Publications by authors named "Cinzia Rapino"

40 Publications

Cannabinoid signalling and effects of cannabis on the male reproductive system.

Nat Rev Urol 2021 Jan 19;18(1):19-32. Epub 2020 Nov 19.

Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.

Marijuana is the most widely consumed recreational drug worldwide, which raises concerns for its potential effects on fertility. Many aspects of human male reproduction can be modulated by cannabis-derived extracts (cannabinoids) and their endogenous counterparts, known as endocannabinoids (eCBs). These latter molecules act as critical signals in a variety of physiological processes through receptors, enzymes and transporters collectively termed the endocannabinoid system (ECS). Increasing evidence suggests a role for eCBs, as well as cannabinoids, in various aspects of male sexual and reproductive health. Although preclinical studies have clearly shown that ECS is involved in negative modulation of testosterone secretion by acting both at central and testicular levels in animal models, the effect of in vivo exposure to cannabinoids on spermatogenesis remains a matter of debate. Furthermore, inconclusive clinical evidence does not seem to support the notion that plant-derived cannabinoids have harmful effects on human sexual and reproductive health. An improved understanding of the complex crosstalk between cannabinoids and eCBs is required before targeting of ECS for modulation of human fertility becomes a reality.
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http://dx.doi.org/10.1038/s41585-020-00391-8DOI Listing
January 2021

Corrigendum to "Artificial Neural Network to Predict Varicocele Impact on Male Fertility through Testicular Endocannabinoid Gene Expression Profiles".

Biomed Res Int 2020 19;2020:2368941. Epub 2020 May 19.

Faculty of Biosciences and Technology for Food, Agriculture and Environment, University of Teramo, 64100 Teramo, Italy.

[This corrects the article DOI: 10.1155/2018/3591086.].
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http://dx.doi.org/10.1155/2020/2368941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275221PMC
May 2020

Characterization of Endocannabinoid System and Interleukin Profiles in Ovine AEC: Cannabinoid Receptors Type-1 and Type-2 as Key Effectors of Pro-Inflammatory Response.

Cells 2020 04 18;9(4). Epub 2020 Apr 18.

Faculty of Bioscience and Agri-Food and Environmental Technology, University of Teramo, Teramo 64100, Italy.

Amniotic epithelial cells (AEC) have been proposed as promising clinical candidates for regenerative medicine therapies due to their immunomodulatory capacity. In this context, the endocannabinoid system (ECS) has been identified as mediating the immune-stem cell dialogue, even if no information on AEC is available to date. Therefore, this study was designed to assess whether ECS is involved in tuning the constitutive and lipopolysaccharide (LPS)-induced ovine AEC anti-inflammatory and pro-inflammatory interleukin (IL-10, IL-4, and IL-12) profiles. Firstly, interleukins and ECS expressions were studied at different stages of gestation. Then, the role of cannabinoid receptors 1 and 2 (CB1 and CB2) on interleukin expression and release was investigated in middle stage AEC using selective agonists and antagonists. AEC displayed a degradative more than a synthetic endocannabinoid metabolism during the early and middle stages of gestation. At the middle stage, cannabinoid receptors mediated the balance between pro-inflammatory (IL-12) and anti-inflammatory (IL-4 and IL-10) interleukins. The activation of both receptors mediated an overall pro-inflammatory shift-CB1 reduced the anti-inflammatory and CB2 increased the pro-inflammatory interleukin release, particularly after LPS stimulation. Altogether, these data pave the way for the comprehension of AEC mechanisms tuning immune-modulation, crucial for the development of new AEC-based therapy protocols.
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http://dx.doi.org/10.3390/cells9041008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226065PMC
April 2020

CSF Levels of the Endocannabinoid Anandamide are Reduced in Patients with Untreated Narcolepsy Type 1: A Pilot Study.

CNS Neurol Disord Drug Targets 2020 ;19(2):142-147

Campus Bio-Medico University of Rome, Italy.

Background: Endocannabinoids (ECs) modulate both excitatory and inhibitory components in the CNS. There is a growing body of evidence that shows ECs influence both hypothalamic orexinergic and histaminergic neurons involved in narcolepsy physiopathology. Therefore, ECs may influence sleep and sleep-wake cycle.

Objective: To evaluate EC levels in the CSF of untreated narcoleptic patients to test whether ECs are dysregulated in Narcolepsy Type 1 (NT1) and Type 2 (NT2).

Methods: We compared CSF Anandamide (AEA), 2-Arachidonoylglycerol (2-AG) and orexin in narcoleptic drug-naïve patients and in a sample of healthy subjects.

Results: We compared NT1 (n=6), NT2 (n=6), and healthy controls (n=6). We found significantly reduced AEA levels in NT1 patients compared to both NT2 and controls. No differences were found between AEA levels in NT2 versus controls and between 2-AG levels in all groups, although a trend toward a decrease in NT1 was evident. Finally, the CSF AEA level was related to CSF orexin levels in all subjects.

Conclusion: We demonstrated that the EC system is dysregulated in NT1.
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http://dx.doi.org/10.2174/1871527319666200309115602DOI Listing
January 2020

The (endo)cannabinoid signaling in female reproduction: What are the latest advances?

Prog Lipid Res 2020 01 18;77:101019. Epub 2019 Dec 18.

Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy; European Center for Brain Research (CERC)/Santa Lucia Foundation, Via del Fosso di Fiorano, 64 - 00143 Rome, Italy. Electronic address:

Cannabis extracts like marijuana have the highest consumption rate worldwide. Yet, their societal acceptance as recreational and therapeutic drugs could represent a serious hazard to female human reproduction, because cannabis ingredients [termed (phyto)cannabinoids] can perturb an endogenous system of lipid signals known as endocannabinoids. Accumulated evidence on animal models and humans has demonstrated a crucial role of these endogenous signals on different aspects of female reproduction, where they act through an ensamble of proteins that synthesize, transport, degrade and traffic them. Several reports have recently evidenced the potential role of endocannabinoids as biomarkers of female infertility for disease treatment and prevention, as well as their possible epigenetic effects on pregnancy. The purpose of this review is to provide an update of data collected in the last decade on the effects of cannabinoids and endocannabinoids on female reproductive events, from development and maturation of follicles and oocytes, to fertilization, oviductal transport, implantation and labor. In this context, a particular attention has been devoted to the ovary and the production of fertilizable oocytes, because recent studies have addressed this hot topic with conflicting results among species.
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http://dx.doi.org/10.1016/j.plipres.2019.101019DOI Listing
January 2020

The endocannabinoid system is affected by cholesterol dyshomeostasis: Insights from a murine model of Niemann Pick type C disease.

