scholarly journals Alternative Targets Within the Endocannabinoid System for Future Treatment of Gastrointestinal Diseases

2011 ◽  
Vol 25 (7) ◽  
pp. 377-383 ◽  
Author(s):  
Rudolf Schicho ◽  
Martin Storr
Keyword(s):  
Cannabinoid Receptors ◽  
De Novo ◽  
Synthetic Cannabinoids ◽  
Endocannabinoid System ◽  
Gastrointestinal Diseases ◽  
Pharmacological Intervention ◽  
De Novo Synthesis ◽  
Promising Alternative ◽  
Beneficial Effects ◽  
Therapeutic Tools

Many beneficial effects of herbal and synthetic cannabinoids on gut motility and inflammation have been demonstrated, suggesting a vast potential for these compounds in the treatment of gastrointestinal disorders. These effects are based on the so-called ‘endocannabinoid system’ (ECS), a cooperating network of molecules that regulate the metabolism of the body’s own and of exogenously administered cannabinoids. The ECS in the gastrointestinal tract quickly responds to homeostatic disturbances by de novo synthesis of its components to maintain homeostasis, thereby offering many potential targets for pharmacological intervention. Of major therapeutic interest are nonpsychoactive cannabinoids or compounds that do not directly target cannabinoid receptors but still possess cannabinoid-like properties. Drugs that inhibit endocannabinoid degradation and raise the level of endocannabinoids are becoming increasingly promising alternative therapeutic tools to manipulate the ECS.

scholarly journals Endocannabinoids in the gastrointestinal tract

2016 ◽  
Vol 311 (4) ◽  
pp. G655-G666 ◽  
Author(s):  
Yunna Lee ◽  
Jeongbin Jo ◽  
Hae Young Chung ◽  
Charalabos Pothoulakis ◽  
Eunok Im
Keyword(s):  
Cannabinoid Receptors ◽  
Transient Receptor Potential ◽  
Synthetic Cannabinoids ◽  
Endocannabinoid System ◽  
Receptor Potential ◽  
Gastrointestinal Diseases ◽  
Transient Receptor Potential Channels ◽  
Therapeutic Benefits ◽  
Potential Channels ◽  
Transient Receptor

The endocannabinoid system mainly consists of endogenously produced cannabinoids (endocannabinoids) and two G protein-coupled receptors (GPCRs), cannabinoid receptors 1 and 2 (CB1 and CB2). This system also includes enzymes responsible for the synthesis and degradation of endocannabinoids and molecules required for the uptake and transport of endocannabinoids. In addition, endocannabinoid-related lipid mediators and other putative endocannabinoid receptors, such as transient receptor potential channels and other GPCRs, have been identified. Accumulating evidence indicates that the endocannabinoid system is a key modulator of gastrointestinal physiology, influencing satiety, emesis, immune function, mucosal integrity, motility, secretion, and visceral sensation. In light of therapeutic benefits of herbal and synthetic cannabinoids, the vast potential of the endocannabinoid system for the treatment of gastrointestinal diseases has been demonstrated. This review focuses on the role of the endocannabinoid system in gut homeostasis and in the pathogenesis of intestinal disorders associated with intestinal motility, inflammation, and cancer. Finally, links between gut microorganisms and the endocannabinoid system are briefly discussed.

The Molecular targets of Cannabinoids in the treatment of Cancer and Inflammation

2021 ◽  
Vol 27 ◽  
Author(s):  
Alenabi Aylar ◽  
Malekinejad Hassan
Keyword(s):  
Cannabinoid Receptors ◽  
Inflammatory Diseases ◽  
Biological Effects ◽  
Synthetic Cannabinoids ◽  
Endocannabinoid System ◽  
Anticancer Effects ◽  
Anti Cancer ◽  
Culture Models ◽  
Cancer And Inflammation ◽  
G Protein Coupled

