New Insights Into Peptide Cannabinoids: Structure, Biosynthesis and Signaling

Classically, the endocannabinoid system (ECS) consists of endogenous lipids, of which the best known are anandamide (AEA) and 2 arachidonoylglycerol (2-AG), their enzyme machinery for synthesis and degradation and their specific receptors, cannabinoid receptor one (CB1) and cannabinoid receptor two (CB2). However, endocannabinoids also bind to other groups of receptors. Furthermore, another group of lipids are considered to be endocannabinoids, such as the fatty acid ethanolamides, the fatty acid primary amides and the monoacylglycerol related molecules. Recently, it has been shown that the hemopressin peptide family, derived from α and β chains of hemoglobins, is a new family of cannabinoids. Some studies indicate that hemopressin peptides are expressed in the central nervous system and peripheral tissues and act as ligands of these receptors, thus suggesting that they play a physiological role. In this review, we examine new evidence on lipid endocannabinoids, cannabinoid receptors and the modulation of their signaling pathways. We focus our discussion on the current knowledge of the pharmacological effects, the biosynthesis of the peptide cannabinoids and the new insights on the activation and modulation of cannabinoid receptors by these peptides. The novel peptide compounds derived from hemoglobin chains and their non-classical activation of cannabinoid receptors are only starting to be uncovered. It will be exciting to follow the ensuing discoveries, not only in reference to what is already known of the classical lipid endocannabinoids revealing more complex aspects of endocannabinoid system, but also as to its possibilities as a future therapeutic tool.

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Specific shifts in the endocannabinoid system in hibernating brown bears

10.21203/rs.3.rs-30282/v3 ◽

2020 ◽

Author(s):

Christian Boyer ◽

Laura Cussonneau ◽

Charlotte Brun ◽

Christiane Deval ◽

Jean-Paul Pais de Barros ◽

...

Keyword(s):

Fatty Acid ◽

Cannabinoid Receptors ◽

External Disturbance ◽

Mrna Level ◽

Endocannabinoid System ◽

Fold Increase ◽

Physiological Adaptation ◽

Acid Oxidation ◽

Brown Bears ◽

Peripheral Tissues

Abstract In small hibernators, global downregulation of the endocannabinoid system (ECS), which is involved in modulating neuronal signaling, feeding behavior, energy metabolism, and circannual rhythms, has been reported to possibly drive physiological adaptation to the hibernating state. In hibernating brown bears ( Ursus arctos ), we hypothesized that beyond an overall suppression of the ECS, seasonal shift in endocannabinoids compounds could be linked to bear’s peculiar features that include hibernation without arousal episodes and capacity to react to external disturbance. We explored circulating lipids in serum and the ECS in plasma and metabolically active tissues in free-ranging subadult Scandinavian brown bears when both active and hibernating. In winter bear serum, in addition to a 2-fold increase in total fatty acid concentration, we found significant changes in relative proportions of circulating fatty acids, such as a 2-fold increase in docosahexaenoic acid C22:6 n-3 and a decrease in arachidonic acid C20:4 n-6. In adipose and muscle tissues of hibernating bears, we found significant lower concentrations of 2-arachidonoylglycerol (2-AG), a major ligand of cannabinoid receptors 1 (CB1) and 2 (CB2). Lower mRNA level for genes encoding CB1 and CB2 were also found in winter muscle and adipose tissue, respectively. The observed reduction in ECS tone may promote fatty acid mobilization from body fat stores, and favor carbohydrate metabolism in skeletal muscle of hibernating bears. Additionally, high circulating level of the endocannabinoid-like compound N-oleoylethanolamide (OEA) in winter could favor lipolysis and fatty acid oxidation in peripheral tissues. We also speculated on a role of OEA in the conservation of an anorexigenic signal and in the maintenance of torpor during hibernation, while sustaining the capacity of bears to sense stimuli from the environment.

