Publications by authors named "Vincenzo Di Marzo"

547 Publications

Synthesis and molecular targets of N-13-hydroxy-octadienoyl-ethanolamine, a novel endogenous bioactive 15-lipoxygenase-derived metabolite of N-linoleoyl-ethanolamine found in the skin and saliva.

Biochim Biophys Acta Mol Cell Biol Lipids 2021 Apr 27;1866(8):158954. Epub 2021 Apr 27.

Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Département de médecine, Faculté de médecine, Université Laval, Québec City, QC G1V 4G5, Canada; Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec City, Canada. Electronic address:

N-Arachidonoyl-ethanolamine (AEA) is an endocannabinoid (eCB) and endogenous lipid mimicking many of the effects of Δ-tetrahydrocannabinol, notably on brain functions, appetite, pain and inflammation. The eCBs and eCB-like compounds contain fatty acids, the main classes being the monoacylglycerols and the N-acyl-ethanolamines (NAEs). Thus, each long chain fatty acid likely exists under the form of a monoacylglycerol and NAE, as it is the case for arachidonic acid (AA) and linoleic acid (LA). Following their biosynthesis, AA and AEA can be further metabolized into additional eicosanoids, notably by the 15-lipoxygenase pathway. Thus, we postulated that NAEs possessing a 1Z,4Z-pentadiene motif, near their omega end, would be transformed into their 15-lipoxygenase metabolites. As a proof of concept, we investigated N-linoleoyl-ethanolamine (LAE). We successfully synthesized LEA and LEA-d as well as their 15-lipoxygenase-derived derivatives, namely 13-hydroxy-9Z,11E-octadecadienoyl-N-ethanolamine (13-HODE-EA) and 13-HODE-EA-d, using Novozyme 435 immobilized on acrylic resin and soybean lipoxygenase respectively. We also show that both human 15-lipoxygenase-1 and -2 can biosynthesize 13-HODE-EA. Co-incubation of LEA and LA with either human 15-lipoxygenase led to the biosynthesis of 13-HODE-EA and 13-HODE in a ratio equal to or greater than 3:1, indicating that LEA is preferred to LA by these enzymes. Finally, we show that 13-HODE-EA is found in human saliva and skin and is a weak although selective TRPV1 agonist. The full biological importance of 13-HODE-EA remains to be explored.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbalip.2021.158954DOI Listing
April 2021

Genetic Manipulation of sn-1-Diacylglycerol Lipase and CB Cannabinoid Receptor Gain-of-Function Uncover Neuronal 2-Linoleoyl Glycerol Signaling in .

Cannabis Cannabinoid Res 2021 Apr 15;6(2):119-136. Epub 2021 Apr 15.

Department of Neuroscience, Biomedicum, Karolinska Institutet, Stockholm, Sweden.

In mammals, sn-1-diacylglycerol lipases (DAGL) generate 2-arachidonoylglycerol (2-AG) that, as the major endocannabinoid, modulates synaptic neurotransmission by acting on CB1 cannabinoid receptors (CBR). Even though the insect genome codes for , which is a DAGL ortholog (dDAGL), its products and their functions remain unknown particularly because insects lack chordate-type cannabinoid receptors. Gain-of-function and loss-of-function genetic manipulations were carried out in , including the generation of both dDAGL-deficient and mammalian CBR-overexpressing flies. Neuroanatomy, dietary manipulations coupled with targeted mass spectrometry determination of arachidonic acid and 2-linoleoyl glycerol (2-LG) production, behavioral assays, and signal transduction profiling for Akt and Erk kinases were employed. Findings from were validated by a CBR-binding assay for 2-LG in mammalian cortical homogenates with functionality confirmed in neurons using high-throughput real-time imaging . In this study, we show that dDAGL is primarily expressed in the brain and nerve cord of during larval development and in adult with 2-LG being its chief product as defined by dietary precursor availability. Overexpression of the human CBR in the ventral nerve cord compromised the mobility of adult . The causality of 2-LG signaling to CBR-induced behavioral impairments was shown by inactivation normalizing defunct motor coordination. The 2-LG-induced activation of transgenic CBRs affected both Akt and Erk kinase cascades by paradoxical signaling. Data from models were substantiated by showing 2-LG-mediated displacement of [H]CP 55,940 in mouse cortical homogenates and reduced neurite extension and growth cone collapsing responses in cultured mouse neurons. Overall, these results suggest that 2-LG is an endocannabinoid-like signal lipid produced by dDAGL in .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/can.2020.0010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064960PMC
April 2021

Oleoylglycine and -Oleoylalanine Do Not Modify Tolerance to Nociception, Hyperthermia, and Suppression of Activity Produced by Morphine.

Front Synaptic Neurosci 2021 9;13:620145. Epub 2021 Mar 9.

Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, Canada.

The endogenous amide -Oleoylglycine (OlGly) and its analog -Oleoylalanine (OlAla), have been shown to interfere with the affective and somatic responses to acute naloxone-precipitated MWD in male rats. Here we evaluated the potential of a single dose (5 mg/kg, ip) which alleviates withdrawal of these endogenous fatty acid amides to modify tolerance to anti-nociception, hyperthermia, and suppression of locomotion produced by morphine in male Sprague-Dawley rats. Although rats did develop tolerance to the hypolocomotor and analgesic effects of morphine, they did not develop tolerance to the hyperthermic effects of this substance. Administration of neither OlGly nor OlAla interfered with the establishment of morphine tolerance, nor did they modify behavioral responses elicited by morphine on any trial. These results suggest that the effects of OlGly and OlAla on opiate dependence may be limited to naloxone-precipitated withdrawal effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnsyn.2021.620145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985545PMC
March 2021

A Glucuronic Acid-Palmitoylethanolamide Conjugate (GLUPEA) Is an Innovative Drug Delivery System and a Potential Bioregulator.

Cells 2021 Feb 20;10(2). Epub 2021 Feb 20.

Istituto di Chimica Biomolecolare, CNR, 80078 Pozzuoli, Napoli, Italy.

