Category Archives: Endocannabinoid System

Adult Neurogenesis Is Regulated by the Endocannabinoid and Kisspeptin Systems

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“Neurogenesis is considered the most robust form of plasticity in the adult brain. To better decipher this process, we evaluated the potential crosstalk of Kisspeptin and Endocannabinoid Systems (KPS and ECS, respectively) on hippocampal neurogenesis.

Male adolescent rats were exposed to kisspeptin-10 (KP10) and the endocannabinoid anandamide (AEA) administered alone or in combination with the type 1 cannabinoid receptor (CB1R) antagonist SR141716A. The expression of Kiss1 and Kisspeptin receptor (Kiss1R) has been characterized for the first time in rat hippocampus together with the expression of the CB1R and the Transient Receptor Potential Vanilloid 1 ion channel receptor (TRPV1).

Results show that both systems inhibit neurogenesis by reducing the extracellular signal-regulated kinase (ERK) signaling. Despite little differences in the expression of Kiss1R and CB1R, TRPV1 is enhanced by both KP10 and AEA treatments, suggesting TRPV1 as a common thread. KP10 administration reduces CB1R expression in the dentate gyrus, while AEA does not. KPS, unlike ECS, promotes the expression of estrogen receptor α (ER-α) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), also upregulating sirtuin 1 (SIRT1), brain-derived-neurotrophic factor (BDNF), and c-Jun.

These findings suggest that the interaction between ECS and KPS could be involved in the fine-tuning of neurogenesis, highlighting a novel role for KPS.”

https://pubmed.ncbi.nlm.nih.gov/40362219/

https://www.mdpi.com/1422-0067/26/9/3977

Nucleolar sequestration of cannabinoid type-2 receptors in triple-negative breast cancer cells

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“Multiple investigations have shown that the different types of cannabinoids, phytocannabinoids, synthetic cannabinoids, and endocannabinoids, possess antiproliferative and anticancer properties.

The cannabinoid type-2 receptor (CB2R) has been proposed as a central player in tumor progression and has been correlated with the aggressiveness of breast cancer. Using immunocytochemistry and confocal microscopy, in the present work, we studied the expression level and subcellular localization of CB2R in two human triple-negative breast cancer (TNBC) cell lines, corresponding to early (stage I, HCC-1395) and metastatic (MDA-MB-231) stages, and they were compared with a non-tumoral mammary epithelial cell line (MCF-10A).

We found that although CB2R was detected at the plasma membrane, it was mainly localized intracellularly, with ~40-fold higher expression in both TNBC cell lines than in MCF-10A (P < 0.0001). Notably, double staining with DAPI or with the nucleoli-specific fluorescent marker (3xnls-mTurquoise2) showed that most of the CB2R overexpressed in the nucleoli of cancer cells.

This finding is supported by the fact that CB2R expression was markedly lower in mitotic cells compared to interphase cells (P < 0.0001). Interestingly, exposure of cancer cells to the specific agonist HU-308 reversed the nucleolar sequestration of CB2R while increasing the presence of the receptor in the nucleoplasm and cytoplasm (P < 0.0001). In addition, we found that this agonist reduced both the cell migration (P < 0.05-0.0001) and proliferation (P < 0.001) of TNBC cells. It remains to determine the function and signaling ability of CB2R in the nucleolus.

Although our study only includes cell lines (tumoral and non-tumoral), we consider that this feature of nucleolar sequestration of CB2R could be a potential diagnostic marker for TNBC from the early stage.”

https://pubmed.ncbi.nlm.nih.gov/40359210/

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0323554

In Vivo and In Vitro Crosstalk Among CBD, Aβ, and Endocannabinoid System Enzymes and Receptors

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“Cannabidiol (CBD), a non-psychotropic compound derived from Cannabis sativa, has garnered attention as a potential therapeutic agent for various neurodegenerative diseases, including Alzheimer’s disease (AD).