Neurobiol Dis 2019 10 11;130:104531. Epub 2019 Jul 11.

Fondazione Santa Lucia, IRCCS, Via del Fosso di Fiorano 64, 00179, Italy; Department of Psychology, Division of Neuroscience and "Daniel Bovet" Neurobiology Research Center, Sapienza University of Rome, Via dei Sardi 70, 00185 Rome, Italy. Electronic address:

The dyshomeostasis of intracellular cholesterol trafficking is typical of the Niemann-Pick type C (NPC) disease, a fatal inherited lysosomal storage disorder presenting with progressive neurodegeneration and visceral organ involvement. In light of the well-established relevance of cholesterol in regulating the endocannabinoid (eCB) system expression and activity, this study was aimed at elucidating whether NPC disease-related cholesterol dyshomeostasis affects the functional status of the brain eCB system. To this end, we exploited a murine model of NPC deficiency for determining changes in the expression and activity of the major molecular components of the eCB signaling, including cannabinoid type-1 and type-2 (CB and CB) receptors, their ligands, N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), along with their main synthesizing/inactivating enzymes. We found a robust alteration of distinct components of the eCB system in various brain regions, including the cortex, hippocampus, striatum and cerebellum, of Npc1-deficient compared to wild-type pre-symptomatic mice. Changes of the eCB component expression and activity differ from one brain structure to another, although 2-AG and AEA are consistently found to decrease and increase in each structure, respectively. The thorough biochemical characterization of the eCB system was accompanied by a behavioral characterization of Npc1-deficient mice using a number of paradigms evaluating anxiety, locomotor activity, spatial learning/memory abilities, and coping response to stressful experience. Our findings provide the first description of an early and region-specific alteration of the brain eCB system in NPC and suggest that defective eCB signaling could contribute at producing and/or worsening the neurological symptoms of this disorder.
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http://dx.doi.org/10.1016/j.nbd.2019.104531DOI Listing
October 2019

Modulation of Endocannabinoid-Binding Receptors in Human Neuroblastoma Cells by Tunicamycin.

Molecules 2019 Apr 11;24(7). Epub 2019 Apr 11.

Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy.

Endocannabinoid (eCB)-binding receptors can be modulated by several ligands and membrane environment, yet the effect of glycosylation remains to be assessed. In this study, we used human neuroblastoma SH-SY5Y cells to interrogate whether expression, cellular localization, and activity of eCB-binding receptors may depend on -linked glycosylation. Following treatment with tunicamycin (a specific inhibitor of -linked glycosylation) at the non-cytotoxic dose of 1 µg/mL, mRNA, protein levels and localization of eCB-binding receptors, as well as -acetylglucosamine (GlcNAc) residues, were evaluated in SH-SY5Y cells by means of quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR), fluorescence-activated cell sorting (FACS), and confocal microscopy, respectively. In addition, the activity of type-1 and type-2 cannabinoid receptors (CB₁ and CB₂) was assessed by means of rapid binding assays. Significant changes in gene and protein expression were found upon tunicamycin treatment for CB₁ and CB₂, as well as for GPR55 receptors, but not for transient receptor potential vanilloid 1 (TRPV1). Deglycosylation experiments with -glycosidase-F and immunoblot of cell membranes derived from SH-SY5Y cells confirmed the presence of one glycosylated form in CB₁ (70 kDa), that was reduced by tunicamycin. Morphological studies demonstrated the co-localization of CB₁ with GlcNAc residues, and showed that tunicamycin reduced CB₁ membrane expression with a marked nuclear localization, as confirmed by immunoblotting. Cleavage of the carbohydrate side chain did not modify CB receptor binding affinity. Overall, these results support -linked glycosylation as an unprecedented post-translational modification that may modulate eCB-binding receptors' expression and localization, in particular for CB₁.
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http://dx.doi.org/10.3390/molecules24071432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479803PMC
April 2019

Artificial Neural Network to Predict Varicocele Impact on Male Fertility through Testicular Endocannabinoid Gene Expression Profiles.

Biomed Res Int 2018 13;2018:3591086. Epub 2018 Nov 13.

Faculty of Biosciences and Technology for Food, Agriculture and Environment, University of Teramo, 64100 Teramo, Italy.

The relationship between varicocele and fertility has always been a matter of debate because of the absence of predictive clinical indicators or molecular markers able to define the severity of this disease. Even though accumulated evidence demonstrated that the endocannabinoid system (ECS) plays a central role in male reproductive biology, particularly in the testicular compartment, to date no data point to a role for ECS in the etiopathogenesis of varicocele. Therefore, the present research has been designed to investigate the relationship between testicular ECS gene expression and fertility, using a validated animal model of experimental varicocele (VAR), taking advantage of traditional statistical approaches and artificial neural network (ANN). Experimental induction of VAR led to a clear reduction of spermatogenesis in left testes ranging from a mild (Johnsen score 7: 21%) to a severe (Johnsen score 4: 58%) damage of the germinal epithelium. However, the mean number of new-borns recorded after two sequential matings was quite variable and independent of the Johnsen score. While the gene expression of biosynthetic and degrading enzymes of AEA (NAPE-PLD and FAAH, respectively) and of 2-AG (DAGL and MAGL, respectively), as well as their binding cannabinoid receptors (CB and CB), did not change between testes and among groups, a significant downregulation of vanilloid (TRPV1) expression was recorded in left testes of VAR rats and positively correlated with animal fertility. Interestingly, an ANN trained by inserting the left and right testicular ECS gene expression profiles (inputs) was able to predict varicocele impact on male fertility in terms of mean number of new-borns delivered (outputs), with a very high accuracy (average prediction error of 1%). The present study provides unprecedented information on testicular ECS gene expression patterns during varicocele, by developing a freely available predictive ANN model that may open new perspectives in the diagnosis of varicocele-associated infertility.
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http://dx.doi.org/10.1155/2018/3591086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258097PMC
March 2019

Neuroprotection by (endo)Cannabinoids in Glaucoma and Retinal Neurodegenerative Diseases.

Curr Neuropharmacol 2018 ;16(7):959-970

Department of Medicine, Campus Bio- Medico University of Rome, 00128 Rome, Italy.

