Publications by authors named "Fabiana Piscitelli"

114 Publications

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.
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http://dx.doi.org/10.3389/fnsyn.2021.622405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890184PMC
February 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.
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http://dx.doi.org/10.1016/j.plefa.2020.102235DOI 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.
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http://dx.doi.org/10.1016/j.phrs.2020.105357DOI Listing
February 2021

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

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.
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http://dx.doi.org/10.2337/db20-0489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576563PMC
November 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.
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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.
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http://dx.doi.org/10.1007/s00213-020-05570-4DOI Listing
September 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.
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http://dx.doi.org/10.1016/j.envpol.2020.114710DOI Listing
September 2020

Altered dopamine D3 receptor gene expression in MAM model of schizophrenia is reversed by peripubertal cannabidiol treatment.

Biochem Pharmacol 2020 07 28;177:114004. Epub 2020 Apr 28.

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

Gestational methylazoxymethanol acetate (MAM) treatment produces offspring with adult phenotype relevant to schizophrenia, including positive- and negative-like symptoms, cognitive deficits, dopaminergic dysfunction, structural and functional abnormalities. Here we show that adult rats prenatally treated with MAM at gestational day 17 display significant increase in dopamine D3 receptor (D3) mRNA expression in prefrontal cortex (PFC), hippocampus and nucleus accumbens, accompanied by increased expression of dopamine D2 receptor (D2) mRNA exclusively in the PFC. Furthermore, a significant change in the blood perfusion at the level of the circle of Willis and hippocampus, paralleled by the enlargement of lateral ventricles, was also detected by magnetic resonance imaging (MRI) techniques. Peripubertal treatment with the non-euphoric phytocannabinoid cannabidiol (30 mg/kg) from postnatal day (PND) 19 to PND 39 was able to reverse in MAM exposed rats: i) the up-regulation of the dopamine D3 receptor mRNA (only partially prevented by haloperidol 0.6 mg/kg/day); and ii) the regional blood flow changes in MAM exposed rats. Molecular modelling predicted that cannabidiol could bind preferentially to dopamine D3 receptor, where it may act as a partial agonist according to conformation of ionic-lock, which is highly conserved in GPCRs. In summary, our results demonstrate that the mRNA expression of both dopamine D2 and D3 receptors is altered in the MAM model; however only the transcript levels of D3 are affected by cannabidiol treatment, likely suggesting that this gene might not only contribute to the schizophrenia symptoms but also represent an unexplored target for the antipsychotic activity of cannabidiol.
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http://dx.doi.org/10.1016/j.bcp.2020.114004DOI Listing
July 2020

Comments on Disruption of the gonadal endocannabinoid system in zebrafish exposed to diisononyl phthalate - Forner-Piquer et al. (2018)": rebuttal to Prosser CM.

Environ Pollut 2020 06 4;261:114028. Epub 2020 Feb 4.

Dipartimento Scienze Della Vita e Dell'Ambiente, Università Politecnica Delle Marche, Via Brecce Bianche, 60131, Ancona, Italy; INBB, Istituto Nazionale Biostrutture e Biosistemi, Consorzio Interuniversitario, 00136, Rome, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.envpol.2020.114028DOI Listing
June 2020

Protective Effects of -Oleoylglycine in a Mouse Model of Mild Traumatic Brain Injury.

ACS Chem Neurosci 2020 04 2;11(8):1117-1128. Epub 2020 Apr 2.

National Research Council, Institute of Biomolecular Chemistry, Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, Naples, Italy.

Traumatic brain injury (TBI) is one of the main causes of death in young people for which currently no efficacious treatment exists. Recently, we have reported that mice with mild-TBI with a specific injury in the insula showed elevated levels of a little investigated -acyl amino acid, -oleoylglycine (OlGly). -acyl amino acids have recently experienced an increased interest because of their important biological activities. They belong to the endocannabinoidome family of lipids with structural similarities with the endocannabinoids (eCBs). The aim of this study was to test the neuroprotective and antihyperalgesic actions of OlGly in a model of mouse mild-TBI (mTBI) and its effect on levels of eCBs and -acylethanolamines at the end of treatment. Following mTBI, mice were administered a daily injection of OlGly (10-50-100 mg/kg i.p.) for 14 days. Treatment with OlGly normalized motor impairment and behavior in the light/dark box test, ameliorated TBI-induced thermal hyperalgesia and mechanical allodynia, and normalized aggressiveness and depression. Moreover, levels of eCBs and some -acylethanolamines underwent significant changes 60 days after TBI, especially in the prefrontal cortex and hypothalamus, and OlGly reversed some of these changes. In conclusion, our findings reveal that OlGly ameliorates the behavioral alterations associated with mTBI in mice, while concomitantly modulating eCB and eCB-like mediator tone.
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http://dx.doi.org/10.1021/acschemneuro.9b00633DOI Listing
April 2020

α-Adrenoceptor agonist induces peripheral antinociception via the endocannabinoid system.

