Publications by authors named "Roberto Coccurello"

46 Publications

Sexually Dimorphic Immune and Neuroimmune Changes Following Peripheral Nerve Injury in Mice: Novel Insights for Gender Medicine.

Int J Mol Sci 2021 Apr 22;22(9). Epub 2021 Apr 22.

IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.

Neuropathic pain (NeP) in humans is often a life-long condition with no effective therapy available. The higher incidence of female gender in NeP onset is worldwide reported, and although the cause is generally attributed to sex hormones, the actual mechanisms and the players involved are still unclear. Glial and immune cells take part in NeP development, and orchestrate the neuroimmune and inflammatory response, releasing pro-inflammatory factors with chemoattractant properties that activate resident immune cells and recruit immune cells from circulation. The neuro-immune crosstalk is a key contributor to pain hypersensitivity following peripheral nervous system injury. Our previous works showed that in spite of the fact that female mice had an earlier analgesic response than males following nerve lesion, the recovery from NeP was never complete, suggesting that this difference could occur in the very early stages after injury. To further investigate gender differences in immune and neuroimmune responses to NeP, we studied the main immune cells and mediators elicited both in plasma and sciatic nerves by peripheral nerve lesion. After injury, we found a different pattern of distribution of immune cell populations showing either a higher infiltration of T cells in nerves from females or a higher infiltration of macrophages in nerves from males. Moreover, in comparison to male mice, the levels of cytokines and chemokines were differently up- and down-regulated in blood and nerve lysates from female mice. Our study provides some novel insights for the understanding of gender-associated differences in the generation and perseveration of NeP as well as for the isolation of specific neurodegenerative mechanisms underlying NeP. The identification of gender-associated inflammatory profiles in neuropathy is of key importance for the development of differential biomarkers and gender-specific personalized medicine.
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http://dx.doi.org/10.3390/ijms22094397DOI Listing
April 2021

Systemic delivery of a specific antibody targeting the pathological N-terminal truncated tau peptide reduces retinal degeneration in a mouse model of Alzheimer's Disease.

Acta Neuropathol Commun 2021 03 9;9(1):38. Epub 2021 Mar 9.

European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161, Rome, Italy.

Retina and optic nerve are sites of extra-cerebral manifestations of Alzheimer's Disease (AD). Amyloid-β (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau protein are detected in eyes from AD patients and transgenic animals in correlation with inflammation, reduction of synapses, visual deficits, loss of retinal cells and nerve fiber. However, neither the pathological relevance of other post-translational tau modifications-such as truncation with generation of toxic fragments-nor the potential neuroprotective action induced by their in vivo clearance have been investigated in the context of AD retinal degeneration. We have recently developed a monoclonal tau antibody (12A12mAb) which selectively targets the neurotoxic 20-22 kDa NH-derived peptide generated from pathological truncation at the N-terminal domain of tau without cross-reacting with its full-length normal protein. Previous studies have shown that 12A12mAb, when intravenously (i.v.)-injected into 6-month-old Tg2576 animals, markedly improves their AD-like, behavioural and neuropathological syndrome. By taking advantage of this well-established tau-directed immunization regimen, we found that 12A12mAb administration also exerts a beneficial action on biochemical, morphological and metabolic parameters (i.e. APP/Aβ processing, tau hyperphosphorylation, neuroinflammation, synaptic proteins, microtubule stability, mitochondria-based energy production, neuronal death) associated with ocular injury in the AD phenotype. These findings prospect translational implications in the AD field by: (1) showing for the first time that cleavage of tau takes part in several pathological changes occurring in vivo in affected retinas and vitreous bodies and that its deleterious effects are successfully antagonized by administration of the specific 12A12mAb; (2) shedding further insights on the tight connections between neurosensory retina and brain, in particular following tau-based immunotherapy. In our view, the parallel response we detected in this preclinical animal model, both in the eye and in the hippocampus, following i.v. 12A12mAb injection opens novel diagnostic and therapeutic avenues for the clinical management of cerebral and extracerebral AD signs in human beings.
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http://dx.doi.org/10.1186/s40478-021-01138-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942014PMC
March 2021

Passive immunotherapy for N-truncated tau ameliorates the cognitive deficits in two mouse Alzheimer's disease models.

Brain Commun 2020 6;2(1):fcaa039. Epub 2020 Apr 6.

European Brain Research Institute (EBRI), 00161 Rome, Italy.

Clinical and neuropathological studies have shown that tau pathology better correlates with the severity of dementia than amyloid plaque burden, making tau an attractive target for the cure of Alzheimer's disease. We have explored whether passive immunization with the 12A12 monoclonal antibody (26-36aa of tau protein) could improve the Alzheimer's disease phenotype of two well-established mouse models, Tg2576 and 3xTg mice. 12A12 is a cleavage-specific monoclonal antibody which selectively binds the pathologically relevant neurotoxic NH26-230 fragment (i.e. NHhtau) of tau protein without cross-reacting with its full-length physiological form(s). We found out that intravenous administration of 12A12 monoclonal antibody into symptomatic (6 months old) animals: (i) reaches the hippocampus in its biologically active (antigen-binding competent) form and successfully neutralizes its target; (ii) reduces both pathological tau and amyloid precursor protein/amyloidβ metabolisms involved in early disease-associated synaptic deterioration; (iii) improves episodic-like type of learning/memory skills in hippocampal-based novel object recognition and object place recognition behavioural tasks; (iv) restores the specific up-regulation of the activity-regulated cytoskeleton-associated protein involved in consolidation of experience-dependent synaptic plasticity; (v) relieves the loss of dendritic spine connectivity in pyramidal hippocampal CA1 neurons; (vi) rescues the Alzheimer's disease-related electrophysiological deficits in hippocampal long-term potentiation at the CA3-CA1 synapses; and (vii) mitigates the neuroinflammatory response (reactive gliosis). These findings indicate that the 20-22 kDa NH-terminal tau fragment is crucial target for Alzheimer's disease therapy and prospect immunotherapy with 12A12 monoclonal antibody as safe (normal tau-preserving), beneficial approach in contrasting the early Amyloidβ-dependent and independent neuropathological and cognitive alterations in affected subjects.
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http://dx.doi.org/10.1093/braincomms/fcaa039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425324PMC
April 2020

P2X7 Receptor in the Management of Energy Homeostasis: Implications for Obesity, Dyslipidemia, and Insulin Resistance.

