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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (31 August 2019) | Viewed by 47933

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Special Issue Editors

Prof. Dr. Melanie Kelly

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Department of Pharmacology, Dalhousie University, Halifax, NS, Canada
Interests: regulation of intraocular pressure; cannabinoids; retinal neurovascular signaling; ocular microcirculation; ocular inflammatory diseases (uveitis, uveoretinitis, proliferative vitreoretinopathy); vasculopathies
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Prof. Dr. Christian Lehmann

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Department of Anesthesiology, Dalhousie University, Halifax, NS, Canada
Interests: cannabinoids; infection; sepsis and its early indications; intravital imaging microcirculation; septic shock stroke
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Despite a 5000-year history of medicinal cannabis use, insights into the modern pharmacology of cannabis and cannabinoids only occurred over a more recent 50 year span, which was triggered when Gaoni and Mechoulam (1964) first identified delta9-tetrahydrocannabinol, the main psychoactive ingredient in cannabis. This was closely followed by the cloning of the cannabinoid type 1 receptor in the late 1980s and, shortly after, the cannabinoid type 2 receptor, both of which are targets for tetrahydrocannabinol (THC) and cannabinoids. Identification of endogenous ligands (i.e., anandamide and 2-arachidonyl glycerol) that activate cannabinoid receptors laid the framework for an endogeous cannabinoid signaling system, which, together with receptors and enzymes for biosynthesis and degradation of endocannabinoids, was coined the “endocannabinoid system”—similar to other endogenous systems (e.g., the endorphin system). Currently, many synthetic agonists and antagonists, as well as naturally occurring “phytocannabinoids” that target the endocannabinoid system, have been investigated and found to exhibit significant potential as medicines in preclinical and clinical studies. This Special Issue of the journal Molecules aims to review the latest progress in cannabinoid research, with a focus on pain and inflammation.

Prof. Dr. Melanie Kelly
Prof. Dr. Christian Lehmann
Guest Editors

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Keywords

Endocannabinoid system
Cannabinoid receptors
Endocannabinoids
Phytocannabinoids
Synthetic cannabinoids

Published Papers (7 papers)

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Research

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20 pages, 5185 KiB

Open AccessArticle

β-Caryophyllene, a CB2-Receptor-Selective Phytocannabinoid, Suppresses Mechanical Allodynia in a Mouse Model of Antiretroviral-Induced Neuropathic Pain

by Esraa Aly, Maitham A. Khajah and Willias Masocha

Molecules 2020, 25(1), 106; https://doi.org/10.3390/molecules25010106 - 27 Dec 2019

Cited by 52 | Viewed by 7560

Abstract

Neuropathic pain associated with nucleoside reverse transcriptase inhibitors (NRTIs), therapeutic agents for human immunodeficiency virus (HIV), responds poorly to available drugs. Smoked cannabis was reported to relieve HIV-associated neuropathic pain in clinical trials. Some constituents of cannabis (Cannabis sativa) activate cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors. However, activation of the CB1 receptor is associated with side effects such as psychosis and physical dependence. Therefore, we investigated the effect of β-caryophyllene (BCP), a CB2-selective phytocannabinoid, in a model of NRTI-induced neuropathic pain. Female BALB/c mice treated with 2′-3′-dideoxycytidine (ddC, zalcitabine), a NRTI, for 5 days developed mechanical allodynia, which was prevented by cotreatment with BCP, minocycline or pentoxifylline. A CB2 receptor antagonist (AM 630), but not a CB1 receptor antagonist (AM 251), antagonized BCP attenuation of established ddC-induced mechanical allodynia. β-Caryophyllene prevented the ddC-induced increase in cytokine (interleukin 1 beta, tumor necrosis factor alpha and interferon gamma) transcripts in the paw skin and brain, as well as the phosphorylation level of Erk1/2 in the brain. In conclusion, BCP prevents NRTI-induced mechanical allodynia, possibly via reducing the inflammatory response, and attenuates mechanical allodynia through CB2 receptor activation. Therefore, BCP could be useful for prevention and treatment of antiretroviral-induced neuropathic pain. Full article