Pharmacol Rep 2020 Feb 10;72(1):96-103. Epub 2020 Jan 10.

Department of Pharmacology, Institute of Biological Sciences, ICB-UFMG, Av. Antônio Carlos, 6627, Pampulha, Belo Horizonte, MG, CEP 31.270-100, Brazil.

Background: Xylazine is an α adrenoceptor agonist that is extensively used in veterinary medicine and animal experimentation procedures to produce analgesia, sedation and muscle relaxation without causing general anesthesia. Considering the lack of knowledge of the mechanisms involved in peripheral antinociception induced by xylazine and the potential interactions between the adrenergic and endocannabinoid systems, the present study investigated the contribution of the latter system in the mechanism of xylazine.

Methods: The rat paw pressure test, in which hyperalgesia was induced by the intraplantar injection of prostaglandin E, was performed.

Results: Xylazine administered via an intraplantar injection (25, 50 and 100 μg) induced a peripheral antinociceptive effect against prostaglandin E (2 μg)-induced hyperalgesia. This effect was blocked by treatment with the selective CB cannabinoid antagonist AM251 (20, 40 and 80 μg) but not by the selective CB cannabinoid antagonist AM630 (100 μg). The anandamide reuptake inhibitor VDM11 (2.5 μg) intensified the peripheral antinociceptive effect of a submaximal dose of xylazine (25 μg), and the inhibitor of endocannabinoid enzymatic hydrolysis, MAFP (0.5 μg), showed a tendency towards this same effect. In addition, liquid-chromatography mass spectrometric analysis indicated that xylazine (100 μg) treatment was associated with an increase in anandamide levels in the rat paws treated with PGE.

Conclusions: The present results provides evidence that the peripheral antinociceptive effect of the α adrenoceptor agonist xylazine probably results from anandamide release and subsequent CB cannabinoid receptor activation.
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http://dx.doi.org/10.1007/s43440-019-00053-6DOI Listing
February 2020

Life-long epigenetic programming of cortical architecture by maternal 'Western' diet during pregnancy.

Mol Psychiatry 2020 01 18;25(1):22-36. Epub 2019 Nov 18.

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

The evolution of human diets led to preferences toward polyunsaturated fatty acid (PUFA) content with 'Western' diets enriched in ω-6 PUFAs. Mounting evidence points to ω-6 PUFA excess limiting metabolic and cognitive processes that define longevity in humans. When chosen during pregnancy, ω-6 PUFA-enriched 'Western' diets can reprogram maternal bodily metabolism with maternal nutrient supply precipitating the body-wide imprinting of molecular and cellular adaptations at the level of long-range intercellular signaling networks in the unborn fetus. Even though unfavorable neurological outcomes are amongst the most common complications of intrauterine ω-6 PUFA excess, cellular underpinnings of life-long modifications to brain architecture remain unknown. Here, we show that nutritional ω-6 PUFA-derived endocannabinoids desensitize CB cannabinoid receptors, thus inducing epigenetic repression of transcriptional regulatory networks controlling neuronal differentiation. We found that cortical neurons lose their positional identity and axonal selectivity when mouse fetuses are exposed to excess ω-6 PUFAs in utero. Conversion of ω-6 PUFAs into endocannabinoids disrupted the temporal precision of signaling at neuronal CB cannabinoid receptors, chiefly deregulating Stat3-dependent transcriptional cascades otherwise required to execute neuronal differentiation programs. Global proteomics identified the immunoglobulin family of cell adhesion molecules (IgCAMs) as direct substrates, with DNA methylation and chromatin accessibility profiling uncovering epigenetic reprogramming at >1400 sites in neurons after prolonged cannabinoid exposure. We found anxiety and depression-like behavioral traits to manifest in adult offspring, which is consistent with genetic models of reduced IgCAM expression, to suggest causality for cortical wiring defects. Overall, our data uncover a regulatory mechanism whose disruption by maternal food choices could limit an offspring's brain function for life.
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http://dx.doi.org/10.1038/s41380-019-0580-4DOI Listing
January 2020

A new mechanism for cannabidiol in regulating the one-carbon cycle and methionine levels in Dictyostelium and in mammalian epilepsy models.