Front Endocrinol (Lausanne) 2020 12;11:199. Epub 2020 May 12.

Preclinical Neuroscience, European Center for Brain Research (CERC)/IRCCS Santa Lucia Foundation, Rome, Italy.

Whole-body energy metabolism entails the highly regulated balance between food intake, nutrient breakdown, energy generation (ATP), and energy storage for the preservation of vital functions and body mass. Purinergic signaling has attracted increasing attention in the regulatory mechanisms not only for the reverse processes of white adipose tissue lipogenesis and lipolysis, but also for brown adipocyte-dependent thermogenesis and leptin production. This regulatory role has remarkable implications in the handling of body's energy expenditure and energy reservoir. Hence, selected purinergic receptors can play a relevant function in lipid metabolism, endocrine activity, glucose uptake, ATP-dependent increased expression of uncoupling protein 1, and browning of adipose tissue. Indeed, purinergic P2 receptors regulate adipogenesis and lipid metabolism and are involved in adipogenic differentiation. In particular, the ionotropic ATP-activated P2X7 subtype is involved in fat distribution, as well as in the modulation of inflammatory pathways in white adipose tissue. Within this context, very recent evidence has established a direct function of P2X7 in energy metabolism. Specifically, either genetic deletion (P2X7 knockout mice) or subchronic pharmacological inhibition of the receptor produces a decrease of whole-body energy expenditure and, concurrently, an increase of carbohydrate oxidation. As further evidence, lipid accumulation, increased fat mass distribution, and weight gain are reported in P2X7-depleted mice. Conversely, the stimulation of P2X7 enhances energy expenditure. Altogether, this knowledge supports the role of P2X7 signaling in the fight against obesity and insulin resistance, as well as in the promotion of adaptive thermogenesis.
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http://dx.doi.org/10.3389/fendo.2020.00199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247848PMC
April 2021

Skeletal-Muscle Metabolic Reprogramming in ALS-SOD1 Mice Predates Disease Onset and Is A Promising Therapeutic Target.

iScience 2020 May 21;23(5):101087. Epub 2020 Apr 21.

IRCCS Fondazione Santa Lucia, Rome, Italy; National Research Council, Institute of Translational Pharmacology (IFT), Rome, Italy. Electronic address:

Patients with ALS show, in addition to the loss of motor neurons in the spinal cord, brainstem, and cerebral cortex, an abnormal depletion of energy stores alongside hypermetabolism. In this study, we show that bioenergetic defects and muscle remodeling occur in skeletal muscle of the SOD1 mouse model of ALS mice prior to disease onset and before the activation of muscle denervation markers, respectively. These changes in muscle physiology were followed by an increase in energy expenditure unrelated to physical activity. Finally, chronic treatment of SOD1 mice with Ranolazine, an FDA-approved inhibitor of fatty acid β-oxidation, led to a decrease in energy expenditure in symptomatic SOD1 mice, and this occurred in parallel with a robust, albeit temporary, recovery of the pathological phenotype.
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http://dx.doi.org/10.1016/j.isci.2020.101087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200935PMC
May 2020

Dietary Fatty Acids and Microbiota-Brain Communication in Neuropsychiatric Diseases.

Biomolecules 2019 12 19;10(1). Epub 2019 Dec 19.

National Research Council (CNR), Institute for Complex System (ISC), 00185 Rome, Italy.

The gut-brain axis is a multimodal communication system along which immune, metabolic, autonomic, endocrine and enteric nervous signals can shape host physiology and determine liability, development and progression of a vast number of human diseases. Here, we broadly discussed the current knowledge about the either beneficial or deleterious impact of dietary fatty acids on microbiota-brain communication (MBC), and the multiple mechanisms by which different types of lipids can modify gut microbial ecosystem and contribute to the pathophysiology of major neuropsychiatric diseases (NPDs), such as schizophrenia (SCZ), depression and autism spectrum disorders (ASD).
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http://dx.doi.org/10.3390/biom10010012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022659PMC
December 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

Stimulation of P2X7 Enhances Whole Body Energy Metabolism in Mice.

Front Cell Neurosci 2019 21;13:390. Epub 2019 Aug 21.

Preclinical Neuroscience, Fondazione Santa Lucia IRCCS, Rome, Italy.

The P2X7 receptor, a member of the ionotropic purinergic P2X family of extracellular ATP-gated receptors, exerts strong trophic effects when tonically activated in cells, in addition to cytotoxic effects after a sustained activation. Because of its widespread distribution, P2X7 regulates several cell- and tissue-specific physiological functions, and is involved in a number of disease conditions. A novel role has recently emerged for P2X7 in the regulation of glucose and energy metabolism. In previous work, we have demonstrated that genetic depletion, and to a lesser extent also pharmacological inhibition of P2X7, elicits a significant decrease of the whole body energy expenditure and an increase of the respiratory exchange ratio. In the present work, we have investigated the effects of P2X7 stimulation on the whole body energy metabolism. Adult mice were daily injected with the specific P2X7 agonist 2'(3')-O-(4-Benzoylbenzoyl)adenosine 5'-triphosphate for 1 week and subjected to indirect calorimetric analysis for 48 h. We report that 2'(3')-O-(4-Benzoylbenzoyl)adenosine 5'-triphosphate increases metabolic rate and O consumption, concomitantly decreasing respiratory rate and upregulating NADPH oxidase 2 in and muscles. Our results indicate a major impact on energy homeostasis and muscle metabolism by activation of P2X7.
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http://dx.doi.org/10.3389/fncel.2019.00390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712077PMC
August 2019

Anhedonia in depression symptomatology: Appetite dysregulation and defective brain reward processing.

Behav Brain Res 2019 10 17;372:112041. Epub 2019 Jun 17.