Palmitoylethanolamide (PEA) is an endogenous anti-inflammatory lipid mediator and a widely used nutraceutical. In this study, we designed, realized, and tested a drug-carrier conjugate between PEA (the active drug) and glucuronic acid (the carrier). The conjugate, named GLUPEA, was characterized for its capability of increasing PEA levels and exerting anti-inflammatory activity both in vitro and in vivo. GLUPEA treatment, compared to the same concentration of PEA, resulted in higher cellular amounts of PEA and the endocannabinoid 2-arachidonoyl glycerol (2-AG), and increased 2-AG-induced transient receptor potential vanilloid type 1 (TRPV1) channel desensitization to capsaicin. GLUPEA inhibited pro-inflammatory monocyte chemoattractant protein 2 (MCP-2) release from stimulated keratinocytes, and it was almost as efficacious as ultra-micronized PEA at reducing colitis in dinitrobenzene sulfonic acid (DNBS)-injected mice when using the same dose. GLUPEA is a novel pro-drug able to efficiently mimic the anti-inflammatory and endocannabinoid enhancing actions of PEA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells10020450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924038PMC
February 2021

Orexin-A/Hypocretin-1 Controls the VTA-NAc Mesolimbic Pathway via Endocannabinoid-Mediated Disinhibition of Dopaminergic Neurons in Obese Mice.

Front Synaptic Neurosci 2021 4;13:622405. Epub 2021 Feb 4.

Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Pozzuoli, Italy.

Disinhibition of orexin-A/hypocretin-1 (OX-A) release occurs to several output areas of the lateral hypothalamus (LH) in the brain of leptin knockout obese mice. In this study, we have investigated whether a similar increase of OX-A release occurs to the ventral tegmental area (VTA), an orexinergic LH output area with functional effects on dopaminergic signaling at the mesolimbic circuit. By confocal and correlative light and electron microscopy (CLEM) morphological studies coupled to molecular, biochemical, and pharmacological approaches, we investigated OX-A-mediated dopaminergic signaling at the LH-VTA-nucleus accumbens (NAc) pathway in obese mice compared to wild-type (wt) lean littermates. We found an elevation of OX-A trafficking and release to the VTA of mice and consequent orexin receptor-1 (OX1R)-mediated over-activation of dopaminergic (DA) neurons via phospholipase C (PLC)/diacylglycerol lipase (DAGL-α)-induced biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). In fact, by retrograde signaling to cannabinoid receptor type 1 (CB1R) at inhibitory inputs to DA neurons, 2-AG inhibited GABA release thus inducing an increase in DA concentration in the VTA and NAc of mice. This effect was prevented by the OX1R antagonist SB-334867 (30 mg/Kg, i.p.), or the CB1R antagonist AM251 (10 mg/Kg, i.p.) and mimicked by OX-A injection (40 μg/Kg, i.p.) in wt lean mice. Enhanced DA signaling to the NAc in mice, or in OX-A-injected wt mice, was accompanied by β-arrestin2-mediated desensitization of dopamine D2 receptor (D2R) in a manner prevented by SB-334867 or the D2R antagonist L741 (1.5 mg/Kg, i.p.). These results further support the role of OX-A signaling in the control of neuroadaptive responses, such as compulsive reward-seeking behavior or binge-like consumption of high palatable food, and suggest that aberrant OX-A trafficking to the DA neurons in the VTA of mice influences the D2R response at NAc, a main target area of the mesolimbic pathway, via 2-AG/CB1-mediated retrograde signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnsyn.2021.622405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890184PMC
February 2021

2-Pentadecyl-2-oxazoline ameliorates memory impairment and depression-like behaviour in neuropathic mice: possible role of adrenergic alpha2- and H3 histamine autoreceptors.

Mol Brain 2021 02 8;14(1):28. Epub 2021 Feb 8.

Department of Experimental Medicine, Pharmacology Division, University of Campania "L. Vanvitelli", 80138, Naples, Italy.

Neuropathic pain (NP) remains an untreatable disease due to the complex pathophysiology that involves the whole pain neuraxis including the forebrain. Sensory dysfunctions such as allodynia and hyperalgesia are only part of the symptoms associated with neuropathic pain that extend to memory and affectivity deficits. The development of multi-target molecules might be a promising therapeutic strategy against the symptoms associated with NP. 2-pentadecyl-2-oxazoline (PEA-OXA) is a plant-derived agent, which has shown effectiveness against chronic pain and associated neuropsychiatric disorders. The molecular mechanisms by which PEA-OXA exerts its effects are, however, only partially known. In the current study, we show that PEA-OXA, besides being an alpha2 adrenergic receptor antagonist, also acts as a modulator at histamine H3 receptors, and report data on its effects on sensory, affective and cognitive symptoms associated with the spared nerve injury (SNI) model of neuropathic pain in mice. Treatment for 14 days with PEA-OXA after the onset of the symptoms associated with neuropathic pain resulted in the following effects: (i) allodynia was decreased; (ii) affective/cognitive impairment associated with SNI (depression, spatial, and working memories) was counteracted; (iii) long-term potentiation in vivo in the lateral entorhinal cortex-dentate gyrus (perforant pathway, LPP) was ameliorated, (iv) hippocampal glutamate, GABA, histamine, norepinephrine and dopamine level alterations after peripheral nerve injury were reversed, (v) expression level of the TH positive neurons in the Locus Coeruleus were normalized. Thus, a 16-day treatment with PEA-OXA alleviates the sensory, emotional, cognitive, electrophysiological and neurochemical alterations associated with SNI-induced neuropathic pain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13041-020-00724-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871413PMC
February 2021

N-palmitoyl-D-glucosamine, a Natural Monosaccharide-Based Glycolipid, Inhibits TLR4 and Prevents LPS-Induced Inflammation and Neuropathic Pain in Mice.

Int J Mol Sci 2021 Feb 2;22(3). Epub 2021 Feb 2.

Department of Experimental Medicine, Pharmacology Division, University of Campania "L. Vanvitelli", 80138 Naples, Italy.

Toll-like receptors (TLRs) are key receptors through which infectious and non-infectious challenges act with consequent activation of the inflammatory cascade that plays a critical function in various acute and chronic diseases, behaving as amplification and chronicization factors of the inflammatory response. Previous studies have shown that synthetic analogues of lipid A based on glucosamine with few chains of unsaturated and saturated fatty acids, bind MD-2 and inhibit TLR4 receptors. These synthetic compounds showed antagonistic activity against TLR4 activation in vitro by LPS, but little or no activity in vivo. This study aimed to show the potential use of -palmitoyl-D-glucosamine (PGA), a bacterial molecule with structural similarity to the lipid A component of LPS, which could be useful for preventing LPS-induced tissue damage or even peripheral neuropathies. Molecular docking and molecular dynamics simulations showed that PGA stably binds MD-2 with a MD-2/(PGA)3 stoichiometry. Treatment with PGA resulted in the following effects: (i) it prevented the NF-kB activation in LPS stimulated RAW264.7 cells; (ii) it decreased LPS-induced keratitis and corneal pro-inflammatory cytokines, whilst increasing anti-inflammatory cytokines; (iii) it normalized LPS-induced miR-20a-5p and miR-106a-5p upregulation and increased miR-27a-3p levels in the inflamed corneas; (iv) it decreased allodynia in peripheral neuropathy induced by oxaliplatin or formalin, but not following spared nerve injury of the sciatic nerve (SNI); (v) it prevented the formalin- or oxaliplatin-induced myelino-axonal degeneration of sciatic nerve. SIGNIFICANCE STATEMENT We report that PGA acts as a TLR4 antagonist and this may be the basis of its potent anti-inflammatory activity. Being unique because of its potency and stability, as compared to other similar congeners, PGA can represent a tool for the optimization of new TLR4 modulating drugs directed against the cytokine storm and the chronization of inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22031491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867376PMC
February 2021

