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18 pages, 10054 KiB

Open AccessArticle

Structural Insights into β-arrestin/CB1 Receptor Interaction: NMR and CD Studies on Model Peptides

by Paula Morales, Marta Bruix and M. Angeles Jiménez

Int. J. Mol. Sci. 2020, 21(21), 8111; https://doi.org/10.3390/ijms21218111 - 30 Oct 2020

Cited by 5 | Viewed by 3127

Activation of the cannabinoid CB1 receptor induces different cellular signaling cascades through coupling to different effector proteins (G-proteins and β-arrestins), triggering numerous therapeutic effects. Conformational changes and rearrangements at the intracellular domain of this GPCR receptor that accompany ligand binding dictate the signaling [...] Read more.

Activation of the cannabinoid CB1 receptor induces different cellular signaling cascades through coupling to different effector proteins (G-proteins and β-arrestins), triggering numerous therapeutic effects. Conformational changes and rearrangements at the intracellular domain of this GPCR receptor that accompany ligand binding dictate the signaling pathways. The GPCR-binding interface for G proteins has been extensively studied, whereas β-arrestin/GPCR complexes are still poorly understood. To gain knowledge in this direction, we designed peptides that mimic the motifs involved in the putative interacting region: β-arrestin1 finger loop and the transmembrane helix 7-helix 8 (TMH7-H8) elbow located at the intracellular side of the CB1 receptor. According to circular dichroism and NMR data, these peptides form a native-like, helical conformation and interact with each other in aqueous solution, in the presence of trifluoroethanol, and using zwitterionic detergent micelles as membrane mimics. These results increase our understanding of the binding mode of β-arrestin and CB1 receptor and validate minimalist approaches to structurally comprehend complex protein systems. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 2.0)

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17 pages, 3305 KiB

Open AccessArticle

Monitoring Cannabinoid CB2 -Receptor Mediated cAMP Dynamics by FRET-Based Live Cell Imaging

by Leonore Mensching, Sebastian Rading, Viacheslav Nikolaev and Meliha Karsak

Int. J. Mol. Sci. 2020, 21(21), 7880; https://doi.org/10.3390/ijms21217880 - 23 Oct 2020

Cited by 6 | Viewed by 3114

Abstract

G-protein coupled cannabinoid CB2 receptor signaling and function is primarily mediated by its inhibitory effect on adenylate cyclase. The visualization and monitoring of agonist dependent dynamic 3′,5′-cyclic adenosine monophosphate (cAMP) signaling at the single cell level is still missing for CB2 receptors. This [...] Read more.

G-protein coupled cannabinoid CB2 receptor signaling and function is primarily mediated by its inhibitory effect on adenylate cyclase. The visualization and monitoring of agonist dependent dynamic 3′,5′-cyclic adenosine monophosphate (cAMP) signaling at the single cell level is still missing for CB2 receptors. This paper presents an application of a live cell imaging while using a Förster resonance energy transfer (FRET)-based biosensor, Epac1-camps, for quantification of cAMP. We established HEK293 cells stably co-expressing human CB2 and Epac1-camps and quantified cAMP responses upon Forskolin pre-stimulation, followed by treatment with the CB2 ligands JWH-133, HU308, β-caryophyllene, or 2-arachidonoylglycerol. We could identify cells showing either an agonist dependent CB2-response as expected, cells displaying no response, and cells with constitutive receptor activity. In Epac1-CB2-HEK293 responder cells, the terpenoid β-caryophyllene significantly modified the cAMP response through CB2. For all of the tested ligands, a relatively high proportion of cells with constitutively active CB2 receptors was identified. Our method enabled the visualization of intracellular dynamic cAMP responses to the stimuli at single cell level, providing insights into the nature of heterologous CB2 expression systems that contributes to the understanding of Gαi-mediated G-Protein coupled receptor (GPCR) signaling in living cells and opens up possibilities for future investigations of endogenous CB2 responses. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 2.0)

