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Special Issue "Novel Insights into Cannabinoid Receptors, Molecular Targets, and Therapeutic Potentials"

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: 30 September 2023 | Viewed by 19071

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Dr. Zhao-Hui Song

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Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA
Interests: cannabinoid receptors; novel cannabinoid targets; cannabinoid signaling; cannabinoid therapeutic potentials

Special Issue Information

Dear Colleagues,

Cannabis has been used as a remedy for illness for centuries in various cultures. Recently, there has been a renewed interest in the uses of cannabis and cannabinoids for medicinal purposes, due to improved legal status in medical cannabis and the advances in cannabinoid research. Cannabinoids are composed of three categories, including phytocannabinoids (the active chemical components of cannabis), endocannabinoids (the cannabinoid-like substances in our body), and synthetic cannabinoids (the cannabinoids prepared in the laboratory). Cannabinoids exert their effects through multiple receptors, targets and signaling pathways. In addition to CB1 and CB2, two well-established cannabinoid receptors, there are numerous molecular targets for cannabinoids, e.g., G-protein-coupled receptors (GPR55, GPR18, GPR3/GPR6/GPR12), transient receptor potential (TRPV) channels, and peroxisome proliferator-activated (PPAR) receptors. These cannabinoid receptors and molecular targets play essential roles for the effects of cannabinoids in health and disease. In addition, they are underscoring the mechanisms of actions for the potential therapeutic effects of a variety of cannabinoids. Recently, there have been tremendous advances in our understanding of these receptors and molecular targets, as well as their implications in the therapeutic potentials of cannabinoids.

The emphasis of this Special Issue is on the recent advances in our knowledge of cannabinoid receptors, molecular targets, and signaling pathways in the context of physiological/pathological conditions, and cannabinoid therapeutic potentials. Review articles summarizing recent discoveries, and original research articles of both basic and clinical studies are welcome.

We look forward to your important contributions.

Dr. Zhao-Hui Song
Guest Editor

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Keywords

Cannabinoid receptor
Molecular target
Signal transduction
Therapeutic potentials

Published Papers (10 papers)

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Research

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Open AccessArticle

The Effects of Cannabidiol on Aqueous Humor Outflow and Trabecular Meshwork Cell Signaling

Alyssa S. Aebersold

and

Zhao-Hui Song

Cells 2022, 11(19), 3006; https://doi.org/10.3390/cells11193006 - 27 Sep 2022

Cited by 1 | Viewed by 1072

Abstract

Intraocular pressure (IOP) is regulated primarily through aqueous humor production by ciliary body and drainage through uveoscleral and trabecular meshwork (TM) tissues. The goal of this study was to measure the effect of non-psychotropic cannabidiol (CBD) on aqueous humor outflow through TM and assess the effect of CBD on the TM cell signaling pathways that are important for regulating outflow. Perfused porcine eye anterior segment explants were used to investigate the effects of CBD on aqueous humor outflow. Cultured porcine TM cells were used to study the effects of CBD on TM cell contractility, myosin light chain (MLC) and myosin phosphatase targeting subunit 1 (MYPT1) phosphorylation, and RhoA activation. In the anterior segment perfusion experiments, aqueous humor outflow was increased significantly within 1 h after adding 1 µM CBD and the effect was sustained over the 5 h of measurement. Treatment of TM cells with 1 µM CBD significantly decreased TM cell-mediated collagen contraction, inhibited phosphorylation of MLC and MYPT1, and reduced RhoA activation. Our data demonstrate, for the first time, that as a potential therapeutic agent for lowering intraocular pressure, CBD can enhance aqueous humor outflow and modify TM cell signaling. Full article

(This article belongs to the Special Issue Novel Insights into Cannabinoid Receptors, Molecular Targets, and Therapeutic Potentials)

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Open AccessArticle

WIN55212-2 Modulates Intracellular Calcium via CB₁ Receptor-Dependent and Independent Mechanisms in Neuroblastoma Cells

