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Biomolecules
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The Endocannabinoid System in Health and Disease
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The Endocannabinoid System in Health and Disease

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Natural and Bio-derived Molecules".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 94822

Special Issue Editors

Dr. Andres Ozaita

E-Mail Website
Guest Editor
Experimental and Health Sciences, University Pompeu Fabra, Barcelona, Spain
Interests: endocannabinoid system; cannabinoid receptor; intellectual disability; intracellular signaling; neurogenesis; cognition; structural plasticity
Dr. Patricia Robledo

E-Mail Website
Guest Editor
Integrative Pharmacology and Systems Neuroscience, IMIM-Hospital del Mar Research Institute, Barcelona, Spain
Interests: endocannabinoid system; serotonin system; animal models of mental disorders; novel biomarkers of psychopathology; olfactory neuroepithelium; schizophrenia; first episode psychosis; cognition

Special Issue Information

Dear Colleagues,

The endocannabinoid system is a relevant homeostatic system in the organism. It was discovered almost 30 years ago while searching for distinct targets of Cannabis sativa plant derivatives. Since then, it has emerged as a crucial neuromodulatory system with specific receptors and endogenous mediators widely distributed at peripheral and central levels during life. In the last decades, researchers have interrogated the interaction of cannabinoid compounds with many physiological systems to understand their therapeutic and recreational effects. In addition, the role of the endocannabinoid system in pathological conditions has also driven important efforts in the search for novel appropriate medicinal targets.

This Special Issue aims to emphasize the diversity of areas in biomedical research where the endocannabinoid system may play important roles from the point of view of pathophysiology and as a promising target for therapeutic intervention. This may include nociception/pain perception, reward system/addiction, metabolism/obesity, epilepsy, cancer, multiple sclerosis, chronic inflammation, psychiatric illnesses, cognitive deregulation, aging, neurodegeneration, and ischemia. We encourage all researchers interested in this topic to present research articles or reviews on these different aspects of the endocannabinoid system. This Special Issue can include state-of-the-art reviews on disorders involving the endocannabinoid system, either from a pathophysiological or from a therapeutic perspective.

Dr. Andres Ozaita
Dr. Patricia Robledo
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Endocannabinoid system
  • Cannabis compounds
  • Pain
  • Addiction
  • Obesity
  • Epilepsy
  • Cancer
  • Multiple sclerosis
  • Inflammation
  • Psychiatric
  • illnesses
  • Cognition
  • Aging
  • Neurodegeneration
  • Ischemia

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Published Papers (7 papers)

