Category Archives: Endocannabinoid System

Cannabinoid receptor-2 attenuates neuroinflammation by promoting autophagy-mediated degradation of the NLRP3 inflammasome post spinal cord injury

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Frontiers - Crunchbase Company Profile & Funding

“Background: Neuroinflammation following spinal cord injury (SCI) results in prolonged neurological damage and locomotor dysfunction. Polarization of microglia is vital to regulation of neuroinflammation, although the underlying mechanisms have not yet been elucidated. Endocannabinoid receptor subtype 2 (CB2R) is reported to ameliorate neurodegeneration via immunomodulation activities. However, the underlying machinery in the context of SCI remains unclear.

Methods: A lipopolysaccharide-induced microglia inflammation model and a mouse model of SCI were employed to investigate the regulatory role of CB2R in the polarization of microglia in response to excess neuroinflammation. Markers of inflammation and autophagy were measured by Western blot analysis, immunofluorescence, flow cytometry, and enzyme-linked immunosorbent assays. Histological staining with hematoxylin and eosin, Nissl, and Luxol® fast blue was conducted using commercial kits. The locomotor function of the hindlimbs of the experimental mice was evaluated with the Basso Mouse Scale, Louisville Swim Scale, and footprint assay.

Results: The results showed that CB2R promoted M2 differentiation, increased interleukin (IL)-10 expression, and inhibited M1 differentiation with decreased expression of IL-1β and IL-6. CB2R activation also increased ubiquitination of the NLRP3 inflammasome and interacted with the autophagy-related proteins p62 and microtubule-associated proteins 1B light chain 3. Treatment with the CB2R activator JWH-133 reduced loss of myelin, apoptosis of neurons, and glial scarring, leading to improved functional recovery of the hindlimbs, while the CB2R antagonist AM630 produced opposite results.

Conclusion: Taken together, these results suggested that CB2R activation attenuated neuroinflammation targeting microglial polarization by promoting NLRP3 clearance, thereby facilitating functional recovery post-SCI.”

https://pubmed.ncbi.nlm.nih.gov/36238284/

https://www.frontiersin.org/articles/10.3389/fimmu.2022.993168/full

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

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

Role of the endocannabinoid system in the pathophysiology of endometriosis and therapeutic implications

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“Endometriosis patients experience debilitating chronic pain, and the first-line treatment is ineffective at managing symptoms. Although surgical removal of the lesions provides temporary relief, more than 50% of the patients experience disease recurrence. Despite being a leading cause of hysterectomy, endometriosis lacks satisfactory treatments and a cure. Another challenge is the poor understanding of disease pathophysiology which adds to the delays in diagnosis and overall compromised quality of life. Endometriosis patients are in dire need of an effective therapeutic strategy that is both economical and effective in managing symptoms, while fertility is unaffected.

Endocannabinoids and phytocannabinoids possess anti-inflammatory, anti-nociceptive, and anti-proliferative properties that may prove beneficial for endometriosis management, given that inflammation, vascularization, and pain are hallmark features of endometriosis.

Endocannabinoids are a complex network of molecules that play a central role in physiological processes including homeostasis and tissue repair, but endocannabinoids have also been associated in the pathophysiology of several chronic inflammatory diseases including endometriosis and cancers. The lack of satisfactory treatment options combined with the recent legalization of recreational cannabinoids in some parts of the world has led to a rise in self-management strategies including the use of cannabinoids for endometriosis-related pain and other symptoms.

In this review, we provide a comprehensive overview of endocannabinoids with a focus on their potential roles in the pathophysiology of endometriosis. We further provide evidence-driven perspectives on the current state of knowledge on endometriosis-associated pain, inflammation, and therapeutic avenues exploiting the endocannabinoid system for its management.”

https://pubmed.ncbi.nlm.nih.gov/36207747/

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-022-00163-8

Identification of CB1 Ligands among Drugs, Phytochemicals and Natural-Like Compounds: Virtual Screening and In Vitro Verification

