The Endocannabinoid System in Pediatric Inflammatory and Immune Diseases.

 ijms-logo“Endocannabinoid system consists of cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors, their endogenous ligands, and the enzymes responsible for their synthesis and degradation. CB2, to a great extent, and CB1, to a lesser extent, are involved in regulating the immune response. They also regulate the inflammatory processes by inhibiting pro-inflammatory mediator release and immune cell proliferation. This review provides an overview on the role of the endocannabinoid system with a major focus on cannabinoid receptors in the pathogenesis and onset of inflammatory and autoimmune pediatric diseases, such as immune thrombocytopenia, juvenile idiopathic arthritis, inflammatory bowel disease, celiac disease, obesity, neuroinflammatory diseases, and type 1 diabetes mellitus. These disorders have a high social impact and represent a burden for the healthcare system, hence the importance of individuating more innovative and effective treatments. The endocannabinoid system could address this need, representing a possible new diagnostic marker and therapeutic target.”

https://www.ncbi.nlm.nih.gov/pubmed/31771129

https://www.mdpi.com/1422-0067/20/23/5875

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Tetrahydrocannabinolic acid A (THCA-A) reduces adiposity and prevents metabolic disease caused by diet-induced obesity.

Biochemical Pharmacology“Medicinal cannabis has remarkable therapeutic potential, but its clinical use is limited by the psychotropic activity of Δ9-tetrahydrocannabinol (Δ9-THC). However, the biological profile of the carboxylated, non-narcotic native precursor of Δ9-THC, the Δ9-THC acid A (Δ9-THCA-A), remains largely unexplored.

Here we present evidence that Δ9-THCA-A is a partial and selective PPARγ modulator, endowed with lower adipogenic activity than the full PPARγ agonist rosiglitazone (RGZ) and enhanced osteoblastogenic effects in hMSC. Docking and in vitro functional assays indicated that Δ9-THCA-A binds to and activates PPARγ by acting at both the canonical and the alternative sites of the ligand-binding domain. Transcriptomic signatures in iWAT from mice treated with Δ9-THCA-A confirmed its mode of action through PPARγ.

Administration of Δ9-THCA-A in a mouse model of HFD-induced obesity significantly reduced fat mass and body weight gain, markedly ameliorating glucose intolerance and insulin resistance, and largely preventing liver steatosis, adipogenesis and macrophage infiltration in fat tissues. Additionally, immunohistochemistry, transcriptomic, and plasma biomarker analyses showed that treatment with Δ9-THCA-A caused browning of iWAT and displayed potent anti-inflammatory actions in HFD mice.

Our data validate the potential of Δ9-THCA-A as a low adipogenic PPARγ agonist, capable of substantially improving the symptoms of obesity-associated metabolic syndrome and inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/31706843

“Δ9-THCA-A is a partial PPARγ ligand agonist with low adipogenic activity. Δ9-THCA-A enhances osteoblastogenesis in bone marrow derived mesenchymal stem cells. Δ9-THCA-A reduces body weight gain, fat mass, and liver steatosis in HFD-fed mice. Δ9-THCA-A improves glucose tolerance, insulin sensitivity, and insulin profiles in vivo. Δ9-THCA-A induces browning of iWAT and has a potent anti-inflammatory activity.”

https://www.sciencedirect.com/science/article/abs/pii/S0006295219303922?via%3Dihub

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Disease associated polymorphisms within the conserved ECR1 enhancer differentially regulate the tissue specific activity of the cannabinoid-1 receptor gene promoter; implications for cannabinoid pharmacogenetics.

Publication cover image“Cannabinoid receptor-1 (CB1) represents a potential drug target against conditions that include obesity and substance abuse. However, drug trials targeting CB1 (encoded by the CNR1 gene) have been compromised by differences in patient response.

Towards addressing the hypothesis that genetic changes within the regulatory regions controlling CNR1 expression contribute to these differences, we characterised the effects of disease associated allelic variation within a conserved regulatory sequence (ECR1) in CNR1 intron 2 that had previously been shown to modulate cannabinoid response, alcohol intake and anxiety-like behaviour.

We used primary cell analysis of reporters carrying different allelic variants of the human ECR1 and found that human specific C-allele variants of ECR1 (ECR1(C)) drove higher levels of CNR1prom activity in primary hippocampal cells than did the ancestral T-allele and demonstrated a differential response to CB1 agonism.

We further demonstrate a role for the AP-1 transcription factor in driving higher ECR1(C) activity and evidence that the ancestral t-allele variant of ECR1 interacted with higher affinity with the insulator binding factor CTCF. The cell-specific approaches used in our study represent an important step in gaining a mechanistic understanding the roles of non-coding polymorphic variation in disease and in the increasingly important field of cannabinoid pharmacogenetics.”

https://www.ncbi.nlm.nih.gov/pubmed/31608546

https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.23931

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Insights into biased signaling at cannabinoid receptors: synthetic cannabinoid receptor agonists.

Biochemical Pharmacology“Cannabinoid receptors type 1 (CB1) and type 2 (CB2) are promising targets for a number of diseases, including obesity, neuropathic pain, and multiple sclerosis, among others.

