scholarly journals Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases

2020 ◽  
Vol 21 (20) ◽  
pp. 7693
Author(s):  
Dhanush Haspula ◽  
Michelle A. Clark
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Inflammatory Diseases ◽  
Endocannabinoid System ◽  
Future Directions ◽  
The Past ◽  
Health And Disease ◽  
Made In

The identification of the human cannabinoid receptors and their roles in health and disease, has been one of the most significant biochemical and pharmacological advancements to have occurred in the past few decades. In spite of the major strides made in furthering endocannabinoid research, therapeutic exploitation of the endocannabinoid system has often been a challenging task. An impaired endocannabinoid tone often manifests as changes in expression and/or functions of type 1 and/or type 2 cannabinoid receptors. It becomes important to understand how alterations in cannabinoid receptor cellular signaling can lead to disruptions in major physiological and biological functions, as they are often associated with the pathogenesis of several neurological, cardiovascular, metabolic, and inflammatory diseases. This review focusses mostly on the pathophysiological roles of type 1 and type 2 cannabinoid receptors, and it attempts to integrate both cellular and physiological functions of the cannabinoid receptors. Apart from an updated review of pre-clinical and clinical studies, the adequacy/inadequacy of cannabinoid-based therapeutics in various pathological conditions is also highlighted. Finally, alternative strategies to modulate endocannabinoid tone, and future directions are also emphasized.

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.

scholarly journals Cannabinoids in health and disease: pharmacological potential in metabolic syndrome and neuroinflammation

2018 ◽  
Vol 36 (2) ◽  
Author(s):  
Andrea Mastinu ◽  
Marika Premoli ◽  
Giulia Ferrari-Toninelli ◽  
Simone Tambaro ◽  
Giuseppina Maccarinelli ◽  
...  
Keyword(s):  
Cannabis Sativa ◽  
Cannabinoid Receptor ◽  
Receptor Type ◽  
History Of ◽  
Health And Disease ◽  
Pharmacological Potential ◽  
The Brain ◽  
Synthesis And Degradation

Abstract The use of different natural and/or synthetic preparations of Cannabis sativa is associated with therapeutic strategies for many diseases. Indeed, thanks to the widespread diffusion of the cannabinoidergic system in the brain and in the peripheral districts, its stimulation, or inhibition, regulates many pathophysiological phenomena. In particular, central activation of the cannabinoidergic system modulates the limbic and mesolimbic response which leads to food craving. Moreover, cannabinoid agonists are able to reduce inflammatory response. In this review a brief history of cannabinoids and the protagonists of the endocannabinoidergic system, i.e. synthesis and degradation enzymes and main receptors, will be described. Furthermore, the pharmacological effects of cannabinoids will be outlined. An overview of the involvement of the endocannabinoidergic system in neuroinflammatory and metabolic pathologies will be made. Finally, particular attention will also be given to the new pharmacological entities acting on the two main receptors, cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2), with particular focus on the neuroinflammatory and metabolic mechanisms involved.

scholarly journals Role of endocannabinoid system in the pathogenesis of obesity: how can we help a patient? From theory to practice

2020 ◽  
Vol 4 (6) ◽  
pp. 382-389
Author(s):  
V.A. Dudareva ◽  
◽  
M.L. Maksimov ◽  
I.G. Djadikova ◽  
A.A. Zveginceva ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Endocannabinoid System ◽  
Medical Society ◽  
Cannabinoid Receptor 1 ◽  
Peripheral Tissues ◽  
Theory To Practice

Obesity that results in various metabolic disorders is one of the central concerns of modern healthcare system. Only 4% to 5% of patients with metabolic syndrome achieve favorable outcomes without any additional pharmacotherapy. Therefore, many patients require weight-loss drugs in addition to non-pharmacological treatments. The endocannabinoid system and the drugs that affect its functions receive a widespread attention of medical society due to its effects on behavioral and cerebral functions and its potential use as a therapeutic “target” in various peripheral and neurological psychiatric disorders. Among known to date cannabinoid receptors, type 1 receptors play a role in the development of obesity. It was demonstrated that the blockade of these receptors in the hypothalamus reduces appetite, inhibits adipocyte activation in peripheral tissues, prevents lipogenesis, and increases the level of adiponectin. The result is the decreased levels of atherogenic lipoproteins and improved insulin resistance. This article addresses the results of fundamental and clinical studies on Dietressa, a drug composed of affine-purified antibodies to cannabinoid receptor 1. Case report of a patient with obesity that analyzes pharmaceutical and non-pharmaceutical treatment approaches is described.KEYWORDS: obesity, metabolic syndrome, diet, endocannabinoid system, cannabinoids, cannabinoid receptors, affine-purified antibodies.FOR CITATION: Dudareva V.A., Maksimov M.L., Djadikova I.G. et al. Role of endocannabinoid system in the pathogenesis of obesity: how can we help a patient? From theory to practice. Russian Medical Inquiry. 2020;4(6):382–389. DOI: 10.32364/2587-6821-2020-4-6-382-389.