Victor M. Pulgar

Allyn C. Howlett

and

Khalil Eldeeb

Cells 2022, 11(19), 2947; https://doi.org/10.3390/cells11192947 - 21 Sep 2022

Viewed by 1105

Abstract

The CB₁ cannabinoid receptor (CB₁R) and extracellular calcium (eCa²⁺)-stimulated Calcium Sensing receptor (CaSR) can exert cellular signaling by modulating levels of intracellular calcium ([Ca²⁺]_i). We investigated the mechanisms involved in the ([Ca²⁺]_i) increase in N18TG2 neuroblastoma cells, which endogenously express both receptors. Changes in [Ca²⁺]_i were measured in cells exposed to 0.25 or 2.5 mM eCa²⁺ by a ratiometric method (Fura-2 fluorescence) and expressed as the difference between baseline and peak responses (ΔF_340/380). The increased ([Ca²⁺]_i) in cells exposed to 2.5 mM eCa²⁺ was blocked by the CaSR antagonist, NPS2143, this inhibition was abrogated upon stimulation with WIN55212-2. WIN55212-2 increased [Ca²⁺]_i at 0.25 and 2.5 mM eCa²⁺ by 700% and 350%, respectively, but this increase was not replicated by CP55940 or methyl-anandamide. The store-operated calcium entry (SOCE) blocker, MRS1845, attenuated the WIN55212-2-stimulated increase in [Ca²⁺]_i at both levels of eCa²⁺. Simultaneous perfusion with the CB₁ antagonist, SR141716 or NPS2143 decreased the response to WIN55212-2 at 0.25 mM but not 2.5 mM eCa²⁺. Co-perfusion with the non-CB₁/CB₂ antagonist O-1918 attenuated the WIN55212-2-stimulated [Ca²⁺]_i increase at both eCa²⁺ levels. These results are consistent with WIN55212-2-mediated intracellular Ca²⁺ mobilization from store-operated calcium channel-filled sources that could occur via either the CB₁R or an O-1918-sensitive non-CB₁R in coordination with the CaSR. Intracellular pathway crosstalk or signaling protein complexes may explain the observed effects. Full article

(This article belongs to the Special Issue Novel Insights into Cannabinoid Receptors, Molecular Targets, and Therapeutic Potentials)

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Open AccessArticle

Cross-Talk between CB₁, AT₁, AT₂ and Mas Receptors Responsible for Blood Pressure Control in the Paraventricular Nucleus of Hypothalamus in Conscious Spontaneously Hypertensive Rats and Their Normotensive Controls

Krzysztof Mińczuk

Eberhard Schlicker

and

Barbara Malinowska

Cells 2022, 11(9), 1542; https://doi.org/10.3390/cells11091542 - 04 May 2022

Cited by 3 | Viewed by 1447

Abstract

We have previously shown that in urethane-anaesthetized rats, intravenous injection of the angiotensin II (Ang II) AT₁ receptor antagonist losartan reversed the pressor effect of the cannabinoid CB₁ receptor agonist CP55940 given in the paraventricular nucleus of hypothalamus (PVN). The aim of our study was to determine the potential interactions in the PVN between CB₁ receptors and AT₁ and AT₂ receptors for Ang II and Mas receptors for Ang 1–7 in blood pressure regulation in conscious spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats. The pressor effects of Ang II, Ang 1–7 and CP55940 microinjected into the PVN were stronger in SHRs than in WKYs. Increases in blood pressure in response to Ang II were strongly inhibited by antagonists of AT₁ (losartan), AT₂ (PD123319) and CB₁ (AM251) receptors, to Ang 1–7 by a Mas antagonist (A-779) and AM251 and to CP55940 by losartan, PD123319 and A-779. Higher (AT₁ and CB₁) and lower (AT₂ and Mas) receptor expression in the PVN of SHR compared to WKY may partially explain the above differences. In conclusion, blood pressure control in the PVN depends on the mutual interaction of CB₁, AT₁, AT₂ and Mas receptors in conscious spontaneously hypertensive rats and their normotensive controls. Full article

(This article belongs to the Special Issue Novel Insights into Cannabinoid Receptors, Molecular Targets, and Therapeutic Potentials)

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Open AccessEditor’s ChoiceArticle

Cannabinoids Alleviate the LPS-Induced Cytokine Storm via Attenuating NLRP3 Inflammasome Signaling and TYK2-Mediated STAT3 Signaling Pathways In Vitro