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19 pages, 2157 KiB

Open AccessArticle

Alterations in Anandamide Synthesis and Degradation during Osteoarthritis Progression in an Animal Model

by Marta Bryk, Jakub Chwastek, Magdalena Kostrzewa, Jakub Mlost, Aleksandra Pędracka and Katarzyna Starowicz

Int. J. Mol. Sci. 2020, 21(19), 7381; https://doi.org/10.3390/ijms21197381 - 06 Oct 2020

Cited by 16 | Viewed by 2835

Abstract

Osteoarthritis (OA) is a degenerative joint disease manifested by movement limitations and chronic pain. Endocannabinoid system (ECS) may modulate nociception via cannabinoid and TRPV1 receptors. The purpose of our study was to examine alterations in the spinal and joint endocannabinoid system during pain [...] Read more.

Osteoarthritis (OA) is a degenerative joint disease manifested by movement limitations and chronic pain. Endocannabinoid system (ECS) may modulate nociception via cannabinoid and TRPV1 receptors. The purpose of our study was to examine alterations in the spinal and joint endocannabinoid system during pain development in an animal model of OA. Wistar rats received intra-articular injection of 3mg of sodium monoiodoacetate (MIA) into the knee joint. Animals were sacrificed on day 2, 7, 14, 21, 28 after injection and lumbar spinal cord, cartilage and synovium were collected. Changes in the transcription levels of the ECS elements were measured. At the spinal level, gene expression levels of the cannabinoid and TRPV1 receptors as well as enzymes involved in anandamide synthesis and degradation were elevated in the advanced OA phase. In the joint, an important role of the synovium was demonstrated, since cartilage degeneration resulted in attenuation of the changes in the gene expression. Enzymes responsible for anandamide synthesis and degradation were upregulated particularly in the early stages of OA, presumably in response to early local joint inflammation. The presented study provides missing information about the MIA-induced OA model and encourages the development of a therapy focused on the molecular role of ECS. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 2.0)

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16 pages, 1531 KiB

Open AccessArticle

Hippocampal 2-Arachidonoyl Glycerol Signaling Regulates Time-of-Day- and Stress-Dependent Effects on Rat Short-Term Memory

by Alessia Santori, Maria Morena, Matthew N. Hill and Patrizia Campolongo

Int. J. Mol. Sci. 2020, 21(19), 7316; https://doi.org/10.3390/ijms21197316 - 03 Oct 2020

Cited by 9 | Viewed by 3213

Abstract

Background: Cannabinoids induce biphasic effects on memory depending on stress levels. We previously demonstrated that different stress intensities, experienced soon after encoding, impaired rat short-term recognition memory in a time-of-day-dependent manner, and that boosting endocannabinoid anandamide (AEA) levels restored memory performance. Here, we [...] Read more.

Background: Cannabinoids induce biphasic effects on memory depending on stress levels. We previously demonstrated that different stress intensities, experienced soon after encoding, impaired rat short-term recognition memory in a time-of-day-dependent manner, and that boosting endocannabinoid anandamide (AEA) levels restored memory performance. Here, we examined if two different stress intensities and time-of-day alter hippocampal endocannabinoid tone, and whether these changes modulate short-term memory. Methods: Male Sprague-Dawley rats were subjected to an object recognition task and exposed, at two different times of the day (i.e., morning or afternoon), to low or high stress conditions, immediately after encoding. Memory retention was assessed 1 hr later. Hippocampal AEA and 2-arachidonoyl glycerol (2-AG) content and the activity of their primary degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), were measured soon after testing. Results: Consistent with our previous findings, low stress impaired 1-hr memory performance only in the morning, whereas exposure to high stress impaired memory independently of testing time. Stress exposure decreased AEA levels independently of memory alterations. Interestingly, exposure to high stress decreased 2-AG content and, accordingly, increased MAGL activity, selectively in the afternoon. Thus, to further evaluate 2-AG’s role in the modulation of short-term recognition memory, rats were given bilateral intra-hippocampal injections of the 2-AG hydrolysis inhibitor KML29 immediately after training, then subjected to low or high stress conditions and tested 1 hr later. Conclusions: KML29 abolished the time-of-day-dependent impairing effects of stress on short-term memory, ameliorating short-term recognition memory performance. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 2.0)