Background: Emerging neuroprotective strategies are being explored to preserve the retina from degeneration, that occurs in eye pathologies like glaucoma, diabetic retinopathy, age-related macular degeneration, and retinitis pigmentosa. Incidentally, neuroprotection of retina is a defending mechanism designed to prevent or delay neuronal cell death, and to maintain neural function following an initial insult, thus avoiding loss of vision.

Methods: Numerous studies have investigated potential neuroprotective properties of plant-derived phytocannabinoids, as well as of their endogenous counterparts collectively termed endocannabinoids (eCBs), in several degenerative diseases of the retina. eCBs are a group of neuromodulators that, mainly by activating G protein-coupled type-1 and type-2 cannabinoid (CB1 and CB2) receptors, trigger multiple signal transduction cascades that modulate central and peripheral cell functions. A fine balance between biosynthetic and degrading enzymes that control the right concentration of eCBs has been shown to provide neuroprotection in traumatic, ischemic, inflammatory and neurotoxic damage of the brain.

Results: Since the existence of eCBs and their binding receptors was documented in the retina of numerous species (from fishes to primates), their involvement in the visual processing has been demonstrated, more recently with a focus on retinal neurodegeneration and neuroprotection.

Conclusion: The aim of this review is to present a modern view of the endocannabinoid system, in order to discuss in a better perspective available data from preclinical studies on the use of eCBs as new neuroprotective agents, potentially useful to prevent glaucoma and retinal neurodegenerative diseases.
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http://dx.doi.org/10.2174/1570159X15666170724104305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120105PMC
October 2018

Modulation of Type-1 and Type-2 Cannabinoid Receptors by Saffron in a Rat Model of Retinal Neurodegeneration.

PLoS One 2016 18;11(11):e0166827. Epub 2016 Nov 18.

Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy.

Experimental studies demonstrated that saffron (Crocus sativus) given as a dietary supplement counteracts the effects of bright continuous light (BCL) exposure in the albino rat retina, preserving both morphology and function and probably acting as a regulator of programmed cell death [1]. The purpose of this study was to ascertain whether the neuroprotective effect of saffron on rat retina exposed to BCL is associated with a modulation of the endocannabinoid system (ECS). To this aim, we used eight experimental groups of Sprague-Dawley rats, of which six were exposed to BCL for 24 hours. Following retinal function evaluation, retinas were quickly removed for biochemical and morphological analyses. Rats were either saffron-prefed or intravitreally injected with selective type-1 (CB1) or type-2 (CB2) cannabinoid receptor antagonists before BCL. Prefeeding and intravitreally injections were combined in two experimental groups before BCL. BCL exposure led to enhanced gene and protein expression of retinal CB1 and CB2 without affecting the other ECS elements. This effect of BCL on CB1 and CB2 was reversed by saffron treatment. Selective CB1 and CB2 antagonists reduced photoreceptor death, preserved morphology and visual function of retina, and mitigated the outer nuclear layer (ONL) damage due to BCL. Of interest, CB2-dependent neuroprotection was more pronounced than that conferred by CB1. These data suggest that BCL modulates only distinct ECS elements like CB1 and CB2, and that saffron and cannabinoid receptors could share the same mechanism in order to afford retinal protection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0166827PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5115823PMC
June 2017

Anandamide Suppresses Proinflammatory T Cell Responses In Vitro through Type-1 Cannabinoid Receptor-Mediated mTOR Inhibition in Human Keratinocytes.

J Immunol 2016 11 30;197(9):3545-3553. Epub 2016 Sep 30.

Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy;

The endocannabinoid system comprises cannabinoid receptors 1 and 2 (CB and CB), their endogenous ligands, anandamide (AEA) and 2-arachidonoylglycerol, and metabolic enzymes of these ligands. The endocannabinoid system has recently been implicated in the regulation of various pathophysiological processes of the skin that include immune competence and/or tolerance of keratinocytes, the disruption of which might promote the development of skin diseases. Recent evidence showed that CB in keratinocytes limits the secretion of proinflammatory chemokines, suggesting that this receptor might also regulate T cell dependent inflammatory diseases of the skin. In this article, we sought to investigate the cytokine profile of IFN-γ-activated keratinocytes, and found that CB activation by AEA suppressed production and release of signature T1- and T17-polarizing cytokines, IL-12 and IL-23, respectively. We also set up cocultures between a conditioned medium of treated keratinocytes and naive T cells to disclose the molecular details that regulate the activation of highly proinflammatory T1 and T17 cells. AEA-treated keratinocytes showed reduced an induction of IFN-γ-producing T1 and IL-17-producing T17 cells, and these effects were reverted by pharmacological inhibition of CB Further analyses identified mammalian target of rapamycin as a proinflammatory signaling pathway regulated by CB, able to promote either IL-12 and IL-23 release from keratinocytes or T1 and T17 polarization. Taken together, these findings demonstrate that AEA suppresses highly pathogenic T cell subsets through CB-mediated mammalian target of rapamycin inhibition in human keratinocytes. Thus, it can be speculated that the latter pathway might be beneficial to the physiological function of the skin, and can be targeted toward inflammation-related skin diseases.
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http://dx.doi.org/10.4049/jimmunol.1500546DOI Listing
November 2016

Potential Therapeutic Value of a Novel FAAH Inhibitor for the Treatment of Anxiety.

PLoS One 2015 11;10(9):e0137034. Epub 2015 Sep 11.

School of Medicine, Campus Bio-Medico University of Rome, Rome, Italy; Centro Europeo di Ricerca sul Cervello (CERC)/IRCCS Fondazione Santa Lucia, Rome, Italy.

Anxiety disorders are among the most prevalent psychiatric diseases with high personal costs and a remarkable socio-economic burden. However, current treatment of anxiety is far from satisfactory. Novel pharmacological targets have emerged in the recent years, and attention has focused on the endocannabinoid (eCB) system, given the increasing evidence that supports its central role in emotion, coping with stress and anxiety. In the management of anxiety disorders, drug development strategies have left apart the direct activation of type-1 cannabinoid receptors to indirectly enhance eCB signalling through the inhibition of eCB deactivation, that is, the inhibition of the fatty acid amide hydrolase (FAAH) enzyme. In the present study, we provide evidence for the anxiolytic-like properties of a novel, potent and selective reversible inhibitor of FAAH, ST4070, orally administered to rodents. ST4070 (3 to 30 mg/kg per os) administered to CD1 male mice induced an increase of time spent in the exploration of the open arms of the elevated-plus maze. A partial reduction of anxiety-related behaviour by ST4070 was also obtained in Wistar male rats, which moderately intensified the time spent in the illuminated compartment of the light-dark box. ST4070 clearly inhibited FAAH activity and augmented the levels of two of its substrates, N-arachidonoylethanolamine (anandamide) and N-palmitoylethanolamine, in anxiety-relevant brain regions. Altogether, ST4070 offers a promising anxiolytic-like profile in preclinical studies, although further studies are warranted to clearly demonstrate its efficacy in the clinic management of anxiety disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137034PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567375PMC
May 2016

Truffles contain endocannabinoid metabolic enzymes and anandamide.