Despite growing interest, additional research is required to clarify the specific mechanisms by which CBD influences the pathological accumulation of β-amyloid (Aβ) associated with AD. Moreover, the interactions between CBD and the endocannabinoid system (ECS), both in the presence and absence of Aβ expression, remain a subject of active investigation.

Elucidating these mechanisms may provide valuable insights for advancing both our understanding and the development of targeted interventions in neurodegenerative disease management. Using a multifaceted approach that integrates pharmacological interventions, immunofluorescence imaging, flow cytometry, and biochemical assays, we examined the effects of CBD on Aβ40 and Aβ42. Additionally, we analyzed the modulation of cannabinoid receptor 1(CB1 receptor) and fatty acid amide hydrolase (FAAH) in the presence or absence of Aβ expression, uncovering the intricate regulatory mechanisms of CBD.

Our findings indicate a nuanced response to CBD; while it may produce side effects in non-pathological cells, it demonstrates an ability to induce autophagy and apoptosis in Aβ-expressing cells via the activation of the Microtubule-associated protein 1 light chain 3 B(LC3B) and Caspase-3 pathways. Furthermore, our investigation into faah-1 involvement highlighted its role in alleviating pharyngeal dysfunction and counteracting weight loss in Aβ-expressing Caenorhabditis elegans(C. elegans) strains. These insights advance our understanding of CBD’s therapeutic potential in addressing neurodegenerative pathologies.”

https://pubmed.ncbi.nlm.nih.gov/40350019/

https://www.sciencedirect.com/science/article/abs/pii/S0014299925004741?via%3Dihub

Efficacy of a Neuroimmune Therapy Including Pineal Methoxyindoles, Angiotensin 1-7, and Endocannabinoids in Cancer, Autoimmune, and Neurodegenerative Diseases

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“Purpose: Recent advancements in psycho-neuro-endocrine-immunology indicate that numerous noncommunicable diseases (NCDs) originate from disruptions in the cytokine immune network, resulting in chronic inflammatory responses. This persistent low-degree inflammation is attributed to deficiencies in crucial endogenous anti-inflammatory neuroendocrine systems, including the pineal gland, the endocannabinoid system, and the angiotensin-converting enzyme 2 / angiotensin 1-7 axis.

The administration of pineal methoxyindoles (melatonin, 5-methoxytryptamine), cannabinoids, and angiotensin 1-7 may entail potential therapeutic benefits for NCDs, particularly for patients who do not respond to conventional treatments.

Patients and methods: This study evaluates the safety and efficacy of a neuroimmune regimen comprising melatonin (100 mg/day at night), 5-methoxytryptamine (30 mg in the early afternoon), angiotensin 1-7 (0.5 mg twice daily), and cannabidiol (20 mg twice daily) in 306 patients with NCDs, including advanced cancer, autoimmune diseases, neurodegenerative disorders, depression, and cardiovascular disease.

Results: The neuroimmune regimen successfully halted cancer progression in 68% of cancer patients, who also reported improvements in mood, sleep, and relief from anxiety, pain, and fatigue. In patients with autoimmune diseases, the treatment effectively controlled the disease process, remarkable in cases of multiple sclerosis. Additionally, positive outcomes were observed in patients with Parkinson’s disease, Alzheimer’s disease, and depression.