Beneficial Effects of Are Not Associated with Major Changes in the Circulating Endocannabinoidome but Linked to Higher Mono-Palmitoyl-Glycerol Levels as New PPARα Agonists.

Cells 2021 01 19;10(1). Epub 2021 Jan 19.

Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Walloon Excellence in Life sciences and BIOtechnology (WELBIO), UCLouvain, Université Catholique de Louvain, Av. E. Mounier, 73 B1.73.11, 1200 Brussels, Belgium.

is considered as one of the next-generation beneficial bacteria in the context of obesity and associated metabolic disorders. Although a first proof-of-concept of its beneficial effects has been established in the context of metabolic syndrome in humans, mechanisms are not yet fully understood. This study aimed at deciphering whether the bacterium exerts its beneficial properties through the modulation of the endocannabinoidome (eCBome). Circulating levels of 25 endogenous endocannabinoid-related lipids were quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS) in the plasma of overweight or obese individuals before and after a 3 months intervention consisting of the daily ingestion of either alive or pasteurized . Results from multivariate analyses suggested that the beneficial effects of were not linked to an overall modification of the eCBome. However, subsequent univariate analysis showed that the decrease in 1-Palmitoyl-glycerol (1-PG) and 2-Palmitoyl-glycerol (2-PG), two eCBome lipids, observed in the placebo group was significantly counteracted by the alive bacterium, and to a lower extent by the pasteurized form. We also discovered that 1- and 2-PG are endogenous activators of peroxisome proliferator-activated receptor alpha (PPARα). We hypothesize that PPARα activation by mono-palmitoyl-glycerols may underlie part of the beneficial metabolic effects induced by in human metabolic syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells10010185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832901PMC
January 2021

Linking the Endocannabinoidome with Specific Metabolic Parameters in an Overweight and Insulin-Resistant Population: From Multivariate Exploratory Analysis to Univariate Analysis and Construction of Predictive Models.

Cells 2021 01 5;10(1). Epub 2021 Jan 5.

Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Walloon Excellence in Life Sciences and Biotechnology (WELBIO), UCLouvain, Université Catholique de Louvain, Av. E. Mounier, 73 B1.73.11, 1200 Brussels, Belgium.

The global obesity epidemic continues to rise worldwide. In this context, unraveling new interconnections between biological systems involved in obesity etiology is highly relevant. Dysregulation of the endocannabinoidome (eCBome) is associated with metabolic complications in obesity. This study aims at deciphering new associations between circulating endogenous bioactive lipids belonging to the eCBome and metabolic parameters in a population of overweight or obese individuals with metabolic syndrome. To this aim, we combined different multivariate exploratory analysis methods: canonical correlation analysis and principal component analysis, revealed associations between eCBome subsets, and metabolic parameters such as leptin, lipopolysaccharide-binding protein, and non-esterified fatty acids (NEFA). Subsequent construction of predictive regression models according to the linear combination of selected endocannabinoids demonstrates good prediction performance for NEFA. Descriptive approaches reveal the importance of specific circulating endocannabinoids and key related congeners to explain variance in the metabolic parameters in our cohort. Analysis of quartiles confirmed that these bioactive lipids were significantly higher in individuals characterized by important levels for aforementioned metabolic variables. In conclusion, by proposing a methodology for the exploration of large-scale data, our study offers additional evidence of the existence of an interplay between eCBome related-entities and metabolic parameters known to be altered in obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells10010071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824762PMC
January 2021

Deletion of the gene encoding prostamide/prostaglandin F synthase reveals an important role in regulating intraocular pressure.

Prostaglandins Leukot Essent Fatty Acids 2021 Feb 5;165:102235. Epub 2021 Jan 5.

Dept. of Bioengineering, Imperial College London, Prince Consort Road, South Kensington, London, SW7 2AZ, United Kingdom.

Prostamide/prostaglandin F synthase (PM/PGFS) is an enzyme with very narrow substrate specificity and is dedicated to the biosynthesis of prostamide F and prostaglandin F (PGF). The importance of this enzyme, relative to the aldo-keto reductase (AKR) series, in providing functional tissue prostamide F levels was determined by creating a line of PM/PGFS gene deleted mice. Deletion of the gene encoding PM/PGFS (Fam213b / Prxl2b) was accomplished by a two exon disruption. Prostamide F levels in wild type (WT) and PM/PGFS knock-out (KO) mice were determined by LC/MS/MS. Deletion of Fam213b (Prxl2b) had no observed effect on behavior, appetite, or fertility. In contrast, tonometrically measured intraocular pressure was significantly elevated by approximately 4 mmHg in PM/PGFS KO mice compared to littermate WT mice. Outflow facility was measured in enucleated mouse eyes using the iPerfusion system. No effect on pressure dependent outflow facility occurred, which is consistent with the effects of prostamide F and PGF increasing outflow through the unconventional pathway. The elevation of intraocular pressure caused by deletion of the gene encoding the PM/PGFS enzyme likely results from a diversion of the endoperoxide precursor pathway to provide increased levels of those prostanoids known to raise intraocular pressure, namely prostaglandin D (PGD) and thromboxane A (TxA). It follows that PM/PGFS may serve an important regulatory role in the eye by providing PGF and prostamide F to constrain the influence of those prostanoids that raise intraocular pressure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.plefa.2020.102235DOI Listing
February 2021

Knockout Mouse Resistance to Diet-Induced Dysmetabolism Is Associated with Altered Gut Microbiota.

Cells 2020 12 17;9(12). Epub 2020 Dec 17.

Département de Médecine, Université Laval, Québec, QC G1V 0A6, Canada.