Santosh V. Suryavanshi

and

Cells 2022, 11(9), 1391; https://doi.org/10.3390/cells11091391 - 20 Apr 2022

Cited by 11 | Viewed by 2920

Abstract

Cannabinoids, mainly cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (THC), are the most studied group of compounds obtained from Cannabis sativa because of their several pharmaceutical properties. Current evidence suggests a crucial role of cannabinoids as potent anti-inflammatory agents for the treatment of chronic inflammatory diseases; however, the mechanisms remain largely unclear. Cytokine storm, a dysregulated severe inflammatory response by our immune system, is involved in the pathogenesis of numerous chronic inflammatory disorders, including coronavirus disease 2019 (COVID-19), which results in the accumulation of pro-inflammatory cytokines. Therefore, we hypothesized that CBD and THC reduce the levels of pro-inflammatory cytokines by inhibiting key inflammatory signaling pathways. The nucleotide-binding and oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome signaling has been implicated in a variety of chronic inflammatory diseases, which results in the release of pyroptotic cytokines, interleukin-1β (IL-1β) and IL-18. Likewise, the activation of the signal transducer and activator of transcription-3 (STAT3) causes increased expression of pro-inflammatory cytokines. We studied the effects of CBD and THC on lipopolysaccharide (LPS)-induced inflammatory response in human THP-1 macrophages and primary human bronchial epithelial cells (HBECs). Our results revealed that CBD and, for the first time, THC significantly inhibited NLRP3 inflammasome activation following LPS + ATP stimulation, leading to a reduction in the levels of IL-1β in THP-1 macrophages and HBECs. CBD attenuated the phosphorylation of nuclear factor-κB (NF-κB), and both cannabinoids inhibited the generation of oxidative stress post-LPS. Our multiplex ELISA data revealed that CBD and THC significantly diminished the levels of IL-6, IL-8, and tumor necrosis factor-α (TNF-α) after LPS treatment in THP-1 macrophages and HBECs. In addition, the phosphorylation of STAT3 was significantly downregulated by CBD and THC in THP-1 macrophages and HBECs, which was in turn attributed to the reduced phosphorylation of tyrosine kinase-2 (TYK2) by CBD and THC after LPS stimulation in these cells. Overall, CBD and THC were found to be effective in alleviating the LPS-induced cytokine storm in human macrophages and primary HBECs, at least via modulation of NLRP3 inflammasome and STAT3 signaling pathways. The encouraging results from this study warrant further investigation of these cannabinoids in vivo. Full article

(This article belongs to the Special Issue Novel Insights into Cannabinoid Receptors, Molecular Targets, and Therapeutic Potentials)

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Open AccessArticle

Artificial Intelligent Deep Learning Molecular Generative Modeling of Scaffold-Focused and Cannabinoid CB2 Target-Specific Small-Molecule Sublibraries

Yuemin Bian

and

Xiang-Qun Xie

Cells 2022, 11(5), 915; https://doi.org/10.3390/cells11050915 - 07 Mar 2022

Cited by 4 | Viewed by 2850

Abstract

Design and generation of high-quality target- and scaffold-specific small molecules is an important strategy for the discovery of unique and potent bioactive drug molecules. To achieve this goal, authors have developed the deep-learning molecule generation model (DeepMGM) and applied it for the de novo molecular generation of scaffold-focused small-molecule libraries. In this study, a recurrent neural network (RNN) using long short-term memory (LSTM) units was trained with drug-like molecules to result in a general model (g-DeepMGM). Sampling practices on indole and purine scaffolds illustrate the feasibility of creating scaffold-focused chemical libraries based on machine intelligence. Subsequently, a target-specific model (t-DeepMGM) for cannabinoid receptor 2 (CB2) was constructed following the transfer learning process of known CB2 ligands. Sampling outcomes can present similar properties to the reported active molecules. Finally, a discriminator was trained and attached to the DeepMGM to result in an in silico molecular design-test circle. Medicinal chemistry synthesis and biological validation was performed to further investigate the generation outcome, showing that XIE9137 was identified as a potential allosteric modulator of CB2. This study demonstrates how recent progress in deep learning intelligence can benefit drug discovery, especially in de novo molecular design and chemical library generation. Full article

(This article belongs to the Special Issue Novel Insights into Cannabinoid Receptors, Molecular Targets, and Therapeutic Potentials)

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Review

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Open AccessReview

Cannabinoid Signaling in Kidney Disease

and

Cells 2023, 12(10), 1419; https://doi.org/10.3390/cells12101419 - 18 May 2023

Viewed by 411

Abstract

Endocannabinoid signaling plays crucial roles in human physiology in the function of multiple systems. The two cannabinoid receptors, CB1 and CB2, are cell membrane proteins that interact with both exogenous and endogenous bioactive lipid ligands, or endocannabinoids. Recent evidence has established that endocannabinoid signaling operates within the human kidney, as well as suggests the important role it plays in multiple renal pathologies. CB1, specifically, has been identified as the more prominent ECS receptor within the kidney, allowing us to place emphasis on this receptor. The activity of CB1 has been repeatedly shown to contribute to both diabetic and non-diabetic chronic kidney disease (CKD). Interestingly, recent reports of acute kidney injury (AKI) have been attributed to synthetic cannabinoid use. Therefore, the exploration of the ECS, its receptors, and its ligands can help provide better insight into new methods of treatment for a range of renal diseases. This review explores the endocannabinoid system, with a focus on its impacts within the healthy and diseased kidney. Full article

