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Role of Cannabinoids in Inflammation

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

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 40871

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Prof. Dr. Eric J. Downer

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Guest Editor

Discipline of Physiology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, University of Dublin, Dublin, Ireland
Interests: cannabinoids; innate immunity; toll-like receptor signalling; inflammation; multiple sclerosis; neuropathic orofacial pain; cell signalling; novel drug targets; patient-orientated research

Special Issue Information

Dear Colleagues,

Cannabinoids incorporate the components of the cannabis plant (phytocannabinoids), endogenous cannabinoids (endocannabinoids), and synthetic cannabinoid ligands. Cannabinoids influence immune function in both the peripheral and the central nervous system (CNS), and the components of the cannabinoid system, the cannabinoid receptors and endocannabinoids, have been detected on immune cells as well as in cells of the CNS. Indeed, the cannabinoid system is linked with all aspects of human physiology. Cannabinoids are under investigation for the treatment and/or management of inflammatory conditions, and the aim of this Special Issue is to present updated findings related to the role of cannabinoids in targeting inflammation.

Prof. Eric J. Downer
Guest Editor

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Keywords

Cannabinoids
Cannabinoid ligands
Phytocannabinoids
Endocannabinoids
Synthetic cannabinoids
Cannabinoid receptors
Immunity
Inflammation
Neuroinflammation
Neurodegeneration
Therapeutics

Published Papers (7 papers)

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Editorial

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3 pages, 162 KiB

Open AccessEditorial

Role of Cannabinoids in Inflammation

by Eric J. Downer

Molecules 2022, 27(2), 478; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27020478 - 12 Jan 2022

Viewed by 1420

Abstract

This Special Issue brings an update on some of the advances in research in the cannabinoid field, with focus on the impact of cannabinoids on inflammation [...] Full article

(This article belongs to the Special Issue Role of Cannabinoids in Inflammation)

Research

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15 pages, 2239 KiB

Open AccessArticle

Pharmacological Blockade of PPAR Isoforms Increases Conditioned Fear Responding in the Presence of Nociceptive Tone

by Jessica C. Gaspar, Bright N. Okine, Alvaro Llorente-Berzal, Michelle Roche and David P. Finn

Molecules 2020, 25(4), 1007; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25041007 - 24 Feb 2020

Cited by 9 | Viewed by 3314

Abstract

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors with three isoforms (PPARα, PPARβ/δ, PPARγ) and can regulate pain, anxiety, and cognition. However, their role in conditioned fear and pain-fear interactions has not yet been investigated. Here, we investigated the effects of systemically administered PPAR antagonists on formalin-evoked nociceptive behaviour, fear-conditioned analgesia (FCA), and conditioned fear in the presence of nociceptive tone in rats. Twenty-three and a half hours following fear conditioning to context, male Sprague-Dawley rats received an intraplantar injection of formalin and intraperitoneal administration of vehicle, PPARα (GW6471), PPARβ/δ (GSK0660) or PPARγ (GW9662) antagonists, and 30 min later were re-exposed to the conditioning arena for 15 min. The PPAR antagonists did not alter nociceptive behaviour or fear-conditioned analgesia. The PPARα and PPARβ/δ antagonists prolonged context-induced freezing in the presence of nociceptive tone without affecting its initial expression. The PPARγ antagonist potentiated freezing over the entire trial. In conclusion, pharmacological blockade of PPARα and PPARβ/δ in the presence of formalin-evoked nociceptive tone, impaired short-term, within-trial fear-extinction in rats without affecting pain response, while blockade of PPARγ potentiated conditioned fear responding. These results suggest that endogenous signalling through these three PPAR isoforms may reduce the expression of conditioned fear in the presence of nociceptive tone. Full article

(This article belongs to the Special Issue Role of Cannabinoids in Inflammation)

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20 pages, 3802 KiB

Open AccessFeature PaperArticle

Abnormal Cannabidiol Affects Production of Pro-Inflammatory Mediators and Astrocyte Wound Closure in Primary Astrocytic-Microglial Cocultures

by Julian Cardinal von Widdern, Tim Hohmann and Faramarz Dehghani

Molecules 2020, 25(3), 496; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25030496 - 23 Jan 2020