Br J Pharmacol 2020 02 3;177(4):912-928. Epub 2020 Jan 3.

Centre for Biomedical Sciences, Department of Biological Sciences, Royal Holloway University of London, Egham, UK.

Background And Purpose: Epidiolex™, a form of highly purified cannabidiol (CBD) derived from Cannabis plants, has demonstrated seizure control activity in patients with Dravet syndrome, without a fully elucidated mechanism of action. We have employed an unbiased approach to investigate this mechanism at a cellular level.

Experimental Approach: We use a tractable biomedical model organism, Dictyostelium, to identify a protein controlling the effect of CBD and characterize this mechanism. We then translate these results to a Dravet syndrome mouse model and an acute in vitro seizure model.

Key Results: CBD activity is partially dependent upon the mitochondrial glycine cleavage system component, GcvH1 in Dictyostelium, orthologous to the human glycine cleavage system component H protein, which is functionally linked to folate one-carbon metabolism (FOCM). Analysis of FOCM components identified a mechanism for CBD in directly inhibiting methionine synthesis. Analysis of brain tissue from a Dravet syndrome mouse model also showed drastically altered levels of one-carbon components including methionine, and an in vitro rat seizure model showed an elevated level of methionine that is attenuated following CBD treatment.

Conclusions And Implications: Our results suggest a novel mechanism for CBD in the regulating methionine levels and identify altered one-carbon metabolism in Dravet syndrome and seizure activity.
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http://dx.doi.org/10.1111/bph.14892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024701PMC
February 2020

Effects of Dietary Bisphenol A on the Reproductive Function of Gilthead Sea Bream () Testes.

Int J Mol Sci 2019 Oct 10;20(20). Epub 2019 Oct 10.

Dipartimento Scienze della Vita e dell'Ambiente, Università Politecnica delle Marche, Via Brecce Bianche, 60131 Ancona, Italy.

Bisphenol A (BPA), a known endocrine disrupting chemical (EDC), was administered by diet to gilthead sea bream () in order to study its effects on the endocannabinoid system (ECS) and gonadal steroidogenesis. 2-year-old male gilthead sea bream were fed with two different concentrations of BPA (LOW at 4 and HIGH at 4000 µg/kg body weight for 21 days during the reproductive season. Exposure to 4000 µg BPA/kg bw/day (BPA HIGH) reduced sperm motility and altered the straight-line velocity (VSL) and linearity (LIN). Effects on steroidogenesis were evident, with testosterone (T) being up-regulated by both treatments and 11-ketotestosterone (11-KT) down-regulated by BPA HIGH. Plasma levels of 17β-estradiol (E) were not affected. The Gonadosomatic Index (GSI) increased in the BPA HIGH group. Interestingly, the levels of endocannabinoids and endocannabinoid-like compounds were significantly reduced after both treatments. Unpredictably, a few changes were noticed in the expression of genes coding for ECS enzymes, while the receptors were up-regulated depending on the BPA dose. Reproductive markers in testis (leptin receptor (), estrogen receptors (, ), progesterone receptors () and the gonadotropin releasing hormone receptor ()) were up-regulated. BPA induced the up-regulation of the hepatic genes involved in oogenesis (vitellogenin () and zona pellucida 1 ()).
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http://dx.doi.org/10.3390/ijms20205003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835794PMC
October 2019

Different Routes to Inhibit Fatty Acid Amide Hydrolase: Do All Roads Lead to the Same Place?

Int J Mol Sci 2019 Sep 11;20(18). Epub 2019 Sep 11.

Fondazione Santa Lucia IRCCS, Preclinical Neuroscience, Via del Fosso di Fiorano 64, 00143 Rome, Italy.

There is robust evidence indicating that enhancing the endocannabinoid (eCB) tone has therapeutic potential in several brain disorders. The inhibition of eCBs degradation by fatty acid amide hydrolase (FAAH) blockade, is the best-known option to increase -acyl-ethanolamines-(NAEs)-mediated signaling. Here, we investigated the hypothesis that intranasal delivery is an effective route for different FAAH inhibitors, such as URB597 and PF-04457845. URB597 and PF-04457845 were subchronically administered in C57BL/6 male mice every other day for 20 days for overall 10 drug treatment, and compared for their ability to inhibit FAAH activity by the way of three different routes of administration: intranasal (i.n.), intraperitoneal (i.p.) and oral (p.o.). Lastly, we compared the efficacy of the three routes in terms of URB597-induced increase of NAEs levels in liver and in different brain areas. Results: We show that PF-04457845 potently inhibits FAAH regardless the route selected, and that URB597 was less effective in the brain after p.o. administration while reached similar effects by i.n. and i.p. routes. Intranasal URB597 delivery always increased NAEs levels in brain areas, whereas a parallel increase was not observed in the liver. By showing the efficacy of intranasal FAAH inhibition, we provide evidence that nose-to-brain delivery is a suitable alternative to enhance brain eCB tone for the treatment of neurodegenerative disorders and improve patients' compliance.
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http://dx.doi.org/10.3390/ijms20184503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771131PMC
September 2019

