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Dive into the research topics where Carmela Belardo is active.

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Featured researches published by Carmela Belardo.


Journal of Neurochemistry | 2015

Genetic deletion of monoacylglycerol lipase leads to impaired cannabinoid receptor CB1R signaling and anxiety‐like behavior

Roberta Imperatore; Giovanna Morello; Livio Luongo; Ulrike Taschler; Rosaria Romano; Danilo De Gregorio; Carmela Belardo; Sabatino Maione; Vincenzo Di Marzo; Luigia Cristino

Endocannabinoids (eCB) are key regulators of excitatory/inhibitory neurotransmission at cannabinoid‐1‐receptor (CB1R)‐expressing axon terminals. The most abundant eCB in the brain, that is 2‐arachidonoylglycerol (2‐AG), is hydrolyzed by the enzyme monoacylglycerol lipase (MAGL), whose chronic inhibition in the brain was reported to cause CB1R desensitization. We employed the MAGL knock‐out mouse (MAGL−/−), a genetic model of congenital and sustained elevation of 2‐AG levels in the brain, to provide morphological and biochemical evidence for β‐arrestin2‐mediated CB1R desensitization in brain regions involved in the control of emotional states, that is, the prefrontal cortex (PFC), amygdala, hippocampus and cerebellar cortex. We found a widespread CB1R/β‐arrestin2 co‐expression in the mPFC, amygdala and hippocampus accompanied by impairment of extracellular signal‐regulated kinase signaling and elevation of vesicular glutamate transporter (VGluT1) at CB1R‐positive excitatory terminals in the mPFC, or vesicular GABA transporter (VGAT) at CB1R‐positive inhibitory terminals in the amygdala and hippocampus. The impairment of CB1R signaling in MAGL−/− mice was also accompanied by enhanced excitatory drive in the basolateral amygdala (BLA)‐mPFC circuit, with subsequent elevation of glutamate release to the mPFC and anxiety‐like and obsessive‐compulsive behaviors, as assessed by the light/dark box and marble burying tests, respectively. Collectively, these data provide evidence for a β‐arrestin2‐mediated desensitization of CB1R in MAGL−/− mice, with impact on the synaptic plasticity of brain circuits involved in emotional functions.


The Journal of Neuroscience | 2016

Age-Related Changes in D-Aspartate Oxidase Promoter Methylation Control Extracellular D-Aspartate Levels and Prevent Precocious Cell Death during Brain Aging.

Daniela Punzo; Francesco d’Errico; Luigia Cristino; Silvia Sacchi; Simona Keller; Carmela Belardo; Livio Luongo; Tommaso Nuzzo; R. Imperatore; Ermanno Florio; V. de Novellis; O. Affinito; S. Migliarini; G. Maddaloni; Maria Josè Sisalli; Massimo Pasqualetti; Loredano Pollegioni; Sabatino Maione; Lorenzo Chiariotti; Alessandro Usiello

