The Enteric Glia and Its Modulation by the Endocannabinoid System, a New Target for Cannabinoid-Based Nutraceuticals?

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“The enteric nervous system (ENS) is a part of the autonomic nervous system that intrinsically innervates the gastrointestinal (GI) tract. Whereas enteric neurons have been deeply studied, the enteric glial cells (EGCs) have received less attention. However, these are immune-competent cells that contribute to the maintenance of the GI tract homeostasis through supporting epithelial integrity, providing neuroprotection, and influencing the GI motor function and sensation. The endogenous cannabinoid system (ECS) includes endogenous classical cannabinoids (anandamide, 2-arachidonoylglycerol), cannabinoid-like ligands (oleoylethanolamide (OEA) and palmitoylethanolamide (PEA)), enzymes involved in their metabolism (FAAH, MAGL, COX-2) and classical (CB1 and CB2) and non-classical (TRPV1, GPR55, PPAR) receptors. The ECS participates in many processes crucial for the proper functioning of the GI tract, in which the EGCs are involved. Thus, the modulation of the EGCs through the ECS might be beneficial to treat some dysfunctions of the GI tract. This review explores the role of EGCs and ECS on the GI tract functions and dysfunctions, and the current knowledge about how EGCs may be modulated by the ECS components, as possible new targets for cannabinoids and cannabinoid-like molecules, particularly those with potential nutraceutical use.”

https://pubmed.ncbi.nlm.nih.gov/36235308/

“Although further studies are needed to define the connections between the ECS and EGCs as a possible target to treat or reduce alterations associated with GI disorders, the use of cannabinoids may be beneficial in prevalent pathologies such as inflammatory bowel disease (IBD) and, maybe, other types of GI pathologies displaying ENS inflammation.”

https://www.mdpi.com/1420-3049/27/19/6773/htm

Hemp in Animal Diets-Cannabidiol

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“In recent years, interest in hemp use has grown owing to its chemical and medicinal properties. Several parts of this plant, such as seeds, leaves, flowers, and stems are used in medicine, industry, and environmental preservation. Although there were legal restrictions on hemp exploitation in some countries due to the trace presence of THC as a psychoactive element, many countries have legalized it in recent years. Cannabidiol or CBD is a non-psychoactive phytocannabinoid that can activate the endocannabinoid system and its receptors in the central and peripheral nervous system in bodies of different species. Cannabidiol has anti-inflammatory, antioxidative, analgesic, and anti-depressant effects. This review investigates various aspects of cannabidiol use and its potential in animals and humans.”

https://pubmed.ncbi.nlm.nih.gov/36230282/

“Plant feed additives have been used in animal diets for improving animal health and welfare. Thus, hemp (Cannabis sativa) and its products received attention and much research has been conducted to evaluate the effects of Cannabis sativa compounds in animals. Among various substances of this plant, cannabidiol showed desirable effects such as relieving pain and inflammation reduction in some studies. Considering the importance of animal welfare, especially in poultry production, the use of cannabidiol can be effective here.”

https://www.mdpi.com/2076-2615/12/19/2541/htm

Photoprotective Effects of Cannabidiol against Ultraviolet-B-Induced DNA Damage and Autophagy in Human Keratinocyte Cells and Mouse Skin Tissue

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“Cannabidiol (CBD) has emerged as a phytocannabinoid with various beneficial effects for the skin, including anti-photoaging effects, but its mechanisms of action are not fully elucidated.

The study assessed CBD’s photoprotective effects against acute ultraviolet B (UVB)-induced damage in HaCaT human keratinocyte cells and murine skin tissue.

CBD (8 μM) alleviated UVB-induced cytotoxicity, apoptosis, and G2/M cell cycle arrest in HaCaT cells. The contents of γH2AX and cyclobutane pyrimidine dimers were decreased after CBD treatment. CBD reduced the production of reactive oxygen species and modulated the expression of antioxidant-related proteins such as nuclear factor erythroid 2-related factor 2 in UVB-stimulated HaCaT cells.

Furthermore, CBD mitigated the UVB-induced cytotoxicity by activating autophagy. In addition, a cream containing 5% CBD showed effectiveness against UVB-induced photodamage in a murine model.