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11 pages, 700 KiB

Open AccessArticle

Disease-Specific Derangement of Circulating Endocannabinoids and N-Acylethanolamines in Myeloproliferative Neoplasms

by Dorian Forte, Flaminia Fanelli, Marco Mezzullo, Martina Barone, Giulia Corradi, Giuseppe Auteri, Daniela Bartoletti, Marina Martello, Emanuela Ottaviani, Carolina Terragna, Antonio Curti, Uberto Pagotto, Francesca Palandri, Michele Cavo and Lucia Catani

Int. J. Mol. Sci. 2020, 21(9), 3399; https://doi.org/10.3390/ijms21093399 - 11 May 2020

Cited by 4 | Viewed by 2863

Abstract

Growing evidence highlights the endocannabinoid (EC) system involvement in cancer progression. Lipid mediators of this system are secreted by hematopoietic cells, including the ECs 2-arachidonoyl-glycerol (2AG) and arachidonoyl-ethanolamide (AEA), the 2AG metabolite 1AG, and members of N-acylethanolamine (NAE) family—palmitoyl-ethanolamide (PEA) and oleoyl-ethanolamide (OEA). [...] Read more.

Growing evidence highlights the endocannabinoid (EC) system involvement in cancer progression. Lipid mediators of this system are secreted by hematopoietic cells, including the ECs 2-arachidonoyl-glycerol (2AG) and arachidonoyl-ethanolamide (AEA), the 2AG metabolite 1AG, and members of N-acylethanolamine (NAE) family—palmitoyl-ethanolamide (PEA) and oleoyl-ethanolamide (OEA). However, the relevance of the EC system in myeloproliferative neoplasms (MPN) was never investigated. We explored the EC plasma profile in 55 MPN patients, including myelofibrosis (MF; n = 41), polycythemia vera (PV; n = 9), and essential thrombocythemia (ET; n = 5) subclasses and in 10 healthy controls (HC). AEA, PEA, OEA, 2AG, and 1AG plasma levels were measured by LC–MS/MS. Overall considered, MPN patients displayed similar EC and NAE levels compared to HC. Nonetheless, AEA levels in MPN were directly associated with the platelet count. MF patients showed higher levels of the sum of 2AG and 1AG compared to ET and PV patients, higher OEA/AEA ratios compared to HC and ET patients, and higher OEA/PEA ratios compared to HC. Furthermore, the sum of 2AG and 1AG positively correlated with JAK2^V617F variant allele frequency and splenomegaly in MF and was elevated in high-risk PV patients compared to in low-risk PV patients. In conclusion, our work revealed specific alterations of ECs and NAE plasma profile in MPN subclasses and potentially relevant associations with disease severity. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 2.0)

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12 pages, 6052 KiB

Open AccessArticle

Sensitivity of the Fasciae to the Endocannabinoid System: Production of Hyaluronan-Rich Vesicles and Potential Peripheral Effects of Cannabinoids in Fascial Tissue

by Caterina Fede, Carmelo Pirri, Lucia Petrelli, Diego Guidolin, Chenglei Fan, Raffaele De Caro and Carla Stecco

Int. J. Mol. Sci. 2020, 21(8), 2936; https://doi.org/10.3390/ijms21082936 - 22 Apr 2020

Cited by 15 | Viewed by 7707

Abstract

The demonstrated expression of endocannabinoid receptors in myofascial tissue suggested the role of fascia as a source and modulator of pain. Fibroblasts can modulate the production of the various components of the extracellular matrix, according to type of stimuli: physical, mechanical, hormonal, and [...] Read more.