(This article belongs to the Special Issue Cannabinoids)

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18 pages, 3948 KiB

Open AccessArticle

Experimental Cannabinoid 2 Receptor Activation by Phyto-Derived and Synthetic Cannabinoid Ligands in LPS-Induced Interstitial Cystitis in Mice

by Geraint Berger, Nipun Arora, Ian Burkovskiy, Yanfang Xia, Anu Chinnadurai, Robert Westhofen, Georg Hagn, Ashley Cox, Melanie Kelly, Juan Zhou and Christian Lehmann

Molecules 2019, 24(23), 4239; https://doi.org/10.3390/molecules24234239 - 21 Nov 2019

Cited by 22 | Viewed by 3914

Abstract

Interstitial cystitis (IC) is a chronic bladder disorder with unclear etiology. The endocannabinoid system has been identified as a key regulator of immune function, with experimental evidence for the involvement of cannabinoid receptors in bladder inflammation. This study used intravital microscopy (IVM) and behavioral testing in lipopolysaccharide-induced IC, to investigate the anti-inflammatory analgesic effects of a natural dietary sesquiterpenoid, beta-caryophyllene (BCP), which is present in cannabis among other plants, and has reported agonist actions at the cannabinoid 2 receptor (CB₂R). BCP’s anti-inflammatory actions were compared to the synthetic CB₂R-selective cannabinoid, HU308, and to an FDA-approved clinical treatment (dimethyl sulfoxide: DMSO). IVM data revealed that intravesical instillation of BCP and/or HU308 significantly reduces the number of adhering leukocytes in submucosal bladder venules and improves bladder capillary perfusion. The effects of BCP were found to be comparable to that of the selective CB₂R synthetic cannabinoid, HU308, and superior to intravesical DMSO treatment. Oral treatment with BCP was also able to reduce bladder inflammation and significantly reduced mechanical allodynia in experimental IC. Based on our findings, we believe that CB₂R activation may represent a viable therapeutic target for IC, and that drugs that activate CB₂R, such as the generally regarded as safe (GRAS) dietary sesquiterpenoid, BCP, may serve as an adjunct and/or alternative treatment option for alleviating symptoms of inflammation and pain in the management of IC. Full article

(This article belongs to the Special Issue Cannabinoids)

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17 pages, 3143 KiB

Open AccessArticle

HU-671, a Novel Oleoyl Serine Derivative, Exhibits Enhanced Efficacy in Reversing Ovariectomy-Induced Osteoporosis and Bone Marrow Adiposity

by Saja Baraghithy, Reem Smoum, Malka Attar-Namdar, Raphael Mechoulam, Itai Bab and Joseph Tam

Molecules 2019, 24(20), 3719; https://doi.org/10.3390/molecules24203719 - 16 Oct 2019

Cited by 5 | Viewed by 3606

Abstract

Oleoyl serine (OS), an endogenous fatty acyl amide (FAA) found in bone, has been shown to have an anti-osteoporotic effect. OS, being an amide, can be hydrolyzed in the body by amidases. Hindering its amide bond by introducing adjacent substituents has been demonstrated as a successful method for prolonging its skeletal activity. Here, we tested the therapeutic efficacy of two methylated OS derivatives, oleoyl α-methyl serine (HU-671) and 2-methyl-oleoyl serine (HU-681), in an ovariectomized mouse model for osteoporosis by utilizing combined micro-computed tomography, histomorphometry, and cell culture analyses. Our findings indicate that daily treatment for 6 weeks with OS or HU-671 completely rescues bone loss, whereas HU-681 has only a partial effect. The increased bone density was primarily due to enhanced trabecular thickness and number. Moreover, the most effective dose of HU-671 was 0.5 mg/kg/day, an order of magnitude lower than with OS. The reversal of bone loss resulted from increased bone formation and decreased bone resorption, as well as reversal of bone marrow adiposity. These results were further confirmed by determining the serum levels of osteocalcin and type 1 collagen C-terminal crosslinks, as well as demonstrating the enhanced antiadipogenic effect of HU-671. Taken together, these data suggest that methylation interferes with OS’s metabolism, thus enhancing its effects by extending its availability to its target cells. Full article