Objective: In this review we discuss the emerging evidence for the effectiveness of cannabinoids in the treatment of cancer and inflammation. The remarkable effects complete the traditional evidence for their successful application in the treatment of pain and cancer-related side effects. Methods: we searched Pub Med (132 articles) and Google scholar (9 articles) databases and gathered the clinical (4 articles), preclinical (28 articles) studies, reports on cell culture models (30 articles) and other original and review articles (78 articles) related to inflammation, cancer and cannabinoids. Results: Cannabinoids are described in three different forms, comprising endo- phyto- and synthetic compounds that exert biological effects. The molecular and cellular pathways of endogenous cannabinoids in the maintenance of homeostasis are well documented. In addition to classical cannabinoid receptors type 1 and 2, Vanilloid receptors and G protein-coupled receptor 55 were identified as common receptors. Subsequently, the effectiveness of phyto- and synthetic cannabinoids mediated by cannabinoid receptors has been demonstrated in the treatment of inflammatory diseases including neurodegenerative diseases as well as gastrointestinal and respiratory inflammations. Another accepted property of cannabinoids is their anti-cancer effects. Cannabinoids were found to be effective in the treatment of lung, colorectal, prostate, breast, pancreas and hepatic cancers. The anticancer effects of cannabinoids were characterized by their anti-proliferative property, inhibition of cancer cells migration, suppression of vascularization and induction of apoptosis. Conclusion: The current review provides and overview the role of endocannabinoid system in the mediation of physiological functions, the type and expression of cannabinoids receptors under physiological and pathological conditions. In additions, the molecular pathways involved in the effects of cannabinoids and the effectiveness of cannabinoids in the treatment of inflammations and cancers are highlighted.

scholarly journals The Endocannabinoid System Contributes to Electroacupuncture Analgesia

2021 ◽  
Vol 14 ◽  
Author(s):  
Iona J. MacDonald ◽  
Yi-Hung Chen
Keyword(s):  
Cognitive Processes ◽  
Cannabinoid Receptors ◽  
Scientific Evidence ◽  
Antinociceptive Effect ◽  
Synthetic Cannabinoids ◽  
Behavioral Responses ◽  
Endocannabinoid System ◽  
Extensive Involvement ◽  
Effective Analgesia

The extensive involvement of the endocannabinoid system (ECS) in vital physiological and cognitive processes of the human body has inspired many investigations into the role of the ECS and drugs, and therapies that target this system and its receptors. Activation of cannabinoid receptors 1 and 2 (CB1 and CB2) by cannabinoid treatments, including synthetic cannabinoids, alleviates behavioral responses to inflammatory and neuropathic pain. An increasing body of scientific evidence details how electroacupuncture (EA) treatments achieve effective analgesia and reduce inflammation by modulating cannabinoid signaling, without the adverse effects resulting from synthetic cannabinoid administration. CB1 receptors in the ventrolateral area of the periaqueductal gray are critically important for the mechanisms of the EA antinociceptive effect, while peripheral CB2 receptors are related to the anti-inflammatory effects of EA. This review explores the evidence detailing the endocannabinoid mechanisms involved in EA antinociception.

scholarly journals The Endocannabinoid System in the Retina: From Physiology to Practical and Therapeutic Applications

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Thomas Schwitzer ◽  
Raymund Schwan ◽  
Karine Angioi-Duprez ◽  
Anne Giersch ◽  
Vincent Laprevote
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cannabinoid Receptors ◽  
Synthetic Cannabinoids ◽  
Endocannabinoid System ◽  
Main Role ◽  
Cannabinoid System ◽  
Retinal Processing ◽  
The Central Nervous System ◽  
The Impact