Monoglyceride lipase (MGLL) regulates metabolism by catabolizing monoacylglycerols (MAGs), including the endocannabinoid 2-arachidonoyl glycerol (2-AG) and some of its bioactive congeners, to the corresponding free fatty acids. knockout mice () exhibit elevated tissue levels of MAGs in association with resistance to the metabolic and cardiovascular perturbations induced by a high fat diet (HFD). The gut microbiome and its metabolic function are disrupted in obesity in a manner modulated by 2-arachidonoyl glycerol (2-AG's) main receptors, the cannabinoid CB1 receptors. We therefore hypothesized that mice have an altered microbiome, that responds differently to diet-induced obesity from that of wild-type (WT) mice. We subjected mice to HFD and assessed changes in the microbiomes after 8 and 22 weeks. As expected, mice showed decreased adiposity, improved insulin sensitivity, and altered circulating incretin/adipokine levels in response to HFD. mice on a chow diet exhibited significantly higher levels of , , and than WT mice. The relative abundance of the and and of the , , _, and genera was significantly altered by HFD in WT but not mice. Differently abundant families were also associated with changes in circulating adipokine and incretin levels in HFD-fed mice. Some gut microbiota family alterations could be reproduced by supplementing 2-AG or MAGs in culturomics experiments carried out with WT mouse fecal samples. We suggest that the altered microbiome of mice contributes to their obesity resistant phenotype, and results in part from increased levels of 2-AG and MAGs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells9122705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765900PMC
December 2020

The gut microbiome, endocannabinoids and metabolic disorders.

J Endocrinol 2021 Feb;248(2):R83-R97

Director, Joint International Research Unit for the Chemical and Biomolecular Study of the Microbiome in Metabolic Health and Nutrition (JIRU-MicroMeNu) between the Consiglio Nazionale delle Ricerche (CNR, Institute of Biomolecular Chemistry) and Université Laval, Naples, Campania, Italy.

Two complex systems are emerging as being deeply involved in the control of energy metabolism. The intestinal microbiota, with its warehouse of genes, proteins and small molecules, that is, the gut microbiome; and the endocannabinoid system, with its recent extension to a more complex signalling apparatus including more than 100 lipid mediators and 50 proteins, that is, the endocannabinoidome. Both systems can become perturbed following bad dietary habits and during obesity, thus contributing to exacerbating this latter condition and its consequences in both peripheral organs and the brain. Here, we discuss some of the multifaceted aspects of the regulation and dysregulation of the gut microbiome and endocannabinoidome in energy metabolism and metabolic disorders, with special emphasis on the emerging functional interactions between the two systems. The potential exploitation of this new knowledge for the development of new pharmacological and nutritional approaches against obesity and its consequences is also briefly touched upon.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/JOE-20-0444DOI Listing
February 2021

Crosstalk between the transcriptional regulation of dopamine D2 and cannabinoid CB1 receptors in schizophrenia: Analyses in patients and in perinatal Δ9-tetrahydrocannabinol-exposed rats.

Pharmacol Res 2021 Feb 4;164:105357. Epub 2020 Dec 4.

Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, Italy; National Institute of Mental Health, Klecany, Czech Republic. Electronic address:

Perinatal exposure to Δ-tetrahydrocannabinol (THC) affects brain development and might increase the incidence of psychopathology later in life, which seems to be related to a dysregulation of endocannabinoid and/or dopaminergic systems. We here evaluated the transcriptional regulation of the genes encoding for the cannabinoid CB1 receptor (Cnr1) and the dopamine D2 receptor (Drd2) in perinatal THC-(pTHC) exposed male rats, focusing on the role of DNA methylation analyzed by pyrosequencing. Simultaneously, the molecular and behavioral abnormalities at two different time points (i.e., neonatal age and adulthood) and the potential preventive effect of peripubertal treatment with cannabidiol, a non-euphoric component of Cannabis, were assessed. The DRD2 methylation was also evaluated in a cohort of subjects with schizophrenia. We observed an increase in both Cnr1 and Drd2 mRNA levels selectively in the prefrontal cortex of adult pTHC-exposed rats with a consistent reduction in DNA methylation at the Drd2 regulatory region, paralleled by social withdrawal and cognitive impairment which were reversed by cannabidiol treatment. These adult abnormalities were preceded at neonatal age by delayed appearance of neonatal reflexes, higher Drd2 mRNA and lower 2-arachidonoylglycerol (2-AG) brain levels, which persisted till adulthood. Alterations of the epigenetic mark for DRD2 were also found in subjects with schizophrenia. Overall, reported data add further evidence to the dopamine-cannabinoid interaction in terms of DRD2 and CNR1 dysregulation which could be implicated in the pathogenesis of schizophrenia spectrum disorders, suggesting that cannabidiol treatment may normalize pTHC-induced psychopathology by modulating the altered dopaminergic activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phrs.2020.105357DOI Listing
February 2021

Fish Oil, Cannabidiol and the Gut Microbiota: An Investigation in a Murine Model of Colitis.

Front Pharmacol 2020 8;11:585096. Epub 2020 Oct 8.

Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy.

Inflammatory bowel disorders can be associated with alterations in gut microbiota (dysbiosis) and behavioral disturbances. In experimental colitis, administration of fish oil (FO) or cannabinoids, such as cannabidiol (CBD), reduce inflammation. We investigated the effect of combined FO/CBD administration on inflammation and dysbiosis in the dextran sulphate sodium (DSS) model of mouse colitis, which also causes behavioral disturbances. Colitis was induced in CD1 mice by 4% w/v DSS in drinking water for five consecutive days followed by normal drinking water. FO (20-75 mg/mouse) was administered once a day starting two days after DSS, whereas CBD (0.3-30 mg/kg), alone or after FO administration, was administered once a day starting 3 days after DSS, until day 8 (d8) or day 14 (d14). Inflammation was assessed at d8 and d14 (resolution phase; RP) by measuring the Disease Activity Index (DAI) score, change in body weight, colon weight/length ratio, myeloperoxidase activity and colonic interleukin (IL)-1β (IL-1β), IL-10, and IL-6 concentrations. Intestinal permeability was measured with the fluorescein isothiocyanate-dextran. Behavioral tests (novel object recognition (NOR) and light/dark box test) were performed at d8. Fecal microbiota composition was determined by ribosomal 16S DNA sequencing of faecal pellets at d8 and d14. DSS-induced inflammation was stronger at d8 and accompanied by anxiety-like behavior and impaired recognition memory. FO (35, 50, 75 mg/mouse) alone reduced inflammation at d8, whereas CBD alone produced no effect at any of the doses tested; however, when CBD (3, 10 mg/kg) was co-administered with FO (75 mg/mouse) inflammation was attenuated. FO (20 mg/mouse) and CBD (1 mg/kg) were ineffective when given alone, but when co-administered reduced all inflammatory markers and the increased intestinal permeability at both d8 and d14, but not the behavioral impairments. FO, CBD, and their combination affected gut bacteria taxa that were not affected by DSS . , a species suggested to afford anti-inflammatory action in colitis, was increased by DSS only at d14, but its levels were significantly elevated by all treatments at d8. FO and CBD co-administered at ineffective doses reduce colon inflammation, in a manner potentially strengthened by their independent elevation of .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2020.585096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580385PMC
October 2020

The endocannabinoidome as a substrate for noneuphoric phytocannabinoid action and gut microbiome dysfunction in neuropsychiatric disorders
.