Upon ligand-mediated activation of these receptors, multiple receptor conformations could be stabilized, resulting in a complex pattern of possible intracellular effects. Although numerous compounds have been developed and widely used to target cannabinoid receptors, their mode of action and signaling properties are often only poorly characterized.

From a drug development point of view, unraveling the underlying complex signaling mechanism could offer the possibility to generate medicines with the desired therapeutic profile.

Recently, an increased interest has emerged for the development of agonists that are signaling pathway-selective and thereby do not evoke on-target adverse effects. This phenomenon, in which specific pathways are preferred upon receptor activation by certain ligands, is also known as ‘biased signaling’.

For a particular group of cannabinoid receptor ligands (i.e. CB1/CB2 agonists), namely the synthetic cannabinoid receptor agonists (SCRAs), the research on biased signaling is still in its infancy and interesting outcomes are only recently being revealed.

Therefore, this review aims at providing insights into the recent knowledge about biased agonism mediated by SCRAs so far. In addition, as these outcomes are obtained using a distinct panel of functional assays, the accompanying difficulties and challenges when comparing functional outcomes are critically discussed. Finally, some guidance on the conceptualization of ideal in vitro assays for the detection of SCRA-mediated biased agonism, which is also relevant for compounds belonging to other chemical classes, is provided.”

https://www.ncbi.nlm.nih.gov/pubmed/31472128

https://www.sciencedirect.com/science/article/abs/pii/S0006295219303132?via%3Dihub

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Dual Inhibition of Cannabinoid-1 Receptor and iNOS Attenuates Obesity-induced Chronic Kidney Disease.

British Journal of Pharmacology banner“Obesity, an important risk factor for developing chronic kidney disease (CKD), affects the kidneys by two main molecular signaling pathways: the endocannabinoid/CB1 R system, whose activation in obesity promotes renal inflammation, fibrosis, and injury; and the inducible nitric oxide synthase (iNOS), which generates reactive oxygen species resulting in oxidative stress. Hence, a combined peripheral inhibitory molecule that targets both CB1 R and iNOS may serve as an efficacious therapeutic agent against obesity-induced CKD.

KEY RESULTS:

Enhanced expression of CB1 R and iNOS in renal tubules was found in human kidney patients with obesity and other CKDs. The hybrid inhibitor ameliorated obesity-induced kidney morphological and functional changes via decreasing kidney inflammation, fibrosis, oxidative stress, and renal injury. Some of these features were independent of the improved metabolic profile mediated via inhibition of CB1 R. An additional interesting finding is that these beneficial effects on the kidney were partially associated with modulating renal adiponectin signaling.

CONCLUSIONS AND IMPLICATIONS:

Collectively, our results highlight the therapeutic relevance of blocking CB1 R and iNOS in ameliorating obesity-induced CKD.”

https://www.ncbi.nlm.nih.gov/pubmed/31454063

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14849

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Prediction and Experimental Confirmation of Novel Peripheral Cannabinoid-1 Receptor Antagonists.

Go to Volume 0, Issue ja “Small molecules targeting peripheral CB1 receptors have therapeutic potential in a variety of disorders including obesity-related, hormonal and metabolic abnormalities, while avoiding the psychoactive effects in the CNS.

We applied our in house algorithm, Iterative Stochastic Elimination, to produce a ligand-based model that distinguishes between CB1R antagonists and random molecules, by physico-chemical properties only. We screened ~2 million commercially available molecules, and found that about 500 of them are potential candidates to antagonize CB1R. We applied a few criteria for peripheral activity and narrowed that set down to 30 molecules, out of which 15 could be purchased. Ten out of those 15 showed good affinity to CB1R and two of them with nanomolar affinities (Ki of ~400 nM). The eight molecules with top affinities were tested for activity: two compounds are pure antagonists, and five others are inverse agonists.

These molecules are now being examined in vivo for their peripheral vs. central distribution, and subsequently will be tested for their effects on obesity in small animals.”

https://www.ncbi.nlm.nih.gov/pubmed/31433190

https://pubs.acs.org/doi/10.1021/acs.jcim.9b00577

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Lifetime marijuana use in relation to insulin resistance in lean, overweight, and obese US adults.

Journal of Diabetes banner“Obese individuals are more likely to show insulin resistance (IR). However, limited population studies on marijuanause with markers of IR have yielded mixed results.

The aim of this study was to examine the association of marijuana use with IR in US adults with different body mass index (BMI) status.

RESULTS:

Of all 129 509 adults aged 18 to 59 years, 50.3% were women. In current obese marijuana consumers, mean FINS in those with less than four uses per month was 52% (95% confidence interval [CI] 19%-71%) lower than in never users. In former obese consumers with eight or more uses per month and who stopped marijuana use <12 months ago, mean FINS was 47% (95% CI 18%-66%) lower than in never users. Mean FINS in those who quit marijuana 12 to 119 and 120 months and more prior the survey was 36% (95% CI 7%-57%) and 36% (95% CI 10%-54%) lower, respectively.