scholarly journals Interference with the Cannabinoid Receptor CB1R Results in Miswiring of GnRH3 and AgRP1 Axons in Zebrafish Embryos

2019 ◽  
Vol 21 (1) ◽  
pp. 168 ◽  
Author(s):  
Giulia Zuccarini ◽  
Ilaria D’Atri ◽  
Erika Cottone ◽  
Ken Mackie ◽  
Inbal Shainer ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Zebrafish Embryos ◽  
Low Doses ◽  
Axonal Projections ◽  
Embryonic Exposure ◽  
G Protein Coupled ◽  
Bioinformatic Approach

The G protein-coupled cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), and their endocannabinoid (eCBs) ligands, have been implicated in several aspects of brain wiring during development. Here we aim to assess whether interfering with CB1R affects development, neuritogenesis and pathfinding of GnRH and AgRP neurons, forebrain neurons that control respectively reproduction and appetite. We pharmacologically and genetically interfered with CB1R in zebrafish strains with fluorescently labeled GnRH3 and the AgRP1 neurons. By applying CB1R antagonists we observed a reduced number of GnRH3 neurons, fiber misrouting and altered fasciculation. Similar phenotypes were observed by CB1R knockdown. Interfering with CB1R also resulted in a reduced number, misrouting and poor fasciculation of the AgRP1 neuron’s axonal projections. Using a bioinformatic approach followed by qPCR validation, we have attempted to link CB1R functions with known guidance and fasciculation proteins. The search identified stathmin-2, a protein controlling microtubule dynamics, previously demonstrated to be coexpressed with CB1R and now shown to be downregulated upon interference with CB1R in zebrafish. Together, these results raise the likely possibility that embryonic exposure to low doses of CB1R-interfering compounds could impact on the development of the neuroendocrine systems controlling sexual maturation, reproduction and food intake.

scholarly journals Characterization of Endocannabinoid System and Interleukin Profiles in Ovine AEC: Cannabinoid Receptors Type-1 and Type-2 as Key Effectors of Pro-Inflammatory Response

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1008 ◽  
Author(s):  
Luana Greco ◽  
Valentina Russo ◽  
Cinzia Rapino ◽  
Clara Di Germanio ◽  
Filomena Fezza ◽  
...  
Keyword(s):  
Immune Modulation ◽  
Cannabinoid Receptors ◽  
Endocannabinoid System ◽  
Middle Stage ◽  
Selective Agonists ◽  
Anti Inflammatory

Amniotic epithelial cells (AEC) have been proposed as promising clinical candidates for regenerative medicine therapies due to their immunomodulatory capacity. In this context, the endocannabinoid system (ECS) has been identified as mediating the immune-stem cell dialogue, even if no information on AEC is available to date. Therefore, this study was designed to assess whether ECS is involved in tuning the constitutive and lipopolysaccharide (LPS)-induced ovine AEC anti-inflammatory and pro-inflammatory interleukin (IL-10, IL-4, and IL-12) profiles. Firstly, interleukins and ECS expressions were studied at different stages of gestation. Then, the role of cannabinoid receptors 1 and 2 (CB1 and CB2) on interleukin expression and release was investigated in middle stage AEC using selective agonists and antagonists. AEC displayed a degradative more than a synthetic endocannabinoid metabolism during the early and middle stages of gestation. At the middle stage, cannabinoid receptors mediated the balance between pro-inflammatory (IL-12) and anti-inflammatory (IL-4 and IL-10) interleukins. The activation of both receptors mediated an overall pro-inflammatory shift—CB1 reduced the anti-inflammatory and CB2 increased the pro-inflammatory interleukin release, particularly after LPS stimulation. Altogether, these data pave the way for the comprehension of AEC mechanisms tuning immune-modulation, crucial for the development of new AEC-based therapy protocols.