Dialogues Clin Neurosci 2020 09;22(3):259-269

Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, Université Laval, Canada; Joint International Unit between Université Laval and Consiglio Nazionale delle Ricerche of Italy on Chemical and Biomolecular Research on the Microbiome and its Impact on Metabolic Health and Nutrition, Istituto di Chimica Biomolecolare, CNR, Pozzuoli (NA), Italy.

The endocannabinoid (eCB) system encompasses the eCBs anandamide and 2-arachidonoylglycerol, their anabolic/catabolic enzymes, and the cannabinoid CB and CB receptors. Its expansion to include several eCB-like lipid mediators, their metabolic enzymes, and their molecular targets, forms the endocannabinoidome (eCBome). This complex signaling system is deeply involved in the onset, progress, and symptoms of major neuropsychiatric disorders and provides a substrate for future therapeutic drugs against these diseases. Such drugs may include not only THC, the major psychotropic component of cannabis, but also other, noneuphoric plant cannabinoids. These compounds, unlike THC, possess a wide therapeutic window, possibly due to their capability of hitting several eCBome and non-eCBome receptors. This is particularly true for cannabidiol, which is one of the most studied cannabinoids and shows promise for the treatment of a wide range of mental and mood disorders. The eCBome plays a role also in the microbiota-gut-brain axis, which is emerging as an important actor in the control of affective and cognitive functions and in their pathological alterations.
.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.31887/DCNS.2020.22.3/vdimarzoDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605024PMC
September 2020

Adverse effects of Δ9-tetrahydrocannabinol on neuronal bioenergetics during postnatal development.

JCI Insight 2020 12 3;5(23). Epub 2020 Dec 3.

Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria.

Ongoing societal changes in views on the medical and recreational roles of cannabis increased the use of concentrated plant extracts with a Δ9-tetrahydrocannabinol (THC) content of more than 90%. Even though prenatal THC exposure is widely considered adverse for neuronal development, equivalent experimental data for young age cohorts are largely lacking. Here, we administered plant-derived THC (1 or 5 mg/kg) to mice daily during P5-P16 and P5-P35 and monitored its effects on hippocampal neuronal survival and specification by high-resolution imaging and iTRAQ proteomics, respectively. We found that THC indiscriminately affects pyramidal cells and both cannabinoid receptor 1+ (CB1R)+ and CB1R- interneurons by P16. THC particularly disrupted the expression of mitochondrial proteins (complexes I-IV), a change that had persisted even 4 months after the end of drug exposure. This was reflected by a THC-induced loss of membrane integrity occluding mitochondrial respiration and could be partially or completely rescued by pH stabilization, antioxidants, bypassed glycolysis, and targeting either mitochondrial soluble adenylyl cyclase or the mitochondrial voltage-dependent anion channel. Overall, THC exposure during infancy induces significant and long-lasting reorganization of neuronal circuits through mechanisms that, in large part, render cellular bioenergetics insufficient to sustain key developmental processes in otherwise healthy neurons.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.135418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714410PMC
December 2020

Design, Synthesis and In Vitro Experimental Validation of Novel TRPV4 Antagonists Inspired by Labdane Diterpenes.

Mar Drugs 2020 Oct 18;18(10). Epub 2020 Oct 18.

Endocannabinoid Research Group (ERG), Institute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy.

Labdane diterpenes are widespread classes of natural compounds present in variety of marine and terrestrial organisms and plants. Many of them represents "natural libraries" of compounds with interesting biological activities due to differently functionalized drimane nucleus exploitable for potential pharmacological applications. The transient receptor potential channel subfamily V member 4 (TRPV4) channel has recently emerged as a pharmacological target for several respiratory diseases, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Inspired by the labdane-like bicyclic core, a series of homodrimane-derived esters and amides was designed and synthesized by modifying the flexible tail in position 1 of (+)-sclareolide, an oxidized derivative of the bioactive labdane-type diterpene sclareol. The potency and selectivity towards rTRPV4 and hTRPV1 receptors were assessed by calcium influx cellular assays. Molecular determinants critical for eliciting TRPV4 antagonism were identified by structure-activity relationships. Among the selective TRPV4 antagonists identified, compound was the most active with an IC of 5.3 μM. This study represents the first report of semisynthetic homodrimane TRPV4 antagonists, selective over TRPV1, and potentially useful as pharmacological tools for the development of novel TRPV4 channel modulators.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/md18100519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594054PMC
October 2020

Efficacy of combined therapy with fish oil and phytocannabinoids in murine intestinal inflammation.

Phytother Res 2021 Jan 30;35(1):517-529. Epub 2020 Sep 30.

Department of Pharmacy, School of Medicine and Pharmacy, University of Naples Federico II, Naples, Italy.

Fish oil (FO) and phytocannabinoids have received considerable attention for their intestinal anti-inflammatory effects. We investigated whether the combination of FO with cannabigerol (CBG) and cannabidiol (CBD) or a combination of all three treatments results in a more pronounced intestinal antiinflammatory action compared to the effects achieved separately. Colitis was induced in mice by 2,4-dinitrobenzenesulfonic acid (DNBS). CBD and CBG levels were detected and quantified by liquid chromatography coupled with time of flight mass spectrometry and ion trap mass spectrometry (LC-MS-IT-TOF). Endocannabinoids and related mediators were assessed by LC-MS. DNBS increased colon weight/colon length ratio, myeloperoxidase activity, interleukin-1β, and intestinal permeability. CBG, but not CBD, given by oral gavage, ameliorated DNBS-induced colonic inflammation. FO pretreatment (at the inactive dose) increased the antiinflammatory action of CBG and rendered oral CBD effective while reducing endocannabinoid levels. Furthermore, the combination of FO, CBD, and a per se inactive dose of CBG resulted in intestinal anti-inflammatory effects. Finally, FO did not alter phytocannabinoid levels in the serum and in the colon. By highlighting the apparent additivity between phytocannabinoids and FO, our preclinical data support a novel strategy of combining these substances for the potential development of a treatment of inflammatory bowel disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ptr.6831DOI Listing
January 2021

Dietary fatty acid intake and gut microbiota determine circulating endocannabinoidome signaling beyond the effect of body fat.

