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Special Issue "Emerging Topics in (Endo)Cannabinoid Signalling"

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

Deadline for manuscript submissions: 31 October 2018

Special Issue Editor

Guest Editor
Prof. Dr. Mauro Maccarrone

Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy;
European Center for Brain Research, Santa Lucia Foundation IRCCS, Rome, Italy
Website | E-Mail
Interests: endocannabinoid signaling; lipoxygenase pathway; Alzheimer's disease; Multiple Sclerosis; apoptosis; arachidonate cascade; resolvins

Special Issue Information

Dear Colleagues,

Extracts of cannabis plants (Cannabis sativa and Cannabis indica) have been used for centuries because of their recreational and therapeutic effects. However, it has only been around 50 years that we have known the identity of their most active principle [Δ9-tetrahydrocannabinol (THC)], and of the >110 compounds collectively termed “phytocannabinoids”. Shortly after the discovery of THC, it was recognized that endogenous ligands of the same targets activated by phytocannabinoids had to be present in our body, a concept that boosted active research leading to the discovery of N-arachidonoylethanolamine, 2-arachidonoylglycerol and other lipids as “endocannabinoids” (eCBs). Then, many more derivatives of ω-6 or ω-3 fatty acids were found to be biologically active eCBs, along with a multitude of compounds that were better considered “eCB-like” substances.

It seems now time to review the manifold actions of phytocannabinoids and eCBs in the central nervous system and at the periphery of our body, and to discuss hot topics and open questions of (endo)cannabinoid signalling that could represent an opportunity to discover new biomarkers and new therapeutic targets for disease treatment.

Prof. Dr. Mauro Maccarrone
Guest Editor

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. Molecules 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 1800 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

  • Biomarkers
  • cannabinoids
  • drug development
  • endocannabinoids
  • epigenetics
  • metabolic enzymes
  • receptors
  • signal transduction
  • trafficking
  • transporters

Published Papers (3 papers)