Cited by 16 | Viewed by 3678

Abstract

Abnormal cannabidiol (abn-CBD) exerts neuroprotective effects in vivo and in vitro. In the present study, we investigated the impact of abn-CBD on the glial production of proinflammatory mediators and scar formation within in vitro models. Primary astrocytic-microglial cocultures and astrocytic cultures from neonatal C57BL/6 mice and CB₂ receptor knockout mice were stimulated with lipopolysaccharide (LPS), and the concentrations of tumor necrosis factor α (TNFα), interleukin-6 (IL-6) and nitrite were determined. Furthermore, we performed a live cell microscopy-based scratch-wound assay. After LPS stimulation, TNFα, IL-6 and nitrite production was more strongly increased in cocultures than in isolated astrocytes. Abn-CBD treatment attenuated the LPS-induced production of TNFα and nitrite in cocultures, while IL-6 production remained unaltered. In isolated astrocytes, only LPS-induced TNFα production was reduced by abn-CBD. Similar effects were observed after abn-CBD application in cocultures of CB₂ knockout mice. Interestingly, LPS-induced TNFα and nitrite levels were far lower in CB₂ knockout cultures compared to wildtypes, while IL-6 levels did not differ. In the scratch-wound assay, treatment with abn-CBD decelerated wound closure when microglial cells were present. Our data shows a differential role of abn-CBD for modulation of glial inflammation and astrocytic scar formation. These findings provide new explanations for mechanisms behind the neuroprotective potential of abn-CBD. Full article

(This article belongs to the Special Issue Role of Cannabinoids in Inflammation)

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16 pages, 2057 KiB

Open AccessArticle

Involvement of CB2 Receptors in the Neurobehavioral Effects of Catha Edulis (Vahl) Endl. (Khat) in Mice

by Berhanu Geresu, Ana Canseco-Alba, Branden Sanabria, Zhicheng Lin, Qing-Rong Liu, Emmanuel S. Onaivi and Ephrem Engidawork

Molecules 2019, 24(17), 3164; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24173164 - 30 Aug 2019

Cited by 8 | Viewed by 3561

Abstract

There is behavioral evidence for the interaction between crude khat extract and the endocannabinoid system, whereby the endocannabinoid system alters khat extract-mediated behavioral effects through modulation of the monoaminergic system. The objective of this study was to investigate the role of the endocannabinoid system on the neurobehavioral effect of khat extract in mice following concomitant administration of khat extract and the CB2R agonist, JWH133. Locomotor activity test, immunohistochemistry, and reverse transcriptase polymerase chain reaction technique were utilized to assess locomotor activity, tyrosine hydroxylase immunoreactivity, and expression of dopamine transporter mRNA gene. The results show sub-acute administration of khat extract alone increased locomotor activity in mice and co-administration of the CB2R agonist, JWH133, reduced khat extract induced hyperlocomotor activity. The data revealed that cell type specific deletion of CB2Rs on dopaminergic neurons increased the hyperlocomotor behavior of khat extract. Furthermore, the results revealed that khat extract attenuated MPTP induced motor deficits, which is enhanced by JWH133. Khat extract also increased expression of tyrosine hydroxylase positive cells and expression of dopamine transporter mRNA gene in wild type mice. Nevertheless, JWH133 did not alter the effect of khat extract on tyrosine hydroxylase immunoreactivity and dopamine transporter mRNA expression when given together with khat extract. Taken together, the results suggest that the CB2Rs selectively interact with khat extract-mediated locomotor effects and could be utilized as therapeutic target in central nervous system movement disorders associated with dopamine dysregulation. Full article

(This article belongs to the Special Issue Role of Cannabinoids in Inflammation)

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Review

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20 pages, 453 KiB

Open AccessReview

A Critical Review of the Role of the Cannabinoid Compounds Δ⁹-Tetrahydrocannabinol (Δ⁹-THC) and Cannabidiol (CBD) and their Combination in Multiple Sclerosis Treatment

by Éamon Jones and Styliani Vlachou

Molecules 2020, 25(21), 4930; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25214930 - 25 Oct 2020