Sci Rep 2020 09 29;10(1):15975. Epub 2020 Sep 29.

Centre Nutrition, Santé et Société (NUTRISS), Institut sur la nutrition et les aliments fonctionnels (INAF), Université Laval, 2440, boulevard Hochelaga, Québec, QC, G1V 0A6, Canada.

The endocannabinoidome encompasses several fatty acid (FA)-derived mediators, including the endocannabinoid anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG), which served as targets for anti-obesity drug development, and their congener N-acyl-ethanolamines (NAEs) and 2-monoacyl-glycerols (2‑MAGs), which are involved in food intake and energy metabolism. Body weight and fat distribution have been suggested as determinants of peripheral endocannabinoid levels. We aimed at investigating factors, beyond body fat composition, that are associated with circulating NAE and 2-MAG levels in a heterogeneous human population. Plasma NAEs and 2-MAGs were measured using LC-MS/MS in a cross-sectional sample of healthy men and women (n = 195) covering a wide range of BMI and individuals before and after a 2-day Mediterranean diet (n = 21). Circulating levels of all 2-MAGs and NAEs, other than N-oleoyl-ethanolamine (OEA), correlated with body fat mass and visceral adipose tissue (0.26 < r < 0.54). NAE levels were elevated in individuals with elevated fat mass, while 2-MAGs were increased in individuals with predominantly visceral body fat distribution. Dietary intakes of specific FAs were associated with 2-AG and omega-3-FA-derived NAEs or 2-MAGs, irrespective of the body fat distribution. Some gut bacterial families (e.g. Veillonellaceae, Peptostreptococcaceae and Akkermansiaceae) were associated with variations in most NAEs or omega-3-FA-derived 2‑MAGs, independently of fat mass and dietary FA intake. Finally, a 2-day Mediterranean diet intervention increased circulating levels of NAEs and 2-MAGs in agreement with changes in FA intake (p < 0.01). Self-reported intake and short-term dietary intervention increased in oleic acid and EPA and DHA intake as well as certain gut microbiota taxa are associated to circulating NAEs and 2‑MAGs independently of adiposity measures, thus highlighting the potential importance of these variables in determining endocannabinoidome signaling in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-72861-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524791PMC
September 2020

Intuitive eating is associated with elevated levels of circulating omega-3-polyunsaturated fatty acid-derived endocannabinoidome mediators.

Appetite 2021 01 21;156:104973. Epub 2020 Sep 21.

Centre Nutrition, Santé et Société (NUTRISS), Institut sur La Nutrition et Les Aliments Fonctionnels (INAF), 2440 Boulevard Hochelaga, Québec, G1V 0A6, QC, Canada; École de Nutrition, Faculté des Sciences de L'agriculture et de L'alimentation (FSAA), Université Laval, 2425 Rue de L'Agriculture, Québec, G1V 0A6, QC, Canada; Canada Research Excellence Chair in the Microbiome-Endocannabinoidome Mediators Axis in Metabolic Health (CERC-MEND), Canada. Electronic address:

The regulation of food intake and eating behaviours involves interactions between different systems. The endocannabinoidome, comprising several fatty acid-derived mediators, plays a central role in the regulation of food intake. Alterations of this system have been suggested to intervene in the aetiology of eating disorders. This study aimed to examine the associations between non-pathological eating behaviours and circulating endocannabinoidome mediators in a heterogeneous human population. Plasma 2-monoacyl-glycerol and N-acyl-ethanolamine congeners were measured by LC-MS/MS in a sample of 190 men and women. Eating behaviours were assessed using the Three-Factor Eating Questionnaire (TFEQ) and the Intuitive Eating Scale-2 (IES-2). Following adjustment for body mass index and age, plasma levels of omega-3 polyunsaturated fatty acid-derived 2-monoacyl-glycerols, 2-eicosapentaenoyl-glycerol (2-EPG) and 2-docosapentaenoyl-glycerol (2-DPG), were associated with higher intuitive eating scores (0.15 ≤ rho ≤ 0.20; p < 0.05). These associations were independent of the dietary intake of the fatty acid precursors of these 2-monoacyl-glycerols. However, almost no association was found between plasma levels of N-acyl-ethanolamine congeners and the TFEQ or the IES-2 scores. The results of the present study suggest the association of 2-monoacyl-glycerols, especially 2-EPG and 2-DPG, in the regulation of intuitive eating and the potential implication therein of bioactive lipids.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.appet.2020.104973DOI Listing
January 2021

Alterations of brain endocannabinoidome signaling in germ-free mice.

Biochim Biophys Acta Mol Cell Biol Lipids 2020 12 11;1865(12):158786. Epub 2020 Aug 11.

Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ), Québec, Canada; Département de médecine, Faculté de Médecine, Université Laval, Québec, Canada; Institut sur la nutrition et les aliments fonctionnels (INAF) and NUTRISS Center, Québec, Canada; École de nutrition, Faculté des sciences de l'agriculture et de l'alimentation (FSAA), Université Laval,Québec, Canada; Joint International Unit between the National Research Council (CNR) of Italy and Université Laval on Chemical and Biomolecular Research on the Microbiome and its Impact on Metabolic Health and Nutrition (UMI-MicroMeNu), Institute of Biomolecular Chemistry, CNR, Pozzuoli, Italy; Canada Research Excellence Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Canada. Electronic address:

We investigated the hypothesis that the endocannabinoidome (eCBome), an extension of the endocannabinoid (eCB) signaling system with important functions in the CNS, may play a role in the microbiota-gut-brain axis. Using LC-MS/MS and qPCR arrays we profiled the brain eCBome of juvenile (4 weeks) and adult (13 weeks) male and female germ-free (GF) mice, which are raised in sterile conditions and virtually devoid of microbiota, present neurophysiological deficits, and were found recently to exhibit a strongly altered gut eCBome in comparison to conventionally raised age/sex-matched controls. The causal effect of the gut microbiome on the eCBome was investigated through the re-introduction into adult male GF mice of a functional gut microbiota by fecal microbiota transfer (FMT). The concentrations of the eCB, 2-arachidonoylglycerol (2-AG), and its 2-monoacylglycerol congeners, were significantly reduced in the brain, but not in the hypothalamus, of both juvenile and adult male and adult female GF mice. FMT rendered these decreases non-statistically significant. The eCB, anandamide (AEA), and its congener N-acylethanolamines (NAEs), were instead increased in the brain of adult female GF mice. Saturated fatty acid-containing NAEs were decreased in adult male GF mouse hypothalamus in a manner not reversed by FMT. Only few changes were observed in the expression of eCBome enzymes and receptors. Our data open the possibility that altered eCBome signaling may underlie some of the brain dysfunctions typical of GF mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbalip.2020.158786DOI Listing
December 2020

Manipulation of Dietary Amino Acids Prevents and Reverses Obesity in Mice Through Multiple Mechanisms That Modulate Energy Homeostasis.

