European Center for Brain Research

Santa Lucia di Serino, Italy

European Center for Brain Research

Santa Lucia di Serino, Italy
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Cabib S.,University of Rome La Sapienza | Cabib S.,European Center for Brain Research | Puglisi-Allegra S.,University of Rome La Sapienza | Puglisi-Allegra S.,European Center for Brain Research
Neuroscience and Biobehavioral Reviews | Year: 2012

Mesoaccumbens dopamine (DA) is involved in the stress response. Although neural mechanisms involved in stress are of paramount importance for both clinical and preclinical research, the results of studies on the stress response by mesoaccumbens DA have received little attention. Therefore, we aimed to review these results and propose a role for mesoaccumbens DA in coping with stress.The data reviewed support the view that fluctuations of tonic levels characterize the mesoaccumbens DA stress response. Stress-induced increase of tonic DA levels in nucleus accumbens (NAc) supports expression of responses aimed at removing and avoiding the stressor through activation of DA D2 receptors, whereas inhibition of DA is associated with cessation of active defensive responses.In novel unescapable/uncontrollable stressful conditions tonic levels of DA in NAc show an initial increase followed by a decrease below pre-stress levels that lasts as long as the stressful situation. This biphasic response fits with the dynamics of the primary and secondary appraisal of a stressor that cannot be removed, escaped or controlled by the organism. In fact, NAc DA fluctuations are controlled by the medial pre-frontal cortex, which is involved in stress appraisal.We propose that enhanced mesoaccumbens DA supports expression of active coping strategies against an event appraised as a stressor and that inhibition of DA is required for passive coping with stressful situations appraised as unescapable/uncontrollable. © 2011 Elsevier Ltd.


Gasbarri A.,University of L'Aquila | Gasbarri A.,European Center for Brain Research | Pompili A.,University of L'Aquila | Pompili A.,European Center for Brain Research
Reviews in the Neurosciences | Year: 2014

The abundant distribution of serotonin (5-HT) in different areas of the central nervous system can explain the involvement of this neurotransmitter in the regulation of several functions, such as sleep, pain, feeding, and sexual and emotional behaviors. Moreover, the serotonergic system is also involved in other more complex roles, such as cognition, including learning and memory processes. Recent studies led to the discovery of various types and subtypes of receptors differentially associated to cognitive mechanisms. 5-HT7is the most recently discovered receptor for 5-HT; therefore, it is also one of the least well characterized. Studies exist hypothesizing the role of 5-HT7on the modulation of learning and memory processes and other cognitive functions. Moreover, much attention has been devoted to the possible role of 5-HT7receptors in psychiatric disorders. Therefore, the aim of this review is to clarify the behavioral role of the recently discovered 5-HT7type receptor and highlight its involvement in the cognitive functions, with particular attention to the modulation of learning and memory processes, thus providing a basis to obtain new therapeutic agents and strategies for the treatment of cognitive disorders.


Bisogno T.,National Research Council Italy | Bisogno T.,University of Rome Tor Vergata | Maccarrone M.,Biomedical University of Rome | Maccarrone M.,European Center for Brain Research
Expert Opinion on Drug Discovery | Year: 2013

Introduction: Fatty acid amide hydrolase (FAAH) is the major catabolic enzyme of the endocannabinoid N-arachidonoylethanolamine (anandamide) that, with different degrees of efficiency, also hydrolyzes other endogenous fatty acid ethanolamides. FAAH is increasingly being considered a relevant therapeutic target, especially in models of inflammatory pain. The opportunity to selectively increase the endocannabinoid tone only in those tissues where such an enhancement can be beneficial might result in a therapeutic benefit with more limited side effects, compared to the use of direct agonists of anandamide-binding receptors. Thus the research for selective FAAH inhibitors has become a hot topic in current drug discovery. Areas covered: This review highlights the advances in the development of different compounds belonging to different chemical families that have been proposed as FAAH inhibitors. Several classes of inhibitors have been reported so far, and they may be classified into two major classes: reversible and irreversible compounds. These inhibitors are reviewed herein with an emphasis on their potency and selectivity. Expert opinion: In recent years, tremendous efforts have been made to develop the FAAH inhibitors, and consequently many novel chemical templates have been discovered. It is still a major challenge to identify the first inhibitor of FAAH suitable for clinical exploitation that satisfies the requirements of potency, selectivity versus proteins related to anandamide activity as well as other potential off-targets, reversibility versus irreversibility, and efficacy toward rat versus human FAAH. © Informa UK, Ltd.