Phytochemistry 2015 Feb 26;110:104-10. Epub 2014 Nov 26.

European Center for Brain Research/IRCCS Santa Lucia Foundation, Rome, Italy; Center of Integrated Research, Campus Bio-Medico University of Rome, Rome, Italy. Electronic address:

Truffles are the fruiting body of fungi, members of the Ascomycota phylum endowed with major gastronomic and commercial value. The development and maturation of their reproductive structure are dependent on melanin synthesis. Since anandamide, a prominent member of the endocannabinoid system (ECS), is responsible for melanin synthesis in normal human epidermal melanocytes, we thought that ECS might be present also in truffles. Here, we show the expression, at the transcriptional and translational levels, of most ECS components in the black truffle Tuber melanosporum Vittad. at maturation stage VI. Indeed, by means of molecular biology and immunochemical techniques, we found that truffles contain the major metabolic enzymes of the ECS, while they do not express the most relevant endocannabinoid-binding receptors. In addition, we measured anandamide content in truffles, at different maturation stages (from III to VI), through liquid chromatography-mass spectrometric analysis, whereas the other relevant endocannabinoid 2-arachidonoylglycerol was below the detection limit. Overall, our unprecedented results suggest that anandamide and ECS metabolic enzymes have evolved earlier than endocannabinoid-binding receptors, and that anandamide might be an ancient attractant to truffle eaters, that are well-equipped with endocannabinoid-binding receptors.
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http://dx.doi.org/10.1016/j.phytochem.2014.11.012DOI Listing
February 2015

A functional interplay between 5-lipoxygenase and μ-calpain affects survival and cytokine profile of human Jurkat T lymphocyte exposed to simulated microgravity.

Biomed Res Int 2014 16;2014:782390. Epub 2014 Sep 16.

European Center for Brain Research (CERC), IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 64-65, 00143 Rome, Italy ; Center of Integrated Research, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy.

A growing body of evidence strongly indicates that both simulated and authentic weightlessness exert a broad range of effects on mammalian tissues and cells, including impairment of immune cell function and increased apoptotic death. We previously reported that microgravity-dependent activation of 5-lipoxygenase (5-LOX) might play a central role in the initiation of apoptosis in human T lymphocytes, suggesting that the upregulation of this enzyme might be (at least in part) responsible for immunodepression observed in astronauts during space flights. Herein, we supplement novel information about the molecular mechanisms underlying microgravity-triggered apoptotic cell death and immune system deregulation, demonstrating that under simulated microgravity human Jurkat T cells increase the content of cytosolic DNA fragments and cytochrome c (typical hallmarks of apoptosis) and have an upregulated expression and activity of µ-calpain. These events were paralleled by the unbalance of interleukin- (IL-) 2 and interferon- (INF-) γ, anti- and proapoptotic cytokines, respectively, that seemed to be dependent on the functional interplay between 5-LOX and µ-calpain. Indeed, we report unprecedented evidence that 5-LOX inhibition reduced apoptotic death, restored the initial IL-2/INF-γ ratio, and more importantly reverted µ-calpain activation induced by simulated microgravity.
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http://dx.doi.org/10.1155/2014/782390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182306PMC
July 2015

Distinct modulation of the endocannabinoid system upon kainic acid-induced in vivo seizures and in vitro epileptiform bursting.

Mol Cell Neurosci 2014 Sep 24;62:1-9. Epub 2014 Jul 24.

European Center for Brain Research/Fondazione Santa Lucia, via del Fosso di Fiorano 65, 00143 Rome, Italy; EBRI-Rita Levi Montalcini, via del Fosso di Fiorano 65, 00143 Rome, Italy. Electronic address:

There is clear evidence on the neuroprotective role of the endocannabinoid (eCB) signaling cascade in various models of epilepsy. In particular, increased levels of eCBs protect against kainic acid (KA)-induced seizures. However, the molecular mechanisms underlying this effect and its age-dependence are still unknown. To clarify this issue, we investigated which step of the biosynthetic and catabolic pathways of the eCBs may be responsible for the eCB-mediated neuroprotection in the hippocampus of P14 and P56-70 KA-treated rats. We found that both anandamide and N-palmitoylethanolamine, together with their biosynthetic enzyme significantly increased in the hippocampus of younger KA-treated rats, while decreasing in adults. In contrast, the levels of the other major eCB, 2-arachidonoylglycerol, similar to its biosynthetic enzyme, were higher in the hippocampus of P56-70 compared to P14 rats. In line with these data, extracellular field recordings in CA1 hippocampus showed that enhancement of endogenous AEA and 2-AG significantly counteracted KA-induced epileptiform bursting in P56-70 and P14 rats, respectively. On the contrary, while the CB1R antagonist SR141716 per se did not affect the population spike, it did worsen KA-induced bursts, confirming increased eCB tone upon KA treatment. Altogether these data indicate an age-specific alteration of the eCB system caused by KA and provide insights for the protective mechanism of the cannabinoid system against epileptiform discharges.
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http://dx.doi.org/10.1016/j.mcn.2014.07.003DOI Listing
September 2014

Prior stimulation of the endocannabinoid system prevents methamphetamine-induced dopaminergic neurotoxicity in the striatum through activation of CB2 receptors.

Neuropharmacology 2014 Dec 5;87:214-21. Epub 2014 Apr 5.