The demonstrated expression of endocannabinoid receptors in myofascial tissue suggested the role of fascia as a source and modulator of pain. Fibroblasts can modulate the production of the various components of the extracellular matrix, according to type of stimuli: physical, mechanical, hormonal, and pharmacological. In this work, fascial fibroblasts were isolated from small samples of human fascia lata of the thigh, collected from three volunteer patients (two men, one woman) during orthopedic surgery. This text demonstrates for the first time that the agonist of cannabinoid receptor 2, HU-308, can lead to in vitro production of hyaluronan-rich vesicles only 3–4 h after treatment, being rapidly released into the extracellular environment. We demonstrated that these vesicles are rich in hyaluronan after Alcian blue and Toluidine blue stainings, immunocytochemistry, and transmission electron microscopy. In addition, incubation with the antagonist AM630 blocked vesicles production by cells, confirming that release of hyaluronan is a cannabinoid-mediated effect. These results may show how fascial cells respond to the endocannabinoid system by regulating and remodeling the formation of the extracellular matrix. This is a first step in our understanding of how therapeutic applications of cannabinoids to treat pain may also have a peripheral effect, altering the biosynthesis of the extracellular matrix in fasciae and, consequently, remodeling the tissue and its properties. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 2.0)

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Review

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25 pages, 1624 KiB

Open AccessReview

The Complex Interplay between Endocannabinoid System and the Estrogen System in Central Nervous System and Periphery

by Antonietta Santoro, Elena Mele, Marianna Marino, Andrea Viggiano, Stefania Lucia Nori and Rosaria Meccariello

Int. J. Mol. Sci. 2021, 22(2), 972; https://doi.org/10.3390/ijms22020972 - 19 Jan 2021

Cited by 29 | Viewed by 4732

Abstract

The endocannabinoid system (ECS) is a lipid cell signaling system involved in the physiology and homeostasis of the brain and peripheral tissues. Synaptic plasticity, neuroendocrine functions, reproduction, and immune response among others all require the activity of functional ECS, with the onset of [...] Read more.

The endocannabinoid system (ECS) is a lipid cell signaling system involved in the physiology and homeostasis of the brain and peripheral tissues. Synaptic plasticity, neuroendocrine functions, reproduction, and immune response among others all require the activity of functional ECS, with the onset of disease in case of ECS impairment. Estrogens, classically considered as female steroid hormones, regulate growth, differentiation, and many other functions in a broad range of target tissues and both sexes through the activation of nuclear and membrane estrogen receptors (ERs), which leads to genomic and non-genomic cell responses. Since ECS function overlaps or integrates with many other cell signaling systems, this review aims at updating the knowledge about the possible crosstalk between ECS and estrogen system (ES) at both central and peripheral level, with focuses on the central nervous system, reproduction, and cancer. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 2.0)

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61 pages, 2740 KiB

Open AccessReview

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

by Dhanush Haspula and Michelle A. Clark

Int. J. Mol. Sci. 2020, 21(20), 7693; https://doi.org/10.3390/ijms21207693 - 17 Oct 2020

Cited by 68 | Viewed by 8335

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 2.0)

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33 pages, 3655 KiB

Open AccessReview

Neural Stem Cells and Cannabinoids in the Spotlight as Potential Therapy for Epilepsy

by Diogo M. Lourenço, Leonor Ribeiro-Rodrigues, Ana M. Sebastião, Maria J. Diógenes and Sara Xapelli

Int. J. Mol. Sci. 2020, 21(19), 7309; https://doi.org/10.3390/ijms21197309 - 03 Oct 2020

Cited by 2 | Viewed by 5300

Abstract

Epilepsy is one of the most common brain diseases worldwide, having a huge burden in society. The main hallmark of epilepsy is the occurrence of spontaneous recurrent seizures, having a tremendous impact on the lives of the patients and of their relatives. Currently, [...] Read more.