scholarly journals On the Role of Central Type-1 Cannabinoid Receptor Gene Regulation in Food Intake and Eating Behaviors

2021 ◽  
Vol 22 (1) ◽  
pp. 398
Author(s):  
Mariangela Pucci ◽  
Elizabeta Zaplatic ◽  
Maria Vittoria Micioni Di Bonaventura ◽  
Emanuela Micioni Di Bonaventura ◽  
Paolo De Cristofaro ◽  
...  
Keyword(s):  
Food Intake ◽  
Eating Behaviors ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Receptor Gene ◽  
Endocannabinoid System ◽  
Central Type ◽  
Type 1 Cannabinoid Receptor

Different neuromodulatory systems are involved in long-term energy balance and body weight and, among these, evidence shows that the endocannabinoid system, in particular the activation of type-1 cannabinoid receptor, plays a key role. We here review current literature focusing on the role of the gene encoding type-1 cannabinoid receptors in the CNS and on the modulation of its expression by food intake and specific eating behaviors. We point out the importance to further investigate how environmental cues might have a role in the development of obesity as well as eating disorders through the transcriptional regulation of this gene in order to prevent or to treat these pathologies.

scholarly journals Cannabinoid receptor type-1: breaking the dogmas

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 990 ◽  
Author(s):  
Arnau Busquets Garcia ◽  
Edgar Soria-Gomez ◽  
Luigi Bellocchio ◽  
Giovanni Marsicano
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Endocannabinoid System ◽  
Cell Types ◽  
Allosteric Modulators ◽  
Receptor Field ◽  
Intracellular Compartments ◽  
Specific Localization ◽  
Brain Connections

The endocannabinoid system (ECS) is abundantly expressed in the brain. This system regulates a plethora of physiological functions and is composed of cannabinoid receptors, their endogenous ligands (endocannabinoids), and the enzymes involved in the metabolism of endocannabinoids. In this review, we highlight the new advances in cannabinoid signaling, focusing on a key component of the ECS, the type-1 cannabinoid receptor (CB1). In recent years, the development of new imaging and molecular tools has demonstrated that this receptor can be distributed in many cell types (e.g., neuronal or glial cells) and intracellular compartments (e.g., mitochondria). Interestingly, cellular and molecular effects are differentially mediated by CB1 receptors according to their specific localization (e.g., glutamatergic or GABAergic neurons). Moreover, this receptor is expressed in the periphery, where it can modulate periphery-brain connections. Finally, the better understanding of the CB1 receptor structure led researchers to propose interesting and new allosteric modulators. Thus, the advances and the new directions of the CB1 receptor field will provide new insights and better approaches to profit from its interesting therapeutic profile.

scholarly journals The Endocannabinoid System in Pediatric Inflammatory and Immune Diseases

2019 ◽  
Vol 20 (23) ◽  
pp. 5875 ◽  
Author(s):  
Maura Argenziano ◽  
Chiara Tortora ◽  
Giulia Bellini ◽  
Alessandra Di Paola ◽  
Francesca Punzo ◽  
...  
Keyword(s):  
Social Impact ◽  
Cannabinoid Receptors ◽  
Immune Cell ◽  
Endocannabinoid System ◽  
Pediatric Diseases ◽  
Inflammatory Processes ◽  
Inflammatory Bowel

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.

scholarly journals URB597 abrogates anxiogenic and depressive behaviors in the methamphetamine-withdrawal mice: Role of the cannabinoid receptor type 1, cannabinoid receptor type 2, and transient receptor potential vanilloid 1 channels

2020 ◽  
pp. 026988112096593
Author(s):  
Mohaddeseh Ebrahimi-Ghiri ◽  
Fatemeh Khakpai ◽  
Mohammad-Reza Zarrindast
Keyword(s):  
Transient Receptor Potential ◽  
Cannabinoid Receptor ◽  
Endocannabinoid System ◽  
Receptor Potential ◽  
Receptor Type ◽  
Anxiety And Depression ◽  
Transient Receptor Potential Vanilloid ◽  
Transient Receptor