INSERM, U1084, Experimental and Clinical Neurosciences Laboratory, Neurobiology and Neuropharmacology of Addiction, F-86022 Poitiers, France; University of Poitiers, U1084, F-86022 Poitiers, France. Electronic address:

Methamphetamine toxicity is associated with cell death and loss of dopamine neuron terminals in the striatum similar to what is found in some neurodegenerative diseases. Conversely, the endocannabinoid system (ECS) has been suggested to be neuroprotective in the brain, and new pharmacological tools have been developed to increase their endogenous tone. In this study, we evaluated whether ECS stimulation could reduce the neurotoxicity of high doses of methamphetamine on the dopamine system. We found that methamphetamine alters the levels of the major endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in the striatum, suggesting that the ECS participates in the brain responses to methamphetamine. Δ(9)-tetrahydrocannabinol (THC), a cannabis-derived agonist of both CB1 and CB2 cannabinoid receptors, or inhibitors of the main enzymes responsible for the degradation of AEA and 2-AG (URB597 and JZL184, respectively), blunted the decrease in striatal protein levels of tyrosine hydroxylase induced by methamphetamine. In addition, antagonists of CB2, but not of CB1, blocked the preventive effects of URB597 and JZL184, suggesting that only the former receptor subtype is engaged in neuroprotection exerted by ECS stimulation. Finally, we found that methamphetamine increases striatal levels of the cytokine tumor necrosis factor alpha, an effect that was blocked by ECS stimulation. Altogether, our results indicate that stimulation of ECS prior to the administration of an overdose of methamphetamine considerably reduces the neurotoxicity of the drug through CB2 receptor activation and highlight a protective function for the ECS against the toxicity induced by drugs and other external insults to the brain. This article is part of the Special Issue entitled 'CNS Stimulants'.
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http://dx.doi.org/10.1016/j.neuropharm.2014.03.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939842PMC
December 2014

Detailed characterization of the endocannabinoid system in human macrophages and foam cells, and anti-inflammatory role of type-2 cannabinoid receptor.

Atherosclerosis 2014 Mar 8;233(1):55-63. Epub 2014 Jan 8.

European Center for Brain Research (CERC)/I.R.C.C.S. Santa Lucia Foundation, Rome, Italy; Center of Integrated Research, Campus Bio-Medico University of Rome, Rome, Italy. Electronic address:

Objective: Cannabinoid receptors are activated in murine macrophages upon exposure to oxidized low-density lipoproteins (oxLDL), and type-1 cannabinoid receptor (CB1R) is considered as a risk factor in atherosclerosis, because it promotes cholesterol accumulation and release of inflammatory mediators. Conversely, accumulated evidence suggests a protective role for type-2 cannabinoid receptor (CB2R). Here, we sought to ascertain whether different elements of the endocannabinoid system (ECS) were activated in human lipid-laden macrophages, and whether CB2R played any role in atherogenesis and inflammation of these cells.

Methods And Results: Human macrophages were exposed to oxLDL in order to obtain lipid-laden foam cells. Liquid chromatography/mass spectrometry (LC/MS) was used to measure the production of the endocannabinoids in both macrophages and foam cells, and radiometric assays were performed to measure cannabinoid receptor binding and activity of endocannabinoid metabolizing enzymes. OxLDL accumulation was investigated by confocal imaging, and cytokine production and release were measured by means of flow cytometry and ELISA. The results showed that human macrophages possess a fully functional ECS, which was modulated by oxLDL. Selective CB2R activation reduced cellular oxLDL accumulation, which was associated with decreased expression of CD36 scavenger receptor, and decreased production of TNFα, IL-12 and IL-10. These anti-atherogenic and anti-inflammatory effects were reverted by the selective CB2R antagonist SR144528.

Conclusions: A fully active ECS is present in human macrophages and macrophage-derived foam cells. Selective activation of CB2R reduces CD36-dependent oxLDL accumulation and modulates production of inflammatory cytokines, thus representing a potential therapeutic strategy to combat atherosclerosis.
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http://dx.doi.org/10.1016/j.atherosclerosis.2013.12.042DOI Listing
March 2014

Endocannabinoids as biomarkers of human reproduction.

Hum Reprod Update 2014 Jul-Aug;20(4):501-16. Epub 2014 Feb 9.

European Center for Brain Research/IRCCS Santa Lucia Foundation, Rome, Italy Center of Integrated Research, Campus Bio-Medico University of Rome, Rome, Italy

Background: Infertility is a condition of the reproductive system that affects ∼10-15% of couples attempting to conceive a baby. More than half of all cases of infertility are a result of female conditions, while the remaining cases can be attributed to male factors, or to a combination of both. The search for suitable biomarkers of pregnancy outcome is a challenging issue in human reproduction, aimed at identifying molecules with predictive significance of the reproductive potential of male and female gametes. Among the various candidates, endocannabinoids (eCBs), and in particular anandamide (AEA), represent potential biomarkers of human fertility disturbances. Any perturbation of the balance between synthesis and degradation of eCBs will result in local changes of their tone in human female and male reproductive tracts, which in turn regulates various pathophysiological processes, oocyte and sperm maturation included.

Methods: PubMed and Web of Science databases were searched for papers using relevant keywords like 'biomarker', 'endocannabinoid', 'infertility', 'pregnancy' and 'reproduction'.

Results: In this review, we discuss different studies on the measurements of AEA and related eCBs in human reproductive cells, tissues and fluids, where the local contribution of these bioactive lipids could be critical in ensuring normal sperm fertilizing ability and pregnancy.

Conclusion: Based on the available data, we suggest that the AEA tone has the potential to be exploited as a novel diagnostic biomarker of infertility, to be used in association with assays of conventional hormones (e.g. progesterone, β-chorionic gonadotrophin) and semen analysis. However further quantitative research of its predictive capacity is required.
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http://dx.doi.org/10.1093/humupd/dmu004DOI Listing
September 2014

Epigenetic control of skin differentiation genes by phytocannabinoids.

Br J Pharmacol 2013 Oct;170(3):581-91

Department of Biomedical Sciences, University of Teramo, Teramo, Italy.

Background And Purpose: Endocannabinoid signalling has been shown to have a role in the control of epidermal physiology, whereby anandamide is able to regulate the expression of skin differentiation genes through DNA methylation. Here, we investigated the possible epigenetic regulation of these genes by several phytocannabinoids, plant-derived cannabinoids that have the potential to be novel therapeutics for various human diseases.

Experimental Approach: The effects of cannabidiol, cannabigerol and cannabidivarin on the expression of skin differentiation genes keratins 1 and 10, involucrin and transglutaminase 5, as well as on DNA methylation of keratin 10 gene, were investigated in human keratinocytes (HaCaT cells). The effects of these phytocannabinoids on global DNA methylation and the activity and expression of four major DNA methyltransferases (DNMT1, 3a, 3b and 3L) were also examined.