Epilepsy is one of the most common brain diseases worldwide, having a huge burden in society. The main hallmark of epilepsy is the occurrence of spontaneous recurrent seizures, having a tremendous impact on the lives of the patients and of their relatives. Currently, the therapeutic strategies are mostly based on the use of antiepileptic drugs, and because several types of epilepsies are of unknown origin, a high percentage of patients are resistant to the available pharmacotherapy, continuing to experience seizures overtime. Therefore, the search for new drugs and therapeutic targets is highly important. One key aspect to be targeted is the aberrant adult hippocampal neurogenesis (AHN) derived from Neural Stem Cells (NSCs). Indeed, targeting seizure-induced AHN may reduce recurrent seizures and shed some light on the mechanisms of disease. The endocannabinoid system is a known modulator of AHN, and due to the known endogenous antiepileptic properties, it is an interesting candidate for the generation of new antiepileptic drugs. However, further studies and clinical trials are required to investigate the putative mechanisms by which cannabinoids can be used to treat epilepsy. In this manuscript, we will review how cannabinoid-induced modulation of NSCs may promote neural plasticity and whether these drugs can be used as putative antiepileptic treatment. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 2.0)

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13 pages, 945 KiB

Open AccessReview

Endocannabinoid-Epigenetic Cross-Talk: A Bridge toward Stress Coping

by Francesco Rusconi, Tiziana Rubino and Elena Battaglioli

Int. J. Mol. Sci. 2020, 21(17), 6252; https://doi.org/10.3390/ijms21176252 - 29 Aug 2020

Cited by 11 | Viewed by 2719

Abstract

There is no argument with regard to the physical and psychological stress-related nature of neuropsychiatric disorders. Yet, the mechanisms that facilitate disease onset starting from molecular stress responses are elusive. Environmental stress challenges individuals’ equilibrium, enhancing homeostatic request in the attempt to steer [...] Read more.

There is no argument with regard to the physical and psychological stress-related nature of neuropsychiatric disorders. Yet, the mechanisms that facilitate disease onset starting from molecular stress responses are elusive. Environmental stress challenges individuals’ equilibrium, enhancing homeostatic request in the attempt to steer down arousal-instrumental molecular pathways that underlie hypervigilance and anxiety. A relevant homeostatic pathway is the endocannabinoid system (ECS). In this review, we summarize recent discoveries unambiguously listing ECS as a stress coping mechanism. As stress evokes huge excitatory responses in emotional-relevant limbic areas, the ECS limits glutamate release via 2-arachydonilglycerol (2-AG) stress-induced synthesis and retrograde cannabinoid 1 (CB1)-receptor activation at the synapse. However, ECS shows intrinsic vulnerability as 2-AG overstimulation by chronic stress rapidly leads to CB1-receptor desensitization. In this review, we emphasize the protective role of 2-AG in stress-response termination and stress resiliency. Interestingly, we discuss ECS regulation with a further nuclear homeostatic system whose nature is exquisitely epigenetic, orchestrated by Lysine Specific Demethylase 1. We here emphasize a remarkable example of stress-coping network where transcriptional homeostasis subserves synaptic and behavioral adaptation, aiming at reducing psychiatric effects of traumatic experiences. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 2.0)

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28 pages, 1682 KiB

Open AccessReview

Distinctive Evidence Involved in the Role of Endocannabinoid Signalling in Parkinson’s Disease: A Perspective on Associated Therapeutic Interventions

by Tapan Behl, Gagandeep Kaur, Simona Bungau, Rishabh Jhanji, Arun Kumar, Vineet Mehta, Gokhan Zengin, Roxana Brata, Syed Shams ul Hassan and Ovidiu Fratila

Int. J. Mol. Sci. 2020, 21(17), 6235; https://doi.org/10.3390/ijms21176235 - 28 Aug 2020

Cited by 23 | Viewed by 5133

Abstract

Current pharmacotherapy of Parkinson’s disease (PD) is symptomatic and palliative, with levodopa/carbidopa therapy remaining the prime treatment, and nevertheless, being unable to modulate the progression of the neurodegeneration. No available treatment for PD can enhance the patient’s life-quality by regressing this diseased state. [...] Read more.

