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Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 3.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 63811

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Dr. Rosaria Meccariello

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Department of Movement and Wellness Sciences, Parthenope University of Naples, Via Medina 40, I-80133 Naples, Italy
Interests: endocannabinoid system; endocannabinoids–GnRH–steroids crosstalk; kisspeptins; reproduction; HPG axis; spermatogenesis; spermatozoa; endocrine disruptors; epigenetics
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Dear Colleagues,

The discovery of the endocannabinoid system (ECS), comprising cannabinoid receptors, their endogenous ligands (endocannabinoids), and synthetic and metabolizing enzymes, triggered a large number of studies in cell lines, animal models, and humans. The ECS modulates many physiological and pathological processes, both in the peripheral and central nervous systems and in peripheral organs. This signaling system has a recognized activity on nervous system development, synaptic plasticity, learning and memory, neuroinflammation, pain and neurodegeneration, stress responsivity, mood and behavior, food intake and metabolism, reproduction, fertility and pregnancy, immune response, cardiac functions, cancer progression, and so much more. As a consequence, the modulation of ECS signaling has potential therapeutic application for a broad range of diseases, including neurodegenerative, reproductive, cardiovascular, and inflammatory disorders, metabolic syndrome and obesity, and cancer. However, despite experimental evidence, the molecular and epigenetic regulatory mechanisms of ECS activity remain to be fully elucidated, hence the need to fill this gap in order to devise clinically successful treatment strategies.

This Special Issue aims at expanding the current knowledge on the ECS in both physiological and pathological conditions and on its possible therapeutic exploitation. Experimental studies in in vitro and in vivo models, review articles, and clinical studies are all welcome for consideration.

Dr. Rosaria Meccariello
Guest Editor

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Keywords

Endocannabinoids
Endocannabinoid system
Synaptic plasticity
Neurological diseases
Energy balance, food intake, and metabolic disorders
Reproduction, fertility, and pregnancy
Immune response
Cardiac functions
Stress
Pain
Cancer progression

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Published Papers (12 papers)

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Research

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12 pages, 1226 KiB

Open AccessArticle

Anticonvulsive Effects and Pharmacokinetic Profile of Cannabidiol (CBD) in the Pentylenetetrazol (PTZ) or N-Methyl-D-Aspartate (NMDA) Models of Seizures in Infantile Rats

by Libor Uttl, Tomáš Hložek, Pavel Mareš, Tomáš Páleníček and Hana Kubová

Int. J. Mol. Sci. 2022, 23(1), 94; https://doi.org/10.3390/ijms23010094 - 22 Dec 2021

Cited by 9 | Viewed by 3951

Abstract

In spite of use of cannabidiol (CBD), a non-psychoactive cannabinoid, in pediatric patients with epilepsy, preclinical studies on its effects in immature animals are very limited. In the present study we investigated anti-seizure activity of CBD (10 and 60 mg/kg administered intraperitoneally) in two models of chemically induced seizures in infantile (12-days old) rats. Seizures were induced either with pentylenetetrazol (PTZ) or N-methyl-D-aspartate (NMDA). In parallel, brain and plasma levels of CBD and possible motor adverse effects were assessed in the righting reflex and the bar holding tests. CBD was ineffective against NMDA-induced seizures, but in a dose 60 mg/kg abolished the tonic phase of PTZ-induced generalized seizures. Plasma and brain levels of CBD were determined up to 24 h after administration. Peak CBD levels in the brain (996 ± 128 and 5689 ± 150 ng/g after the 10- and 60-mg/kg doses, respectively) were reached 1–2 h after administration and were still detectable 24 h later (120 ± 12 and 904 ± 63 ng/g, respectively). None of the doses negatively affected motor performance within 1 h after administration, but CBD in both doses blocked improvement in the bar holding test with repeated exposure to this task. Taken together, anti-seizure activity of CBD in infantile animals is dose and model dependent, and at therapeutic doses CBD does not cause motor impairment. The potential risk of CBD for motor learning seen in repeated motor tests has to be further examined. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 3.0)

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18 pages, 3280 KiB

Open AccessArticle

Development of [¹⁸F]LU14 for PET Imaging of Cannabinoid Receptor Type 2 in the Brain

by Rodrigo Teodoro, Daniel Gündel, Winnie Deuther-Conrad, Lea Ueberham, Magali Toussaint, Guy Bormans, Peter Brust and Rareş-Petru Moldovan

Int. J. Mol. Sci. 2021, 22(15), 8051; https://doi.org/10.3390/ijms22158051 - 28 Jul 2021