Conclusion: Randomized controlled trials are required to assess this therapeutic approach for NCDs that includes endogenous neuroendocrine molecules regulating immune responses in an anti-inflammatory manner.”

https://pubmed.ncbi.nlm.nih.gov/40330271/

“This study highlights the potential of leveraging endogenous molecules to treat NCDs by modulating cell proliferation, inflammation, immune responses, metabolism, and neurological functions. The findings suggest that a neuroimmune regimen incorporating melatonin, angiotensin 1–7, and other bioactive compounds could offer a low-cost, minimally toxic therapeutic approach.”

https://www.dovepress.com/efficacy-of-a-neuroimmune-therapy-including-pineal-methoxyindoles-angi-peer-reviewed-fulltext-article-CIA

Cannabigerol and Cannabinoid Receptors in Major Depressive Disorder: Network Pharmacology, Molecular Docking, and In-vivo Analysis

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“Introduction: Cannabigerol (CBG), being one of the non-psychotropic phyto-cannabinoid, has been labelled and recognized to be antioxidant and neuroprotective; it may conceivably hold depression-relieving activity. Consequently, the objective of the present research procedure was to explore the depression-alleviating competence of cannabigerol in both stressed and unstressed mice using computational/in-silico modelling, followed by in-vivo analysis.

Method: Target genes for Major Depressive Disorder (MDD) were identified using GeneCards and Swiss Target Prediction, with common targets screened via Venny software. STRING database anal-ysis established protein-protein interactions (PPI), identifying CNR2 (CB2 receptor) as a key target. Molecular docking of CBG with CB2 (PDB ID: 8GUR) showed strong binding, prompting in vivo evaluation. ADME profiling via Schrödinger Maestro v10.5 confirmed CBG’s high oral absorption and favorable pharmacokinetics. Male Swiss albino mice underwent chronic unpredictable mild stress (CUMS) for three successive weeks, with CBG (10, 20, 40 mg/kg) and imipramine (15 mg/kg) administered and various behavioral and biochemical parameters being analyzed.

Results: Cannabigerol demonstrated maximum oral absorption in ADME predictions using Schrö-dinger’s Maestro (v10.5). Wayne diagram illustrated MDD-related targets, with CB2 (CNR2) rank-ings in top targets, based on SwissADME and Venny software analysis. Docking analysis revealed a high binding affinity (-10.53) for CB2, outperforming cannabidiol (-9.56) and comparable to Δ9-THC (-10.11). During in vivo evaluation, CBG (40 mg/kg) and Imipramine 15mg/kg significantly reduced CUMS-induced exalted plasma corticosterone, nitrite quantities, and monoamine oxidase-A action in the brain of stressed mice. Additionally, both treatments substantially reversed the unpre-dictable chronic stress-induced decline in catalase action, demonstrating CBG’s possible potential in alleviating depression-like symptoms in mice.

Conclusion: Cannabigerol has shown significant depressive alleviating potential in mice exposed to chronic and unpredictable stress regimes, possibly via interaction with cannabinoid receptors as in-dicated by in-silico modelling, which has been validated by our findings of the in-vivo protocol.”

https://pubmed.ncbi.nlm.nih.gov/40326034/

https://www.eurekaselect.com/article/148152

Targeting the Endocannabinoidome: A Novel Approach to Managing Extraintestinal Complications in Inflammatory Bowel Disease

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“Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder marked by persistent gastrointestinal inflammation and a spectrum of systemic effects, including extraintestinal manifestations (EIMs) that impact the joints, skin, liver, and eyes. Conventional therapies primarily target intestinal inflammation, yet they frequently fail to ameliorate these systemic complications. Recent investigations have highlighted the complex interplay among the immune system, gut, and nervous system in IBD pathogenesis, thereby underscoring the need for innovative therapeutic approaches. 

Methods: We conducted a comprehensive literature search using databases such as PubMed, Scopus, Web of Science, Science Direct, and Google Scholar. Keywords including “cannabinoids”, “endocannabinoid system”, “endocannabinoidome”, “inflammatory bowel disease”, and “extraintestinal manifestations” were used to identify peer-reviewed original research and review articles that explore the role of the endocannabinoidome (eCBome) in IBD. 