Impaired brain endocannabinoid tone in the activity-based model of anorexia nervosa.

Int J Eat Disord 2019 11 27;52(11):1251-1262. Epub 2019 Aug 27.

Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Italy.

Objective: Despite the growing knowledge on the functional relationship between an altered endocannabinoid (eCB) system and development of anorexia nervosa (AN), to date no studies have investigated the central eCB tone in the activity-based anorexia (ABA) model that reproduces key aspects of human AN.

Method: We measured levels of two major eCBs, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), those of two eCB-related lipids, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), and the cannabinoid type-1 receptor (CB1R) density in the brain of female ABA rats, focusing on areas involved in homeostatic and rewarding-related regulation of feeding behavior (i.e., prefrontal cortex, nucleus accumbens, caudato putamen, amygdala, hippocampus and hypothalamus). Analysis was carried out also at the end of recovery from the ABA condition.

Results: At the end of the ABA induction phase, 2-AG was significantly decreased in ABA rats in different brain areas but not in the caudato putamen. No changes were detected in AEA levels in any region, whereas the levels of OEA and PEA were decreased exclusively in the hippocampus and hypothalamus. Furthermore, CB1R density was decreased in the dentate gyrus of hippocampus and in the lateral hypothalamus. After recovery, both 2-AG levels and CB1R density were partially normalized in some areas. In contrast, AEA levels became markedly reduced in all the analyzed areas.

Discussion: These data demonstrate an altered brain eCB tone in ABA rats, further supporting the involvement of an impaired eCB system in AN pathophysiology that may contribute to the maintenance of some symptomatic aspects of the disease.
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http://dx.doi.org/10.1002/eat.23157DOI Listing
November 2019

Role of the Endocannabinoidome in Human and Mouse Atherosclerosis.

Curr Pharm Des 2019 ;25(29):3147-3164

Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ), 2725 Chemin Sainte-Foy, Québec, QC, G1V 4G5, Canada.

The Endocannabinoid (eCB) system and its role in many physiological and pathological conditions is well described and accepted, and includes cardiovascular disorders. However, the eCB system has been expanded to an "-ome"; the endocannabinoidome (eCBome) that includes endocannabinoid-related mediators, their protein targets and metabolic enzymes, many of which significantly impact upon cardiometabolic health. These recent discoveries are here summarized with a special focus on their potential involvement in atherosclerosis. We described the role of classical components of the eCB system (eCBs, CB1 and CB2 receptors) and eCB-related lipids, their regulatory enzymes and molecular targets in atherosclerosis. Furthermore, since increasing evidence points to significant cross-talk between the eCBome and the gut microbiome and the gut microbiome and atherosclerosis, we explore the possibility that a gut microbiome - eCBome axis has potential implications in atherosclerosis.
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http://dx.doi.org/10.2174/1381612825666190826162735DOI Listing
June 2020

Altered Metabolism of Phospholipases, Diacylglycerols, Endocannabinoids, and -Acylethanolamines in Patients with Mastocytosis.

J Immunol Res 2019 1;2019:5836476. Epub 2019 Jul 1.

Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, WAO Center of Excellence, Naples, Italy.

Background: Mastocytosis is a condition characterized by the expansion and accumulation of mast cells (MCs) in various organs. The symptoms are related to the increased release of MC-derived mediators that exert local and distant effects. MCs are a source and target of phospholipase enzymes (PLs), which catalyze the cleavage of membrane phospholipids releasing lipid mediators (e.g., diacylglycerols (DAGs) and the endocannabinoid (EC) 2-arachidonoylglycerol (2-AG)). To date, there are no data on the role of these lipid mediators in mastocytosis. Here, we analyzed plasma levels of PLA, PLC, DAG, ECs, and EC-related -acylethanolamines in patients with mastocytosis.