(This article belongs to the Special Issue Cannabinoids)

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15 pages, 889 KiB

Open AccessArticle

Preliminary Study: Comparison of Antioxidant Activity of Cannabidiol (CBD) and α-Tocopherol Added to Refined Olive and Sunflower Oils

by Matilde Tura, Mara Mandrioli and Tullia Gallina Toschi

Molecules 2019, 24(19), 3485; https://doi.org/10.3390/molecules24193485 - 26 Sep 2019

Cited by 28 | Viewed by 5472

Abstract

This study evaluates the antioxidant activity of cannabidiol (CBD), added to model systems of refined olive (ROO) and sunflower (SO) oils, by measuring the peroxide value, oxidative stability index (OSI), electron spin resonance (ESR) forced oxidation, and DPPH^• assays. Free acidity, a parameter of hydrolytic rancidity, was also examined. CBD was compared using the same analytical scheme with α-tocopherol. CBD, compared to α-tocopherol, showed a higher scavenging capacity, measured by DPPH^• assay, but not better oxidative stability (OSI) of the oily systems considered. In particular, α-tocopherol (0.5%) showed an antioxidant activity only in SO, registered by an increase of more than 30% of the OSI (from 4.15 ± 0.07 to 6.28 ± 0.11 h). By ESR-forced oxidation assay, the concentration of free radicals (μM) in ROO decreased from 83.33 ± 4.56 to 11.23 ± 0.28 and in SO from 19.21 ± 1.39 to 6.90 ± 0.53 by adding 0.5% α-tocopherol. On the contrary, the addition of 0.5% CBD caused a worsening of the oxidative stability of ROO (from 23.58 ± 0.32 to 17.28 ± 0.18 h) and SO (from 4.93 ± 0.04 to 3.98 ± 0.04 h). Furthermore, 0.5% of CBD did not lower dramatically the concentration of free radicals (μM) as for α-tocopherol, which passed from 76.94 ± 9.04 to 72.25 ± 4.13 in ROO and from 17.91 ± 0.95 to 16.84 ± 0.25 in SO. Full article

(This article belongs to the Special Issue Cannabinoids)

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Review

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36 pages, 1871 KiB

Open AccessReview

Kynurenines and the Endocannabinoid System in Schizophrenia: Common Points and Potential Interactions

by Ferenc Zádor, Gábor Nagy-Grócz, Gabriella Kekesi, Szabolcs Dvorácskó, Edina Szűcs, Csaba Tömböly, Gyongyi Horvath, Sándor Benyhe and László Vécsei

Molecules 2019, 24(20), 3709; https://doi.org/10.3390/molecules24203709 - 15 Oct 2019

Cited by 15 | Viewed by 5378

Abstract

Schizophrenia, which affects around 1% of the world’s population, has been described as a complex set of symptoms triggered by multiple factors. However, the exact background mechanisms remain to be explored, whereas therapeutic agents with excellent effectivity and safety profiles have yet to be developed. Kynurenines and the endocannabinoid system (ECS) play significant roles in both the development and manifestation of schizophrenia, which have been extensively studied and reviewed previously. Accordingly, kynurenines and the ECS share multiple features and mechanisms in schizophrenia, which have yet to be reviewed. Thus, the present study focuses on the main common points and potential interactions between kynurenines and the ECS in schizophrenia, which include (i) the regulation of glutamatergic/dopaminergic/γ-aminobutyric acidergic neurotransmission, (ii) their presence in astrocytes, and (iii) their role in inflammatory mechanisms. Additionally, promising pharmaceutical approaches involving the kynurenine pathway and the ECS will be reviewed herein. Full article

(This article belongs to the Special Issue Cannabinoids)