Cannabisis one of the most prevalent drugs used in industrialized countries. The main effects ofCannabisare mediated by two major exogenous cannabinoids: ∆9-tetrahydroxycannabinol and cannabidiol. They act on specific endocannabinoid receptors, especially types 1 and 2. Mammals are endowed with a functional cannabinoid system including cannabinoid receptors, ligands, and enzymes. This endocannabinoid signaling pathway is involved in both physiological and pathophysiological conditions with a main role in the biology of the central nervous system. As the retina is a part of the central nervous system due to its embryonic origin, we aim at providing the relevance of studying the endocannabinoid system in the retina. Here, we review the distribution of the cannabinoid receptors, ligands, and enzymes in the retina and focus on the role of the cannabinoid system in retinal neurobiology. This review describes the presence of the cannabinoid system in critical stages of retinal processing and its broad involvement in retinal neurotransmission, neuroplasticity, and neuroprotection. Accordingly, we support the use of synthetic cannabinoids as new neuroprotective drugs to prevent and treat retinal diseases. Finally, we argue for the relevance of functional retinal measures in cannabis users to evaluate the impact of cannabis use on human retinal processing.

scholarly journals Cannabinoid Signalling in Immune–Reproductive Crosstalk during Human Pregnancy

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 267
Author(s):  
Harmeet Gurm ◽  
Jeremy A. Hirota ◽  
Sandeep Raha
Keyword(s):  
Natural Killer Cells ◽  
Natural Killer ◽  
Cannabinoid Receptors ◽  
Synthetic Cannabinoids ◽  
Endocannabinoid System ◽  
Therapeutic Benefit ◽  
Killer Cells ◽  
Uterine Natural Killer Cells ◽  
Extravillous Trophoblasts ◽  
Uterine Natural Killer

Despite the intricate involvement of the endocannabinoid system in various physiological processes, it remains one of the most under-studied biological systems of the human body. The scope of endocannabinoid signalling is widespread, ranging from modulation of immune responses in innate and adaptive immunity to gestational processes in female physiology. Cannabinoid receptors are ubiquitously distributed in reproductive tissues and are thought to play a role in regulating the immune–reproductive interactions required for successful pregnancy, specifically among uterine natural killer cells and placental extravillous trophoblasts. The use of cannabis during pregnancy, however, can perturb endocannabinoid homeostasis through effects mediated by its major constituents, Δ-9-tetrahydrocannabinol and cannabidiol. Decidualization of the endometrium, invasion, and angiogenesis may be impaired as a consequence, leading to clinical complications such as miscarriage and preeclampsia. In this review, the crosstalk between endocannabinoid signalling in uterine natural killer cells and placental extravillous trophoblasts will be examined in healthy and complicated pregnancies. This lays a foundation for discussing the potential of targeting the endocannabinoid system for therapeutic benefit, particularly with regard to the emerging field of synthetic cannabinoids.

scholarly journals The Endocannabinoid System May Modulate Sleep Disorders in Aging

2020 ◽  
Vol 18 (2) ◽  
pp. 97-108
Author(s):  
Eric Murillo-Rodríguez ◽  
Henning Budde ◽  
André Barciela Veras ◽  
Nuno Barbosa Rocha ◽  
Diogo Telles-Correia ◽  
...  
Keyword(s):  
Sleep Disorders ◽  
Sleep Disturbances ◽  
Sleep Problems ◽  
Endocannabinoid System ◽  
The Elderly ◽  
Therapeutic Approaches ◽  
Beneficial Effects ◽  
Demographic Projections ◽  
Age Related ◽  
Therapeutic Tools

Aging is an inevitable process that involves changes across life in multiple neurochemical, neuroanatomical, hormonal systems, and many others. In addition, these biological modifications lead to an increase in age-related sickness such as cardiovascular diseases, osteoporosis, neurodegenerative disorders, and sleep disturbances, among others that affect activities of daily life. Demographic projections have demonstrated that aging will increase its worldwide rate in the coming years. The research on chronic diseases of the elderly is important to gain insights into this growing global burden. Novel therapeutic approaches aimed for treatment of age-related pathologies have included the endocannabinoid system as an effective tool since this biological system shows beneficial effects in preclinical models. However, and despite these advances, little has been addressed in the arena of the endocannabinoid system as an option for treating sleep disorders in aging since experimental evidence suggests that some elements of the endocannabinoid system modulate the sleep-wake cycle. This article addresses this less-studied field, focusing on the likely perspective of the implication of the endocannabinoid system in the regulation of sleep problems reported in the aged. We conclude that beneficial effects regarding the putative efficacy of the endocannabinoid system as therapeutic tools in aging is either inconclusive or still missing.