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Research

Open AccessArticle The Effect of Long-Term Administration of Fatty Acid Amide Hydrolase Inhibitor URB597 on Oxidative Metabolism in the Heart of Rats with Primary and Secondary Hypertension
Molecules 2018, 23(9), 2350; https://doi.org/10.3390/molecules23092350
Received: 26 July 2018 / Revised: 4 September 2018 / Accepted: 12 September 2018 / Published: 14 September 2018
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Abstract
Fatty acid amide hydrolase (FAAH) inhibitor [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate (URB597) may influence redox balance and blood pressure through the modulation of endocannabinoids levels. Therefore, this study aimed to compare changes in oxidative metabolism and apoptosis in the hearts of rats with spontaneous hypertension
[...] Read more.
Fatty acid amide hydrolase (FAAH) inhibitor [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate (URB597) may influence redox balance and blood pressure through the modulation of endocannabinoids levels. Therefore, this study aimed to compare changes in oxidative metabolism and apoptosis in the hearts of rats with spontaneous hypertension (SHR) and secondary hypertension (11-deoxycorticosterone acetate; DOCA-salt rats) treated by URB597 via intraperitoneal injection for 14 days. The results showed that URB597 decreased the activity of NADPH and xanthine oxidases in both groups of rats. Moreover, in the heart of SHR rats, URB597 led to an increase of enzymatic and nonenzymatic antioxidant activity and levels (catalase, vitamin C, glutathione/glutathione disulfide [GSH/GSSG]) and upregulation of the thioredoxin system; however, NRf2 expression was downregulated. The opposite effect in relation to Nrf2 activity and the thioredoxin system was observed in DOCA-salt rats after URB597 administration. Despite improvement in antioxidant parameters, URB597 enhanced oxidative modifications of phospholipids (4-hydroxynonenal and isoprostanes) and proteins (carbonyl groups) in SHR heart, whereas 4-hydroxynonenal and carbonyl groups levels decreased in the heart of DOCA-salt rats. Obtained results suggest that examined lipid mediators are involved in peroxisome proliferator-activated receptors (PPAR)-independent and PPAR-dependent modulation of cardiac inflammatory reactions. Furthermore, decreased expression of pro-apoptotic proteins (Bax and caspase 3 and 9) was observed after URB597 administration in the heart of both groups of hypertensive rats, whereas expression of the antiapoptotic protein (Bcl-2) increased in SHR rats. Long-term administration of URB597 altered cardiac redox status depending on the type of hypertension. URB597 enhanced oxidative metabolism and reduced pro-apoptotic factors in the heart of SHR rats, increasing the probability of heart metabolic disorders occurrence or progression. Full article
(This article belongs to the Special Issue Emerging Topics in (Endo)Cannabinoid Signalling)
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Open AccessArticle Cannabinoid CB2 Receptor Gene and Environmental Interaction in the Development of Psychiatric Disorders
Molecules 2018, 23(8), 1836; https://doi.org/10.3390/molecules23081836
Received: 24 May 2018 / Revised: 18 July 2018 / Accepted: 20 July 2018 / Published: 24 July 2018
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Abstract
CB2 cannabinoid receptor (CB2R) gene is associated with depression. We investigated the gene-environment interaction between CB2R function and diverse stressors. First, anxiety-like behavior during chronic-mild-stress (CMS) was evaluated in C57BL/6JJmsSlc mice following treatment with CB2R agonist JWH015 or inverse-agonist AM630. Second, locomotor activity
[...] Read more.
CB2 cannabinoid receptor (CB2R) gene is associated with depression. We investigated the gene-environment interaction between CB2R function and diverse stressors. First, anxiety-like behavior during chronic-mild-stress (CMS) was evaluated in C57BL/6JJmsSlc mice following treatment with CB2R agonist JWH015 or inverse-agonist AM630. Second, locomotor activity and anxiety-like behavior were measured following exposure to an immune poly I:C stressor. Gene expressions of HPA axis related molecules, Fkbp5, Nr3c1 and Crf and pro-inflammatory cytokine Il-1b, as well as Bdnf as a key neurotrophin that supports neuron health, function, and synaptic plasticity, were determined in hippocampus of Cnr2 knockout mice, as indicators of stressful environment. CMS-induced anxiety-like behavior was enhanced by AM630 and reduced by JWH015 and fluvoxamine. Poly I:C reduced locomotor activity and increased anxiety-like behavior, and these effects were pronounced in the heterozygote than in the wild type mice. Fkbp5 and Nr3c1 expression were lower in the Cnr2 heterozygotes than in the wild type mice with Poly I:C treatment. These findings indicate that interaction between CB2R gene and stressors increases the risk of depression-like behaviors that may be linked with neuro-immune crosstalk. Further studies in human subjects are necessary to determine the role of CB2R and environmental interaction in the development of depression. Full article
(This article belongs to the Special Issue Emerging Topics in (Endo)Cannabinoid Signalling)
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Open AccessArticle In Vitro Inhibitory Effects of Synthetic Cannabinoid EAM-2201 on Cytochrome P450 and UDP-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes
Molecules 2018, 23(4), 920; https://doi.org/10.3390/molecules23040920
Received: 28 March 2018 / Revised: 11 April 2018 / Accepted: 13 April 2018 / Published: 16 April 2018
Cited by 1 | PDF Full-text (3793 KB) | HTML Full-text | XML Full-text
Abstract
EAM-2201, a synthetic cannabinoid, is a potent agonist of the cannabinoid receptors that is widely abused as an illicit recreational drug in combination with other drugs. To evaluate the potential of EAM-2201 as a perpetrator of drug–drug interactions, the inhibitory effects of EAM-2201
[...] Read more.
EAM-2201, a synthetic cannabinoid, is a potent agonist of the cannabinoid receptors that is widely abused as an illicit recreational drug in combination with other drugs. To evaluate the potential of EAM-2201 as a perpetrator of drug–drug interactions, the inhibitory effects of EAM-2201 on major drug-metabolizing enzymes, cytochrome P450s (CYPs) and uridine 5′-diphospho-glucuronosyltransferases (UGTs) were evaluated in pooled human liver microsomes using liquid chromatography–tandem mass spectrometry (LC-MS/MS). EAM-2201 at doses up to 50 µM negligibly inhibited the activities of eight major human CYPs (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) and five UGTs (1A1, 1A4, 1A6, 1A9 and 2B7) in human liver microsomes. EAM-2201 exhibited time-dependent inhibition of CYP2C8-catalyzed amodiaquine N-deethylation, CYP2C9-catalyzed diclofenac 4′-hydroxylation, CYP2C19-catalyzed [S]-mephenytoin 4′-hydroxylation and CYP3A4-catalyzed midazolam 1′-hydroxylation with Ki values of 0.54 µM (kinact: 0.0633 min−1), 3.0 µM (kinact: 0.0462 min−1), 3.8 µM (kinact: 0.0264 min−1) and 4.1 µM (kinact: 0.0250 min−1), respectively and competitively inhibited UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-glucuronidation, with a Ki value of 2.4 µM. Based on these in vitro results, we conclude that EAM-2201 has the potential to trigger in vivo pharmacokinetic drug interactions when co-administered with substrates of CYP2C8, CYP2C9, CYP2C19, CYP3A4 and UGT1A3. Full article
(This article belongs to the Special Issue Emerging Topics in (Endo)Cannabinoid Signalling)
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