Methods: In 23 patients with mastocytosis and 23 healthy individuals, we measured plasma PLA and PLC activities, DAG, 2-AG, anandamide (AEA), palmitoylethanolamide (PEA), and oleoylethanolamide (OEA).

Results: Plasma PLA and PLC activities were increased in mastocytosis patients compared to controls. Concentrations of DAG (18:1 20:4 and 18:0 20:4), two second messengers produced by PLC, were higher in mastocytosis compared to controls, whereas the concentrations of their metabolite, 2-AG, were not altered. AEA was decreased in mastocytosis patients compared to controls; by contrast, AEA congener, PEA, was increased. PLA and PLC activities were increased only in patients with mediator-related symptoms. Moreover, PLC activity was positively correlated with disease severity and tryptase concentrations. By contrast, AEA was negatively correlated with tryptase concentrations.

Conclusions: PLs and some lipid mediators are altered in patients with mastocytosis. Our results may pave the way for investigating the functions of these mediators in the pathophysiology of mastocytosis and provide new potential biomarkers and therapeutic targets.
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http://dx.doi.org/10.1155/2019/5836476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636572PMC
December 2019

Cannabidivarin completely rescues cognitive deficits and delays neurological and motor defects in male mutant mice.

J Psychopharmacol 2019 07 14;33(7):894-907. Epub 2019 May 14.

1 Department of Biotechnology and Life Sciences (DBSV), University of Insubria, Varese, Italy.

Background: Recent evidence suggests that 2-week treatment with the non-psychotomimetic cannabinoid cannabidivarin (CBDV) could be beneficial towards neurological and social deficits in early symptomatic mutant mice, a model of Rett syndrome (RTT).

Aim: The aim of this study was to provide further insights into the efficacy of CBDV in -null mice using a lifelong treatment schedule (from 4 to 9 weeks of age) to evaluate its effect on recognition memory and neurological defects in both early and advanced stages of the phenotype progression.

Methods: CBDV 0.2, 2, 20 and 200 mg/kg/day was administered to -null mice from 4 to 9 weeks of age. Cognitive and neurological defects were monitored during the whole treatment schedule. Biochemical analyses were carried out in brain lysates from 9-week-old wild-type and knockout mice to evaluate brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1) levels as well as components of the endocannabinoid system.

Results: CBDV rescues recognition memory deficits in mutant mice and delays the appearance of neurological defects. At the biochemical level, it normalizes BDNF/IGF1 levels and the defective PI3K/AKT/mTOR pathway in mutant mice at an advanced stage of the disease. deletion upregulates CB1 and CB2 receptor levels in the brain and these changes are restored after CBDV treatment.

Conclusions: CBDV administration exerts an enduring rescue of memory deficits in mutant mice, an effect that is associated with the normalization of BDNF, IGF-1 and rpS6 phosphorylation levels as well as CB1 and CB2 receptor expression. CBDV delays neurological defects but this effect is only transient.
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http://dx.doi.org/10.1177/0269881119844184DOI Listing
July 2019

Oleoyl glycine: interference with the aversive effects of acute naloxone-precipitated MWD, but not morphine reward, in male Sprague-Dawley rats.

Psychopharmacology (Berl) 2019 Sep 16;236(9):2623-2633. Epub 2019 Apr 16.

Department of Psychology and Collaborative, University of Guelph, Guelph, Ontario, N1H 2GW, Canada.

Rationale: Oleoyl glycine (OlGly), a recently discovered fatty acid amide that is structurally similar to N- acylethanolamines, which include the endocannabinoid, anandamide (AEA), as well as endogenous peroxisome proliferator-activated receptor alpha (PPARα) agonists oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), has been shown to interfere with nicotine reward and dependence in mice.

Objectives And Methods: Behavioral and molecular techniques were used to investigate the ability of OlGly to interfere with the affective properties of morphine and morphine withdrawal (MWD) in male Sprague-Dawley rats.

Results: Synthetic OlGly (1-30 mg/kg, intraperitoneal [ip]) produced neither a place preference nor aversion on its own; however, at doses of 1 and 5 mg/kg, ip, it blocked the aversive effects of MWD in a place aversion paradigm. This effect was reversed by the cannabinoid 1 (CB1) receptor antagonist, AM251 (1 mg/kg, ip), but not the PPARα antagonist, MK886 (1 mg/kg, ip). OlGly (5 or 30 mg/kg, ip) did not interfere with a morphine-induced place preference or reinstatement of a previously extinguished morphine-induced place preference. Ex vivo analysis of tissue (nucleus accumbens, amygdala, prefrontal cortex, and interoceptive insular cortex) collected from rats experiencing naloxone-precipitated MWD revealed that OlGly was selectively elevated in the nucleus accumbens. MWD did not modify levels of the endocannabinoids 2-AG and AEA, nor those of the PPARα ligands, OEA and PEA, in any region evaluated.