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9 pages, 1248 KiB

Open AccessReview

Cannabinoid Receptor Interacting Protein 1a (CRIP1a): Function and Structure

by William T. Booth, Noah B. Walker, W. Todd Lowther and Allyn C. Howlett

Molecules 2019, 24(20), 3672; https://doi.org/10.3390/molecules24203672 - 12 Oct 2019

Cited by 22 | Viewed by 4813

Abstract

Cannabinoid receptor interacting protein 1a (CRIP1a) is an important CB₁ cannabinoid receptor-associated protein, first identified from a yeast two-hybrid screen to modulate CB₁-mediated N-type Ca²⁺ currents. In this paper we review studies of CRIP1a function and structure based upon in vitro experiments and computational chemistry, which elucidate the specific mechanisms for the interaction of CRIP1a with CB₁ receptors. N18TG2 neuronal cells overexpressing or silencing CRIP1a highlighted the ability of CRIP1 to regulate cyclic adenosine 3′,5′monophosphate (cAMP) production and extracellular signal-regulated kinase (ERK1/2) phosphorylation. These studies indicated that CRIP1a attenuates the G protein signaling cascade through modulating which Gi/o subtypes interact with the CB₁ receptor. CRIP1a also attenuates CB₁ receptor internalization via β-arrestin, suggesting that CRIP1a competes for β-arrestin binding to the CB₁ receptor. Predictions of CRIP1a secondary structure suggest that residues 34-110 are minimally necessary for association with key amino acids within the distal C-terminus of the CB₁ receptor, as well as the mGlu_8a metabotropic glutamate receptor. These interactions are disrupted through phosphorylation of serines and threonines in these regions. Through investigations of the function and structure of CRIP1a, new pharmacotherapies based upon the CRIP-CB₁ receptor interaction can be designed to treat diseases such as epilepsy, motor dysfunctions and schizophrenia. Full article

(This article belongs to the Special Issue Cannabinoids)

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21 pages, 1040 KiB

Open AccessReview

Cannabidiol Treatment Might Promote Resilience to Cocaine and Methamphetamine Use Disorders: A Review of Possible Mechanisms

by Claudia Calpe-López, M. Pilar García-Pardo and Maria A. Aguilar

Molecules 2019, 24(14), 2583; https://doi.org/10.3390/molecules24142583 - 16 Jul 2019

Cited by 51 | Viewed by 16336

Abstract

Currently, there are no approved pharmacotherapies for addiction to cocaine and other psychostimulant drugs. Several studies have proposed that cannabidiol (CBD) could be a promising treatment for substance use disorders. In the present work, the authors describe the scarce preclinical and human research about the actions of CBD on the effects of stimulant drugs, mainly cocaine and methamphetamine (METH). Additionally, the possible mechanisms underlying the therapeutic potential of CBD on stimulant use disorders are reviewed. CBD has reversed toxicity and seizures induced by cocaine, behavioural sensitization induced by amphetamines, motivation to self-administer cocaine and METH, context- and stress-induced reinstatement of cocaine and priming-induced reinstatement of METH seeking behaviours. CBD also potentiated the extinction of cocaine- and amphetamine-induced conditioned place preference (CPP), impaired the reconsolidation of cocaine CPP and prevented priming-induced reinstatement of METH CPP. Observational studies suggest that CBD may reduce problems related with crack-cocaine addiction, such as withdrawal symptoms, craving, impulsivity and paranoia (Fischer et al., 2015). The potential mechanisms involved in the protective effects of CBD on addiction to psychostimulant drugs include the prevention of drug-induced neuroadaptations (neurotransmitter and intracellular signalling pathways changes), the erasure of aberrant drug-memories, the reversion of cognitive deficits induced by psychostimulant drugs and the alleviation of mental disorders comorbid with psychostimulant abuse. Further, preclinical studies and future clinical trials are necessary to fully evaluate the potential of CBD as an intervention for cocaine and methamphetamine addictive disorders. Full article

(This article belongs to the Special Issue Cannabinoids)

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