Results: Emerging evidence suggests that eCBome-a network comprising lipid mediators, receptors (e.g., CB1, CB2, GPR55, GPR35, PPARα, TRPV1), and metabolic enzymes-plays a critical role in modulating immune responses, maintaining gut barrier integrity, and regulating systemic inflammation. Targeting eCBome not only improves intestinal inflammation but also appears to mitigate metabolic, neurological, and extraintestinal complications such as arthritis, liver dysfunction, and dermatological disorders. 

Conclusions: Modulation of eCBome represents a promising strategy for comprehensive IBD management by addressing both local and systemic disease components. These findings advocate for further mechanistic studies to develop targeted interventions that leverage eCBome as a novel therapeutic avenue in IBD.”

https://pubmed.ncbi.nlm.nih.gov/40283915/

“Extraintestinal manifestations of IBD pose a significant and diverse array of clinical challenges, significantly impacting patients’ lives and healthcare utilization. While conventional therapies primarily target gut inflammation, the endocannabinoidome emerges as a promising and versatile target for managing inflammatory, metabolic, and extraintestinal complications of IBD. Preliminary evidence highlights its therapeutic potential, but further research is essential to optimize clinical applications and ensure safety.”

https://www.mdpi.com/1424-8247/18/4/478

The Role of Endocannabinoids in Physiological Processes and Disease Pathology: A Comprehensive Review

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“The endocannabinoid system is a complex communication system involved in maintaining homeostasis in various physiological processes, including metabolism, immune response, pain modulation, and neuroprotection. Endocannabinoids, mainly anandamide and 2-arachidonoylglycerol, are natural ligands of the cannabinoid receptors CB1 and CB2, which are widely distributed throughout the central nervous system and peripheral tissues. Their biosynthesis, degradation, and interaction with other signaling pathways play crucial roles in both health and disease. This article provides a comprehensive overview of the physiological and pathological roles of endocannabinoids, discusses their potential as therapeutic targets, and highlights recent advances in endocannabinoid-based treatments.”

https://pubmed.ncbi.nlm.nih.gov/40283681/

https://www.mdpi.com/2077-0383/14/8/2851

“The endocannabinoid system plays a crucial role in maintaining physiological balance and regulating functions such as pain perception, immune response, metabolism, and neurological processes . Due to the multifaceted biological actions of the components of the ECS, researchers are seeking agonists/antagonists of cannabinoid receptors or other kinds of compounds with potential applications in targeted pharmacotherapy aimed at the endocannabinoid system. Although plant-derived cannabinoids have long been used in medicine, there are increasing attempts to use synthetic compounds as ligands for cannabinoid receptors or modulators of enzymes involved in endocannabinoid metabolism. Rimonabant, a selective CB1 receptor antagonist, was registered in Europe for the treatment of obesity from 2006 to 2008, particularly in patients with type 2 diabetes or metabolic syndrome. However, the European Medicines Agency determined that the risks of using the drug outweighed its benefits due to the serious psychiatric side effects, including depression and suicidal thoughts. Several novel drugs targeting ECS are under investigation. Notable examples include endocannabinoid reuptake inhibitors (eCBRIs) such as SYT-510 (currently under development), which are designed to treat anxiety, mood, and traumatic stress disorders, and AM404, an active metabolite of paracetamol, which inhibits AEA uptake. The other group consists of inhibitors of enzymes degrading AEA (fatty acid amide hydrolase—FAAH) and 2-AG (monoacyloglycerol lipase—MAGL) being explored for their potential in treating anxiety and pain. Drugs that modulate ECS hold promise for a variety of therapeutic applications, including glucose metabolism, obesity, neuroprotection, psychiatric disorders, pain management, and inflammation control, also in the context of chronic diseases. Further studies are needed to fully understand the complexities of this system and develop safe, effective treatments.”