Conclusion: Here, we show that OlGly interferes with the aversive properties of acute naloxone-precipitated morphine withdrawal in rats. These results suggest that OlGly may reduce the impact of MWD and may possess efficacy in treating opiate withdrawal.
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http://dx.doi.org/10.1007/s00213-019-05237-9DOI Listing
September 2019

Altered gut microbiota and endocannabinoid system tone in vitamin D deficiency-mediated chronic pain.

Brain Behav Immun 2020 03 3;85:128-141. Epub 2019 Apr 3.

Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy. Electronic address:

Recent evidence points to the gut microbiota as a regulator of brain and behavior, although it remains to be determined if gut bacteria play a role in chronic pain. The endocannabinoid system is implicated in inflammation and chronic pain processing at both the gut and central nervous system (CNS) levels. In the present study, we used low Vitamin D dietary intake in mice and evaluated possible changes in gut microbiota, pain processing and endocannabinoid system signaling. Vitamin D deficiency induced a lower microbial diversity characterized by an increase in Firmicutes and a decrease in Verrucomicrobia and Bacteroidetes. Concurrently, vitamin D deficient mice showed tactile allodynia associated with neuronal hyperexcitability and alterations of endocannabinoid system members (endogenous mediators and their receptors) at the spinal cord level. Changes in endocannabinoid (anandamide and 2-arachidonoylglycerol) levels were also observed in the duodenum and colon. Remarkably, the anti-inflammatory anandamide congener, palmitoylethanolamide, counteracted both the pain behaviour and spinal biochemical changes in vitamin D deficient mice, whilst increasing the levels of Akkermansia, Eubacterium and Enterobacteriaceae, as compared with vehicle-treated mice. Finally, induction of spared nerve injury in normal or vitamin D deficient mice was not accompanied by changes in gut microbiota composition. Our data suggest the existence of a link between Vitamin D deficiency - with related changes in gut bacterial composition - and altered nociception, possibly via molecular mechanisms involving the endocannabinoid and related mediator signaling systems.
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http://dx.doi.org/10.1016/j.bbi.2019.04.006DOI Listing
March 2020

Systemic administration of serotonin exacerbates abdominal pain and colitis via interaction with the endocannabinoid system.

Biochem Pharmacol 2019 03 3;161:37-51. Epub 2019 Jan 3.

Department Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland. Electronic address:

Background And Aims: Molecular basis of abdominal pain in IBD is not fully characterized. Serotonin (5-HT) increases visceral pain severity and contributes to exacerbation of inflammation. Moreover, it is well established that decreased anandamide (AEA) signaling in the gut increases visceral pain severity. The aim of this study was to investigate the interplay between 5-HT and endocannabinoid signaling in colitis.

Methods: We used 3% DSS in drinking water to induce colitis in mice. From day 3 5-HT was administered for 5 days and each day visceromotor response to colorectal distention (CRD) was measured. Expression of cannabinoid (CB) receptors as well as enzymes responsible of biosynthesis and degradation of endocannabinoids were investigated. Moreover, endocannabinoid levels were assessed by mass spectrometry. Additionally, we measured the expression of enzymes synthesizing 5-HT and AEA in the colon of IBD patients and healthy controls.

Results: Chronic exposure to 5-HT increased visceromotor response to CRD and worsened colitis, which was associated with decrease of AEA via 5-HT and 5-HT receptors. Moreover, exposure to 5-HT led to the downregulation of CB1 receptors. Colonic levels of N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD), which is responsible for synthesis of AEA, significantly declined after chronic treatment with 5-HT and this effect was reversed by the 5-HT and 5-HT receptor antagonists. NAPE-PLD was also downregulated in the colon of UC patients.

Conclusions: Our study shows a link between 5-HT and endocannabinoid signaling pathways in IBD. Thus, pharmacological blockade of 5-HT signaling or supplementation with endocannabinoids in the gut might be of benefit in severe cases of abdominal pain in IBD.
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http://dx.doi.org/10.1016/j.bcp.2019.01.001DOI Listing
March 2019

Effects of diisononyl phthalate (DiNP) on the endocannabinoid and reproductive systems of male gilthead sea bream (Sparus aurata) during the spawning season.

Arch Toxicol 2019 03 2;93(3):727-741. Epub 2019 Jan 2.