Current pharmacotherapy of Parkinson’s disease (PD) is symptomatic and palliative, with levodopa/carbidopa therapy remaining the prime treatment, and nevertheless, being unable to modulate the progression of the neurodegeneration. No available treatment for PD can enhance the patient’s life-quality by regressing this diseased state. Various studies have encouraged the enrichment of treatment possibilities by discovering the association of the effects of the endocannabinoid system (ECS) in PD. These reviews delineate the reported evidence from the literature on the neuromodulatory role of the endocannabinoid system and expression of cannabinoid receptors in symptomatology, cause, and treatment of PD progression, wherein cannabinoid (CB) signalling experiences alterations of biphasic pattern during PD progression. Published papers to date were searched via MEDLINE, PubMed, etc., using specific key words in the topic of our manuscript. Endocannabinoids regulate the basal ganglia neuronal circuit pathways, synaptic plasticity, and motor functions via communication with dopaminergic, glutamatergic, and GABAergic signalling systems bidirectionally in PD. Further, gripping preclinical and clinical studies demonstrate the context regarding the cannabinoid compounds, which is supported by various evidence (neuroprotection, suppression of excitotoxicity, oxidative stress, glial activation, and additional benefits) provided by cannabinoid-like compounds (much research addresses the direct regulation of cannabinoids with dopamine transmission and other signalling pathways in PD). More data related to endocannabinoids efficacy, safety, and pharmacokinetic profiles need to be explored, providing better insights into their potential to ameliorate or even regress PD. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 2.0)

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16 pages, 995 KiB

Open AccessReview

Cannabinoid Receptor Type 2: A Possible Target in SARS-CoV-2 (CoV-19) Infection?

by Francesca Rossi, Chiara Tortora, Maura Argenziano, Alessandra Di Paola and Francesca Punzo

Int. J. Mol. Sci. 2020, 21(11), 3809; https://doi.org/10.3390/ijms21113809 - 27 May 2020

Cited by 55 | Viewed by 17099

Abstract

In late December 2019, a novel coronavirus (SARS-CoV-2 or CoV-19) appeared in Wuhan, China, causing a global pandemic. SARS-CoV-2 causes mild to severe respiratory tract inflammation, often developing into lung fibrosis with thrombosis in pulmonary small vessels and causing even death. COronaVIrus Disease [...] Read more.

In late December 2019, a novel coronavirus (SARS-CoV-2 or CoV-19) appeared in Wuhan, China, causing a global pandemic. SARS-CoV-2 causes mild to severe respiratory tract inflammation, often developing into lung fibrosis with thrombosis in pulmonary small vessels and causing even death. COronaVIrus Disease (COVID-19) patients manifest exacerbated inflammatory and immune responses, cytokine storm, prevalence of pro-inflammatory M1 macrophages and increased levels of resident and circulating immune cells. Men show higher susceptibility to SARS-CoV-2 infection than women, likely due to estrogens production. The protective role of estrogens, as well as an immune-suppressive activity that limits the excessive inflammation, can be mediated by cannabinoid receptor type 2 (CB2). The role of this receptor in modulating inflammation and immune response is well documented in fact in several settings. The stimulation of CB2 receptors is known to limit the release of pro-inflammatory cytokines, shift the macrophage phenotype towards the anti-inflammatory M2 type and enhance the immune-modulating properties of mesenchymal stromal cells. For these reasons, we hypothesize that CB2 receptor can be a therapeutic target in COVID-19 pandemic emergency. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 2.0)

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