Key Results: Cannabidiol and cannabigerol significantly reduced the expression of all the genes tested in differentiated HaCaT cells, by increasing DNA methylation of keratin 10 gene, but cannabidivarin was ineffective. Remarkably, cannabidiol reduced keratin 10 mRNA through a type-1 cannabinoid (CB1 ) receptor-dependent mechanism, whereas cannabigerol did not affect either CB1 or CB2 receptors of HaCaT cells. In addition, cannabidiol, but not cannabigerol, increased global DNA methylation levels by selectively enhancing DNMT1 expression, without affecting DNMT 3a, 3b or 3L.

Conclusions And Implications: These findings show that the phytocannabinoids cannabidiol and cannabigerol are transcriptional repressors that can control cell proliferation and differentiation. This indicates that they (especially cannabidiol) have the potential to be lead compounds for the development of novel therapeutics for skin diseases.
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http://dx.doi.org/10.1111/bph.12309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791996PMC
October 2013

Emotional, endocrine and brain anandamide response to social challenge in infant male rats.

Psychoneuroendocrinology 2013 Oct 6;38(10):2152-62. Epub 2013 May 6.

Sect. Behavioural Neuroscience, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena, 299, Rome, 00161, Italy.

Individual response to stress is orchestrated by hypothalamus-pituitary axis corticosteroids, although critically modulated by the central endocannabinoid (eCB) system. Whilst the role of the eCB system in stress response and emotional homeostasis in adult animals has been extensively studied, it has only been scarcely investigated in developing animals. Herein, we aimed to investigate the participation of eCB ligands in the stress responses of neonate rats. Twelve days-old Wistar male rats were exposed to a social challenge (repeated brief isolations from dam and littermates), which resulted in a significant increase in serum corticosterone levels. This stressful social challenge also decreased spontaneous rat pups' behaviours and augmented isolation-induced ultrasonic vocalizations. Notably, a specific decrease in anandamide content (not 2-AG) was observed within the hippocampus (not in the striatum). However, the enhancement of eCB signalling by URB597 administration (0.1mg/kg) did not affect the adrenocortical and behavioural responses to this postnatal social challenge. The influence of gestational stress was also evaluated in the infant offspring of rats dams exposed to restraint stress (PRS, three episodes/day, on gestation days 14 till delivery); however, PRS did not modify neonate responses to this postnatal challenge. Present findings provide evidence for the participation of the eCB system in the acute response to a social challenge in infant male rats. However, the lack of evidences from the pharmacological study encourages the investigation of alternative and/or indirect mechanisms that may participate in the behavioural and endocrine response to stress in developing animals. Further experiments are still needed to clarify the interactions between the HPA axis and the eCB system in stress reactivity at early postnatal stages.
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http://dx.doi.org/10.1016/j.psyneuen.2013.04.004DOI Listing
October 2013

Altered expression of type-1 and type-2 cannabinoid receptors in celiac disease.

PLoS One 2013 19;8(4):e62078. Epub 2013 Apr 19.

Department of Biomedical Sciences, University of Teramo, Teramo, Italy.

Anandamide (AEA) is the prominent member of the endocannabinoid family and its biological action is mediated through the binding to both type-1 (CB1) and type-2 (CB2) cannabinoid receptors (CBR). The presence of AEA and CBR in the gastrointestinal tract highlighted their pathophysiological role in several gut diseases, including celiac disease. Here, we aimed to investigate the expression of CBR at transcriptional and translational levels in the duodenal mucosa of untreated celiac patients, celiac patients on a gluten-free diet for at least 12 months and control subjects. Also biopsies from treated celiac patients cultured ex vivo with peptic-tryptic digest of gliadin were investigated. Our data show higher levels of both CB1 and CB2 receptors during active disease and normal CBR levels in treated celiac patients. In conclusion, we demonstrate an up-regulation of CB1 and CB2 mRNA and protein expression, that points to the therapeutic potential of targeting CBR in patients with celiac disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0062078PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631143PMC
November 2013

Differences in the endocannabinoid system of sperm from fertile and infertile men.

PLoS One 2012 17;7(10):e47704. Epub 2012 Oct 17.

School of Medicine, Centre for Public Health, Queen's University Belfast, Institute of Clinical Science, Belfast, United Kingdom.

Male infertility is a major cause of problems for many couples in conceiving a child. Recently, lifestyle pastimes such as alcohol, tobacco and marijuana have been shown to have further negative effects on male reproduction. The endocannabinoid system (ECS), mainly through the action of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) at cannabinoid (CB(1), CB(2)) and vanilloid (TRPV1) receptors, plays a crucial role in controlling functionality of sperm, with a clear impact on male reproductive potential. Here, sperm from fertile and infertile men were used to investigate content (through LC-ESI-MS), mRNA (through quantitative RT-PCR), protein (through Western Blotting and ELISA) expression, and functionality (through activity and binding assays) of the main metabolic enzymes of AEA and 2-AG (NAPE-PLD and FAAH, for AEA; DAGL and MAGL for 2-AG), as well as of their binding receptors CB(1), CB(2) and TRPV1. Our findings show a marked reduction of AEA and 2-AG content in infertile seminal plasma, paralleled by increased degradation: biosynthesis ratios of both substances in sperm from infertile versus fertile men. In addition, TRPV1 binding was detected in fertile sperm but was undetectable in infertile sperm, whereas that of CB(1) and CB(2) receptors was not statistically different in the two groups. In conclusion, this study identified unprecedented alterations of the ECS in infertile sperm, that might impact on capacitation and acrosome reaction, and hence fertilization outcomes. These alterations might also point to new biomarkers to determine male reproductive defects, and identify distinct ECS elements as novel targets for therapeutic exploitation of ECS-oriented drugs to treat male fertility problems.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0047704PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3474715PMC
April 2013

The novel reversible fatty acid amide hydrolase inhibitor ST4070 increases endocannabinoid brain levels and counteracts neuropathic pain in different animal models.

J Pharmacol Exp Ther 2012 Jul 18;342(1):188-95. Epub 2012 Apr 18.

Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina km. 30,400, 00040 Pomezia, Italy.