Diabetes 2020 11 10;69(11):2324-2339. Epub 2020 Aug 10.

Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.

Reduced activation of energy metabolism increases adiposity in humans and other mammals. Thus, exploring dietary and molecular mechanisms able to improve energy metabolism is of paramount medical importance because such mechanisms can be leveraged as a therapy for obesity and related disorders. Here, we show that a designer protein-deprived diet enriched in free essential amino acids can ) promote the brown fat thermogenic program and fatty acid oxidation, ) stimulate uncoupling protein 1 (UCP1)-independent respiration in subcutaneous white fat, ) change the gut microbiota composition, and ) prevent and reverse obesity and dysregulated glucose homeostasis in multiple mouse models, prolonging the healthy life span. These effects are independent of unbalanced amino acid ratio, energy consumption, and intestinal calorie absorption. A brown fat-specific activation of the mechanistic target of rapamycin complex 1 seems involved in the diet-induced beneficial effects, as also strengthened by in vitro experiments. Hence, our results suggest that brown and white fat may be targets of specific amino acids to control UCP1-dependent and -independent thermogenesis, thereby contributing to the improvement of metabolic health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db20-0489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576563PMC
November 2020

Anticonvulsive Properties of Cannabidiol in a Model of Generalized Seizure Are Transient Receptor Potential Vanilloid 1 Dependent.

Cannabis Cannabinoid Res 2020 Jun 5;5(2):145-149. Epub 2020 Jun 5.

GW Research Ltd., Cambridge, United Kingdom.

Highly purified cannabidiol (CBD) (approved as Epidiolex in the United States) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut or Dravet syndrome in four randomized controlled trials. CBD possesses affinity for many target classes with functional effects relevant to the pathophysiology of many disease types, including epilepsy. Although the mechanism of action of CBD underlying the reduction of seizures in humans is unknown, transient receptor potential vanilloid 1 (TRPV1) represents a plausible target because (1) CBD activates and then desensitizes TRPV1, (2) TRPV1 is overexpressed in models of temporal lobe epilepsy and patients with epilepsy, (3) and TRPV1 modulates neuronal excitability. To investigate a potential role of TRPV1 in the anticonvulsive effects of CBD, the effect of CBD on seizure threshold was assessed using a mouse maximal electroshock threshold model of generalized seizure in TRPV1 knockout and wildtype mice. The dose dependence of the CBD effect was determined and compared with that of the positive comparator diazepam and vehicle. At 50 and 100 mg/kg, CBD significantly (<0.0001) increased seizure threshold in wildtype mice compared with TRPV1 knockout and vehicle controls. This effect was observed only at 100 mg/kg in TRPV1 knockout mice compared with knockout vehicle mice, in which gene deletion partially attenuated the CBD-increased seizure threshold. The effect of high-dose CBD in wildtype mice was nevertheless significantly different from vehicle-treated TRPV1 knockout mice (<0.0001). Bioanalysis confirmed that genotype-specific differential brain exposure to CBD was not responsible for the observed effect on seizure threshold. These data strongly implicate TRPV1 in the potential mechanisms of action for the anticonvulsive effects of CBD. The partial inhibition of the anticonvulsive effect of high-dose CBD in TRPV1 knockout mice may indicate the involvement of targets other than TRPV1. Further characterization of TRPV1 in the anticonvulsive effect of CBD in validated models of seizure is warranted, as is pharmacological investigation of the molecular interaction between CBD and TRPV1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/can.2019.0028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347071PMC
June 2020

Role of 2-Arachidonoyl-Glycerol and CB1 Receptors in Orexin-A-Mediated Prevention of Oxygen-Glucose Deprivation-Induced Neuronal Injury.

Cells 2020 06 20;9(6). Epub 2020 Jun 20.

Endocannabinoid Research Group, Institute of Biomolecular Chemistry (ICB), National Research Council (CNR), 80078 Pozzuoli (NA), Italy.

Orexin-A (OX-A) protects the brain against oxidative stress-mediated ischemic injury. Since the endocannabinoid 2-arachidonoylglycerol (2-AG) and cannabinoid type-1 (CB1) receptors were previously shown to mediate some of the effects of OX-A exerted through the orexin-1 receptor (OX-1R), we investigated the involvement of 2-AG in OX-A-induced neuroprotection following oxygen and glucose deprivation (OGD) in mouse cortical neurons. OGD-induced reactive oxygen species (ROS) accumulation and neuronal death were prevented by both OX-A and arachidonyl-2'-chloroethylamide (ACEA), a synthetic CB1 receptor agonist, in a manner sensitive to OX-1R and CB1 receptor antagonists, SB334867 and AM251. OX-A stimulated 2-AG biosynthesis in cortical neurons. In neurons isolated from monoacylglycerol lipase (MAGL, a 2-AG hydrolyzing enzyme) null mice, 10-fold higher 2-AG concentrations were found and OGD failed to induce ROS production and cell death, whereas AM251 restored these noxious effects. OX-A-induced neuroprotection was mediated by the phosphoinositide-3-kinase/Akt (PI3K/Akt) survival pathway since both OX-A and ACEA induced phosphorylation of Akt and prevented OGD-induced cytochrome c release from the mitochondria, in a manner counteracted by SB334867 or AM251. Administration of OX-A reduced infarct volume and elevated brain 2-AG levels in a mouse model of transient ischemia. These results suggest that 2-AG and CB1 receptor mediate OX-A prevention of ischemia-induced neuronal apoptosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells9061507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349736PMC
June 2020

Oleoyl alanine (HU595): a stable monomethylated oleoyl glycine interferes with acute naloxone precipitated morphine withdrawal in male rats.