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“Cannabinoid receptor type 1 (CB1) is an important modulator of many key physiological functions and thus a compelling molecular target. However, safe CB1 targeting is a non-trivial task. In recent years, there has been a surge of data indicating that drugs successfully used in the clinic for years (e.g. paracetamol) show CB1 activity. Moreover, there is a lot of promise in finding CB1 ligands in plants other than Cannabis sativa. In this study, we searched for possible CB1 activity among already existing drugs, their metabolites, phytochemicals, and natural-like molecules. We conducted two iterations of virtual screening, verifying the results with in vitro binding and functional assays. The in silico procedure consisted of a wide range of structure- and ligand-based methods, including docking, molecular dynamics, and quantitative structure-activity relationship (QSAR). As a result, we identified travoprost and ginkgetin as CB1 ligands, which provides a starting point for future research on the impact of their metabolites or preparations on the endocannabinoid system. Moreover, we found five natural-like compounds with submicromolar or low micromolar affinity to CB1, including one mixed partial agonist/antagonist viable for hit-to-lead phase. Finally, the computational procedure established in this work will be of use for future screening campaigns for novel CB1 ligands.”

https://pubmed.ncbi.nlm.nih.gov/36197801/

https://pubs.acs.org/doi/10.1021/acschemneuro.2c00502

A Cannabinoid Hairy-Tale: Hair Loss or Hair Gain?

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Journal of Cosmetic Dermatology

“Background: Few studies have reported on the use of cannabinoid products to treat hair loss.

Aim: This article aims to reconcile cannabinoids’ impact on hair growth.

Method: A comprehensive and structured search was conducted in PubMed and Google Scholar on 23 June 2022.

Result: While cannabidiol (CBD), a phytocannabinoid, may cause hair growth, several other phytocannabinoids may lead to hair loss. Additionally, the effect of CBD on hair growth may be concentration-dependent. CBD may cause hair loss at high concentrations (≥10 μM). Therefore, the concentration of CBD needs to be adjusted so that it is optimal for hair growth. One trial found that once-daily application of CBD-rich topical cannabis extract for six months increased nonvellus hair count by approximately 93.5% in 35 Caucasian AGA patients: 28 males aged 28-72 years [average 43 years] and 7 females aged 46-76 years [average 61 years]. Each application contained 3-4 mg of CBD. The CBD-rich topical cannabis extract was prepared by ultra-pulverizing Cannabis sativa [hemp] flower into a green chalk-like powder [10.78% CBD and 0.21% tetrahydrocannabinol] and then infusing the powder into a lanolin paste and Emu oil carrier.

Conclusion: Topical CBD preparations require further studies to establish their safety and efficacy profile. An ideal topical cannabinoid preparation should contain CBD at the right concentration and lack phytocannabinoid adulterants.”

https://pubmed.ncbi.nlm.nih.gov/36181341/

https://onlinelibrary.wiley.com/doi/10.1111/jocd.15427


Cannabinoid receptors in the inflammatory cells of canine atopic dermatitis

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Frontiers in Veterinary Science accepted into PubMed Central - Science & research news | Frontiers

“Background: Atopic dermatitis (AD) is one of the most common cutaneous inflammatory and pruritic diseases in dogs. Considering its multifactorial nature, AD can be a challenging disease to manage, and the therapeutic strategy must often be multimodal. In recent years, research has been moving toward the use of natural products which have beneficial effects on inflammation and itching, and no side effects. Cannabinoid receptors have been demonstrated to be expressed in healthy and diseased skin; therefore, one of the potential alternative therapeutic targets for investigating AD is the endocannabinoid system (ECS).

Objective: To immunohistochemically investigate the expression of the cannabinoid receptor type 2 (CB2R), and the cannabinoid-related receptors G protein-coupled receptor 55 (GPR55), transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) in mast cells (MCs), macrophages, dendritic cells (DCs), T cells, and neutrophils of the skin of dogs with AD.

Animals: Samples of skin tissues were collected from eight dogs with AD (AD-dogs).

Materials and methods: The immunofluorescent stained cryosections of the skins of 8 dogs with AD having antibodies against CB2R, GPR55, TRPV1, TRPA1 were semiquantitatively evaluated. The inflammatory cells were identified using antibodies against tryptase (mast cells), ionized calcium binding adaptor molecule 1 (IBA1) (macrophages/DCs), CD3 (T cells), and calprotectin (neutrophils). The proportions of MCs, macrophages/DCs, T cells, and neutrophils expressing CB2R, GPR55, TRPV1 and TRPA1 were evaluated.