National Research Council - CNR, Institute for Complex System (ISC), Via dei Taurini, 19, 00185, Rome, Italy; IRCCS - S. Lucia Foundation (FSL), Via del Fosso di Fiorano, 64, 00143, Rome, Italy. Electronic address:

Anhedonia is an elusive symptom in depression symptomatology. The present review frames the notion of anhedonia as reduced ability to experience pleasure and diminished sensitivity to rewarding stimuli such as palatable food or social interaction within the context of appetite dysregulation in depression, addressing the main neural networks involved in the alteration of brain reward processing. This circuit-based framework focuses on selected brain regions such as lateral hypothalamus, ventral pallidum, lateral habenula and mesocorticolimbic target areas such as nucleus accumbens and ventral tegmental area. The examination in particular of the role of dopamine, orexin and GABAergic neurotransmission is complemented by the exploration of the endocannabinoid signaling as homeostatic, anti-stress system and its relevance in depression pathophysiology and anhedonia symptoms.
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http://dx.doi.org/10.1016/j.bbr.2019.112041DOI Listing
October 2019

Effects of caloric restriction on neuropathic pain, peripheral nerve degeneration and inflammation in normometabolic and autophagy defective prediabetic Ambra1 mice.

PLoS One 2018 10;13(12):e0208596. Epub 2018 Dec 10.

National Research Council-CNR, Institute of Cell Biology and Neurobiology, Rome, Italy.

There is a growing interest on the role of autophagy in diabetes pathophysiology, where development of neuropathy is one of the most frequent comorbidities. We have previously demonstrated that neuropathic pain after nerve damage is exacerbated in autophagy-defective heterozygous Ambra1 mice. Here, we show the existence of a prediabetic state in Ambra1 mice, characterized by hyperglycemia, intolerance to glucose and insulin resistance. Thus, we further investigate the hypothesis that prediabetes may account for the exacerbation of allodynia and chronic pain and that counteracting the autophagy deficit may relieve the neuropathic condition. We took advantage from caloric restriction (CR) able to exert a double action: a powerful increase of autophagy and a control on the metabolic status. We found that CR ameliorates neuropathy throughout anti-inflammatory and metabolic mechanisms both in Ambra1 and in WT animals subjected to nerve injury. Moreover, we discovered that nerve lesion represents, per se, a metabolic stressor and CR reinstates glucose homeostasis, insulin resistance, incomplete fatty acid oxidation and energy metabolism. As autophagy inducer, CR promotes and anticipates Schwann cell autophagy via AMP-activated protein kinase (AMPK) that facilitates remyelination in peripheral nerve. In summary, we provide new evidence for the role of autophagy in glucose metabolism and identify in energy depletion by dietary restriction a therapeutic approach in the fight against neuropathic pain.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208596PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287902PMC
May 2019

Lack of cyclin D3 induces skeletal muscle fiber-type shifting, increased endurance performance and hypermetabolism.

Sci Rep 2018 08 24;8(1):12792. Epub 2018 Aug 24.

National Research Council (CNR), Institute of Cell Biology and Neurobiology, IRCCS Santa Lucia Foundation, Rome, 00143, Italy.

The mitogen-induced D-type cyclins (D1, D2 and D3) are regulatory subunits of the cyclin-dependent kinases CDK4 and CDK6 that drive progression through the G1 phase of the cell cycle. In skeletal muscle, cyclin D3 plays a unique function in controlling the proliferation/differentiation balance of myogenic progenitor cells. Here, we show that cyclin D3 also performs a novel function, regulating muscle fiber type-specific gene expression. Mice lacking cyclin D3 display an increased number of myofibers with higher oxidative capacity in fast-twitch muscle groups, primarily composed of myofibers that utilize glycolytic metabolism. The remodeling of myofibers toward a slower, more oxidative phenotype is accompanied by enhanced running endurance and increased energy expenditure and fatty acid oxidation. In addition, gene expression profiling of cyclin D3-/- muscle reveals the upregulation of genes encoding proteins involved in the regulation of contractile function and metabolic markers specifically expressed in slow-twitch and fast-oxidative myofibers, many of which are targets of MEF2 and/or NFAT transcription factors. Furthermore, cyclin D3 can repress the calcineurin- or MEF2-dependent activation of a slow fiber-specific promoter in cultured muscle cells. These data suggest that cyclin D3 regulates muscle fiber type phenotype, and consequently whole body metabolism, by antagonizing the activity of MEF2 and/or NFAT.
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http://dx.doi.org/10.1038/s41598-018-31090-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109157PMC
August 2018

Fluoxetine or Sox2 reactivate proliferation-defective stem and progenitor cells of the adult and aged dentate gyrus.

Neuropharmacology 2018 10 22;141:316-330. Epub 2018 Aug 22.

Institute of Cell Biology and Neurobiology, National Research Council, Fondazione S.Lucia, Via Del Fosso di Fiorano 64, 00143, Rome, Italy. Electronic address:

The dentate gyrus of the hippocampus and the subventricular zone are neurogenic niches where the production of new neurons from glia-like stem cells continues throughout adult life. It is not clear whether the pool of stem cells is fated to be exhausted or is conserved until old age. We observed that the antiproliferative gene Btg1 maintains the quiescence of stem cells, and its ablation causes an increase of stem/progenitor cells proliferation in neonatal mice followed by progressive loss of proliferation during adulthood. Fluoxetine is an antidepressant, which exerts a powerful neurogenic effect on dentate gyrus progenitor cells, but is ineffective on stem cells. Here we show that adult dentate gyrus stem cells in the Btg1 knockout mice, with reduced self-renewal and proliferative capability, can be reactivated by fluoxetine, which increases their number greatly above the level of control or fluoxetine-treated wild-type mice. The increase of mitotic index above wild-type in Btg1 knockout fluoxetine-treated stem cells indicates that fluoxetine forces quiescent stem cells to enter the cycle. Stem cell proliferation undergoes continuous reactivation until fluoxetine is administered. Remarkably, fluoxetine reactivates proliferation-defective stem cells also in aged Btg1 knockout mice (15-month-old), an effect absent in wild-type aged mice. Moreover, overexpression of Sox2 retrovirally transduced in Btg1 knockout dentate gyrus cells significantly increases the number of neuroblasts, indicating that Sox2 is able to promote the self-renewal of proliferation-defective stem cells. Overall, the deletion of an antiproliferative gene, such as Btg1, reveals that dentate gyrus stem cells retain a hidden plasticity for self-renewal also in old age, in agreement with a model of permanent self-renewal.
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http://dx.doi.org/10.1016/j.neuropharm.2018.08.023DOI Listing
October 2018

Chronic psychosocial defeat differently affects lipid metabolism in liver and white adipose tissue and induces hepatic oxidative stress in mice fed a high-fat diet.