Maccarrone M.,Biomedical University of Rome | Maccarrone M.,European Center for Brain Research
Frontiers in Molecular Neuroscience | Year: 2017

Cannabis extracts have been used for centuries, but its main active principle ∆9 -tetrahydrocannabinol (THC) was identified about 50 years ago. Yet, it is only 25 years ago that the first endogenous ligand of the same receptors engaged by the cannabis agents was discovered. This “endocannabinoid (eCB)” was identified as N-arachidonoylethanolamine (or anandamide (AEA)), and was shown to have several receptors, metabolic enzymes and transporters that altogether drive its biological activity. Here I report on the latest advances about AEA metabolism, with the aim of focusing open questions still awaiting an answer for a deeper understanding of AEA activity, and for translating AEA-based drugs into novel therapeutics for human diseases. © 2017 Maccarrone.


MacCarrone M.,Biomedical University of Rome | MacCarrone M.,European Center for Brain Research | Guzman M.,Complutense University of Madrid | MacKie K.,Indiana University | And 3 more authors.
Nature Reviews Neuroscience | Year: 2014

Among the many signalling lipids, endocannabinoids are increasingly recognized for their important roles in neuronal and glial development. Recent experimental evidence suggests that, during neuronal differentiation, endocannabinoid signalling undergoes a fundamental switch from the prenatal determination of cell fate to the homeostatic regulation of synaptic neurotransmission and bioenergetics in the mature nervous system. These studies also offer novel insights into neuropsychiatric disease mechanisms and contribute to the public debate about the benefits and the risks of cannabis use during pregnancy and in adolescence. © 2015 Macmillan Publishers Limited.


Galve-Roperh I.,Complutense University of Madrid | Chiurchiu V.,University of Teramo | Chiurchiu V.,European Center for Brain Research | Diaz-Alonso J.,Complutense University of Madrid | And 4 more authors.
Progress in Lipid Research | Year: 2013

Cannabinoids, the active components of cannabis (Cannabis sativa) extracts, have attracted the attention of human civilizations for centuries, much earlier than the discovery and characterization of their substrate of action, the endocannabinoid system (ECS). The latter is an ensemble of endogenous lipids, their receptors [in particular type-1 (CB1) and type-2 (CB 2) cannabinoid receptors] and metabolic enzymes. Cannabinoid signaling regulates cell proliferation, differentiation and survival, with different outcomes depending on the molecular targets and cellular context involved. Cannabinoid receptors are expressed and functional from the very early developmental stages, when they regulate embryonic and trophoblast stem cell survival and differentiation, and thus may affect the formation of manifold adult specialized tissues derived from the three different germ layers (ectoderm, mesoderm and endoderm). In the ectoderm-derived nervous system, both CB1 and CB2 receptors are present in neural progenitor/stem cells and control their self-renewal, proliferation and differentiation. CB1 and CB2 show opposite patterns of expression, the former increasing and the latter decreasing along neuronal differentiation. Recently, endocannabinoid (eCB) signaling has also been shown to regulate proliferation and differentiation of mesoderm-derived hematopoietic and mesenchymal stem cells, with a key role in determining the formation of several cell types in peripheral tissues, including blood cells, adipocytes, osteoblasts/osteoclasts and epithelial cells. Here, we will review these new findings, which unveil the involvement of eCB signaling in the regulation of progenitor/stem cell fate in the nervous system and in the periphery. The developmental regulation of cannabinoid receptor expression and cellular/subcellular localization, together with their role in progenitor/stem cell biology, may have important implications in human health and disease. © 2013 Elsevier Ltd. All rights reserved.