The effect of the enol carbamate 1-biphenyl-4-ylethenyl piperidine-1-carboxylate (ST4070), a novel reversible inhibitor of fatty acid amide hydrolase (FAAH), was investigated for acute pain sensitivity and neuropathic pain in rats and mice. Brain enzymatic activity of FAAH and the endogenous levels of its substrates, anandamide (AEA; N-arachidonoylethanolamine), 2-arachidonoylglycerol (2-AG), and N-palmitoylethanolamine (PEA), were measured in control and ST4070-treated mice. ST4070 (10, 30, and 100 mg/kg) was orally administered to assess mechanical nociceptive thresholds and allodynia by using the Randall-Selitto and von Frey tests, respectively. Neuropathy was induced in rats by either the chemotherapeutic agent vincristine or streptozotocin-induced diabetes, whereas the chronic constriction injury (CCI) model was chosen to evaluate neuropathy in mice. ST4070 produced a significant increase of nociceptive threshold in rats and counteracted the decrease of nociceptive threshold in the three distinct models of neuropathic pain. In diabetic mice, ST4070 inhibited FAAH activity and increased the brain levels of AEA and PEA, without affecting that of 2-AG. The administration of ST4070 generated long-lasting pain relief compared with pregabalin and the FAAH inhibitors 1-oxo-1[5-(2-pyridyl)-2-yl]-7-phenylheptane (OL135) and cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-ylester (URB597) in CCI neuropathic mice. The antiallodynic effects of ST4070 were prevented by pretreatment with cannabinoid type 1 and cannabinoid type 2 receptor antagonists and by the selective peroxisome proliferator-activated receptor α antagonist [(2S)-2-[[(1Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl]amino]-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl]-carbamic acid ethyl ester (GW6471). The administration of ST4070 generated long-lasting neuropathic pain relief compared with pregabalin and the FAAH inhibitors OL135 and URB597. Taken together, the reversible FAAH inhibitor ST4070 seems to be a promising novel therapeutic agent for the management of neuropathic pain.
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http://dx.doi.org/10.1124/jpet.111.191403DOI Listing
July 2012

Endocannabinoids stimulate human melanogenesis via type-1 cannabinoid receptor.

J Biol Chem 2012 May 19;287(19):15466-78. Epub 2012 Mar 19.

Department of Biomedical Sciences, University of Teramo, 64100 Teramo, Italy.

We show that a fully functional endocannabinoid system is present in primary human melanocytes (normal human epidermal melanocyte cells), including anandamide (AEA), 2-arachidonoylglycerol, the respective target receptors (CB(1), CB(2), and TRPV1), and their metabolic enzymes. We also show that at higher concentrations AEA induces normal human epidermal melanocyte apoptosis (∼3-fold over controls at 5 μM) through a TRPV1-mediated pathway that increases DNA fragmentation and p53 expression. However, at lower concentrations, AEA and other CB(1)-binding endocannabinoids dose-dependently stimulate melanin synthesis and enhance tyrosinase gene expression and activity (∼3- and ∼2-fold over controls at 1 μM). This CB(1)-dependent activity was fully abolished by the selective CB(1) antagonist SR141716 or by RNA interference of the receptor. CB(1) signaling engaged p38 and p42/44 mitogen-activated protein kinases, which in turn activated the cyclic AMP response element-binding protein and the microphthalmia-associated transcription factor. Silencing of tyrosinase or microphthalmia-associated transcription factor further demonstrated the involvement of these proteins in AEA-induced melanogenesis. In addition, CB(1) activation did not engage the key regulator of skin pigmentation, cyclic AMP, showing a major difference compared with the regulation of melanogenesis by α-melanocyte-stimulating hormone through melanocortin 1 receptor.
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http://dx.doi.org/10.1074/jbc.M111.314880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3346111PMC
May 2012

5-Lipoxygenase-dependent apoptosis of human lymphocytes in the International Space Station: data from the ROALD experiment.

FASEB J 2012 May 17;26(5):1791-8. Epub 2012 Jan 17.

Department of Biomedical Sciences, University of Teramo, Piazza A. Moro 45, I-64100 Teramo, Italy.

The functional adaptation of the immune system to the surrounding environment is also a fundamental issue in space. It has been suggested that a decreased number of lymphocytes might be a cause of immunosuppression, possibly due to the induction of apoptosis. Early activation of 5-lipoxygenase (5-LOX) might play a central role in the initiation of the apoptotic program. The goal of the role of apoptosis in lymphocyte depression (ROALD) experiment, flown on the International Space Station as part of the BIO-4 mission of the European Space Agency, was to ascertain the induction of apoptosis in human lymphocytes under authentic microgravity, and to elucidate the possible involvement of 5-LOX. Our results demonstrate that exposure of human lymphocytes to microgravity for 48 h onboard the ISS remarkably increased apoptotic hallmarks such as DNA fragmentation (∼3-fold compared to ground-based controls) and cleaved-poly (ADP-ribose) polymerase (PARP) protein expression (∼3-fold), as well as mRNA levels of apoptosis-related markers such as p53 (∼3-fold) and calpain (∼4-fold); these changes were paralleled by an early increase of 5-LOX activity (∼2-fold). Our findings provide a molecular background for the immune dysfunction observed in astronauts during space missions, and reveal potential new markers to monitor health status of ISS crew members.
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http://dx.doi.org/10.1096/fj.11-199406DOI Listing
May 2012

Abnormal anandamide metabolism in celiac disease.

J Nutr Biochem 2012 Oct 29;23(10):1245-8. Epub 2011 Dec 29.

Department of Biomedical Sciences, University of Teramo, Teramo, Italy.

The endocannabinoid system has been extensively investigated in experimental colitis and inflammatory bowel disease, but not in celiac disease, where only a single study showed increased levels of the major endocannabinoid anandamide in the atrophic mucosa. On this basis, we aimed to investigate anandamide metabolism in celiac disease by analyzing transcript levels (through quantitative real-time reverse transcriptase-polymerase chain reaction), protein concentration (through immunoblotting) and activity (through radioassays) of enzymes responsible for anandamide synthesis (N-acylphosphatidyl-ethanolamine specific phospholipase D, NAPE-PLD) and degradation (fatty acid amide hydrolase, FAAH) in the duodenal mucosa of untreated celiac patients, celiac patients on a gluten-free diet for at least 12 months and control subjects. Also, treated celiac biopsies cultured ex vivo with peptic-tryptic digest of gliadin were investigated. Our in vivo experiments showed that mucosal NAPE-PLD expression and activity are higher in untreated celiac patients than treated celiac patients and controls, with no significant difference between the latter two groups. In keeping with the in vivo data, the ex vivo activity of NAPE-PLD was significantly enhanced by incubation of peptic-tryptic digest of gliadin with treated celiac biopsies. On the contrary, in vivo mucosal FAAH expression and activity did not change in the three groups of patients, and accordingly, mucosal FAAH activity was not influenced by treatment with peptic-tryptic digest of gliadin. In conclusion, our findings provide a possible pathophysiological explanation for the increased anandamide concentration previously shown in active celiac mucosa.
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http://dx.doi.org/10.1016/j.jnutbio.2011.06.017DOI Listing
October 2012

Social encounter with a novel partner in adolescent rats: activation of the central endocannabinoid system.