Dipartimento Scienze Della Vita e dell'Ambiente, Università Politecnica Delle Marche, Via Brecce Bianche, 60131, Ancona, Italy.

Diisononyl phthalate (DiNP) is a plasticizer used to improve plastic performance in a large variety of items which has been reported as an endocrine-disrupting chemical (EDC) in several organisms. The endocannabinoid system (ECS) is a cellular signaling system, whose functionality is tightly involved with reproductive function. The aim of the present study was the assessment of the effects of DiNP on the gonadal ECS and on the reproductive function of male gilthead sea bream Sparus aurata, an important marine aquacultured species in Europe, during the reproductive season. Fish were fed for 21 days with two diets contaminated with different nominal concentrations of DiNP (DiNP LOW at 15 µg DiNP kg bw day and DiNP HIGH at 1500 µg DiNP kg bw day), based on the tolerable daily intake (TDI) ruled by the European Food Safety Authority for humans. The transcription of several genes related to the ECS was affected by the DiNP. Specifically, DiNP reduced the levels of endocannabinoids and endocannabinoid-like mediators, concomitant with the increase of fatty acid amide hydrolase (FAAH) activity. At the histological level, DiNP LOW induced the highest occurrence of individuals with regressed testes. Steroidogenesis was affected significantly, since plasma 11-ketotestosterone (11-KT), the main active androgen in fish, was significantly decreased by the DiNP HIGH treatment, while plasma 17β-estradiol (E) levels were raised, associated with an increase of the gonadosomatic index (GSI). Additionally, the level of testosterone (T) was significantly increased in the DiNP LOW group, however, the same DiNP concentration reduced the levels of 17,20β-dihydroxy-4-pregnen-3-one (17,20β-P). The production of sperm was in general not affected, since spermiation index, sperm density, survival and the duration of forward motility did not exhibit any changes compared to controls. However, computer-assisted sperm analysis (CASA) showed that DiNP reduced the percentage of motile cells. The results clearly suggest a negative effect of DiNP via the diet on the male endocrine system of gilthead sea bream during the reproductive season.
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http://dx.doi.org/10.1007/s00204-018-2378-6DOI Listing
March 2019

Peripubertal cannabidiol treatment rescues behavioral and neurochemical abnormalities in the MAM model of schizophrenia.

Neuropharmacology 2019 03 26;146:212-221. Epub 2018 Nov 26.

Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, School of Medicine, University of Catania, Catania, Italy; CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic; National Institute of Mental Health, Klecany, Czech Republic. Electronic address:

In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produced long-lasting behavioral alterations such as social withdrawal and cognitive impairment in the social interaction test and in the novel object recognition test, respectively. At the molecular level, an increased cannabinoid receptor type-1 (CB1) mRNA and protein expression, which might be due to reduction in DNA methylation at the gene promoter in the prefrontal cortex (PFC), coincided with deficits in the social interaction test and in the novel object recognition test in MAM rats. Both the schizophrenia-like phenotype and altered transcriptional regulation of CB1 receptors were reversed by peripubertal treatment (from PND 19 to PND 39) with the non-psychotropic phytocannabinoid cannabidiol (30 mg/kg/day), or, in part, by treatment with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day), but not with haloperidol (0.6 mg/kg/day). These results suggest that early treatment with cannabidiol may prevent both the appearance of schizophrenia-like deficits as well as CB1 alterations in the PFC at adulthood, supporting that peripubertal cannabidiol treatment might be protective against MAM insult.
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http://dx.doi.org/10.1016/j.neuropharm.2018.11.035DOI Listing
March 2019

Ultra-micronized palmitoylethanolamide rescues the cognitive decline-associated loss of neural plasticity in the neuropathic mouse entorhinal cortex-dentate gyrus pathway.

Neurobiol Dis 2019 01 25;121:106-119. Epub 2018 Sep 25.