Results: The cells of the inflammatory infiltrate showed immunoreactivity (IR) for all or for some of the cannabinoid and cannabinoid-related receptors studied. In particular, MCs and macrophages/DCs showed CB2R-, GPR55-, TRPA1-, and TRPV1-IR; T cells showed CB2R-, GPR55- and TRPA1-IR, and neutrophils expressed GPR55-IR. Co-localization studies indicated that CB2R-IR was co-expressed with TRPV1-, TRPA1-, and GPR55-IR in different cellular elements of the dermis of the AD-dogs.

Conclusions and clinical importance: Cannabinoid receptor 2, and cannabinoid-related receptors GPR55, TRPV1 and TRPA1 were widely expressed in the inflammatory infiltrate of the AD-dogs. Based on the present findings, the ECS could be considered to be a potential therapeutic target for dogs with AD, and may mitigate itch and inflammation.”

https://pubmed.ncbi.nlm.nih.gov/36187821/

“The evidence regarding the effect of cannabinoid and cannabinoid-related receptors on MCs, macrophages and DCs (CB2R, GPR55, TRPV1, TRPA1), T-cells (CB2R, GPR55, TRPA1), and on neutrophils (GPR55) suggests the possibility that the manipulation of the inflammatory cell functions with endocannabinoids and cannabinoids could result in a novel approach to the treatment of AD. Phytocannabinoids could potentially modulate inflammatory responses by regulating more than one underlying mechanism (inflammatory cells, keratinocytes, sensory nerves, fibroblasts, etc.).”

https://www.frontiersin.org/articles/10.3389/fvets.2022.987132/full

Changes in the expression of endocannabinoid system components in an experimental model of chemotherapy-induced peripheral neuropathic pain: Evaluation of sex-related differences

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Experimental Neurology

“Chemotherapy-induced neuropathic pain is a serious clinical problem and one of the major side effects in cancer treatment. The endocannabinoid system (ECS) plays a crucial role in regulating pain neurotransmission, and changes in the expression of different components of the ECS have been reported in experimental models of persistent pain. In addition, sex differences have been observed in ECS regulation and function. The aim of our study was to evaluate whether administration of oxaliplatin, a neurotoxic antineoplastic agent, induced changes in the expression of ECS components in peripheral and central stations of the pain pathway, and if those changes exhibited sexual dimorphism. Adult male and female rats were injected with oxaliplatin or saline, and mechanical and cold hypersensitivity and allodynia were evaluated using Von Frey and Choi Tests. The mRNA levels corresponding to cannabinoid receptors (CB1, CB2), cannabinoid-related receptors (GPR55, 5HT1A, TRPV1) and to the main enzymes involved in the synthesis (DAGL, DAGL, NAPE-PLD) and degradation (MGL, FAAH) of endocannabinoids were assessed in lumbar dorsal root ganglia (DRGs) and spinal cord by using real time RT-PCR. In addition, the levels of the main endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), were evaluated using commercial ELISA kits. Oxaliplatin administration induced the development of mechanical and cold hypersensitivity and allodynia in male and female animals. Oxaliplatin also induced early and robust changes in the expression of several components of the ECS in DRGs. A marked upregulation of CB1, CB2, 5HT1A and TRPV1 was detected in both sexes. Interestingly, while DAGL mRNA levels remained unchanged, DAGL was downregulated in male and upregulated in female rats. Finally, MGL and NAPE-PLD showed increased levels only in male animals, while FAAH resulted upregulated in both sexes. In parallel, reduced 2-AG and AEA levels were detected in DRGs from male or female rats, respectively. In the lumbar spinal cord, only TRPV1 mRNA levels were found to be upregulated in both sexes. Our results reveal previously unreported changes in the expression of cannabinoid receptors, ligands and enzymes occurring mainly in the peripheral nervous system and displaying certain sexual dimorphism. These changes may contribute to the physiopathology of oxaliplatin-induced neuropathic pain in male and female rats. A better understanding of these dynamic changes will facilitate the development of mechanism- and sex-specific approaches to optimize the use of cannabinoid-based medicines for the treatment of chemotherapy-induced pain.”

https://pubmed.ncbi.nlm.nih.gov/36179876/

https://www.sciencedirect.com/science/article/abs/pii/S0014488622002576?via%3Dihub