Behav Brain Res 2011 Jun 2;220(1):140-5. Epub 2011 Feb 2.

Section of Behavioural Neuroscience, Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Roma, Italy.

The endocannabinoid system is critically involved in the modulation of affect, motivation, and emotion. Here, we investigated the hypothesis that changes in the content of endocannabinoid levels might underlie adaptation to positive social conditions during adolescence. To this aim, separate pairs of adolescent (postnatal days 32-35) male Wistar rats were allowed to interact in a neutral cage under two different testing conditions, i.e. familiar (FAM) and non-familiar (NFAM) social partners. We found that adolescent rats that encountered a NFAM partner spent significantly more time Sniffing and Following the companion than subjects exposed to a FAM partner, whereas no changes in levels of rough-and-tumble play were observed. Notably, the NFAM social encounter significantly increased striatal anandamide (AEA) levels compared to both non-social controls and animals that encountered a FAM partner. Changes in AEA levels appeared to be region-specific, since no changes were observed in the other brain regions analysed, neither were they observed in the activity of the AEA-hydrolase (FAAH) nor in the content of the other major endocannabinoid 2-arachidonylglycerol. In addition, animals that encountered a NFAM partner tended to explore less extensively the illuminated compartment of the light-dark box when compared to animals that had previously encountered a FAM companion. In conclusion, striatal AEA levels seem to participate in the emotional arousal resulting from a NFAM social encounter in adolescent rats, and to be particularly important for coping response to novel social contexts.
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http://dx.doi.org/10.1016/j.bbr.2011.01.044DOI Listing
June 2011

Abnormal mGlu 5 receptor/endocannabinoid coupling in mice lacking FMRP and BC1 RNA.

Neuropsychopharmacology 2010 Jun 10;35(7):1500-9. Epub 2010 Mar 10.

Dipartimento di Scienze Biomediche, Università degli Studi di Teramo, Teramo, Italy.

Transcriptional silencing of the gene encoding the fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS). FMRP acts as a translational repressor at central synapses, and molecular and synaptic plasticity studies have shown that the absence of this protein alters metabotropic glutamate 5 receptors (mGlu5Rs)-mediated signaling. In the striatum of mice lacking FMRP, we found enhanced activity of diacylglycerol lipase (DAGL), the enzyme limiting 2-arachidonoylglicerol (2-AG) synthesis, associated with altered sensitivity of GABA synapses to the mobilization of this endocannabinoid by mGlu5R stimulation with DHPG. Mice lacking another repressor of synaptic protein synthesis, BC1 RNA, also showed potentiated mGlu5R-driven 2-AG responses, indicating that both FMRP and BC1 RNA act as physiological constraints of mGlu5R/endocannabinoid coupling at central synapses. The effects of FMRP ablation on DAGL activity and on DHPG-mediated inhibition of GABA synapses were enhanced by simultaneous genetic inactivation of FMRP and BC1 RNA. In double FMRP and BC1 RNA lacking mice, striatal levels of 2-AG were also enhanced compared with control animals and to single mutants. Our data indicate for the first time that mGlu5R-driven endocannabinoid signaling in the striatum is under the control of both FMRP and BC1 RNA. The abnormal mGlu5R/2-AG coupling found in FMRP-KO mice emphasizes the involvement of mGlu5Rs in the synaptic defects of FXS, and identifies the modulation of the endocannabinoid system as a novel target for the treatment of this severe neuropsychiatric disorder.
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http://dx.doi.org/10.1038/npp.2010.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055456PMC
June 2010

The endocannabinoid system in gp120-mediated insults and HIV-associated dementia.

Exp Neurol 2010 Jul 29;224(1):74-84. Epub 2010 Mar 29.

Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy.

Endocannabinoids (eCBs) include a group of lipid mediators that act as endogenous agonists at cannabinoid (CB(1), CB(2)) and vanilloid (TRPV1) receptors. In the last two decades a number of eCBs-metabolizing enzymes have been discovered that, together with eCBs and congeners, target receptors and proteins responsible for their transport and intracellular trafficking form the so-called "endocannabinoid system" (ECS). Within the central nervous system ECS elements participate in neuroprotection against neuroinflammatory/neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. More recently, a role for eCBs has been documented also in human immunodeficiency virus-1 (HIV-1) envelope glycoprotein gp120-mediated insults, and in HIV-associated dementia (HAD). The modulation of ECS in the latter disease conditions is the subject of this review, that will also address the molecular mechanisms underlying the neuroprotective effects of eCBs. In particular, the interactions between neurons and glia during neuroinflammation, and the alterations of ECS in these cells upon gp120 insults and HAD will be discussed, along with the potential therapeutic exploitation of ECS-oriented drugs for the treatment of HAD and related disorders.
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http://dx.doi.org/10.1016/j.expneurol.2010.03.025DOI Listing
July 2010

Anandamide increases swelling and reduces calcium sensitivity of mitochondria.

Biochem Biophys Res Commun 2009 Oct 11;388(2):439-42. Epub 2009 Aug 11.

Department of Biomedical Sciences, University of Teramo, Piazza Aldo Moro 45, 64100 Teramo, Italy.

The endocannabinoid anandamide alters mitochondria-dependent signal transduction, thus controlling key cellular events like energy homeostasis and induction of apoptosis. Here, the ability of anandamide to directly affect the integrity of mitochondria was investigated on isolated organelles. We found that anandamide dose-dependently increases mitochondrial swelling, and reduces cytochrome c release induced by calcium ions. The effects of anandamide were independent of its target receptors (e.g., cannabinoid or vanilloid receptors), and were paralleled by decreased membrane potential and increased membrane fluidity. Overall, our data suggest that anandamide can impact mitochondrial physiology, by reducing calcium sensitivity and perturbing membrane properties of these organelles.
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http://dx.doi.org/10.1016/j.bbrc.2009.08.037DOI Listing
October 2009