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

Chronic pain is associated with cognitive deficits. Palmitoylethanolamide (PEA) has been shown to ameliorate pain and pain-related cognitive impairments by restoring glutamatergic synapses functioning in the spared nerve injury (SNI) of the sciatic nerve in mice. SNI reduced mechanical and thermal threshold, spatial memory and LTP at the lateral entorhinal cortex (LEC)-dentate gyrus (DG) pathway. It decreased also postsynaptic density, volume and dendrite arborization of DG and increased the expression of metabotropic glutamate receptor 1 and 7 (mGluR1 and mGluR7), of the GluR1, GluR1s845 and GluR1s831 subunits of AMPA receptor and the levels of glutamate in the DG. The level of the endocannabinoid 2-arachidonoylglycerol (2-AG) was instead increased in the LEC. Chronic treatment with PEA, starting from when neuropathic pain was fully developed, was able to reverse mechanical allodynia and thermal hyperalgesia, memory deficit and LTP in SNI wild type, but not in PPARα null, mice. PEA also restored the level of glutamate and the expression of phosphorylated GluR1 subunits, postsynaptic density and neurogenesis. Altogether, these results suggest that neuropathic pain negatively affects cognitive behavior and related LTP, glutamatergic synapse and synaptogenesis in the DG. In these conditions PEA treatment alleviates pain and cognitive impairment by restoring LTP and synaptic maladaptative changes in the LEC-DG pathway. These outcomes open new perspectives for the use of the N-acylethanolamines, such as PEA, for the treatment of neuropathic pain and its central behavioural sequelae.
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http://dx.doi.org/10.1016/j.nbd.2018.09.023DOI Listing
January 2019

Genetic and pharmacological regulation of the endocannabinoid CB1 receptor in Duchenne muscular dystrophy.

Nat Commun 2018 09 27;9(1):3950. Epub 2018 Sep 27.

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

The endocannabinoid system refers to a widespread signaling system and its alteration is implicated in a growing number of human diseases. However, the potential role of endocannabinoids in skeletal muscle disorders remains unknown. Here we report the role of the endocannabinoid CB1 receptors in Duchenne's muscular dystrophy. In murine and human models, CB1 transcripts show the highest degree of expression at disease onset, and then decline overtime. Similar changes are observed for PAX7, a key regulator of muscle stem cells. Bioinformatics and biochemical analysis reveal that PAX7 binds and upregulates the CB1 gene in dystrophic more than in healthy muscles. Rimonabant, an antagonist of CB1, promotes human satellite cell differentiation in vitro, increases the number of regenerated myofibers, and prevents locomotor impairment in dystrophic mice. In conclusion, our study uncovers a PAX7-CB1 cross talk potentially exacerbating DMD and highlights the role of CB1 receptors as target for potential therapies.
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http://dx.doi.org/10.1038/s41467-018-06267-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160489PMC
September 2018

FAAH-Catalyzed C-C Bond Cleavage of a New Multitarget Analgesic Drug.

ACS Chem Neurosci 2019 01 4;10(1):424-437. Epub 2018 Oct 4.

Department of Chemical Sciences , University of Naples "Federico II" , Naples 80126 , Italy.

The discovery of extended catalytic versatilities is of great importance in both the chemistry and biotechnology fields. Fatty acid amide hydrolase (FAAH) belongs to the amidase signature superfamily and is a major endocannabinoid inactivating enzyme using an atypical catalytic mechanism involving hydrolysis of amide and occasionally ester bonds. FAAH inhibitors are efficacious in experimental models of neuropathic pain, inflammation, and anxiety, among others. We report a new multitarget drug, AGN220653, containing a carboxyamide-4-oxazole moiety and endowed with efficacious analgesic and anti-inflammatory activities, which are partly due to its capability of achieving inhibition of FAAH, and subsequently increasing the tissue concentrations of the endocannabinoid anandamide. This inhibitor behaves as a noncompetitive, slowly reversible inhibitor. Autoradiography of purified FAAH incubated with AGN220653, opportunely radiolabeled, indicated covalent binding followed by fragmentation of the molecule. Molecular docking suggested a possible nucleophilic attack by FAAH-Ser241 on the carbonyl group of the carboxyamide-4-oxazole moiety, resulting in the cleavage of the C-C bond between the oxazole and the carboxyamide moieties, instead of either of the two available amide bonds. MRM-MS analyses only detected the Ser241-assisted formation of the carbamate intermediate, thus confirming the cleavage of the aforementioned C-C bond. Quantum mechanics calculations were fully consistent with this mechanism. The study exemplifies how FAAH structural features and mechanism of action may override the binding and reactivity propensities of substrates. This unpredicted mechanism could pave the way to the future development of a completely new class of amidase inhibitors, of potential use against pain, inflammation, and mood disorders.
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http://dx.doi.org/10.1021/acschemneuro.8b00315DOI Listing
January 2019

Author Correction: CB receptor activation induces intracellular Ca mobilization and 2-arachidonoylglycerol release in rodent spinal cord astrocytes.

Sci Rep 2018 Sep 7;8(1):13715. Epub 2018 Sep 7.

Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-30573-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128844PMC
September 2018