that in addition to CB1 and CB2, there are non-CB1 and non-CB2 cannabinoid-related orphan GPCRs including GPR18, GPR55, and GPR119. In addition, CB1 and CB2 display allosteric binding and biased signaling, revealing correlations between biased signaling and functional outcomes. Interestingly, new investigations have indicated that CB1 is functionally present within mitochondria of striated and heart muscles directly regulating intramitochondrial signaling and respiration.

CONCLUSION:

In this review, we summarize the recent progress in cannabinoid-related orphan GPCRs, CB1/CB2 structure, Gi/Gs coupling, allosteric ligands and biased signaling, and mitochondria-localized CB1, and discuss the future promise of this research.”

https://www.ncbi.nlm.nih.gov/pubmed/30767756

http://www.eurekaselect.com/170011/article

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Spontaneous, anecdotal, retrospective, open-label study on the efficacy, safety and tolerability of cannabis galenical preparation (Bedrocan).

International Journal of Pharmacy Practice banner

“Our main aim was to investigate the short-term therapeutic effects, safety/tolerability and potential side effects of the cannabis galenical preparation (Bedrocan) in patients with a range of chronic conditions unresponsive to other treatments.

METHODS:

In this retrospective, ‘compassionate use’, observational, open-label study, 20 patients (age 18-80 years) who had appealed to our ‘Second Opinion Medical Consulting Network’ (Modena, Italy), were instructed to take sublingually the galenical oil twice a day for 3 months of treatment. The usual starting dose was low (0.5 ml/day) and gradually titrated upward to the highest recommended dose (1 ml/day). Tolerability and adverse effects were assessed at baseline and monthly thereafter during the treatment period through direct contact (email or telephone) or visit if required. Patients’ quality of life was evaluated at baseline and 3 months using the medical outcome short-form health survey questionnaire (SF-36).

KEY FINDINGS:

From baseline to 6 months post-treatment, SF-36 scores showed: reductions in total pain (P < 0.03); improvements in the physical component (P < 0.02); vitality (P < 0.03); social role functioning (P < 0.02); and general health state (P < 0.02). No changes in role limitations (P = 0.02) due to emotional state (e.g. panic, depression, mood alteration) were reported. Monthly reports of psychoactive adverse effects showed significant insomnia reduction (P < 0.03) and improvement in mood (P < 0.03) and concentration (P < 0.01).

CONCLUSIONS:

These data suggest that a cannabis galenical preparation may be therapeutically effective and safe for the symptomatic treatment of some chronic diseases. Further studies on the efficacy of cannabis as well as cannabinoid system involvement in the pathophysiology are warranted.”

https://www.ncbi.nlm.nih.gov/pubmed/30768819

https://onlinelibrary.wiley.com/doi/full/10.1111/ijpp.12514

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Therapeutic targeting of HER2-CB2R heteromers in HER2-positive breast cancer.

 Proceedings of the National Academy of Sciences: 116 (6)

“Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New therapeutic approaches and diagnostic tools for identification, stratification, and treatment of patients at higher risk of resistance and recurrence are therefore warranted.

Here, we unveil a mechanism controlling the oncogenic activity of HER2: heteromerization with the cannabinoid receptor CB2R. We show that HER2 physically interacts with CB2R in breast cancer cells, and that the expression of these heteromers correlates with poor patient prognosis.

The cannabinoid Δ9-tetrahydrocannabinol (THC) disrupts HER2-CB2R complexes by selectively binding to CB2R, which leads to (i) the inactivation of HER2 through disruption of HER2-HER2 homodimers, and (ii) the subsequent degradation of HER2 by the proteasome via the E3 ligase c-CBL. This in turn triggers antitumor responses in vitro and in vivo. Selective targeting of CB2R transmembrane region 5 mimicked THC effects.

Together, these findings define HER2-CB2R heteromers as new potential targets for antitumor therapies and biomarkers with prognostic value in HER2-positive breast cancer.”

https://www.ncbi.nlm.nih.gov/pubmed/30733293

https://www.pnas.org/content/early/2019/02/06/1815034116

“Pharmacological activation of cannabinoid receptors elicits antitumoral responses in different cancer models. Our findings reveal an unprecedented role of CB2 as a pivotal regulator of HER2 pro-oncogenic signaling in breast cancer” http://www.ncbi.nlm.nih.gov/pubmed/25855725
“Extensive preclinical research has demonstrated that cannabinoids, the active ingredients of Cannabis sativa, trigger antitumor responses in different models of cancer. Together, our results suggest that standardized cannabis drug preparations, rather than pure cannabinoids, could be considered as part of the therapeutic armamentarium to manage breast cancer.” https://www.ncbi.nlm.nih.gov/pubmed/29940172
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Lower circulating endocannabinoid levels in children with autism spectrum disorder.