(This article belongs to the Special Issue Novel Insights into Cannabinoid Receptors, Molecular Targets, and Therapeutic Potentials)

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Open AccessReview

Cannabinoid Compounds as a Pharmacotherapeutic Option for the Treatment of Non-Cancer Skin Diseases

Robert Ramer

and

Burkhard Hinz

Cells 2022, 11(24), 4102; https://doi.org/10.3390/cells11244102 - 16 Dec 2022

Cited by 3 | Viewed by 1759

Abstract

The endocannabinoid system has been shown to be involved in various skin functions, such as melanogenesis and the maintenance of redox balance in skin cells exposed to UV radiation, as well as barrier functions, sebaceous gland activity, wound healing and the skin’s immune response. In addition to the potential use of cannabinoids in the treatment and prevention of skin cancer, cannabinoid compounds and derivatives are of interest as potential systemic and topical applications for the treatment of various inflammatory, fibrotic and pruritic skin conditions. In this context, cannabinoid compounds have been successfully tested as a therapeutic option for the treatment of androgenetic alopecia, atopic and seborrhoeic dermatitis, dermatomyositis, asteatotic and atopic eczema, uraemic pruritis, scalp psoriasis, systemic sclerosis and venous leg ulcers. This review provides an insight into the current literature on cannabinoid compounds as potential medicines for the treatment of skin diseases. Full article

(This article belongs to the Special Issue Novel Insights into Cannabinoid Receptors, Molecular Targets, and Therapeutic Potentials)

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Open AccessReview

Neutral CB1 Receptor Antagonists as Pharmacotherapies for Substance Use Disorders: Rationale, Evidence, and Challenge

Omar Soler-Cedeno

and

Zheng-Xiong Xi

Cells 2022, 11(20), 3262; https://doi.org/10.3390/cells11203262 - 17 Oct 2022

Cited by 2 | Viewed by 1514

Abstract

Cannabinoid receptor 1 (CB1R) has been one of the major targets in medication development for treating substance use disorders (SUDs). Early studies indicated that rimonabant, a selective CB1R antagonist with an inverse agonist profile, was highly promising as a therapeutic for SUDs. However, its adverse side effects, such as depression and suicidality, led to its withdrawal from clinical trials worldwide in 2008. Consequently, much research interest shifted to developing neutral CB1R antagonists based on the recognition that rimonabant’s side effects may be related to its inverse agonist profile. In this article, we first review rimonabant’s research background as a potential pharmacotherapy for SUDs. Then, we discuss the possible mechanisms underlying its therapeutic anti-addictive effects versus its adverse effects. Lastly, we discuss the rationale for developing neutral CB1R antagonists as potential treatments for SUDs, the supporting evidence in recent research, and the challenges of this strategy. We conclude that developing neutral CB1R antagonists without inverse agonist profile may represent attractive strategies for the treatment of SUDs. Full article

(This article belongs to the Special Issue Novel Insights into Cannabinoid Receptors, Molecular Targets, and Therapeutic Potentials)

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Open AccessReview

Microglial Endocannabinoid Signalling in AD

Lucia Scipioni

Francesca Ciaramellano

and

Cells 2022, 11(7), 1237; https://doi.org/10.3390/cells11071237 - 06 Apr 2022

Cited by 7 | Viewed by 1761

Abstract

Chronic inflammation in Alzheimer’s disease (AD) has been recently identified as a major contributor to disease pathogenesis. Once activated, microglial cells, which are brain-resident immune cells, exert several key actions, including phagocytosis, chemotaxis, and the release of pro- or anti-inflammatory mediators, which could have opposite effects on brain homeostasis, depending on the stage of disease and the particular phenotype of microglial cells. The endocannabinoids (eCBs) are pleiotropic bioactive lipids increasingly recognized for their essential roles in regulating microglial activity both under normal and AD-driven pathological conditions. Here, we review the current literature regarding the involvement of this signalling system in modulating microglial phenotypes and activity in the context of homeostasis and AD-related neurodegeneration. Full article

(This article belongs to the Special Issue Novel Insights into Cannabinoid Receptors, Molecular Targets, and Therapeutic Potentials)

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Open AccessReview

Why Do Marijuana and Synthetic Cannabimimetics Induce Acute Myocardial Infarction in Healthy Young People?