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Endocannabinoid System: Overview and Therapeutic Relevance

10.2310/cannabis.17021 ◽

2021 ◽

Author(s):

Alex Mabou Tagne

Keyword(s):

Fatty Acid ◽

Cannabinoid Receptors ◽

Cannabinoid Receptor ◽

Fatty Acid Amide Hydrolase ◽

Acid Amide ◽

Endocannabinoid System ◽

Receptor Subtypes ◽

Monoacylglycerol Lipase ◽

Amide Hydrolase ◽

Fatty Acid Amide

The endocannabinoid system (ECS) modulates a variety of physiological processes, attracting considerable attention as a potential target for therapeutic intervention. This complex system is activated by the lipid-derived mediators anandamide and 2-arachidonoyl-sn-glycerol (2-AG), which mainly engage the cannabinoid receptor subtypes 1 (CB1) and 2 (CB2). The biological actions of anandamide and 2-AG are terminated by internalization and intracellular enzymatic hydrolysis catalyzed primarily by the serine hydrolases fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL), respectively. Here, we provide an overview of ECS and discuss the implications for advancing pharmacological tools that interfere with such a system as next-generation therapeutics. This review contains 4 figures, 3 tables and 41 references Keywords: Endocannabinoid; anandamide; 2-Arachidonoyl-sn-glycerol; fatty acid amide hydrolase; monoacylglycerol lipase; cannabinoid receptors; N-acylethanolamine acid amidase; Δ9-tetrahydrocannabinol.

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Cancer Initiation, Progression and Resistance: Are Phytocannabinoids from Cannabis sativa L. Promising Compounds?

Molecules ◽

10.3390/molecules26092668 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2668

Author(s):

Ersilia Nigro ◽

Marialuisa Formato ◽

Giuseppina Crescente ◽

Aurora Daniele

Keyword(s):

Molecular Mechanisms ◽

Cannabinoid Receptors ◽

Cannabis Sativa ◽

Current Knowledge ◽

Endocannabinoid System ◽

Peripheral Tissues ◽

Positive Effects ◽

Cancer Initiation

Cannabis sativa L. is a source of over 150 active compounds known as phytocannabinoids that are receiving renewed interest due to their diverse pharmacologic activities. Indeed, phytocannabinoids mimic the endogenous bioactive endocannabinoids effects through activation of CB1 and CB2 receptors widely described in the central nervous system and peripheral tissues. All phytocannabinoids have been studied for their protective actions towards different biological mechanisms, including inflammation, immune response, oxidative stress that, altogether, result in an inhibitory activity against the carcinogenesis. The role of the endocannabinoid system is not yet completely clear in cancer, but several studies indicate that cannabinoid receptors and endogenous ligands are overexpressed in different tumor tissues. Recently, in vitro and in vivo evidence support the effectiveness of phytocannabinoids against various cancer types, in terms of proliferation, metastasis, and angiogenesis, actions partially due to their ability to regulate signaling pathways critical for cell growth and survival. The aim of this review was to report the current knowledge about the action of phytocannabinoids from Cannabis sativa L. against cancer initiation and progression with a specific regard to brain, breast, colorectal, and lung cancer as well as their possible use in the therapies. We will also report the known molecular mechanisms responsible for such positive effects. Finally, we will describe the actual therapeutic options for Cannabis sativa L. and the ongoing clinical trials.

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

Russian Medical Inquiry ◽

10.32364/2587-6821-2020-4-6-382-389 ◽

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.

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Innovative Therapeutic Potential of Cannabinoid Receptors as Targets in Alzheimer’s Disease and Less Well-Known Diseases

Current Medicinal Chemistry ◽

10.2174/0929867325666180226095132 ◽

2019 ◽

Vol 26 (18) ◽

pp. 3300-3340 ◽

Cited By ~ 5

Author(s):