Psychopharmacology (Berl) 2020 Sep 16;237(9):2753-2765. Epub 2020 Jun 16.

Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, N1G 2W1, Canada.

Rationale: Oleoyl glycine, a little studied fatty acid amide similar in structure to anandamide, interferes with nicotine addiction in mice and acute naloxone-precipitated morphine withdrawal (MWD) in rats. Because endogenous oleoyl glycine is subject to rapid enzymatic deactivation, we evaluated the potential of more stable analogs to interfere with opiate withdrawal.

Objectives: The potential of monomethylated oleoyl glycine (oleoyl alanine, HU595) to interfere with somatic and aversive effects of acute naloxone-precipitated MWD, its duration, and mechanism of action was assessed in male Sprague Dawley rats. The potential of dimethylated oleoyl glycine (HU596) to interfere with the aversive effects of naloxone-precipitated MWD was also investigated.

Results: Oleoyl alanine (HU595) interfered with somatic and aversive effects produced by naloxone-precipitated MWD at equivalent doses (1 and 5 mg/kg, i.p.) as we have reported for oleoyl glycine; however, oleoyl alanine produced a longer lasting (60 min) interference, yet did not produce rewarding or aversive effects on its own and did not modify locomotor activity. HU596 was not effective. The interference with aversive effects of naloxone-precipitated MWD by oleoyl alanine was prevented by both a PPARα antagonist and a CB receptor antagonist. Accordingly, the compound was found to inhibit FAAH and activate PPARα in vitro. Finally, oleoyl alanine also reduced acute naloxone-precipitated MWD anhedonia, as measured by decreased saccharin preference.

Conclusions: Oleoyl alanine (also an endogenous fatty acid) may be a more stable and effective treatment for opiate withdrawal than oleoyl glycine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00213-020-05570-4DOI Listing
September 2020

Design, Synthesis, and Physicochemical and Pharmacological Profiling of 7-Hydroxy-5-oxopyrazolo[4,3-]pyridine-6-carboxamide Derivatives with Antiosteoarthritic Activity In Vivo.

J Med Chem 2020 07 22;63(13):7369-7391. Epub 2020 Jun 22.

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.

The hallmark of joint diseases, such as osteoarthritis (OA), is pain, originating from both inflammatory and neuropathic components, and compounds able to modulate the signal transduction pathways of the cannabinoid type-2 receptor (CB2R) can represent a helpful option in the treatment of OA. In this perspective, a set of 18 cannabinoid type-2 receptor (CB2R) ligands was developed based on an unprecedented structure. With the aim of improving the physicochemical properties of previously reported 4-hydroxy-2-quinolone-3-carboxamides, a structural optimization program led to the discovery of isosteric 7-hydroxy-5-oxopyrazolo[4,3-]pyridine-6-carboxamide derivatives. These new compounds are endowed with high affinity for the CB2R and moderate to good selectivity over the cannabinoid type-1 receptor (CB1R), associated with good physicochemical characteristics. As to the functional activity at the CB2R, compounds able to act either as agonists or as inverse agonists/antagonists were discovered. Among them, compound emerged as a potent CB2R agonist able to reduce pain in rats carrying OA induced by injection of monoiodoacetic acid (MIA).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c00595DOI Listing
July 2020

Hepatic NAPE-PLD Is a Key Regulator of Liver Lipid Metabolism.

Cells 2020 05 18;9(5). Epub 2020 May 18.

Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), UCLouvain, Université Catholique de Louvain, Av. E. Mounier, 73 B1.73.11, 1200 Bruxelles, Belgium.

Diverse metabolic disorders have been associated with an alteration of -acylethanolamine (NAE) levels. These bioactive lipids are synthesized mainly by -acylphosphatidylethanolamine-selective phospholipase D (NAPE-PLD) and influence host metabolism. We have previously discovered that NAPE-PLD in the intestine and adipose tissue is connected to the pathophysiology of obesity. However, the physiological function of NAPE-PLD in the liver remains to be deciphered. To study the role of liver NAPE-PLD on metabolism, we generated a new mouse model of inducible hepatocyte-specific deletion ( mice). In this study, we report that mice develop a high-fat diet-like phenotype, characterized by an increased fat mass gain, hepatic steatosis and we show that mice are more sensitive to liver inflammation. We also demonstrate that the role of liver NAPE-PLD goes beyond the mere synthesis of NAEs, since the deletion of NAPE-PLD is associated with a marked modification of various bioactive lipids involved in host homeostasis such as oxysterols and bile acids. Collectively these data suggest that NAPE-PLD in hepatocytes is a key regulator of liver bioactive lipid synthesis and a dysregulation of this enzyme leads to metabolic complications. Therefore, deepening our understanding of the regulation of NAPE-PLD could be crucial to tackle obesity and related comorbidities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells9051247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291298PMC
May 2020

Effects of BPA on zebrafish gonads: Focus on the endocannabinoid system.

Environ Pollut 2020 Sep 1;264:114710. Epub 2020 May 1.

Dipartimento Scienze della Vita e dell'Ambiente, Università Politecnica delle Marche, Via Brecce Bianche, 60131, Ancona, Italy; INBB - Consorzio Interuniversitario di Biosistemi e Biostrutture, 00136, Roma, Italy. Electronic address:

Bisphenol A (BPA), a monomer used for polycarbonate manufacture, has been widely reported as an endocrine-disrupting chemical (EDC). Among other alterations, BPA induces reproductive dysfunctionalities. Changes in the endocannabinoid system (ECS) have been recently shown to be associated with reproductive disorders. The ECS is a lipid-based signaling system (cannabinoid receptors, endocannabinoids and enzymatic machinery) involved in several physiological functions. The main goal of the present study was to assess the effects of two environmental concentrations of BPA (10 and 20 μg/L) on the ECS in 1-year old zebrafish gonads. In males, BPA increased the gonadosomatic index (GSI) and altered testicular levels of endocannabinoids as well as reduced the testicular area occupied by spermatogonia. In male liver, exposure to 20 μg/L BPA significantly increased vitellogenin (vtg) transcript levels. In female zebrafish, BPA altered ovarian endocannabinoid levels, elevated hepatic vtg mRNA levels as well as increased the percentage of vitellogenic oocytes in the ovaries. In conclusion, exposure to two environmentally relevant concentrations of BPA altered the ECS and consequently, gonadal function in both male and female zebrafish.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envpol.2020.114710DOI Listing
September 2020