Background: Methamphetamine is an addictive stimulant that possesses toxicity in the brain when taken repeatedly or at higher doses. Methamphetamine neurotoxicity is associated with numerous forms of mental impairment, including depression and anxiety. Evidence has also demonstrated that the endocannabinoid system is involved in the regulation of anxiety and depression. Aims: This study was designed to determine the involvement of the endocannabinoid system in anxiety- and depression-related behaviors in methamphetamine-withdrawal male NMRI mice. Methods: The elevated plus maze and forced swim test were used to assess the level of anxiety and depression. Results: We found that methamphetamine (30 mg/kg, intraperitoneal) evoked depressive- and anxiogenic-like effects at 3 days post-administration. Injection of URB597 (5–10 ng/mouse, intracerebroventricular), 10 min before the test, prevented the emotional deficits induced by methamphetamine withdrawal. Moreover, the cannabinoid receptor type 1 antagonist AM251 (1 μg/mouse) or cannabinoid receptor type 2 antagonist AM630 (5 and 10 μg/mouse) suppressed the antidepressant activity in the methamphetamine-withdrawal mice treated with URB597. The transient receptor potential vanilloid 1 antagonist capsazepine (25 μg/mouse) prevented while capsazepine (100 μg/mouse) potentiated the antidepressant efficacy in the methamphetamine-withdrawal mice treated with URB597. The higher dose of AM630 and two higher doses of capsazepine had antidepressant efficacy, by themselves. Furthermore, capsazepine (50 μg/mouse) increased locomotion in the methamphetamine-withdrawal mice treated with URB597. Conclusions: The results suggest that URB597 has a potential for preventing methamphetamine withdrawal-evoked anxiety and depression. Cannabinoid type 1 receptors, cannabinoid type 2 receptors and transient receptor potential vanilloid 1 differently affect depression-related behaviors in methamphetamine-withdrawal mice treated with URB597.

scholarly journals In vitro and in vivo pharmacological activity of minor cannabinoids isolated from Cannabis sativa

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ayat Zagzoog ◽  
Kawthar A. Mohamed ◽  
Hye Ji J. Kim ◽  
Eunhyun D. Kim ◽  
Connor S. Frank ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabis Sativa ◽  
Cannabinoid Receptor ◽  
Partial Agonist ◽  
Chinese Hamster ◽  
Cannabidiolic Acid

AbstractThe Cannabis sativa plant contains more than 120 cannabinoids. With the exceptions of ∆9-tetrahydrocannabinol (∆9-THC) and cannabidiol (CBD), comparatively little is known about the pharmacology of the less-abundant plant-derived (phyto) cannabinoids. The best-studied transducers of cannabinoid-dependent effects are type 1 and type 2 cannabinoid receptors (CB1R, CB2R). Partial agonism of CB1R by ∆9-THC is known to bring about the ‘high’ associated with Cannabis use, as well as the pain-, appetite-, and anxiety-modulating effects that are potentially therapeutic. CB2R activation by certain cannabinoids has been associated with anti-inflammatory activities. We assessed the activity of 8 phytocannabinoids at human CB1R, and CB2R in Chinese hamster ovary (CHO) cells stably expressing these receptors and in C57BL/6 mice in an attempt to better understand their pharmacodynamics. Specifically, ∆9-THC, ∆9-tetrahydrocannabinolic acid (∆9-THCa), ∆9-tetrahydrocannabivarin (THCV), CBD, cannabidiolic acid (CBDa), cannabidivarin (CBDV), cannabigerol (CBG), and cannabichromene (CBC) were evaluated. Compounds were assessed for their affinity to receptors, ability to inhibit cAMP accumulation, βarrestin2 recruitment, receptor selectivity, and ligand bias in cell culture; and cataleptic, hypothermic, anti-nociceptive, hypolocomotive, and anxiolytic effects in mice. Our data reveal partial agonist activity for many phytocannabinoids tested at CB1R and/or CB2R, as well as in vivo responses often associated with activation of CB1R. These data build on the growing body of literature showing cannabinoid receptor-dependent pharmacology for these less-abundant phytocannabinoids and are critical in understanding the complex and interactive pharmacology of Cannabis-derived molecules.

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