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Research

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19 pages, 2418 KiB  
Article
Gene Expression Analysis of Astrocyte and Microglia Endocannabinoid Signaling during Autoimmune Demyelination
by Álvaro Moreno-García, Ana Bernal-Chico, Teresa Colomer, Alfredo Rodríguez-Antigüedad, Carlos Matute and Susana Mato
Biomolecules 2020, 10(9), 1228; https://doi.org/10.3390/biom10091228 - 24 Aug 2020
Cited by 30 | Viewed by 4890
Abstract
The endocannabinoid system is associated with protective effects in multiple sclerosis (MS) that involve attenuated innate immune cell responses. Astrocytes and microglia are modulated by endocannabinoids and participate in the biosynthesis and metabolism of these compounds. However, the role of neuroglial cells as [...] Read more.
The endocannabinoid system is associated with protective effects in multiple sclerosis (MS) that involve attenuated innate immune cell responses. Astrocytes and microglia are modulated by endocannabinoids and participate in the biosynthesis and metabolism of these compounds. However, the role of neuroglial cells as targets and mediators of endocannabinoid signaling in MS is poorly understood. Here we used a microfluidic RT-qPCR screen to assess changes in the expression of the main endocannabinoid signaling genes in astrocytes and microglia purified from female mice during the time-course of experimental autoimmune encephalomyelitis (EAE). We show that astrocytes and microglia upregulate the expression of genes encoding neurotoxic A1 and pro-inflammatory molecules at the acute disease with many of these transcripts remaining elevated during the recovery phase. Both cell populations exhibited an early onset decrease in the gene expression levels of 2-arachidonoylglycerol (2-AG) hydrolytic enzymes that persisted during EAE progression as well as cell-type-specific changes in the transcript levels for genes encoding cannabinoid receptors and molecules involved in anandamide (AEA) signaling. Our results demonstrate that astrocytes and microglia responses to autoimmune demyelination involve alterations in the expression of multiple endocannabinoid signaling-associated genes and suggest that this system may regulate the induction of neurotoxic and pro-inflammatory transcriptional programs in both cell types during MS. Full article
(This article belongs to the Special Issue The Endocannabinoid System in Health and Disease)
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15 pages, 2075 KiB  
Article
CB2 Receptors and Neuron–Glia Interactions Modulate Neurotoxicity Generated by MAGL Inhibition
by Estefania Rojo-Bustamante, Ignacio Íñigo-Marco, Miguel Angel Abellanas, Rodrigo Vinueza-Gavilanes, Ana Baltanás, Esther Luquin, Montserrat Arrasate and Maria S. Aymerich
Biomolecules 2020, 10(8), 1198; https://doi.org/10.3390/biom10081198 - 18 Aug 2020
Cited by 12 | Viewed by 3640
Abstract
Monoacylglycerol lipase inhibition (MAGL) has emerged as an interesting therapeutic target for neurodegenerative disease treatment due to its ability to modulate the endocannabinoid system and to prevent the production of proinflammatory mediators. To obtain a beneficial response, it is necessary to understand how [...] Read more.
Monoacylglycerol lipase inhibition (MAGL) has emerged as an interesting therapeutic target for neurodegenerative disease treatment due to its ability to modulate the endocannabinoid system and to prevent the production of proinflammatory mediators. To obtain a beneficial response, it is necessary to understand how this inhibition affects the neuron–glia crosstalk and neuron viability. In this study, the effect of MAGL inhibition by KML29 was evaluated in two types of rat cortical primary cultures; mixed cultures, including neuron and glial cells, and neuron-enriched cultures. The risk of neuronal death was estimated by longitudinal survival analysis. The spontaneous neuronal risk of death in culture was higher in the absence of glial cells, a process that was enhanced by KML29 addition. In contrast, neuronal survival was not compromised by MAGL inhibition in the presence of glial cells. Blockade of cannabinoid type 2 (CB2) receptors expressed mainly by microglial cells did not affect the spontaneous neuronal death risk but decreased neuronal survival when KML29 was added. Modulation of cannabinoid type 1 (CB1) receptors did not affect neuronal survival. Our results show that neuron–glia interactions are essential for neuronal survival. CB2 receptors play a key role in these protective interactions when neurons are exposed to toxic conditions. Full article
(This article belongs to the Special Issue The Endocannabinoid System in Health and Disease)
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16 pages, 1693 KiB  
Article
Effects of Cannabis Use on the Protein and Lipid Profile of Olfactory Neuroepithelium Cells from Schizophrenia Patients Studied by Synchrotron-Based FTIR Spectroscopy