scholarly journals Targeting Cannabinoid Receptors: Current Status and Prospects of Natural Products

2020 ◽  
Vol 21 (14) ◽  
pp. 5064 ◽  
Author(s):  
Dongchen An ◽  
Steve Peigneur ◽  
Louise Antonia Hendrickx ◽  
Jan Tytgat
Keyword(s):  
Natural Products ◽  
Cannabinoid Receptors ◽  
Structural Information ◽  
Critical Role ◽  
Synthetic Cannabinoids ◽  
Endocannabinoid System ◽  
Current Status ◽  
Therapeutic Effects ◽  
Drug Leads

Cannabinoid receptors (CB1 and CB2), as part of the endocannabinoid system, play a critical role in numerous human physiological and pathological conditions. Thus, considerable efforts have been made to develop ligands for CB1 and CB2, resulting in hundreds of phyto- and synthetic cannabinoids which have shown varying affinities relevant for the treatment of various diseases. However, only a few of these ligands are clinically used. Recently, more detailed structural information for cannabinoid receptors was revealed thanks to the powerfulness of cryo-electron microscopy, which now can accelerate structure-based drug discovery. At the same time, novel peptide-type cannabinoids from animal sources have arrived at the scene, with their potential in vivo therapeutic effects in relation to cannabinoid receptors. From a natural products perspective, it is expected that more novel cannabinoids will be discovered and forecasted as promising drug leads from diverse natural sources and species, such as animal venoms which constitute a true pharmacopeia of toxins modulating diverse targets, including voltage- and ligand-gated ion channels, G protein-coupled receptors such as CB1 and CB2, with astonishing affinity and selectivity. Therefore, it is believed that discovering novel cannabinoids starting from studying the biodiversity of the species living on planet earth is an uncharted territory.

Route of administration (enteral or parenteral) affects the contribution of l-glutamine to de novo l-arginine synthesis in mice: a stable-isotope study

2006 ◽  
Vol 291 (4) ◽  
pp. E683-E690 ◽  
Author(s):  
Petra G. Boelens ◽  
Gerdien C. Melis ◽  
Paul A. van Leeuwen ◽  
Gabrie A. ten Have ◽  
Nicolaas E. Deutz
Keyword(s):  
De Novo ◽  
Route Of Administration ◽  
High Dose ◽  
Trauma Patients ◽  
De Novo Synthesis ◽  
Beneficial Effects ◽  
Parenteral Route ◽  
Steady State Model ◽  
Isotope Study ◽  
Stable Isotope Study

A pathway from enteral l-glutamine as substrate for l-arginine synthesis is suggested by previous studies. l-Glutamine and l-glutamine dipeptides exhibit numerous beneficial effects in experimental and clinical studies. In trauma patients, enteral l-glutamine supply increased plasma l-arginine. The present study was designed to quantify the contribution of l-glutamine to the de novo l-citrulline and l-arginine synthesis in mice when l-glutamine is administered in a high dose of labeled l-glutamine or l-alanyl-l-glutamine by the enteral or parenteral route. For this purpose, male Swiss mice ( n = 43) underwent a laparotomy, and catheters were inserted for sampling and infusion. A primed, constant, and continuous infusion of l-alanyl-l-[2-15N]glutamine (dipeptide groups) or l-[2-15N]glutamine (free l-glutamine groups), simultaneously with l-[ureido-13C,2H2]citrulline and l-[guanidino-15N2,2H2]arginine, was given (steady-state model). Mice received the l-glutamine tracers intravenously (jugular vein) or enterally (duodenum). Enrichments of metabolites were measured by LC-MS. Arterial l-glutamine concentrations were the highest in the intravenous dipeptide group. l-Glutamine was converted to l-citrulline and l-arginine when l-[2-15N]glutamine and l-alanyl-l-[2-15N]glutamine were given by enteral or parenteral route. The contribution of l-glutamine to the de novo synthesis of l-citrulline and l-arginine was higher in the enteral groups when compared with the intravenous groups ( P < 0.005). Therefore, the route of administration (enteral or parenteral) affects the contribution of l-glutamine, provided as free molecule or dipeptide, to the de novo synthesis of l-arginine in mice.