Juan A. Páez ◽

Nuria E. Campillo

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cannabinoid Receptors ◽

Cannabinoid Receptor ◽

Therapeutic Potential ◽

Current Knowledge ◽

Endocrine System ◽

Endocannabinoid System ◽

Energy Regulation ◽

Endogenous Ligands

: The discovery of cannabinoid receptors at the beginning of the 1990s, CB1 cloned in 1990 and CB2 cloned in 1993, and the availability of selective and potent cannabimimetics could only be justified by the existence of endogenous ligands that are capable of binding to them. Thus, the characterisation and cloning of the first cannabinoid receptor (CB1) led to the isolation and characterisation of the first endocannabinoid, arachidonoylethanolamide (AEA), two years later and the subsequent identification of a family of lipid transmitters known as the fatty acid ester 2-arachidonoylglycerol (2-AG). : The endogenous cannabinoid system is a complex signalling system that comprises transmembrane endocannabinoid receptors, their endogenous ligands (the endocannabinoids), the specific uptake mechanisms and the enzymatic systems related to their biosynthesis and degradation. : The endocannabinoid system has been implicated in a wide diversity of biological processes, in both the central and peripheral nervous systems, including memory, learning, neuronal development, stress and emotions, food intake, energy regulation, peripheral metabolism, and the regulation of hormonal balance through the endocrine system. : In this context, this article will review the current knowledge of the therapeutic potential of cannabinoid receptor as a target in Alzheimer’s disease and other less well-known diseases that include, among others, multiple sclerosis, bone metabolism, and Fragile X syndrome. : The therapeutic applications will be addressed through the study of cannabinoid agonists acting as single drugs and multi-target drugs highlighting the CB2 receptor agonist.

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Different Dietary n-3 Polyunsaturated Fatty Acid Formulations Distinctively Modify Fatty Acid and N-Acylethanolamine Profiles in Rat Brain

Current Developments in Nutrition ◽

10.1093/cdn/nzab037_059 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 349-349

Author(s):

Elisabetta Murru ◽

Gianfranca Carta ◽

Armita Abolghasemi ◽

Claudia Manca ◽

José AM Prates ◽

...

Keyword(s):

Fatty Acid ◽

Soybean Oil ◽

Cannabinoid Receptors ◽

Partial Agonist ◽

Linseed Oil ◽

Endocannabinoid System ◽

Funding Sources ◽

Epa And Dha ◽

The Central Nervous System ◽

The Brain

Abstract Objectives Dietary n-3 polyunsaturated fatty acids (n-3PUFA) may influence the brain fatty acid (FA) profile and, thereby, the biosynthesis of FA bioactive metabolite, such as N-acylethanolamines (NAE). We investigated the influence of different dietary formulation of n-3PUFA from vegetable or marine oils on rat FA incorporation and modulation of NAE biosynthesis. Methods Rats were fed for 10 weeks with diets containing 12% of fat from milk + 4% soybean oil and 4% of oils with different n-3 PUFA species: soybean oil as control (MilkFat), linseed oil with α-linolenic (ALA) (LSO), Buglossoides arvensis oil with ALA and stearidonic (SDA) (Buglos), fish oil with EPA and DHA (FO), Nannochloropsis microalga oil with EPA (Nanno) or Schizochytrium microalga oil with DHA (Schy). Brain FA and NAE profile were assessed LC-DAD-MS/MS. Statistical Kruskal-Wallis test followed by Dunn's correction was applied. Results Different dietary n-3PUFA formulations induced FA change in the brain, compared to MilkFat group, DHA levels remained unchanged despite its elevated intake with FO and Schy diets. However, we found 9 fold (P < 0.001) increase of EPA with FO, arachidonic (AA) decreased significantly about 16% (P < 0.05) with LSO and FO diets. n-6 PUFA docosatetraenoic (DTA) (26% P < 0.05) and docosapentaenoic (DPA) (73% P < 0.05) were reduced with FO, probably due to a competition with EPA in the incorporation into phospholipids. We observed a 44% (P < 0.05) significant decrease of N-arachidonoylethanolamine (AEA) with LSO and FO, and a reduction of N-linoleoylethanolamine (LEA) by 49% (P < 0.05) with LSO. On the other hand, we found an increase of N-eicosapentanoylethanolamine (EPEA), derived from EPA, by 225% (P < 0.05) with FO, compared to MilkFat group. Conclusions Our data indicate that reduction of AEA levels might attenuate its effects on the CB1 cannabinoid receptors, the main molecular target of the endogenous partial agonist AEA, which regulate physiological processes in the central nervous system. Therefore, in those pathophysiological conditions where is desirable to downregulate an overactive endocannabinoid system, a mixture of EPA and DHA as in FO, and ALA as in LSO, may potentially be a preferred nutritional source of n-3 PUFA. Funding Sources University of Cagliari (FIR 2019) and Fundação FCT (Portugal).