 Image result for bmc molecular autism

“The endocannabinoid system (ECS) is a major regulator of synaptic plasticity and neuromodulation. Alterations of the ECS have been demonstrated in several animal models of autism spectrum disorder (ASD). In some of these models, activating the ECS rescued the social deficits. Evidence for dysregulations of the ECS in human ASD are emerging, but comprehensive assessments and correlations with disease characteristics have not been reported yet.

METHODS:

Serum levels of the main endocannabinoids, N-arachidonoylethanolamine (AEA or anandamide) and 2-arachidonoylglycerol (2-AG), and their related endogenous compounds, arachidonic acid (AA), N-palmitoylethanolamine (PEA), and N-oleoylethanolamine (OEA), were analyzed by liquid chromatography/tandem mass spectrometry in 93 children with ASD (age = 13.1 ± 4.1, range 6-21; 79% boys) and 93 age- and gender-matched neurotypical children (age = 11.8 ± 4.3, range 5.5-21; 79% boys). Results were associated with gender and use of medications, and were correlated with age, BMI, and adaptive functioning of ASD participants as reflected by scores of Autism Diagnostic Observation Schedule (ADOS-2), Vineland Adaptive Behavior Scale-II (VABS-II), and Social Responsiveness Scale-II (SRS-2).

RESULTS:

Children with ASD had lower levels (pmol/mL, mean ± SEM) of AEA (0.722 ± 0.045 vs. 1.252 ± 0.072, P < 0.0001, effect size 0.91), OEA (17.3 ± 0.80 vs. 27.8 ± 1.44, P < 0.0001, effect size 0.94), and PEA (4.93 ± 0.32 vs. 7.15 ± 0.37, P < 0.0001, effect size 0.65), but not AA and 2-AG. Serum levels of AEA, OEA, and PEA were not significantly associated or correlated with age, gender, BMI, medications, and adaptive functioning of ASD participants. In children with ASD, but not in the control group, younger age and lower BMI tended to correlate with lower AEA levels. However, these correlations were not statistically significant after a correction for multiple comparisons.

CONCLUSIONS:

We found lower serum levels of AEA, PEA, and OEA in children with ASD. Further studies are needed to determine whether circulating endocannabinoid levels can be used as stratification biomarkers that identify clinically significant subgroups within the autism spectrum and if they reflect lower endocannabinoid “tone” in the brain, as found in animal models of ASD.”

https://www.ncbi.nlm.nih.gov/pubmed/30728928

https://molecularautism.biomedcentral.com/articles/10.1186/s13229-019-0256-6

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Cutting Edge: Dysregulated Endocannabinoid-Rheostat for Plasmacytoid Dendritic Cell Activation in a Systemic Lupus Endophenotype.

The Journal of Immunology

“Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, characterized by loss of tolerance toward self nuclear Ags. Systemic induction of type I IFNs plays a pivotal role in SLE, a major source of type I IFNs being the plasmacytoid dendritic cells (pDCs). Several genes have been linked with susceptibility to SLE in genome-wide association studies. We aimed at exploring the role of one such gene, α/β-hydrolase domain-containing 6 (ABHD6), in regulation of IFN-α induction in SLE patients. We discovered a regulatory role of ABHD6 in human pDCs through modulating the local abundance of its substrate, the endocannabinoid 2-arachidonyl glycerol (2-AG), and elucidated a hitherto unknown cannabinoid receptor 2 (CB2)-mediated regulatory role of 2-AG on IFN-α induction by pDCs. We also identified an ABHD6High SLE endophenotype wherein reduced local abundance of 2-AG relieves the CB2-mediated steady-state resistive tuning on IFN-α induction by pDCs, thereby contributing to SLE pathogenesis.”

https://www.ncbi.nlm.nih.gov/pubmed/30728209

http://www.jimmunol.org/content/early/2019/02/05/jimmunol.1801521

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Muscle cannabinoid 1 receptor regulates Il-6 and myostatin expression, governing physical performance and whole-body metabolism.