FASEB J 2019 01 22;33(1):1428-1439. Epub 2018 Aug 22.

Department of Physiology and Pharmacology V. Erspamer, Sapienza University of Rome, Rome, Italy.

It is widely accepted that chronic stress may alter the homeostatic mechanisms of body weight control. In this study, we followed the metabolic changes occurring in mice when chronic stress caused by psychosocial defeat (CPD) is associated with ad libitum exposure to a palatable high-fat diet (HFD). In this model, CPD mice consumed more HFD than unstressed (Un) mice without gaining body weight. We focused on metabolic processes involved in weight control, such as de novo lipogenesis (DNL), fatty acid β-oxidation (FAO), and thermogenesis. The activity and expression of DNL enzymes were reduced in the liver and white adipose tissue of mice consuming the HFD. Such effects were particularly evident in stressed mice. In both CPD and Un mice, HFD consumption increased the hepatic expression of the mitochondrial FAO enzyme carnitine palmitoyltransferase-1. In the liver of mice consuming the HFD, stress exposure prevented accumulation of triacylglycerols; however, accumulation of triacylglycerols was observed in Un mice under the same dietary regimen. In brown adipose tissue, stress increased the expression of uncoupling protein-1, which is involved in energy dissipation, both in HFD and control diet-fed mice. We consider increased FAO and energy dissipation responsible for the antiobesity effect seen in CPD/HFD mice. However, CPD associated with HFD induced hepatic oxidative stress.-Giudetti, A. M., Testini, M., Vergara, D., Priore, P., Damiano, F., Gallelli, C. A., Romano, A., Villani, R., Cassano, T., Siculella, L., Gnoni, G. V., Moles, A., Coccurello, R., Gaetani, S. Chronic psychosocial defeat differently affects lipid metabolism in liver and white adipose tissue and induces hepatic oxidative stress in mice fed a high-fat diet.
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http://dx.doi.org/10.1096/fj.201801130RDOI Listing
January 2019

Loss of P2X7 receptor function dampens whole body energy expenditure and fatty acid oxidation.

Purinergic Signal 2018 09 12;14(3):299-305. Epub 2018 May 12.

Institute of Cell Biology and Neurobiology (IBCN), National Research Council (C.N.R.), Rome, Italy.

The established role of ATP-responsive P2X7 receptor in inflammatory, neurodegenerative, and immune diseases is now expanding to include several aspects of metabolic dysregulation. Indeed, P2X7 receptors are involved in β cell function, insulin secretion, and liability to diabetes, and loss of P2X7 function may increase the risk of hepatic steatosis and disrupt adipogenesis. Recently, body weight gain, abnormal lipid accumulation, adipocyte hyperplasia, increased fat mass, and ectopic fat distribution have been found in P2X7 KO mice. Here, we hypothesized that such clinical picture of dysregulated lipid metabolism might be the result of altered in vivo energy metabolism. By indirect calorimetry, we assessed 24 h of energy expenditure (EE) and respiratory exchange ratio (RER) as quotient of carbohydrate to fat oxidation in P2X7 KO mice. Moreover, we assessed the same parameters in aged-matched WT counterparts that underwent a 7-day treatment with the P2X7 antagonist A804598. We found that loss of P2X7 function elicits a severe decrease of EE that was less pronounced in A804598-treated mice. In parallel, P2X7KO mice show a drastic increase of RER, thus indicating the occurrence of a greater ratio of carbohydrate to fat oxidation. Decreased EE and fat oxidation is predictive of body weight gain, which was here confirmed. Taken together, our data provide evidence that P2X7 loss of function produces defective energy homeostasis that, together with disrupted adipogenesis, might help to explain accumulation of adipose tissue and contribute to disclose the potential role of P2X7 in metabolic diseases.
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http://dx.doi.org/10.1007/s11302-018-9610-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107461PMC
September 2018

Hedonic Eating and the "Delicious Circle": From Lipid-Derived Mediators to Brain Dopamine and Back.

Front Neurosci 2018 24;12:271. Epub 2018 Apr 24.

Laboratory of Neurochemistry of Lipids, European Center for Brain Research (CERC), IRRCS Santa Lucia Foundation, Rome, Italy.

Palatable food can be seductive and hedonic eating can become irresistible beyond hunger and negative consequences. This is witnessed by the subtle equilibrium between eating to provide energy intake for homeostatic functions, and reward-induced overeating. In recent years, considerable efforts have been devoted to study neural circuits, and to identify potential factors responsible for the derangement of homeostatic eating toward hedonic eating and addiction-like feeding behavior. Here, we examined recent literature on "old" and "new" players accountable for reward-induced overeating and possible liability to eating addiction. Thus, the role of midbrain dopamine is positioned at the intersection between selected hormonal signals involved in food reward information processing (namely, leptin, ghrelin, and insulin), and lipid-derived neural mediators such as endocannabinoids. The impact of high fat palatable food and dietary lipids on endocannabinoid formation is reviewed in its pathogenetic potential for the derangement of feeding homeostasis. Next, endocannabinoid signaling that regulates synaptic plasticity is discussed as a key mechanism acting both at hypothalamic and mesolimbic circuits, and affecting both dopamine function and interplay between leptin and ghrelin signaling. Outside the canonical hypothalamic feeding circuits involved in energy homeostasis and the notion of "feeding center," we focused on lateral hypothalamus as neural substrate able to confront food-associated homeostatic information with food salience, motivation to eat, reward-seeking, and development of compulsive eating. Thus, the lateral hypothalamus-ventral tegmental area-nucleus accumbens neural circuitry is reexamined in order to interrogate the functional interplay between ghrelin, dopamine, orexin, and endocannabinoid signaling. We suggested a pivotal role for endocannabinoids in food reward processing within the lateral hypothalamus, and for orexin neurons to integrate endocrine signals with food reinforcement and hedonic eating. In addition, the role played by different stressors in the reinstatement of preference for palatable food and food-seeking behavior is also considered in the light of endocannabinoid production, activation of orexin receptors and disinhibition of dopamine neurons. Finally, type-1 cannabinoid receptor-dependent inhibition of GABA-ergic release and relapse to reward-associated stimuli is linked to ghrelin and orexin signaling in the lateral hypothalamus-ventral tegmental area-nucleus accumbens network to highlight its pathological potential for food addiction-like behavior.
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http://dx.doi.org/10.3389/fnins.2018.00271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928395PMC
April 2018