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Specific shifts in the endocannabinoid system in hibernating brown bears

10.21203/rs.3.rs-30282/v2 ◽

2020 ◽

Author(s):

Christian Boyer ◽

Laura Cussonneau ◽

Charlotte Brun ◽

Christiane Deval ◽

Jean-Paul Pais de Barros ◽

...

Keyword(s):

Fatty Acid ◽

Cannabinoid Receptors ◽

External Disturbance ◽

Mrna Level ◽

Endocannabinoid System ◽

Fold Increase ◽

Physiological Adaptation ◽

Acid Oxidation ◽

Brown Bears ◽

Peripheral Tissues

Abstract In small hibernators, global downregulation of the endocannabinoid system (ECS), which is involved in modulating neuronal signaling, feeding behavior, energy metabolism, and circannual rhythms, has been reported to possibly drive physiological adaptation to the hibernating state. In hibernating brown bears (Ursus arctos), we hypothesized that beyond an overall suppression of the ECS, seasonal shift in endocannabinoids compounds could be linked to bear’s peculiar features that include hibernation without arousal episodes and capacity to react to external disturbance. We explored circulating lipids in serum and the ECS in plasma and metabolically active tissues in free-ranging subadult Scandinavian brown bears when both active and hibernating. In winter bear serum, in addition to a 2-fold increase in total fatty acid concentration, we found significant changes in relative proportions of circulating fatty acids, such as a 2-fold increase in docosahexaenoic acid C22:6 n-3 and a decrease in arachidonic acid C20:4 n-6. In adipose and muscle tissues of hibernating bears, we found significant lower concentrations of 2-arachidonoylglycerol (2-AG), a major ligand of cannabinoid receptors 1 (CB1) and 2 (CB2). Lower mRNA level for genes encoding CB1 and CB2 were also found in winter muscle and adipose tissue, respectively. The observed reduction in ECS tone may promote fatty acid mobilization from body fat stores, and favor carbohydrate metabolism in skeletal muscle of hibernating bears. Additionally, high circulating level of the endocannabinoid-like compound N-oleoylethanolamide (OEA) in winter could favor lipolysis and fatty acid oxidation in peripheral tissues. We also speculated on a role of OEA in the conservation of an anorexigenic signal and in the maintenance of torpor during hibernation, while sustaining the capacity of bears to sense stimuli from the environment.

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Specific shifts in the endocannabinoid system in hibernating brown bears

Frontiers in Zoology ◽

10.1186/s12983-020-00380-y ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Christian Boyer ◽

Laura Cussonneau ◽

Charlotte Brun ◽

Christiane Deval ◽

Jean-Paul Pais de Barros ◽

...

Keyword(s):

Fatty Acid ◽

Cannabinoid Receptors ◽

External Disturbance ◽

Mrna Level ◽

Endocannabinoid System ◽

Fold Increase ◽

Physiological Adaptation ◽

Acid Oxidation ◽

Brown Bears ◽

Peripheral Tissues

AbstractIn small hibernators, global downregulation of the endocannabinoid system (ECS), which is involved in modulating neuronal signaling, feeding behavior, energy metabolism, and circannual rhythms, has been reported to possibly drive physiological adaptation to the hibernating state. In hibernating brown bears (Ursus arctos), we hypothesized that beyond an overall suppression of the ECS, seasonal shift in endocannabinoids compounds could be linked to bear’s peculiar features that include hibernation without arousal episodes and capacity to react to external disturbance. We explored circulating lipids in serum and the ECS in plasma and metabolically active tissues in free-ranging subadult Scandinavian brown bears when both active and hibernating. In winter bear serum, in addition to a 2-fold increase in total fatty acid concentration, we found significant changes in relative proportions of circulating fatty acids, such as a 2-fold increase in docosahexaenoic acid C22:6 n-3 and a decrease in arachidonic acid C20:4 n-6. In adipose and muscle tissues of hibernating bears, we found significant lower concentrations of 2-arachidonoylglycerol (2-AG), a major ligand of cannabinoid receptors 1 (CB1) and 2 (CB2). Lower mRNA level for genes encoding CB1 and CB2 were also found in winter muscle and adipose tissue, respectively. The observed reduction in ECS tone may promote fatty acid mobilization from body fat stores, and favor carbohydrate metabolism in skeletal muscle of hibernating bears. Additionally, high circulating level of the endocannabinoid-like compound N-oleoylethanolamide (OEA) in winter could favor lipolysis and fatty acid oxidation in peripheral tissues. We also speculated on a role of OEA in the conservation of an anorexigenic signal and in the maintenance of torpor during hibernation, while sustaining the capacity of bears to sense stimuli from the environment.