CONCLUSIONS:

Marijuana use is associated with lower FINS and HOMA-IR in obese but not non-obese adults, even at low frequency of less than four uses per month. Former marijuana consumers with high lifetime use had significantly lower FINS levels that persisted, independent of the duration of time since last use.”

https://www.ncbi.nlm.nih.gov/pubmed/31152633

https://onlinelibrary.wiley.com/doi/abs/10.1111/1753-0407.12958

“Cannabis linked to lower insulin levels in adults at risk of type 2 diabetes”   https://www.diabetes.co.uk/News/2019/Jul/cannabis-linked-to-lower-insulin-levels-in-adults-at-risk-of-type-2-diabetes-99514193.html

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Impact of lifetime marijuana use on fasting plasma insulin levels and HOMA-IR score in obese adults with and without insulin resistance.

 

“To explore the association of marijuana use with mean plasma fasting insulin levels and homeostasis model assessment of insulin resistance (HOMA-IR) score in obese adults with different HOMA-IR.

RESULTS:

A total of 65,209 obese individuals aged 18 to 59 years were included. In obese individuals who never used marijuana(reference), the mean value (± standard deviation) was 19.0 (± 12.8) μU/mL for plasma fasting insulin and 4.78 (± 3.49) for HOMA-IR. In individuals with HOMA-IR < 2.13 or ≥ 5.72, we found no association of marijuana use with HOMA-IR. In those with HOMA-IR < 5.72, the highest tertile of MLU (i.e., ≥ 1799 times) was associated with 12% decrease (95% confidence intervals, 4-19%) in the fasting insulin and 10% decrease in HOMA-IR (95% CI 1-19%), as compared with their counterparts who never used marijuana. In those with HOMA-IR ≥ 2.13, we found a marked impact of marijuana use only in adults who used marijuana ≥ 1799 times, with 13% decrease (95% CI 5-19%) in fasting insulin and 10% decrease (95% CI 3-18%) in HOMA-IR score.

CONCLUSIONS:

Marijuana use is associated with reduced fasting insulin levels and HOMA-IR score in US obese adults with HOMA-IR ≥ 2.13, but not in those with HOMA-IR < 2.13 or ≥ 5.72. The impact of marijuana use is the greatest after long-term exposure and is independent of BMI.”

https://www.ncbi.nlm.nih.gov/pubmed/31367991

https://link.springer.com/article/10.1007%2Fs00592-019-01390-x

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Overcoming the psychiatric side effects of the cannabinoid CB1 receptor antagonists: Current approaches for therapeutics development.

“The cannabinoid receptor 1 (CBR1) is involved in a variety of physiological pathways and has long been considered a golden target for therapeutic manipulation. A large body of evidence in both animal and human studies suggests that CB1R antagonism is highly effective for the treatment of obesity, metabolic disorders and drug addiction. However, the first-in-class CB1R antagonist/inverse agonist, rimonabant, though demonstrating effectiveness for obesity treatment and smoking cessation, displays serious psychiatric side effects, including anxiety, depression and even suicidal ideation, resulting in its eventual withdrawal from the European market. Several strategies are currently being pursued to circumvent the mechanisms leading to these side effects by developing neutral antagonists, peripherally restricted ligands, and allosteric modulators. In this review, we describe the progress in the development of therapeutics targeting the cannabinoid receptor 1 in the last two decades.”

https://www.ncbi.nlm.nih.gov/pubmed/31284863

http://www.eurekaselect.com/173316/article

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Diet, endocannabinoids, and health.

Nutrition Research“Healthy aging includes freedom from disease, ability to engage in physical activity, and maintenance of cognitive skills for which diet is a major lifestyle factor. Aging, diet, and health are at the forefront of well-being for the growing population of older adults with the caveat of reducing and controlling pain. Obesity and diabetes risk increase in frequency in adults, and exercise is encouraged to control weight, reduce risk of type II diabetes, and maintain muscle mass and mobility.

One area of research that appears to integrate many aspects of healthy aging is focused on understanding the endocannabinoid system (ECS) because of its role in systemic energy metabolism, inflammation, pain, and brain biology. Physical activity is important for maintaining health throughout the life cycle. The benefits of exercise facilitate macronutrient use, promote organ health, and augment the maintenance of metabolic activity and physiological functions. One outcome of routine exercise is a generalized well-being, and perhaps, this is linked to the ECS.

The purpose of this review is to briefly present the current knowledge of key components of the ECS that contribute to appetite and influence systemic energy metabolism, and dietary factors that alter the responses of ligand binding and activation of cannabinoidreceptors and its role in the brain. Herein, the objectives are to (1) explain the role of the ECS in the body, (2) describe the relationship between dietary polyunsaturated fatty acids and macronutrient intake and systemic metabolism, and (3) present areas of promising research where exercise induces endocannabinoid production in the brain to benefit well-being. There are many gaps in the knowledge of how the ECS participates in controlling pain through exercise; however, emerging research will reveal key relationships to understand this system in the brain and body.”

https://www.ncbi.nlm.nih.gov/pubmed/31280882

https://www.sciencedirect.com/science/article/pii/S027153171930572X?via%3Dihub

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