scholarly journals Relevance of Peroxisome Proliferator Activated Receptors in Multitarget Paradigm Associated with the Endocannabinoid System

2021 ◽  
Vol 22 (3) ◽  
pp. 1001
Author(s):  
Ana Lago-Fernandez ◽  
Sara Zarzo-Arias ◽  
Nadine Jagerovic ◽  
Paula Morales
Keyword(s):  
Cannabinoid Receptors ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Synergistic Effects ◽  
Synthetic Cannabinoids ◽  
Endocannabinoid System ◽  
Receptor Potential ◽  
Therapeutic Effects ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptors

Cannabinoids have shown to exert their therapeutic actions through a variety of targets. These include not only the canonical cannabinoid receptors CB1R and CB2R but also related orphan G protein-coupled receptors (GPCRs), ligand-gated ion channels, transient receptor potential (TRP) channels, metabolic enzymes, and nuclear receptors. In this review, we aim to summarize reported compounds exhibiting their therapeutic effects upon the modulation of CB1R and/or CB2R and the nuclear peroxisome proliferator-activated receptors (PPARs). Concomitant actions at CBRs and PPARα or PPARγ subtypes have shown to mediate antiobesity, analgesic, antitumoral, or neuroprotective properties of a variety of phytogenic, endogenous, and synthetic cannabinoids. The relevance of this multitargeting mechanism of action has been analyzed in the context of diverse pathologies. Synergistic effects triggered by combinatorial treatment with ligands that modulate the aforementioned targets have also been considered. This literature overview provides structural and pharmacological insights for the further development of dual cannabinoids for specific disorders.

scholarly journals Cannabinoids induce functional Tregs by promoting tolerogenic DCs via autophagy and metabolic reprograming

2021 ◽  
Author(s):  
Alba Angelina ◽  
Mario Pérez-Diego ◽  
Jacobo López-Abente ◽  
Beate Rückert ◽  
Ivan Nombela ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Inflammatory Diseases ◽  
Endocannabinoid System ◽  
Mitochondrial Activity ◽  
Immune Mediated ◽  
Therapeutic Tools ◽  
Tolerogenic Dcs

AbstractThe generation of functional regulatory T cells (Tregs) is essential to keep tissue homeostasis and restore healthy immune responses in many biological and inflammatory contexts. Cannabinoids have been pointed out as potential therapeutic tools for several diseases. Dendritic cells (DCs) express the endocannabinoid system, including the cannabinoid receptors CB1 and CB2. However, how cannabinoids might regulate functional properties of DCs is not completely understood. We uncover that the triggering of cannabinoid receptors promote human tolerogenic DCs that are able to prime functional FOXP3+ Tregs in the context of different inflammatory diseases. Mechanistically, cannabinoids imprint tolerogenicity in human DCs by inhibiting NF-κB, MAPK and mTOR signalling pathways while inducing AMPK and functional autophagy flux via CB1- and PPARα-mediated activation, which drives metabolic rewiring towards increased mitochondrial activity and oxidative phosphorylation. Cannabinoids exhibit in vivo protective and anti-inflammatory effects in LPS-induced sepsis and also promote the generation of FOXP3+ Tregs. In addition, immediate anaphylactic reactions are decreased in peanut allergic mice and the generation of allergen-specific FOXP3+ Tregs are promoted, demonstrating that these immunomodulatory effects take place in both type 1- and type 2-mediated inflammatory diseases. Our findings might open new avenues for novel cannabinoid-based interventions in different inflammatory and immune-mediated diseases.

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