Cannabinoids and the endocannabinoid system in liver diseases

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“Cannabinoids are biologically active substances acting via feedback-coupled CB1 and CB2 receptors. Their expression in myofibroblasts and liver endothelial cells is reported to be elevated in chronic liver diseases. The effect of CB1 receptor stimulation is to increase fibrosis and inflammatory activity in the liver by stimulating stellate cells, while activation of the CB2 receptor results in inhibition of fibrosis. Stimulation of the CB1 receptor may also lead to progression of liver steatosis and carcinogenesis. In end-stage liver disease, the endocannabinoid system plays an important role in the pathogenesis of encephalopathy and vascular effects, such as portal hypertension, splanchnic vasodilatation and cirrhotic cardiomyopathy. It seems that interference in endocannabinoid transmission may serve as an attractive target for the development of hepatological drugs.”

https://pubmed.ncbi.nlm.nih.gov/40290527/

https://www.termedia.pl/Cannabinoids-and-the-endocannabinoid-system-in-liver-diseases,80,55209,0,1.html

The Endocannabinoid System in Cancer Biology: A Mini-Review of Mechanisms and Therapeutic Potential

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“The Endocannabinoid System (ECS) plays a critical role in maintaining physiological homeostasis, influencing a range of processes such as neuroprotection, inflammation, energy metabolism, and immune responses.

Comprising cannabinoid receptors (CB1 and CB2), endogenous ligands (endocannabinoids), and the enzymes responsible for their synthesis and degradation, the ECS has attracted increasing attention in cancer research. Cannabinoid receptor activation has been associated with the regulation of cancer-related processes, including cell proliferation, apoptosis, and angiogenesis, suggesting that the ECS may have a role in tumor progression and cancer treatment.

Preclinical studies have shown that cannabinoids, through their interaction with CB1 and CB2 receptors, can inhibit tumor cell growth, induce programmed cell death, and suppress the formation of new blood vessels in various cancer models.

Despite these encouraging findings, the clinical translation of ECS-targeted therapies remains in its early stages. The complexity of tumor heterogeneity, the variability in patient responses, and the challenges associated with the pharmacokinetics of cannabinoids are significant obstacles to the broader application of these findings in clinical settings.

This review provides an overview of the current understanding of the ECS’s involvement in cancer biology, focusing on key mechanisms by which it may influence carcinogenesis. Additionally, we discuss the therapeutic potential of targeting the ECS in cancer treatment, while highlighting the limitations and uncertainties that need to be addressed through ongoing research.”

https://www.frontiersin.org/journals/oncology-reviews/articles/10.3389/or.2025.1573797/abstract

The endocannabinoid and paracannabinoid systems in natural reward processes: possible pharmacological targets?

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“Natural rewards such as food, mating, and social interaction are essential for survival and species preservation, and their regulation involves a complex interplay of motivational, cognitive, and emotional processes.

Over the past two decades, increasing attention has been directed toward the endocannabinoid system and its paracannabinoid counterpart as key modulators of these behaviors.

This review aims to provide an integrated overview of the roles played by the endocannabinoid and paracannabinoid systems in regulating natural reward-driven behaviors, focusing on feeding, reproductive behavior, and social interaction.

We highlight how the endocannabinoid system – mainly through CB1 receptor signaling – modulates central and peripheral circuits involved in energy homeostasis, reward processing, and emotional regulation. In parallel, we explore the role of paracannabinoids, such as oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA), which act primarily via non-cannabinoid receptors and contribute to the regulation of appetite, sexual motivation, and social behavior.

Special attention is given to the relevance of these systems in the pathophysiology of obesity, eating disorders, sexual dysfunctions, and social impairments, as well as their potential as pharmacological targets.

Overall, the evidence discussed supports a broader conceptualization of endocannabinoid and paracannabinoid signaling as pivotal regulators of natural rewards and opens new avenues for the development of targeted interventions for motivational and reward-related disorders.”

https://pubmed.ncbi.nlm.nih.gov/40274041/

“Endocannabinoid/paracannabinoid therapies offer promising innovative drug development.”

https://www.sciencedirect.com/science/article/pii/S0031938425001301?via%3Dihub