Early alteration of distribution and activity of hippocampal type-1 cannabinoid receptor in Alzheimer's disease-like mice overexpressing the human mutant amyloid precursor protein.

Pharmacol Res 2018 04 14;130:366-373. Epub 2018 Feb 14.

European Center for Brain Research (CERC)/Santa Lucia Foundation IRCCS, Rome, Italy; Faculty of Veterinary Medicine, University of Teramo, Teramo, Italy. Electronic address:

Besides its involvement in Alzheimer's disease (AD) as precursor of the neurotoxic amyloid peptides, the pathophysiological impact of brain accumulation of amyloid precursor protein (APP) is not yet well understood. Recent studies reported that APP interacts with other membrane proteins, including G protein coupled receptors, affecting their biological functions. Here, we focused on the study of the potential impact of human mutant APP on expression, distribution and activity of type-1 cannabinoid (CB) receptor in the hippocampus of Tg2576 mice, an AD-like mice model. By using biochemical and electrophysiological measures, we found that in a presymptomatic phase, when amyloid plaques have not yet formed and there is no sign of cognitive deficits, the over-expression of full-length APP in the hippocampus of Tg2576 mice altered membrane localization and inhibitory signalling activity of CB receptor, possibly by binding to the receptor and reducing its specific interaction with caveolin-1 and G proteins.
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http://dx.doi.org/10.1016/j.phrs.2018.02.009DOI Listing
April 2018

The neuronal Shc adaptor in Alzheimer's Disease.

Aging (Albany NY) 2018 01;10(1):5-6

Institute of Cell Biology and Neurobiology (IBCN), National Research Council (CNR), Rome, Italy.

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http://dx.doi.org/10.18632/aging.101368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811251PMC
January 2018

What is "Hyper" in the ALS Hypermetabolism?

Mediators Inflamm 2017 7;2017:7821672. Epub 2017 Sep 7.

Institute of Cell Biology and Neurobiology (IBCN), National Research Council (CNR), Via del Fosso di Fiorano 64, 00143 Rome, Italy.

The progressive and fatal loss of upper (brain) and lower (spinal cord) motor neurons and muscle denervation concisely condenses the clinical picture of amyotrophic lateral sclerosis (ALS). Despite the multiple mechanisms believed to underlie the selective loss of motor neurons, ALS aetiology remains elusive and obscure. Likewise, there is also a cluster of alterations in ALS patients in which muscle wasting, body weight loss, eating dysfunction, and abnormal energy dissipation coexist. Defective energy metabolism characterizes the ALS progression, and such paradox of energy balance stands as a challenge for the understanding of ALS pathogenesis. The hypermetabolism in ALS will be examined from tissue-specific energy imbalance (e.g., skeletal muscle) to major energetic pathways (e.g., AMP-activated protein kinase) and whole-body energy alterations including glucose and lipid metabolism, nutrition, and potential involvement of interorgan communication. From the point of view here expressed, the hypermetabolism in ALS should be evaluated as a magnifying glass through which looking at the ALS pathogenesis is from a different perspective in which defective metabolism can disclose novel mechanistic interpretations and lines of intervention.
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http://dx.doi.org/10.1155/2017/7821672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610793PMC
June 2018

Impact of Dietary Fats on Brain Functions.

Curr Neuropharmacol 2018 ;16(7):1059-1085

Department of Movement and Wellness Sciences, Parthenope University of Naples, Naples, Italy.

Background: Adequate dietary intake and nutritional status have important effects on brain functions and on brain health. Energy intake and specific nutrients excess or deficiency from diet differently affect cognitive processes, emotions, behaviour, neuroendocrine functions and synaptic plasticity with possible protective or detrimental effects on neuronal physiology. Lipids, in particular, play structural and functional roles in neurons. Here the importance of dietary fats and the need to understand the brain mechanisms activated by peripheral and central metabolic sensors. Thus, the manipulation of lifestyle factors such as dietary interventions may represent a successful therapeutic approach to maintain and preserve brain health along lifespan.

Methods: This review aims at summarizing the impact of dietary fats on brain functions.

Results: Starting from fat consumption, nutrient sensing and food-related reward, the impact of gut-brain communications will be discussed in brain health and disease. A specific focus will be on the impact of fats on the molecular pathways within the hypothalamus involved in the control of reproduction via the expression and the release of Gonadotropin-Releasing Hormone. Lastly, the effects of specific lipid classes such as polyunsaturated fatty acids and of the "fattest" of all diets, commonly known as "ketogenic diets", on brain functions will also be discussed.

Conclusion: Despite the knowledge of the molecular mechanisms is still a work in progress, the clinical relevance of the manipulation of dietary fats is well acknowledged and such manipulations are in fact currently in use for the treatment of brain diseases.
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http://dx.doi.org/10.2174/1570159X15666171017102547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120115PMC
October 2018

NGF and BDNF Alterations by Prenatal Alcohol Exposure.

Curr Neuropharmacol 2019 ;17(4):308-317

Institute of Cell Biology and Neurobiology (IBCN-CNR), Rome, Italy.

Background: It is now widely established that the devastating effects of prenatal alcohol exposure on the embryo and fetus development cause marked cognitive and neurobiological deficits in the newborns. The negative effects of the gestational alcohol use have been well documented and known for some time. However, also the subtle role of alcohol consumption by fathers prior to mating is drawing special attention.