Jolanta Weresa

Anna Pędzińska-Betiuk

Krzysztof Mińczuk

Barbara Malinowska

and

Eberhard Schlicker

Cells 2022, 11(7), 1142; https://doi.org/10.3390/cells11071142 - 28 Mar 2022

Cited by 8 | Viewed by 2875

Abstract

The use of cannabis preparations has steadily increased. Although cannabis was traditionally assumed to only have mild vegetative side effects, it has become evident in recent years that severe cardiovascular complications can occur. Cannabis use has recently even been added to the risk factors for myocardial infarction. This review is dedicated to pathogenetic factors contributing to cannabis-related myocardial infarction. Tachycardia is highly important in this respect, and we provide evidence that activation of CB₁ receptors in brain regions important for cardiovascular regulation and of presynaptic CB₁ receptors on sympathetic and/or parasympathetic nerve fibers are involved. The prototypical factors for myocardial infarction, i.e., thrombus formation and coronary constriction, have also been considered, but there is little evidence that they play a decisive role. On the other hand, an increase in the formation of carboxyhemoglobin, impaired mitochondrial respiration, cardiotoxic reactions and tachyarrhythmias associated with the increased sympathetic tone are factors possibly intensifying myocardial infarction. A particularly important factor is that cannabis use is frequently accompanied by tobacco smoking. In conclusion, additional research is warranted to decipher the mechanisms involved, since cannabis use is being legalized increasingly and Δ⁹-tetrahydrocannabinol and its synthetic analogue nabilone are indicated for the treatment of various disease states. Full article

(This article belongs to the Special Issue Novel Insights into Cannabinoid Receptors, Molecular Targets, and Therapeutic Potentials)

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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: The early chronic administration of Cannabidivarin prevents the neurobehavioral abnormalities of the Fmr1-KO mouse model for Fragile X syndrome
Authors: Marika Premoli1,2 *, William Fyke1,3*, Luigi Bellocchio4, Valerie Lemaire1, Marie Wolley-Roberts5, Wim E. Crusio1, Bruno Bontempi1 and Susanna Pietropaolo1
Affiliation: 1 Univ. Bordeaux, CNRS, EPHE, INCIA, UMR 5287, F-33000 Bordeaux, France 2University of Brescia, Department of Molecular and Translational Medicine, Brescia, Italy 3Graduate Program in Neural and Behavioral Science, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA 4University of Bordeaux, INSERM, U1215, NeuroCentre Magendie, Group Endocannabinoids and Neuroadaptation, Bordeaux 33077, France. 5GW GW Research Ltd, Cambridge, UK
Abstract: Converging lines of evidence have recently highlighted the therapeutic potential of phytocannabinoids, such as Cannabidivarin (CBDV), in several neurodevelopmental pathologies. Nonetheless, the therapeutic value of CBDV has never been tested in Fragile X syndrome (FXS), i.e., a major developmental monogenic disorder. Here we characterized the neurobehavioral effects of CBDV in the Fmr1-KO mouse model of FXS. CBDV was administered intraperitoneally at the daily doses of 20 and 100 mg/kg, either sub-chronically during adulthood (Study 1) or chronically at adolescence (Study 2). Behavioral tests assessing FXS-like abnormalities including anxiety, locomotor, cognitive, social and sensory alterations were performed. Inflammatory (e.g., interleukins) and plasticity (e.g., brain derived neurotrophic factor) markers were also assessed in cortical and hippocampal brain areas. When administered during adulthood (Study 1), CBDV exerted marginal and exclusively behavioral effects, i.e., rescuing at the dose of 20 mg/Kg only the acoustic hyper-responsiveness displayed by Fmr1-KO mice. When administered during adolescence (Study 2), chronic CBDV at both doses rescued the cognitive, social and acoustic alterations of mutant mice and exerted several brain effects in both Fmr1-KO and WT animals. These results support the therapeutic potential of CBDV for treating FXS, highlighting the relevance of the duration and timing of the treatments.

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Special Issue "Novel Insights into Cannabinoid Receptors, Molecular Targets, and Therapeutic Potentials"

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