“Sarcopenic obesity, the combination of skeletal muscle mass and function loss with an increase in body fat, is associated with physical limitations, cardiovascular diseases, metabolic stress, and increased risk of mortality. Cannabinoid receptor type 1 (CB1R) plays a critical role in the regulation of whole-body energy metabolism because of its involvement in controlling appetite, fuel distribution, and utilization. Inhibition of CB1R improves insulin secretion and insulin sensitivity in pancreatic β-cells and hepatocytes. We have now developed a skeletal muscle-specific CB1R-knockout (Skm-CB1R-/-) mouse to study the specific role of CB1R in muscle. Muscle-CB1R ablation prevented diet-induced and age-induced insulin resistance by increasing IR signaling. Moreover, muscle-CB1R ablation enhanced AKT signaling, reducing myostatin expression and increasing IL-6 secretion. Subsequently, muscle-CB1R ablation increased myogenesis through its action on MAPK-mediated myogenic gene expression. Consequently, Skm-CB1R-/- mice had increased muscle mass and whole-body lean/fat ratio in obesity and aging. Muscle-CB1R ablation improved mitochondrial performance, leading to increased whole-body muscle energy expenditure and improved physical endurance, with no change in body weight. These results collectively show that CB1R in muscle is sufficient to regulate whole-body metabolism and physical performance and is a novel target for the treatment of sarcopenic obesity.”

https://www.ncbi.nlm.nih.gov/pubmed/30726112

https://www.fasebj.org/doi/10.1096/fj.201801145R

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Synergistic action of CB1 and 5-HT2B receptors in preventing pilocarpine-induced status epilepticus in rats.

Neurobiology of Disease

“Endocannabinoids (eCBs) and serotonin (5-HT) play a neuromodulatory role in the central nervous system. Both eCBs and 5-HT regulate neuronal excitability and their pharmacological potentiation has been shown to control seizures in pre-clinical and human studies.

Compelling evidence indicates that eCB and 5-HT systems interact to modulate several physiological and pathological brain functions, such as food intake, pain, drug addiction, depression, and anxiety.

Nevertheless, there is no evidence of an eCB/5-HT interaction in experimental and human epilepsies, including status epilepticus (SE). Here, we performed video-EEG recording in behaving rats treated with the pro-convulsant agent pilocarpine (PILO), in order to study the effect of the activation of CB1/5-HT2receptors and their interaction on SE.

Synthetic cannabinoid agonist WIN55,212-2 (WIN) decreased behavioral seizure severity of PILO-induced SE at 2 mg/kg (but not at 1 and 5 mg/kg, i.p.), while 5-HT2B/2C receptor agonist RO60-0175 (RO; 1, 3, 10 mg/kg, i.p.) was devoid of any effect. RO 3 mg/kg was instead capable of potentiating the effect of WIN 2 mg/kg on the Racine scale score.

Surprisingly, neither WIN 2 mg/kg nor RO 3 mg/kg had any effect on the incidence and the intensity of EEG seizures when administered alone. However, WIN+RO co-administration reduced the incidence and the severity of EEG SE and increased the latency to SE onset after PILO injection. WIN+RO effects were blocked by the selective CB1R antagonist AM251 and the 5-HT2BR antagonist RS127445, but not by the 5-HT2CR antagonist SB242084 or the 5-HT2AR antagonist MDL11,939.

These data revealed a synergistic interaction between CB1R/5-HT2BR in the expression of PILO-induced SE.”

https://www.ncbi.nlm.nih.gov/pubmed/30716469

https://www.sciencedirect.com/science/article/pii/S0969996119300336?via%3Dihub

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Ketamine induces central antinociception mediated by endogenous cannabinoids and activation of CB1 receptors.

Neuroscience Letters

“The participation of endocannabinoids in central and peripheral antinociception induced by several compounds has been shown by our group.

In this study, we investigated the effect of endocannabinoids on the central antinociception induced by ketamine.

It was concluded that central antinociception induced by ketamine involves the activation of CB1 cannabinoidreceptors.

Mobilization of cannabinoids might be required for the activation of those receptors, since inhibitors of the endogenous cannabinoids potentiate the effect of Ketamine.”

https://www.ncbi.nlm.nih.gov/pubmed/30716423

https://www.sciencedirect.com/science/article/abs/pii/S0304394019300771?via%3Dihub

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Hemisphere-dependent endocannabinoid system activity in prefrontal cortex and hippocampus of the Flinders Sensitive Line rodent model of depression.

Neurochemistry International“Altered endocannabinoid (eCB) signaling is suggested as an important contributor to the pathophysiology of depression.

In summary, our data suggest a decreased eCB signalling in the FSL rats, which could contribute to the depressive-like behaviour.

Interestingly, the altered eCB system activity appear to be hemisphere-specific in the limbic regions.

Our study support the existing literature and showed altered eCB system activity in this particular animal model of depression.”

https://www.ncbi.nlm.nih.gov/pubmed/30716357

https://www.sciencedirect.com/science/article/abs/pii/S0197018618305151?via%3Dihub

“Antidepressant-like effect of delta9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L. Results of this study show that Delta(9)-THC and other cannabinoids exert antidepressant-like actions, and thus may contribute to the overall mood-elevating properties of cannabis.”   https://www.ncbi.nlm.nih.gov/pubmed/20332000

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