The CBD cream improved the skin’s condition by lowering the photodamage scores, reducing abnormal skin proliferation, and decreasing expression of the inflammation-related protein cyclooxygenase-2 in UVB-irradiated skin tissue.

These findings indicate that CBD might be beneficial in alleviating UVB-induced skin damage in humans. The photoprotective effects of CBD might be attributed to its modulatory effects on redox homeostasis and autophagy.”

https://pubmed.ncbi.nlm.nih.gov/36235276/

“These findings, along with evidence reported from other studies, suggest that CBD is a phytocannabinoid with promising beneficial effects for the skin against UV-induced photodamage.”

https://www.mdpi.com/1420-3049/27/19/6740/htm

Mitofusin-2 mediates cannabidiol-induced neuroprotection against cerebral ischemia in rats

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Acta Pharmacologica Sinica

“Cannabidiol (CBD) reportedly exerts protective effects against many psychiatric disorders and neurodegenerative diseases, but the mechanisms are poorly understood. In this study, we explored the molecular mechanism of CBD against cerebral ischemia. HT-22 cells or primary cortical neurons were subjected to oxygen-glucose deprivation insult followed by reoxygenation (OGD/R). In both HT-22 cells and primary cortical neurons, CBD pretreatment (0.1, 0.3, 1 μM) dose-dependently attenuated OGD/R-induced cell death and mitochondrial dysfunction, ameliorated OGD/R-induced endoplasmic reticulum (ER) stress, and increased the mitofusin-2 (MFN2) protein level in HT-22 cells and primary cortical neurons. Knockdown of MFN2 abolished the protective effects of CBD. CBD pretreatment also suppressed OGD/R-induced binding of Parkin to MFN2 and subsequent ubiquitination of MFN2. Overexpression of Parkin blocked the effects of CBD in reducing MFN2 ubiquitination and reduced cell viability, whereas overexpressing MFN2 abolished Parkin’s detrimental effects. In vivo experiments were conducted on male rats subjected to middle cerebral artery occlusion (MCAO) insult, and administration of CBD (2.5, 5 mg · kg-1, i.p.) dose-dependently reduced the infarct volume and ER stress in the brains. Moreover, the level of MFN2 within the ischemic penumbra of rats was increased by CBD treatment, while the binding of Parkin to MFN2 and the ubiquitination of MFN2 was decreased. Finally, short hairpin RNA against MFN2 reversed CBD’s protective effects. Together, these results demonstrate that CBD protects brain neurons against cerebral ischemia by reducing MFN2 degradation via disrupting Parkin’s binding to MFN2, indicating that MFN2 is a potential target for the treatment of cerebral ischemia.”

https://pubmed.ncbi.nlm.nih.gov/36229600/

https://www.nature.com/articles/s41401-022-01004-3

The Effects of Cannabidiol on Aqueous Humor Outflow and Trabecular Meshwork Cell Signaling

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“Intraocular pressure (IOP) is regulated primarily through aqueous humor production by ciliary body and drainage through uveoscleral and trabecular meshwork (TM) tissues. The goal of this study was to measure the effect of non-psychotropic cannabidiol (CBD) on aqueous humor outflow through TM and assess the effect of CBD on the TM cell signaling pathways that are important for regulating outflow. Perfused porcine eye anterior segment explants were used to investigate the effects of CBD on aqueous humor outflow. Cultured porcine TM cells were used to study the effects of CBD on TM cell contractility, myosin light chain (MLC) and myosin phosphatase targeting subunit 1 (MYPT1) phosphorylation, and RhoA activation. In the anterior segment perfusion experiments, aqueous humor outflow was increased significantly within 1 h after adding 1 µM CBD and the effect was sustained over the 5 h of measurement. Treatment of TM cells with 1 µM CBD significantly decreased TM cell-mediated collagen contraction, inhibited phosphorylation of MLC and MYPT1, and reduced RhoA activation. Our data demonstrate, for the first time, that as a potential therapeutic agent for lowering intraocular pressure, CBD can enhance aqueous humor outflow and modify TM cell signaling.”