Objective: Both paternal and maternal alcohol exposure has been shown to affect the neurotrophins' signalling pathways in the brain and in target organs of ethanol intoxication. Neurotrophins, in particular nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are molecules playing a pivotal role in the survival, development and function of the peripheral and central nervous systems but also in the pathogenesis of developmental defects caused by alcohol exposure.

Methods: New researches from the available literature and experimental data from our laboratory are presented in this review to offer the most recent findings regarding the effects of maternal and paternal prenatal ethanol exposure especially on the neurotrophins' signalling pathways.

Results: NGF and BDNF changes play a subtle role in short- and long-lasting effects of alcohol in ethanol target tissues, including neuronal cell death and severe cognitive and physiological deficits in the newborns.

Conclusion: The review suggests a possible therapeutic intervention based on the use of specific molecules with antioxidant properties in order to induce a potential prevention of the harmful effects of the paternal and/or maternal alcohol exposure.
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http://dx.doi.org/10.2174/1570159X15666170825101308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482479PMC
August 2019

Virtual Morris task responses in individuals in an abstinence phase from alcohol.

Can J Physiol Pharmacol 2018 Feb 1;96(2):128-136. Epub 2017 Aug 1.

c Institute of Cell Biology and Neurobiology, National Research Council (IBCN-CNR)/Santa Lucia Foundation, 00143 Rome, Italy.

The present study was aimed at examining spatial learning and memory, in 33 men and 12 women with alcohol use disorder (AUD) undergoing ethanol detoxification, by using a virtual Morris task. As controls, we recruited 29 men and 10 women among episodic drinkers without a history of alcohol addiction or alcohol-related diseases. Elevated latency to the first movement in all trials was observed only in AUD persons; furthermore, control women had longer latencies compared with control men. Increased time spent to reach the hidden platform in the learning phase was found for women of both groups compared with men, in particular during trial 3. As predicted, AUD persons (more evident in men) spent less time in the target quadrant during the probe trial; however, AUD women had longer latencies to reach the platform in the visible condition during trials 6 and 7 that resulted in a greater distance moved. As for the probe trial, men of both groups showed increased virtual locomotion compared with the women of both groups. The present investigation confirms and extends previous studies showing (i) different gender responses in spatial learning tasks, (ii) some alterations due to alcohol addiction in virtual spatial learning, and (iii) differences between AUD men and AUD women in spatial-behaviour-related paradigms.
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http://dx.doi.org/10.1139/cjpp-2017-0013DOI Listing
February 2018

Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer's disease.

Nat Commun 2017 04 3;8:14727. Epub 2017 Apr 3.

Department of Experimental Neurosciences, IRCCS Santa Lucia Foundation, 00143 Rome, Italy.

Alterations of the dopaminergic (DAergic) system are frequently reported in Alzheimer's disease (AD) patients and are commonly linked to cognitive and non-cognitive symptoms. However, the cause of DAergic system dysfunction in AD remains to be elucidated. We investigated alterations of the midbrain DAergic system in the Tg2576 mouse model of AD, overexpressing a mutated human amyloid precursor protein (APPswe). Here, we found an age-dependent DAergic neuron loss in the ventral tegmental area (VTA) at pre-plaque stages, although substantia nigra pars compacta (SNpc) DAergic neurons were intact. The selective VTA DAergic neuron degeneration results in lower DA outflow in the hippocampus and nucleus accumbens (NAc) shell. The progression of DAergic cell death correlates with impairments in CA1 synaptic plasticity, memory performance and food reward processing. We conclude that in this mouse model of AD, degeneration of VTA DAergic neurons at pre-plaque stages contributes to memory deficits and dysfunction of reward processing.
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http://dx.doi.org/10.1038/ncomms14727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382255PMC
April 2017

Increased intake of energy-dense diet and negative energy balance in a mouse model of chronic psychosocial defeat.

Eur J Nutr 2018 Jun 17;57(4):1485-1498. Epub 2017 Mar 17.

Department of Physiology and Pharmacology V. Erspamer, Sapienza University of Rome, P.le A. Moro, 5, 00185, Roma, Italy.

Purpose: Chronic exposure to stress may represent a risk factor for developing metabolic and eating disorders, mostly driven by the overconsumption of easily accessible energy-dense palatable food, although the mechanisms involved remain still unclear. In this study, we used an ethologically oriented murine model of chronic stress caused by chronic psychosocial defeat (CPD) to investigate the effects of unrestricted access to a palatable high fat diet (HFD) on food intake, body weight, energy homeostasis, and expression of different brain neuropeptides. Our aim was to shed light on the mechanisms responsible for body weight and body composition changes due to chronic social stress.

Methods: In our model of subordinate (defeated), mice (CPD) cohabitated in constant sensory contact with dominants, being forced to interact on daily basis, and were offered ad libitum access either to an HFD or to a control diet (CD). Control mice (of the same strain as CPD mice) were housed in pairs and left unstressed in their home cage (UN). In all these mice, we evaluated body weight, different adipose depots, energy metabolism, caloric intake, and neuropeptide expression.

Results: CPD mice increased the intake of HFD and reduced body weight in the presence of enhanced lipid oxidation. Resting energy expenditure and interscapular brown adipose tissue (iBAT) were increased in CPD mice, whereas epididymal adipose tissue increased only in HFD-fed unstressed mice. Propiomelanocortin mRNA levels in hypothalamic arcuate nucleus increased only in HFD-fed unstressed mice. Oxytocin mRNA levels in the paraventricular nucleus and neuropeptide Y mRNA levels within the arcuate were increased only in CD-fed CPD mice. In the arcuate, CART was increased in HFD-fed UN mice and in CD-fed CPD mice, while HFD intake suppressed CART increase in defeated animals. In the basolateral amygdala, CART expression was increased only in CPD animals on HFD.

Conclusions: CPD appears to uncouple the intake of HFD from energy homeostasis causing higher HFD intake, larger iBAT accumulation, increased energy expenditure and lipid oxidation, and lower body weight. Overall, the present study confirms the notion that the chronic activation of the stress response can be associated with metabolic disorders, altered energy homeostasis, and changes of orexigenic and anorexigenic signaling. These changes might be relevant to better understand the etiology of stress-induced obesity and eating disorders and might represent a valid therapeutic approach for the development of new therapies in this field.
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http://dx.doi.org/10.1007/s00394-017-1434-yDOI Listing
June 2018

Olive polyphenol effects in a mouse model of chronic ethanol addiction.