Cited by 10 | Viewed by 2539

Abstract

Cannabinoid receptors type 2 (CB2R) represent an attractive therapeutic target for neurodegenerative diseases and cancer. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor receptor density and/or occupancy during a CB2R-tailored therapy, we herein describe the radiosynthesis of cis-[¹⁸F]1-(4-fluorobutyl-N-((1s,4s)-4-methylcyclohexyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide ([¹⁸F]LU14) starting from the corresponding mesylate precursor. The first biological evaluation revealed that [¹⁸F]LU14 is a highly affine CB2R radioligand with >80% intact tracer in the brain at 30 min p.i. Its further evaluation by PET in a well-established rat model of CB2R overexpression demonstrated its ability to selectively image the CB2R in the brain and its potential as a tracer to further investigate disease-related changes in CB2R expression. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 3.0)

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18 pages, 1335 KiB

Open AccessArticle

Influence of Cannabinoid Receptor 1 Genetic Variants on the Subjective Effects of Smoked Cannabis

by Thomas Murphy, Justin Matheson, Robert E. Mann, Bruna Brands, Christine M. Wickens, Arun K. Tiwari, Clement C. Zai, James Kennedy and Bernard Le Foll

Int. J. Mol. Sci. 2021, 22(14), 7388; https://doi.org/10.3390/ijms22147388 - 9 Jul 2021

Cited by 6 | Viewed by 4142

Abstract

As many jurisdictions consider relaxing cannabis legislation and usage is increasing in North America and other parts of the world, there is a need to explore the possible genetic differences underlying the subjective effects of cannabis. This pilot study investigated specific genetic variations within the cannabinoid receptor 1 (CNR1) gene for association with the subjective effects of smoked cannabis. Data were obtained from a double-blinded, placebo-controlled clinical trial studying the impact of cannabis intoxication on driving performance. Participants randomized to the active cannabis group who consented to secondary genetic analysis (n = 52) were genotyped at the CNR1 rs1049353 and rs2023239 polymorphic areas. Maximum value and area under the curve (AUC) analyses were performed on subjective measures data. Analysis of subjective effects by genotype uncovered a global trend towards greater subjective effects for rs1049353 T-allele- and rs2023239 C-allele-carrying subjects. However, significant differences attributed to allelic identity were only documented for a subset of subjective effects. Our findings suggest that rs1049353 and rs2023239 minor allele carriers experience augmented subjective effects during acute cannabis intoxication. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 3.0)

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16 pages, 5736 KiB

Open AccessArticle

Lack of Cannabinoid Receptor Type-1 Leads to Enhanced Age-Related Neuronal Loss in the Locus Coeruleus

by Alessandra Gargano, Eva Beins, Andreas Zimmer and Andras Bilkei-Gorzo

Int. J. Mol. Sci. 2021, 22(1), 5; https://doi.org/10.3390/ijms22010005 - 22 Dec 2020

Cited by 4 | Viewed by 3419

Abstract

Our laboratory and others have previously shown that cannabinoid receptor type-1 (CB1r) activity is neuroprotective and a modulator of brain ageing; a genetic disruption of CB1r signaling accelerates brain ageing, whereas the pharmacological stimulation of CB1r activity had the opposite effect. In this study, we have investigated if the lack of CB1r affects noradrenergic neurons in the locus coeruleus (LC), which are vulnerable to age-related changes; their numbers are reduced in patients with neurodegenerative diseases and probably also in healthy aged individuals. Thus, we compared LC neuronal numbers between cannabinoid 1 receptor knockout (Cnr1^−/−) mice and their wild-type littermates. Our results reveal that old Cnr1^−/− mice have less noradrenergic neurons compared to their age-matched wild-type controls. This result was also confirmed by the analysis of the density of noradrenergic terminals which proved that Cnr1^−/− mice had less compared to the wild-type controls. Additionally, we assessed pro-inflammatory glial activity in the LC. Although the density of microglia in Cnr1^−/− mice was enhanced, they did not show enhanced inflammatory profile. We hypothesize that CB1r activity is necessary for the protection of noradrenergic neurons, but its anti-inflammatory effect probably only plays a minor role in it. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 3.0)

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Review

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20 pages, 1253 KiB

Open AccessReview

The Endocannabinoid System in Glial Cells and Their Profitable Interactions to Treat Epilepsy: Evidence from Animal Models

by Jon Egaña-Huguet, Edgar Soria-Gómez and Pedro Grandes

Int. J. Mol. Sci. 2021, 22(24), 13231; https://doi.org/10.3390/ijms222413231 - 8 Dec 2021