https://pubmed.ncbi.nlm.nih.gov/36230968/

“In summary, in this study we discovered, for the first time, that at 1 μM concentration CBD increases aqueous humor outflow in perfused anterior segments. In addition, using cultured TM cells, we demonstrated that CBD at 1 μM concentration inhibits TM cell contractility, MLC phosphorylation, MYPT1 phosphorylation and RhoA activation. Overall, our data support the concept that by altering the Rho/Rho kinase signaling to MLC, CBD was able to decrease the contractility of TM cells and enhance aqueous humor outflow via the TM route. There are many IOP-lowering drugs available to reduce aqueous humor production, but there are only limited drugs available to increase aqueous humor outflow directly through the TM route. This study demonstrated that as a potential therapeutic agent for lowering IOP, CBD is able to modify TM cell signaling and enhance aqueous humor outflow, which is often blocked in glaucoma.”

https://www.mdpi.com/2073-4409/11/19/3006/htm

Cannabidiolic acid activates the expression of the PPARβ/δ target genes in MDA-MB-231 cells

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Archives of Biochemistry and Biophysics

“Cannabidiolic acid (CBDA) can activate peroxisome proliferator-activated receptor-α (PPARα) and PPARγ. Whether CBDA can activate PPARβ/δ has not been examined sufficiently to date. Since previous studies showed that triple-negative breast cancer cells respond to activation of PPARβ/δ, the present study examined the effect of CBDA in MDA-MB-231 cells and compared the activities of CBDA with known PPARβ/δ agonists/antagonists. Expression of the PPARβ/δ target genes angiopoietin-like 4 (ANGPTL4) and adipocyte differentiation-related protein (ADRP) was increased by CBDA. Interestingly, ligand activation of PPARβ/δ with GW501516 caused an increase in expression of both ANGPTL4 and ADRP, but the magnitude of this effect was markedly increased when co-treated with CBDA. Specificity of these effects were confirmed by showing that CBDA-induced expression of ANGPTL4 and ADRP is mitigated in the presence of either a PPARβ/δ antagonist or an inverse agonist. Results from these studies suggest that CBDA can synergize with PPARβ/δ and might interact with endogenous agonists that modulate PPARβ/δ function.”

https://pubmed.ncbi.nlm.nih.gov/36228705/

“Cannabidiolic acid (CBDA) is a crucial biologically active component of the fiber-type cannabis plant. Many studies have suggested that CBDA can be used for treating different medical conditions including use as an antibacterial agent, or as an anti-nausea/vomiting agent. Furthermore, CBDA can inhibit cyclooxygenase-2 (COX-2) activity and expression, and thus has potential for treating inflammatory-dependent diseases. Indeed, CBDA-containing products are commonly used in many countries, in particular due to medical and recreational marijuana usage in the United States.”

https://www.sciencedirect.com/science/article/abs/pii/S0003986122003137?via%3Dihub

Cloudy with a chance of munchies: Assessing the impact of recreational marijuana legalization on obesity

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“Obesity in the US arguably constitutes the most significant health epidemic over the past century. Recent legislative changes allowing for recreational marijuana use further create a need to better understand the relationship between marijuana use and health choices, leading to obesity. We examine this relationship by using a synthetic control approach to examine the impact of legalized recreational marijuana access on obesity rates by comparing Washington State to a synthetically constructed counterfactual. We find that recreational marijuana’s introduction did not lead to increased obesity rates and may have led to decreases in obesity.”

https://onlinelibrary.wiley.com/doi/abs/10.1002/hec.4598

Therapeutic Effects of Medicinal Cannabinoids on the Gastrointestinal System in Pediatric Patients: A Systematic Review

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“Changes in cannabis legalization have generated interest in medicinal cannabinoids for therapeutic uses, including those that target the gastrointestinal (GI) tract. These effects are mediated through interactions with the endocannabinoid system. Given the increasing societal awareness of the therapeutic potential of cannabinoids, it is important to ensure pediatric representation in clinical studies investigating cannabinoid use.

This systematic review aims to assess the efficacy of medicinal cannabinoids in treating GI symptoms in pediatric patients. A literature search of Medline, Embase, CINAHL, Web of Science, and the Cochrane Library was performed from inception until June 23, 2020. Study design, patient characteristics, type, dose and duration of medicinal cannabinoid therapy, and GI outcomes were extracted. From 7303 records identified, 5 studies met all inclusion criteria. Included studies focused on chemotherapy-induced nausea, inflammatory bowel disease, and GI symptoms associated with severe complex motor disorders.