by Sergi Saladrigas-Manjón, Tanja Dučić, Liliana Galindo, Cristina Fernández-Avilés, Víctor Pérez, Rafael de la Torre and Patricia Robledo
Biomolecules 2020, 10(2), 329; https://doi.org/10.3390/biom10020329 - 19 Feb 2020
Cited by 7 | Viewed by 3820
Abstract
Schizophrenia (SCZ) is a neurodevelopmental disorder with a high genetic component, but the presence of environmental stressors can be important for its onset and progression. Cannabis use can be a major risk factor for developing SCZ. However, despite the available data on the [...] Read more.
Schizophrenia (SCZ) is a neurodevelopmental disorder with a high genetic component, but the presence of environmental stressors can be important for its onset and progression. Cannabis use can be a major risk factor for developing SCZ. However, despite the available data on the neurobiological underpinnings of SCZ, there is an important lack of studies in human neuronal tissue and living cells addressing the effects of cannabis in SCZ patients. In this study, we analysed the most relevant bio-macromolecular constituents in olfactory neuroepithelium (ON) cells of healthy controls non-cannabis users, healthy cannabis users, SCZ patients non-cannabis users, and SCZ patients cannabis users using Synchrotron Radiation-Fourier Transform Infrared (SR-FTIR) spectrometry and microscopy. Our results revealed that SCZ patients non-cannabis users, and healthy cannabis users exhibit similar alterations in the macromolecular profile of ON cells, including disruption in lipid composition, increased lipid membrane renewal rate and lipid peroxidation, altered proteins containing more β-sheet structures, and showed an increase in DNA and histone methylation. Notably, these alterations were not observed in SCZ patients who use cannabis regularly. These data suggest a differential effect of cannabis in healthy controls and in SCZ patients in terms of the macromolecular constituents of ON cells. Full article
(This article belongs to the Special Issue The Endocannabinoid System in Health and Disease)
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8 pages, 679 KiB  
Article
Pharmacokinetics of Sativex® in Dogs: Towards a Potential Cannabinoid-Based Therapy for Canine Disorders
by María Fernández-Trapero, Carmen Pérez-Díaz, Francisco Espejo-Porras, Eva de Lago and Javier Fernández-Ruiz
Biomolecules 2020, 10(2), 279; https://doi.org/10.3390/biom10020279 - 11 Feb 2020
Cited by 28 | Viewed by 7528
Abstract
The phytocannabinoid-based medicine Sativex® is currently marketed for the treatment of spasticity and pain in multiple sclerosis patients and is being investigated for other central and peripheral pathological conditions. It may also serve in Veterinary Medicine for the treatment of domestic animals, [...] Read more.
The phytocannabinoid-based medicine Sativex® is currently marketed for the treatment of spasticity and pain in multiple sclerosis patients and is being investigated for other central and peripheral pathological conditions. It may also serve in Veterinary Medicine for the treatment of domestic animals, in particular for dogs affected by different pathologies, including human-like pathological conditions. With the purpose of assessing different dosing paradigms for using Sativex in Veterinary Medicine, we investigated its pharmacokinetics when administered to naïve dogs via sublingual delivery. In the single dose arm of the study, adult Beagle dogs were treated with 3 consecutive sprays of Sativex, and blood samples were collected at 12 intervals up to 24 h later. In the multiple dose arm of the study, Beagle dogs received 3 sprays daily for 14 days, and blood samples were collected for 24 h post final dose. Blood was used to obtain plasma samples and to determine the levels of cannabidiol (CBD), Δ9-tetrahydrocannabinol (Δ9-THC) and its metabolite 11-hydroxy-Δ9-THC. Maximal plasma concentrations of both Δ9-THC (Cmax = 18.5 ng/mL) and CBD (Cmax = 10.5 ng/mL) were achieved 2 h after administration in the single dose condition and at 1 h in the multiple dose treatment (Δ9-THC: Cmax = 24.5 ng/mL; CBD: Cmax = 15.2 ng/mL). 11-hydroxy-Δ9-THC, which is mainly formed in the liver from Δ9-THC, was almost undetected, which is consistent with the use of sublingual delivery. A potential progressive accumulation of both CBD and Δ9-THC was detected following repeated exposure, with maximum plasma concentrations for both cannabinoids being achieved following multiple dose. Neurological status, body temperature, respiratory rate and some hemodynamic parameters were also recorded in both conditions, but in general, no changes were observed. In conclusion, this study demonstrates that single or multiple dose sublingual administration of Sativex to naïve dogs results in the expected pharmacokinetic profile, with maximal levels of phytocannabinoids detected at 1–2 h and suggested progressive accumulation after the multiple dose treatment. Full article
(This article belongs to the Special Issue The Endocannabinoid System in Health and Disease)
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Review