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Endocannabinoid System Dysregulation from Acetaminophen Use May Lead to Autism Spectrum Disorder: Could Cannabinoid Treatment Be Efficacious?

Molecules ◽

10.3390/molecules26071845 ◽

2021 ◽

Vol 26 (7) ◽

pp. 1845

Author(s):

Stephen Schultz ◽

Georgianna G. Gould ◽

Nicola Antonucci ◽

Anna Lisa Brigida ◽

Dario Siniscalco

Keyword(s):

Autism Spectrum Disorder ◽

Cannabinoid Receptors ◽

Current Knowledge ◽

Endocannabinoid System ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Blood Levels ◽

Increased Risk ◽

Patterns Of Behavior ◽

Arachidonoyl Glycerol

Persistent deficits in social communication and interaction, and restricted, repetitive patterns of behavior, interests or activities, are the core items characterizing autism spectrum disorder (ASD). Strong inflammation states have been reported to be associated with ASD. The endocannabinoid system (ECS) may be involved in ASD pathophysiology. This complex network of lipid signaling pathways comprises arachidonic acid and 2-arachidonoyl glycerol-derived compounds, their G-protein-coupled receptors (cannabinoid receptors CB1 and CB2) and the associated enzymes. Alterations of the ECS have been reported in both the brain and the immune system of ASD subjects. ASD children show low EC tone as indicated by low blood levels of endocannabinoids. Acetaminophen use has been reported to be associated with an increased risk of ASD. This drug can act through the ECS to produce analgesia. It may be that acetaminophen use in children increases the risk for ASD by interfering with the ECS.This mini-review article summarizes the current knowledge on this topic.

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Therapeutic Attributes of Endocannabinoid System against Neuro-Inflammatory Autoimmune Disorders

Molecules ◽

10.3390/molecules26113389 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3389

Author(s):

Ishtiaq Ahmed ◽

Saif Ur Rehman ◽

Shiva Shahmohamadnejad ◽

Muhammad Anjum Zia ◽

Muhammad Ahmad ◽

...

Keyword(s):

Cannabinoid Receptors ◽

Cannabinoid Receptor ◽

Therapeutic Potential ◽

Endocannabinoid System ◽

Cell Types ◽

Autoimmune Disorders ◽

Specific Receptors ◽

Different Cell Types

In humans, various sites like cannabinoid receptors (CBR) having a binding affinity with cannabinoids are distributed on the surface of different cell types, where endocannabinoids (ECs) and derivatives of fatty acid can bind. The binding of these substance(s) triggers the activation of specific receptors required for various physiological functions, including pain sensation, memory, and appetite. The ECs and CBR perform multiple functions via the cannabinoid receptor 1 (CB1); cannabinoid receptor 2 (CB2), having a key effect in restraining neurotransmitters and the arrangement of cytokines. The role of cannabinoids in the immune system is illustrated because of their immunosuppressive characteristics. These characteristics include inhibition of leucocyte proliferation, T cells apoptosis, and induction of macrophages along with reduced pro-inflammatory cytokines secretion. The review seeks to discuss the functional relationship between the endocannabinoid system (ECS) and anti-tumor characteristics of cannabinoids in various cancers. The therapeutic potential of cannabinoids for cancer—both in vivo and in vitro clinical trials—has also been highlighted and reported to be effective in mice models in arthritis for the inflammation reduction, neuropathic pain, positive effect in multiple sclerosis and type-1 diabetes mellitus, and found beneficial for treating in various cancers. In human models, such studies are limited; thereby, further research is indispensable in this field to get a conclusive outcome. Therefore, in autoimmune disorders, therapeutic cannabinoids can serve as promising immunosuppressive and anti-fibrotic agents.

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