Results varied based on the symptom being treated, the type of cannabinoid, and the patient population. Medicinal cannabinoids may have a potential role in treating specific GI symptoms in specific patient populations. The limited number and heterogenicity of included studies highlight the demand for future research to distinguish effects among different cannabinoid types and patient populations and to examine drug interactions. As interest increases, higher quality studies are needed to understand the efficacy of cannabinoids as a pediatric GI treatment and whether these benefits outweigh the associated risks (Registration Number: PROSPERO CRD42020202486).”

https://pubmed.ncbi.nlm.nih.gov/36219741/

https://www.liebertpub.com/doi/10.1089/can.2022.0192

Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome

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“Williams-Beuren syndrome (WBS) is a rare genetic multisystemic disorder characterized by mild-to-moderate intellectual disability and hypersocial phenotype, while the most life-threatening features are cardiovascular abnormalities. Nowadays, there are no pharmacological treatments to directly ameliorate the main traits of WBS.

The endocannabinoid system (ECS), given its relevance for both cognitive and cardiovascular function, could be a potential druggable target in this syndrome.

We analyzed the components of the ECS in the complete deletion (CD) mouse model of WBS and assessed the impact of its pharmacological modulation in key phenotypes relevant for WBS. CD mice showed the characteristic hypersociable phenotype with no preference for social novelty and poor short-term object-recognition performance.

Brain cannabinoid type-1 receptor (CB1R) in CD male mice showed alterations in density and coupling with no detectable change in main endocannabinoids. Endocannabinoid signaling modulation with subchronic (10 days) JZL184, a selective inhibitor of monoacylglycerol lipase, specifically normalized the social and cognitive phenotype of CD mice. Notably, JZL184 treatment improved cardiovascular function and restored gene expression patterns in cardiac tissue.

These results reveal the modulation of the ECS as a promising novel therapeutic approach to improve key phenotypic alterations in WBS.”

https://pubmed.ncbi.nlm.nih.gov/36217821/

“Taken together, the results of this study are of great importance given the few preclinical studies addressing potential treatments for WBS. In this regard, the modulation of the ECS may be an appropriate novel therapeutic strategy to tackle not only the social phenotype but also memory shortfalls and cardiovascular deficits in WBS.”

https://elifesciences.org/articles/72560

[Activation of cannabinoid receptor 2 alleviates acute lung injury in rats with lipopolysaccharide-induced sepsis]

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南方医科大学学报

“Objective: To investigate the protective effect of cannabinoid receptor 2 (CB2) activation against acute lung injury in rats with lipopolysaccharide (LPS)-induced sepsis and explore the underlying mechanism.

Results: The rat models of sepsis showed severe damage of alveolar structures with significantly decreased fluid clearance rate, lowered pulmonary expressions of CB2, occludin and ZO-1 mRNA and proteins, increased water content in the lung tissue, and increased phosphorylation level of P38 MAPK and TNF-α and IL-1β levels in lung lavage fluid (all P < 0.05). Treatment with JWH133 improved alveolar pathology in the septic rats, but there was still inflammatory infiltration; lung tissue water content, phosphorylation of P38 MAPK, and TNF-α and IL-1β levels in lung lavage fluid were all significantly decreased, and the fluid clearance rate, pulmonary expressions of CB2, occludin and ZO-1 were significantly increased (all P < 0.05). Additional treatment with SB203580 resulted in further improvements of alveolar pathologies, lowered phosphorylation levels of P38 MAPK in the lung tissue and TNF-α and IL-1β levels in lung lavage fluid, and increased the protein expressions of occludin and ZO-1 (P < 0.05) without causing significant changes in mRNA and protein expression of CB2 (P > 0.05).

Conclusion: In rats with LPS-induced sepsis, activation of CB2 can inhibit the p38 MAPK signaling pathway, reduce the release of inflammatory factors in the lung tissues, promote tight junction protein expressions, and thus offer protection against acute lung injury.”

https://pubmed.ncbi.nlm.nih.gov/36210711/

https://www.j-smu.com/CN/10.12122/j.issn.1673-4254.2022.09.14