Increased expression of cannabinoid CB2 and serotonin 5-HT1A heteroreceptor complexes in a model of newborn hypoxic-ischemic brain damage.

Posted on February 10, 2019 by David

Neuropharmacology

“Preclinical work shows cannabidiol as a promising drug to manage neonatal hypoxic-ischemic brain damage (NHIBD). The molecular mechanism is not well defined but the beneficial effects of this phytocannabinoid are blocked by antagonists of both cannabinoid CB₂(CB₂R) and serotonin 5-HT_1A (5-HT1AR) receptors that, in addition, may form heteromers in a heterologous expression system. Using bioluminescence energy transfer, we have shown a direct interaction of the two receptors that leads to a particular signaling in a heterologous system. A property attributed to the heteromer, namely cross-antagonism, was found in primary cultures of neurons thus indicating the occurrence of the receptor heteromer in the CNS. Oxygen-glucose deprivation to neurons led to an increase of CB₂R-mediated signaling and an upregulation of CB₂-5-HT_1A heteroreceptor complex expression. In situ proximity ligation assays in brain cortical section were performed to compare the expression of CB₂-5-HT_1A complexes in rat E20 fetuses and at different postnatal days. The expression, which is elevated in fetus and shortly after birth, was sharply reduced at later ages (even at P7). The expression of heteromer receptors was more marked in a model of NHIBD and, remarkably, the drop in expression was significantly delayed with respect to controls. These results indicate that CB₂-5-HT_1A heteroreceptor complex may be considered as a target in the therapy of the NHIBD.”

https://www.ncbi.nlm.nih.gov/pubmed/30738036

https://www.sciencedirect.com/science/article/pii/S0028390819300462?via%3Dihub

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

Posted on February 9, 2019 by David

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

http://www.thctotalhealthcare.com/category/breast-cancer/

Lower circulating endocannabinoid levels in children with autism spectrum disorder.

Posted on February 9, 2019 by David

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

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

Posted on February 9, 2019 by David

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 ABHD6^High 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

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

Posted on February 8, 2019 by David

“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

An Update of Current Cannabis-Based Pharmaceuticals in Pain Medicine.

Posted on February 6, 2019 by David

“Cannabis users have long reported therapeutic properties of the plant for a variety of conditions, some of which include nausea, emesis, seizures, cancer, neurogenic diseases and pain control. Research has elucidated many cannabinoid pharmacodynamic and pharmacokinetic properties, expanding the potential use of cannabinoids as a medical therapy.

Due to the inconsistent delivery and control of the active components involved with smoking, pharmaceutical companies are investigating and prioritizing routes other than smoke inhalation for therapeutic use of cannabinoids. In this relatively new field of pharmaceutical development, ongoing drug development promises great benefit from targeted endocannabinoid receptor agonism.

Available in Canada and Europe, nabiximols, a specific extract from the Cannabis plant, has demonstrated great benefit in the treatment of pain related to spasticity in multiple sclerosis, cancer and otherwise chronic pain conditions.

The cannabidiol oral solution Epidiolex®, which is available in the USA, is indicated for management of refractory epilepsy but may offer therapeutic relief to chronic pain conditions as well.

Current investigative drugs, such as those developed by Cara Therapeutics and Zynerba Pharmaceuticals, are synthetic cannabinoids which show promise to specifically target neuropsychiatric conditions and chronic pain symptoms such as neuropathy and allodynia.

The objective of this review is to provide clinicians with an update of currently available and promising developmental cannabis pharmaceutical derivatives which may stand to greatly benefit patients with otherwise difficult-to-treat chronic conditions.”

https://www.ncbi.nlm.nih.gov/pubmed/30721403

https://link.springer.com/article/10.1007%2Fs40122-019-0114-4

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

Posted on February 5, 2019 by David

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-HT_2B/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-HT_2BR antagonist RS127445, but not by the 5-HT_2CR antagonist SB242084 or the 5-HT_2AR antagonist MDL11,939.

These data revealed a synergistic interaction between CB₁R/5-HT_2BR 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

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

Posted on February 5, 2019 by David

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

Synthetic Cannabinoids Influence the Invasion of Glioblastoma Cell Lines in a Cell- and Receptor-Dependent Manner.

Posted on February 3, 2019 by David

“The current treatment of glioblastoma is not sufficient, since they are heterogeneous and often resistant to chemotherapy.

Earlier studies demonstrated effects of specific cannabinoid receptor (CB) agonists on the invasiveness of glioblastoma cell lines, but the exact mechanism remained unclear.

Three human glioblastoma cell lines were treated with synthetic CB ligands. The effect of cannabinoids on microRNAs (miRs), Akt, and on the expression of proliferation and apoptosis markers were analyzed.

Furthermore, in a model of organotypic hippocampal slice cultures cannabinoid mediated changes in the invasiveness were assessed. MicroRNAs and the activation of Akt which are related to cell migration, apoptosis, and proliferation were evaluated and found not to be associated with changes in the invasiveness after treatment with CB ligands.

Also proliferation and/or apoptosis were not altered after treatment. The effects of cannabinoids on invasiveness could be blocked by the application of receptor antagonists and are likely mediated via CB₁/CB₂.

In conclusion, our results suggest that cannabinoids can influence glioblastoma cell invasion in a receptor and cell type specific manner that is independent of proliferation and apoptosis. Thus, cannabinoids can potentially be used in the future as an addition to current therapy.”

https://www.ncbi.nlm.nih.gov/pubmed/30709059

https://www.mdpi.com/2072-6694/11/2/161

Opposite effects of cannabinoid CB1 and CB2 receptors on antipsychotic clozapine-induced cardiotoxicity.

Posted on February 3, 2019 by David

Publication cover image

“Clozapine is an atypical antipsychotic drug that is very efficacious in treating psychosis but the risk of severe cardiotoxicity limits its clinical use.

The present study investigated the myocardial injury effects of clozapine and assessed the involvement of cannabinoid receptors in clozapine cardiotoxicity.

Our data provided evidence that cannabinoid CB1 and CB2 receptors had opposite effects and selective antagonists of CB1R or agonists of CB2R might confer protective effects against clozapine.”

https://www.ncbi.nlm.nih.gov/pubmed/30707759

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14591