Cited by 36 | Viewed by 7951

Abstract

Many people with MS (pwMS) use unregulated cannabis or cannabis products to treat the symptoms associated with the disease. In line with this, Sativex, a synthetic combination of cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (Δ⁹-THC) has been approved to treat symptoms of spasticity. In animals, CBD is effective in reducing the amounts of T-cell infiltrates in the spinal cord, suggesting CBD has anti-inflammatory properties. By doing this, CBD has shown to delay symptom onset in animal models of multiple sclerosis and slow disease progression. Importantly, combinations of CBD and Δ⁹-THC appear more effective in treating animal models of multiple sclerosis. While CBD reduces the amounts of cell infiltrates in the spinal cord, Δ⁹-THC reduces scores of spasticity. In human studies, the results are less encouraging and conflict with the findings in animals. Drugs which deliver a combination of Δ⁹-THC and CBD in a 1:1 ratio appear to be only moderately effective in reducing spasticity scores, but appear to be almost as effective as current front-line treatments and cause less severe side effects than other treatments, such as baclofen (a GABA-B receptor agonist) and tizanidine (an α2 adrenergic receptor agonist). The findings of the studies reviewed suggest that cannabinoids may help treat neuropathic pain in pwMS as an add-on therapy to already established pain treatments. It is important to note that treatment with cannabinoid compounds may cause significant cognitive dysfunction. Long term double-blind placebo studies are greatly needed to further our understanding of the role of cannabinoids in multiple sclerosis treatment. Full article

(This article belongs to the Special Issue Role of Cannabinoids in Inflammation)

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23 pages, 962 KiB

Open AccessReview

Cannabinoids in the Pathophysiology of Skin Inflammation

by Cristian Scheau, Ioana Anca Badarau, Livia-Gratiela Mihai, Andreea-Elena Scheau, Daniel Octavian Costache, Carolina Constantin, Daniela Calina, Constantin Caruntu, Raluca Simona Costache and Ana Caruntu

Molecules 2020, 25(3), 652; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25030652 - 04 Feb 2020

Cited by 60 | Viewed by 12311

Abstract

Cannabinoids are increasingly-used substances in the treatment of chronic pain, some neuropsychiatric disorders and more recently, skin disorders with an inflammatory component. However, various studies cite conflicting results concerning the cellular mechanisms involved, while others suggest that cannabinoids may even exert pro-inflammatory behaviors. This paper aims to detail and clarify the complex workings of cannabinoids in the molecular setting of the main dermatological inflammatory diseases, and their interactions with other substances with emerging applications in the treatment of these conditions. Also, the potential role of cannabinoids as antitumoral drugs is explored in relation to the inflammatory component of skin cancer. In vivo and in vitro studies that employed either phyto-, endo-, or synthetic cannabinoids were considered in this paper. Cannabinoids are regarded with growing interest as eligible drugs in the treatment of skin inflammatory conditions, with potential anticancer effects, and the readiness in monitoring of effects and the facility of topical application may contribute to the growing support of the use of these substances. Despite the promising early results, further controlled human studies are required to establish the definitive role of these products in the pathophysiology of skin inflammation and their usefulness in the clinical setting. Full article

(This article belongs to the Special Issue Role of Cannabinoids in Inflammation)

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39 pages, 574 KiB

Open AccessReview

Microglial Phenotypes and Their Relationship to the Cannabinoid System: Therapeutic Implications for Parkinson’s Disease

by Rachel Kelly, Valerie Joers, Malú G. Tansey, Declan P. McKernan and Eilís Dowd

Molecules 2020, 25(3), 453; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25030453 - 21 Jan 2020

Cited by 29 | Viewed by 7660

Abstract

Parkinson’s disease is a neurodegenerative disorder, the motor symptoms of which are associated classically with Lewy body formation and nigrostriatal degeneration. Neuroinflammation has been implicated in the progression of this disease, by which microglia become chronically activated in response to α-synuclein pathology and dying neurons, thereby acquiring dishomeostatic phenotypes that are cytotoxic and can cause further neuronal death. Microglia have a functional endocannabinoid signaling system, expressing the cannabinoid receptors in addition to being capable of synthesizing and degrading endocannabinoids. Alterations in the cannabinoid system—particularly an upregulation in the immunomodulatory CB₂ receptor—have been demonstrated to be related to the microglial activation state and hence the microglial phenotype. This paper will review studies that examine the relationship between the cannabinoid system and microglial activation, and how this association could be manipulated for therapeutic benefit in Parkinson’s disease. Full article

(This article belongs to the Special Issue Role of Cannabinoids in Inflammation)

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