Cited by 7 | Viewed by 4115

Abstract

Epilepsy is one of the most common neurological conditions. Yearly, five million people are diagnosed with epileptic-related disorders. The neuroprotective and therapeutic effect of (endo)cannabinoid compounds has been extensively investigated in several models of epilepsy. Therefore, the study of specific cell-type-dependent mechanisms underlying cannabinoid effects is crucial to understanding epileptic disorders. It is estimated that about 100 billion neurons and a roughly equal number of glial cells co-exist in the human brain. The glial population is in charge of neuronal viability, and therefore, their participation in brain pathophysiology is crucial. Furthermore, glial malfunctioning occurs in a wide range of neurological disorders. However, little is known about the impact of the endocannabinoid system (ECS) regulation over glial cells, even less in pathological conditions such as epilepsy. In this review, we aim to compile the existing knowledge on the role of the ECS in different cell types, with a particular emphasis on glial cells and their impact on epilepsy. Thus, we propose that glial cells could be a novel target for cannabinoid agents for treating the etiology of epilepsy and managing seizure-like disorders. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 3.0)

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13 pages, 651 KiB

Open AccessReview

The CB₂ Receptor as a Novel Therapeutic Target for Epilepsy Treatment

by Xiaoyu Ji, Yang Zeng and Jie Wu

Int. J. Mol. Sci. 2021, 22(16), 8961; https://doi.org/10.3390/ijms22168961 - 20 Aug 2021

Cited by 16 | Viewed by 4824

Abstract

Epilepsy is characterized by repeated spontaneous bursts of neuronal hyperactivity and high synchronization in the central nervous system. It seriously affects the quality of life of epileptic patients, and nearly 30% of individuals are refractory to treatment of antiseizure drugs. Therefore, there is an urgent need to develop new drugs to manage and control refractory epilepsy. Cannabinoid ligands, including selective cannabinoid receptor subtype (CB₁ or CB₂ receptor) ligands and non-selective cannabinoid (synthetic and endogenous) ligands, may serve as novel candidates for this need. Cannabinoid appears to regulate seizure activity in the brain through the activation of CB₁ and CB₂ cannabinoid receptors (CB₁R and CB₂R). An abundant series of cannabinoid analogues have been tested in various animal models, including the rat pilocarpine model of acquired epilepsy, a pentylenetetrazol model of myoclonic seizures in mice, and a penicillin-induced model of epileptiform activity in the rats. The accumulating lines of evidence show that cannabinoid ligands exhibit significant benefits to control seizure activity in different epileptic models. In this review, we summarize the relationship between brain CB₂ receptors and seizures and emphasize the potential mechanisms of their therapeutic effects involving the influences of neurons, astrocytes, and microglia cells. The unique features of CB₂Rs, such as lower expression levels under physiological conditions and high inducibility under epileptic conditions, make it an important target for future research on drug-resistant epilepsy. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 3.0)

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14 pages, 3440 KiB

Open AccessReview

Cannabinoid Receptors in Myocardial Injury: A Brother Born to Rival

by Xinru Tang, Zheng Liu, Xiaoqing Li, Jing Wang and Liliang Li

Int. J. Mol. Sci. 2021, 22(13), 6886; https://doi.org/10.3390/ijms22136886 - 26 Jun 2021

Cited by 14 | Viewed by 2699

Abstract

Cannabinoid receptors typically include type 1 (CB1) and type 2 (CB2), and they have attracted extensive attention in the central nervous system (CNS) and immune system. Due to more in-depth studies in recent years, it has been found that the typical CB1 and CB2 receptors confer functional importance far beyond the CNS and immune system. In particular, many works have reported the critical involvement of the CB1 and CB2 receptors in myocardial injuries. Both pharmacological and genetic approaches have been used for studying CB1 and CB2 functions in these studies, revealing that the brother receptors have many basic differences and sometimes antagonistic functions in a variety of myocardial injuries, despite some sequence or location identity they share. Herein, we introduce the general differences of CB1 and CB2 cannabinoid receptors, and summarize the functional rivalries between the two brother receptors in the setting of myocardial injuries. We point out the importance of individual receptor-based modulation, instead of dual receptor modulators, when treating myocardial injuries. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 3.0)

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28 pages, 1060 KiB

Open AccessReview

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

by Ana Lago-Fernandez, Sara Zarzo-Arias, Nadine Jagerovic and Paula Morales

Int. J. Mol. Sci. 2021, 22(3), 1001; https://doi.org/10.3390/ijms22031001 - 20 Jan 2021

Cited by 29 | Viewed by 4553

Abstract

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. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 3.0)

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31 pages, 2247 KiB

Open AccessReview

Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment

by Anna Stasiłowicz, Anna Tomala, Irma Podolak and Judyta Cielecka-Piontek

Int. J. Mol. Sci. 2021, 22(2), 778; https://doi.org/10.3390/ijms22020778 - 14 Jan 2021