Rapino C.,University of Teramo | Rapino C.,StemTeCh Group | Battista N.,University of Teramo | Battista N.,European Center for Brain Research | And 4 more authors.
Human Reproduction Update | Year: 2014

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. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


Bari M.,University of Rome Tor Vergata | Battista N.,University of Teramo | Pirazzi V.,University of Teramo | Maccarrone M.,University of Teramo | Maccarrone M.,European Center for Brain Research
Frontiers in Bioscience | Year: 2011

Epidemiological studies have highlighted the ever growing use of illegal drugs among teenagers. The negative effects of marijuana (a Cannabis sativa extract) on reproductive health are poorly known among young people, although chronic exposure to delta-9-tetrahydrocannabinol, the main psychoactive constituent of marijuana, impairs human reproductive potential by disrupting menstrual cycle, suppressing oogenesis and impairing embryo implantation and development, in women, and by increasing ejaculation problems, reducing sperm count and motility, and generating loss of libido and impotence, in men. Endocannabinoids, their metabolic enzymes and target receptors form the so called "endocannabinoid system" and they have been demonstrated to respond to fertility signals. In addition, they interfere with hormones, cytokines and other signalling molecules in both female and male reproductive events. In this review, we shall summarize the current knowledge on the endocannabinoid system, and on the multifaceted roles played by endocannabinoids in reproduction along the evolutionary axis from invertebrates to mammals. Furthermore, we shall discuss the potential use of distinct elements of the endocannabinoid system for the diagnosis and/or treatment of human infertility.


Karasu T.,University of Leicester | Marczylo T.H.,University of Leicester | Maccarrone M.,University of Teramo | Maccarrone M.,European Center for Brain Research | Konje J.C.,University of Leicester
Human Reproduction Update | Year: 2011

Background: Marijuana, the most used recreational drug, has been shown to have adverse effects on human reproduction. Endogenous cannabinoids (also called endocannabinoids) bind to the same receptors as those of Δ9-tetrahydrocannabinol (THC), the psychoactive component of Cannabis sativa. The most extensively studied endocannabinoids are anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol. The endocannabinoids, their congeners and the cannabinoid receptors, together with the metabolic enzymes and putative transporters form the endocannabinoid system (ECS). In this review, we summarize current knowledge about the relationships of ECS, sex steroid hormones and cytokines in female fertility, and underline the importance of this endocannabinoid-hormone-cytokine network. Methods: Pubmed and the Web of Science databases were searched for studies published since 1985, looking into the ECS, sex hormones, type-1/2 T-helper (Th1/Th2) cytokines, leukaemia inhibitory factor, leptin and reproduction. Results: The ECS plays a pivotal role in human reproduction. The enzymes involved in the synthesis and degradation of endocannabinoids normalize levels of AEA for successful implantation. The AEA degrading enzyme (fatty acid amide hydrolase) activity as well as AEA content in blood may potentially be used for the monitoring of early pregnancies. Progesterone and oestrogen are involved in the maintenance of endocannabinoid levels. The ECS plays an important role in the immune regulation of human fertility. Conclusions: The available studies suggest that tight control of the endocannabinoid-hormone-cytokine network is required for successful implantation and early pregnancy maintenance. This hormone-cytokine network is a key element at the maternal-foetal interface, and any defect in such a network may result in foetal loss. © The Author 2011. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


Chiurchiu V.,European Center for Brain Research
Current Topics in Medicinal Chemistry | Year: 2014

Despite multiple sclerosis (MS) represents one of the most fascinating mystery of modern medicine due to its unknown etiology and the incomplete knowledge of a clear mechanism of pathogenesis, progress against this disease has made giant leaps. Current management of MS takes advantage of many disease- modifying therapeutics of anti-inflammatory and immunomodulatory nature, whose primary aims are halting immune responses during attacks, preventing new attacks and avoiding disability. In this review, a synopsis on effective therapies targeting both immune-mediated responses and neurodegenerative processes is appointed. Oxidative stress has been also implicated in both the inflammatory and neurodegenerative pathological mechanisms underlying MS. The role of redox metabolism in MS is thus also reported, with particular focus on the latest improvements in the identification of oxidative stress as a potential new therapeutic target. © 2014 Bentham Science Publishers.

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