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22 pages, 2356 KiB  
Review
Cannabinoid Receptor Interacting Protein 1a (CRIP1a) in Health and Disease
by Emily E. Oliver, Erin K. Hughes, Meaghan K. Puckett, Rong Chen, W. Todd Lowther and Allyn C. Howlett
Biomolecules 2020, 10(12), 1609; https://doi.org/10.3390/biom10121609 - 27 Nov 2020
Cited by 18 | Viewed by 5361
Abstract
Endocannabinoid signaling depends upon the CB1 and CB2 cannabinoid receptors, their endogenous ligands anandamide and 2-arachidonoylglycerol, and intracellular proteins that mediate responses via the C-terminal and other intracellular receptor domains. The CB1 receptor regulates and is regulated by associated G [...] Read more.
Endocannabinoid signaling depends upon the CB1 and CB2 cannabinoid receptors, their endogenous ligands anandamide and 2-arachidonoylglycerol, and intracellular proteins that mediate responses via the C-terminal and other intracellular receptor domains. The CB1 receptor regulates and is regulated by associated G proteins predominantly of the Gi/o subtypes, β-arrestins 1 and 2, and the cannabinoid receptor-interacting protein 1a (CRIP1a). Evidence for a physiological role for CRIP1a is emerging as data regarding the cellular localization and function of CRIP1a are generated. Here we summarize the neuronal distribution and role of CRIP1a in endocannabinoid signaling, as well as discuss investigations linking CRIP1a to development, vision and hearing sensory systems, hippocampus and seizure regulation, and psychiatric disorders including schizophrenia. We also examine the genetic and epigenetic association of CRIP1a within a variety of cancer subtypes. This review provides evidence upon which to base future investigations on the function of CRIP1a in health and disease. Full article
(This article belongs to the Special Issue The Endocannabinoid System in Health and Disease)
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34 pages, 807 KiB  
Review
Cannabidiol: A Potential New Alternative for the Treatment of Anxiety, Depression, and Psychotic Disorders
by María S. García-Gutiérrez, Francisco Navarrete, Ani Gasparyan, Amaya Austrich-Olivares, Francisco Sala and Jorge Manzanares
Biomolecules 2020, 10(11), 1575; https://doi.org/10.3390/biom10111575 - 19 Nov 2020
Cited by 177 | Viewed by 61862
Abstract
The potential therapeutic use of some Cannabis sativa plant compounds has been attracting great interest, especially for managing neuropsychiatric disorders due to the relative lack of efficacy of the current treatments. Numerous studies have been carried out using the main phytocannabinoids, tetrahydrocannabinol (THC) [...] Read more.
The potential therapeutic use of some Cannabis sativa plant compounds has been attracting great interest, especially for managing neuropsychiatric disorders due to the relative lack of efficacy of the current treatments. Numerous studies have been carried out using the main phytocannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD). CBD displays an interesting pharmacological profile without the potential for becoming a drug of abuse, unlike THC. In this review, we focused on the anxiolytic, antidepressant, and antipsychotic effects of CBD found in animal and human studies. In rodents, results suggest that the effects of CBD depend on the dose, the strain, the administration time course (acute vs. chronic), and the route of administration. In addition, certain key targets have been related with these CBD pharmacological actions, including cannabinoid receptors (CB1r and CB2r), 5-HT1A receptor and neurogenesis factors. Preliminary clinical trials also support the efficacy of CBD as an anxiolytic, antipsychotic, and antidepressant, and more importantly, a positive risk-benefit profile. These promising results support the development of large-scale studies to further evaluate CBD as a potential new drug for the treatment of these psychiatric disorders. Full article
(This article belongs to the Special Issue The Endocannabinoid System in Health and Disease)
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43 pages, 380 KiB  
Review
Targeting the Endocannabinoid CB1 Receptor to Treat Body Weight Disorders: A Preclinical and Clinical Review of the Therapeutic Potential of Past and Present CB1 Drugs
by Thomas Murphy and Bernard Le Foll
Biomolecules 2020, 10(6), 855; https://doi.org/10.3390/biom10060855 - 4 Jun 2020
Cited by 29 | Viewed by 6966
Abstract
Obesity rates are increasing worldwide and there is a need for novel therapeutic treatment options. The endocannabinoid system has been linked to homeostatic processes, including metabolism, food intake, and the regulation of body weight. Rimonabant, an inverse agonist for the cannabinoid CB1 receptor, [...] Read more.
Obesity rates are increasing worldwide and there is a need for novel therapeutic treatment options. The endocannabinoid system has been linked to homeostatic processes, including metabolism, food intake, and the regulation of body weight. Rimonabant, an inverse agonist for the cannabinoid CB1 receptor, was effective at producing weight loss in obese subjects. However, due to adverse psychiatric side effects, rimonabant was removed from the market. More recently, we reported an inverse relationship between cannabis use and BMI, which has now been duplicated by several groups. As those results may appear contradictory, we review here preclinical and clinical studies that have studied the impact on body weight of various cannabinoid CB1 drugs. Notably, we will review the impact of CB1 inverse agonists, agonists, partial agonists, and neutral antagonists. Those findings clearly point out the cannabinoid CB1 as a potential effective target for the treatment of obesity. Recent preclinical studies suggest that ligands targeting the CB1 may retain the therapeutic potential of rimonabant without the negative side effect profile. Such approaches should be tested in clinical trials for validation. Full article
(This article belongs to the Special Issue The Endocannabinoid System in Health and Disease)
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