Cited by 63 | Viewed by 13380

Abstract

Cannabis sativa L. turned out to be a valuable source of chemical compounds of various structures, showing pharmacological activity. The most important groups of compounds include phytocannabinoids and terpenes. The pharmacological activity of Cannabis (in epilepsy, sclerosis multiplex (SM), vomiting and nausea, pain, appetite loss, inflammatory bowel diseases (IBDs), Parkinson’s disease, Tourette’s syndrome, schizophrenia, glaucoma, and coronavirus disease 2019 (COVID-19)), which has been proven so far, results from the affinity of these compounds predominantly for the receptors of the endocannabinoid system (the cannabinoid receptor type 1 (CB₁), type two (CB₂), and the G protein-coupled receptor 55 (GPR₅₅)) but, also, for peroxisome proliferator-activated receptor (PPAR), glycine receptors, serotonin receptors (5-HT), transient receptor potential channels (TRP), and GPR, opioid receptors. The synergism of action of phytochemicals present in Cannabis sp. raw material is also expressed in their increased bioavailability and penetration through the blood–brain barrier. This review provides an overview of phytochemistry and pharmacology of compounds present in Cannabis extracts in the context of the current knowledge about their synergistic actions and the implications of clinical use in the treatment of selected diseases. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 3.0)

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16 pages, 1564 KiB

Open AccessReview

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

by Mariangela Pucci, Elizabeta Zaplatic, Maria Vittoria Micioni Di Bonaventura, Emanuela Micioni Di Bonaventura, Paolo De Cristofaro, Mauro Maccarrone, Carlo Cifani and Claudio D’Addario

Int. J. Mol. Sci. 2021, 22(1), 398; https://doi.org/10.3390/ijms22010398 - 1 Jan 2021

Cited by 16 | Viewed by 4525

Abstract

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. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 3.0)

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27 pages, 1397 KiB

Open AccessReview

CB2 Receptor in Microglia: The Guardian of Self-Control

by Joanna Agnieszka Komorowska-Müller and Anne-Caroline Schmöle

Int. J. Mol. Sci. 2021, 22(1), 19; https://doi.org/10.3390/ijms22010019 - 22 Dec 2020

Cited by 93 | Viewed by 7893

Abstract

Microglia are key to maintaining the homeostasis of the brain. These immune cells of the brain can be our biggest ally in fighting infections, but can worsen pathology or hinder recovery when uncontrolled. Thus, understanding how microglia contribute to neuroinflammatory processes and how their activity can be controlled is of great importance. It is known that activation of endocannabinoid system, and especially the cannabinoid type 2 receptor (CB2R), decreases inflammation. Alongside its non-psychoactive effect, it makes the CB2R receptor a perfect target for treating diseases accompanied by neuroinflammation including neurodegenerative diseases. However, the exact mechanisms by which CB2R regulates microglial activity are not yet understood. Here, we review the current knowledge on the roles of microglial CB2R from in vitro and in vivo studies. We look into CB2R function under physiological and pathological conditions and focus on four different disease models representing chronic and acute inflammation. We highlight open questions and controversies and provide an update on the latest discoveries that were enabled by the development of novel technologies. Also, we discuss the recent findings on the role of microglia CB2R in cognition and its role in neuron–microglia communication. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 3.0)

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25 pages, 702 KiB

Open AccessReview

The Immune Endocannabinoid System of the Tumor Microenvironment

by Melanie Kienzl, Julia Kargl and Rudolf Schicho

Int. J. Mol. Sci. 2020, 21(23), 8929; https://doi.org/10.3390/ijms21238929 - 25 Nov 2020

Cited by 28 | Viewed by 6055

Abstract

Leukocytes are part of the tumor microenvironment (TME) and are critical determinants of tumor progression. Because of the immunoregulatory properties of cannabinoids, the endocannabinoid system (ECS) may have an important role in shaping the TME. Members of the ECS, an entity that consists of cannabinoid receptors, endocannabinoids and their synthesizing/degrading enzymes, have been associated with both tumor growth and rejection. Immune cells express cannabinoid receptors and produce endocannabinoids, thereby forming an “immune endocannabinoid system”. Although in vitro effects of exogenous cannabinoids on immune cells are well described, the role of the ECS in the TME, and hence in tumor development and immunotherapy, is still elusive. This review/opinion discusses the possibility that the “immune endocannabinoid system” can fundamentally influence tumor progression. The widespread influence of cannabinoids on immune cell functions makes the members of the ECS an interesting target that could support immunotherapy. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 3.0)

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