Nutrition 2017 Jan 20;33:65-69. Epub 2016 Sep 20.

Institute of Cell Biology and Neurobiology, CNR; IRCCS S. Lucia Foundation, Italy. Electronic address:

Objectives: Alcohol addiction elicits oxidative imbalance and it is well known that polyphenols possess antioxidant properties. We investigated whether or not polyphenols could confer a protective potential against alcohol-induced oxidative stress.

Methods: We administered (per os) for two months 20 mg/kg of olive polyphenols containing mostly hydroxytyrosol in alcoholic adult male mice. Hydroxytyrosol metabolites as hydroxytyrosol sulfate 1 and hydroxytyrosol sulfate 2 were found in the serum of mice administered with polyphenols with the highest amount in animals treated with both polyphenols and alcohol. Oxidative stress was evaluated by FORT (free oxygen radical test) and FORD (free oxygen radical defense) tests.

Results: Alcoholic mice showed a worse oxidative status than nonalcoholic mice (higher FORT and lower FORD) but polyphenol supplementation partially counteracted the alcohol pro-oxidant effects, as evidenced by FORT.

Conclusions: A better understanding of the antioxidant protection provided by polyphenols might be of primary interest for drug discovery and dietary-based prevention of the damage associated with chronic alcohol abuse.
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http://dx.doi.org/10.1016/j.nut.2016.08.014DOI Listing
January 2017

Histone Modifications in a Mouse Model of Early Adversities and Panic Disorder: Role for Asic1 and Neurodevelopmental Genes.

Sci Rep 2016 04 28;6:25131. Epub 2016 Apr 28.

Department of Psychiatry, University Of Toronto, Toronto, Canada.

Hyperventilation following transient, CO2-induced acidosis is ubiquitous in mammals and heritable. In humans, respiratory and emotional hypersensitivity to CO2 marks separation anxiety and panic disorders, and is enhanced by early-life adversities. Mice exposed to the repeated cross-fostering paradigm (RCF) of interference with maternal environment show heightened separation anxiety and hyperventilation to 6% CO2-enriched air. Gene-environment interactions affect CO2 hypersensitivity in both humans and mice. We therefore hypothesised that epigenetic modifications and increased expression of genes involved in pH-detection could explain these relationships. Medullae oblongata of RCF- and normally-reared female outbred mice were assessed by ChIP-seq for H3Ac, H3K4me3, H3K27me3 histone modifications, and by SAGE for differential gene expression. Integration of multiple experiments by network analysis revealed an active component of 148 genes pointing to the mTOR signalling pathway and nociception. Among these genes, Asic1 showed heightened mRNA expression, coherent with RCF-mice's respiratory hypersensitivity to CO2 and altered nociception. Functional enrichment and mRNA transcript analyses yielded a consistent picture of enhancement for several genes affecting chemoception, neurodevelopment, and emotionality. Particularly, results with Asic1 support recent human findings with panic and CO2 responses, and provide new perspectives on how early adversities and genes interplay to affect key components of panic and related disorders.
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http://dx.doi.org/10.1038/srep25131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848503PMC
April 2016

Paternal alcohol exposure in mice alters brain NGF and BDNF and increases ethanol-elicited preference in male offspring.

Addict Biol 2016 07 4;21(4):776-87. Epub 2015 May 4.

Institute of Cell Biology and Neurobiology (IBCN)/IRCCS S. Lucia Foundation, Italy.

Ethanol (EtOH) exposure during pregnancy induces cognitive and physiological deficits in the offspring. However, the role of paternal alcohol exposure (PAE) on offspring EtOH sensitivity and neurotrophins has not received much attention. The present study examined whether PAE may disrupt nerve growth factor (NGF) and/or brain-derived neurotrophic factor (BDNF) and affect EtOH preference/rewarding properties in the male offspring. CD1 sire mice were chronically addicted for EtOH or administered with sucrose. Their male offsprings when adult were assessed for EtOH preference by a conditioned place preference paradigm. NGF and BDNF, their receptors (p75(NTR) , TrkA and TrkB), dopamine active transporter (DAT), dopamine receptors D1 and D2, pro-NGF and pro-BDNF were also evaluated in brain areas. PAE affected NGF levels in frontal cortex, striatum, olfactory lobes, hippocampus and hypothalamus. BDNF alterations in frontal cortex, striatum and olfactory lobes were found. PAE induced a higher susceptibility to the EtOH rewarding effects mostly evident at the lower concentration (0.5 g/kg) that was ineffective in non-PAE offsprings. Moreover, higher ethanol concentrations (1.5 g/kg) produced an aversive response in PAE animals and a significant preference in non-PAE offspring. PAE affected also TrkA in the hippocampus and p75(NTR) in the frontal cortex. DAT was affected in the olfactory lobes in PAE animals treated with 0.5 g/kg of ethanol while no differences were found on D1/D2 receptors and for pro-NGF or pro-BDNF. In conclusion, this study shows that: PAE affects NGF and BDNF expression in the mouse brain; PAE may induce ethanol intake preference in the male offspring.
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http://dx.doi.org/10.1111/adb.12255DOI Listing
July 2016

Satiety factor oleoylethanolamide recruits the brain histaminergic system to inhibit food intake.

Proc Natl Acad Sci U S A 2014 Aug 21;111(31):11527-32. Epub 2014 Jul 21.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco, e Salute del Bambino, Sezione di Farmacologia e Tossicologia, Università di Firenze, 50139 Florence, Italy;

Key factors driving eating behavior are hunger and satiety, which are controlled by a complex interplay of central neurotransmitter systems and peripheral stimuli. The lipid-derived messenger oleoylethanolamide (OEA) is released by enterocytes in response to fat intake and indirectly signals satiety to hypothalamic nuclei. Brain histamine is released during the appetitive phase to provide a high level of arousal in anticipation of feeding, and mediates satiety. However, despite the possible functional overlap of satiety signals, it is not known whether histamine participates in OEA-induced hypophagia. Using different experimental settings and diets, we report that the anorexiant effect of OEA is significantly attenuated in mice deficient in the histamine-synthesizing enzyme histidine decarboxylase (HDC-KO) or acutely depleted of histamine via interocerebroventricular infusion of the HDC blocker α-fluoromethylhistidine (α-FMH). α-FMH abolished OEA-induced early occurrence of satiety onset while increasing histamine release in the CNS with an H3 receptor antagonist-increased hypophagia. OEA augmented histamine release in the cortex of fasted mice within a time window compatible to its anorexic effects. OEA also increased c-Fos expression in the oxytocin neurons of the paraventricular nuclei of WT but not HDC-KO mice. The density of c-Fos immunoreactive neurons in other brain regions that receive histaminergic innervation and participate in the expression of feeding behavior was comparable in OEA-treated WT and HDC-KO mice. Our results demonstrate that OEA requires the integrity of the brain histamine system to fully exert its hypophagic effect and that the oxytocin neuron-rich nuclei are the likely hypothalamic area where brain histamine influences the central effects of OEA.
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http://dx.doi.org/10.1073/pnas.1322016111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128140PMC
August 2014

Oleoylethanolamide: a novel potential pharmacological alternative to cannabinoid antagonists for the control of appetite.

Biomed Res Int 2014 3;2014:203425. Epub 2014 Apr 3.

Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Roma, Italy.

The initial pharmaceutical interest for the endocannabinoid system as a target for antiobesity therapies has been restricted by the severe adverse effects of the CB1 antagonist rimonabant. This study points at oleoylethanolamide (OEA), a monounsaturated analogue, and functional antagonist of anandamide, as a potential and safer antiobesity alternative to CB1 antagonism. Mice treated with equal doses (5 or 10 mg/kg, i.p.) of OEA or rimonabant were analyzed for the progressive expression of spontaneous behaviors (eating, grooming, rearing, locomotion, and resting) occurring during the development of satiety, according to the paradigm called behavioral satiety sequence (BSS). Both drugs reduced food (wet mash) intake to a similar extent. OEA treatment decreased eating activity within the first 30 min and caused a temporary increase of resting time that was not accompanied by any decline of horizontal, vertical and total motor activity. Besides decreasing eating activity, rimonabant caused a marked increase of the time spent grooming and decreased horizontal motor activity, alterations that might be indicative of aversive nonmotivational effects on feeding. These results support the idea that OEA suppresses appetite by stimulating satiety and that its profile of action might be predictive of safer effects in humans as a novel antiobesity treatment.
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http://dx.doi.org/10.1155/2014/203425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3996326PMC
January 2015

Brief maternal separation affects brain α1-adrenoceptors and apoptotic signaling in adult mice.

Prog Neuropsychopharmacol Biol Psychiatry 2014 Jan 12;48:161-9. Epub 2013 Oct 12.

Institute of Cell Biology and Neurobiology (IBCN), National Research Council (CNR)/S. Lucia Foundation, Via del Fosso di Fiorano 64, 00143 Rome, Italy.

Exposure to adversity during early life is a risk factor for the development of different mood and psychiatric disorders, including depressive-like behaviors. Here, neonatal mice were temporarily but repeatedly (day 1 to day 13) separated from mothers and placed in a testing environment containing a layer of odorless clean bedding (CB). We assessed in adult animals the impact of this early experience on binding sites and mRNA expression of α1-adrenergic receptor subtypes, heat shock proteins (HSPs) and proapoptotic and antiapoptotic members of the Bcl-2 family proteins in different brain regions involved in processing of olfactory information and rewarding stimuli. We found that repeated exposure to CB experience produced anhedonic-like behavior in terms of reduced saccharin intake and α1-adrenoceptor downregulation in piriform and somatosensory cortices, hippocampus, amygdala and discrete thalamic nuclei. We also found a selective decrease of α1B-adrenoceptor binding sites in the cingulate cortex and hippocampus and an increase of hippocampal α1A and α1B receptor, but not of α1D-adrenoceptor, mRNA levels. Moreover, while a significant decrease of antiapoptotic heat shock proteins Hsp72 and Hsp90 was identified in the prefrontal cortex, a parallel increase of antiapoptotic members of Bcl-2 family proteins was found at the hippocampal level. Together, these data provide evidence that the early exposure to CB experience produced enduring downregulation of α1-adrenoceptors in the prefrontal-limbic forebrain/limbic midbrain network, which plays a key role in the processing of olfactory information and reaction to rewarding stimuli. Finally, these data show that CB experience can "prime" the hippocampal circuitry and promote the expression of antiapoptotic factors that can confer potential neuroprotection to subsequent adversity.
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http://dx.doi.org/10.1016/j.pnpbp.2013.10.004DOI Listing
January 2014

The satiety signal oleoylethanolamide stimulates oxytocin neurosecretion from rat hypothalamic neurons.

Peptides 2013 Nov 16;49:21-6. Epub 2013 Aug 16.

Department of Physiology and Pharmacology, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.

The anandamide monounsaturated analogue oleoylethanolamide (OEA) acts as satiety signal released from enterocytes upon the ingestion of dietary fats to prolong the interval to the next meal. This effect, which requires intact vagal fibers and intestinal PPAR-alpha receptors, is coupled to the increase of c-fos and oxytocin mRNA expression in neurons of the paraventricular nucleus (PVN) and is prevented by the intracerebroventricular administration of a selective oxytocin antagonist, thus suggesting a necessary role of oxytocinergic neurotransmission in the pro-satiety effect of OEA. By brain microdialysis and immunohistochemistry, in this study we demonstrate that OEA treatment can stimulate oxytocin neurosecretion from the PVN and enhance oxytocin expression at both axonal and somatodendritic levels of hypothalamic neurons. Such effects, which are maximum 2h after OEA administration, support the hypothesis that the satiety-inducing action of OEA is mediated by the activation of oxytocin hypothalamic neurons.
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http://dx.doi.org/10.1016/j.peptides.2013.08.006DOI Listing
November 2013