The endogenous NMDA receptor (NMDAR) agonist d-aspartate occurs transiently in the mammalian brain because it is abundant during embryonic and perinatal phases before drastically decreasing during adulthood. It is well established that postnatal reduction of cerebral d-aspartate levels is due to the concomitant onset of d-aspartate oxidase (DDO) activity, a flavoenzyme that selectively degrades bicarboxylic d-amino acids. In the present work, we show that d-aspartate content in the mouse brain drastically decreases after birth, whereas Ddo mRNA levels concomitantly increase. Interestingly, postnatal Ddo gene expression is paralleled by progressive demethylation within its putative promoter region. Consistent with an epigenetic control on Ddo expression, treatment with the DNA-demethylating agent, azacitidine, causes increased mRNA levels in embryonic cortical neurons. To indirectly evaluate the effect of a putative persistent Ddo gene hypermethylation in the brain, we used Ddo knock-out mice (Ddo−/−), which show constitutively suppressed Ddo expression. In these mice, we found for the first time substantially increased extracellular content of d-aspartate in the brain. In line with detrimental effects produced by NMDAR overstimulation, persistent elevation of d-aspartate levels in Ddo−/− brains is associated with appearance of dystrophic microglia, precocious caspase-3 activation, and cell death in cortical pyramidal neurons and dopaminergic neurons of the substantia nigra pars compacta. This evidence, along with the early accumulation of lipufuscin granules in Ddo−/− brains, highlights an unexpected importance of Ddo demethylation in preventing neurodegenerative processes produced by nonphysiological extracellular levels of free d-aspartate. SIGNIFICANCE STATEMENT The enzyme d-aspartate oxidase (DDO) catalyzes the degradation of the NMDA receptor agonist, d-aspartate. In the brain, DDO is expressed only during postnatal life, thus reducing the embryonic storage of d-aspartate and keeping this d-amino acid at low levels during adulthood. Although the presence of DDO in mammals is long established, its biological role in the brain and the mechanism regulating its expression are still unclear. Here, we found that Ddo promoter demethylation enables the postnatal expression of Ddo. Moreover, persistent suppression of Ddo expression leads to persistent spillover of extracellular d-aspartate and produces precocious cell death in the mouse brain, thus suggesting a key role for DDO in preventing early neurodegeneration triggered by excessive NMDA receptor stimulation.


Scientific Reports | 2017

Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity

Silvia Sacchi; Vito de Novellis; Giovanna Paolone; Tommaso Nuzzo; Monica Iannotta; Carmela Belardo; Marta Squillace; Paolo Bolognesi; Elena Rosini; Zoraide Motta; Martina Frassineti; Alessandro Bertolino; Loredano Pollegioni; Michele Morari; Sabatino Maione; Francesco d’Errico; Alessandro Usiello

D-aspartate levels in the brain are regulated by the catabolic enzyme D-aspartate oxidase (DDO). D-aspartate activates NMDA receptors, and influences brain connectivity and behaviors relevant to schizophrenia in animal models. In addition, recent evidence reported a significant reduction of D-aspartate levels in the post-mortem brain of schizophrenia-affected patients, associated to higher DDO activity. In the present work, microdialysis experiments in freely moving mice revealed that exogenously administered D-aspartate efficiently cross the blood brain barrier and stimulates L-glutamate efflux in the prefrontal cortex (PFC). Consistently, D-aspartate was able to evoke L-glutamate release in a preparation of cortical synaptosomes through presynaptic stimulation of NMDA, mGlu5 and AMPA/kainate receptors. In support of a potential therapeutic relevance of D-aspartate metabolism in schizophrenia, in vitro enzymatic assays revealed that the second-generation antipsychotic olanzapine, differently to clozapine, chlorpromazine, haloperidol, bupropion, fluoxetine and amitriptyline, inhibits the human DDO activity. In line with in vitro evidence, chronic systemic administration of olanzapine induces a significant extracellular release of D-aspartate and L-glutamate in the PFC of freely moving mice, which is suppressed in Ddo knockout animals. These results suggest that the second-generation antipsychotic olanzapine, through the inhibition of DDO activity, increases L-glutamate release in the PFC of treated mice.


Neuroscience Letters | 2017

d-Aspartic acid ameliorates painful and neuropsychiatric changes and reduces β-amyloid Aβ1-42 peptide in a long lasting model of neuropathic pain

Antimo D’Aniello; Livio Luongo; Rosaria Romano; Monica Iannotta; Ida Marabese; Serena Boccella; Carmela Belardo; Vito de Novellis; Claudio Arra; Antonio Barbieri; Biagio D’Aniello; Anna Scandurra; Laura Magliozzi; George H. Fisher; Francesca Guida; Sabatino Maione

Depressive symptoms and other neuropsychiatric dysfunctions are common in neurodegenerative disorders, including chronic pain and dementia. A correlation between the β-amyloid protein accumulation and the development of depression has been suggested, however the underlying mechanisms are unknown. d-Aspartate (d-Asp) is a free d-amino acid found in the mammalian brain and involved in neurological and psychiatric processes, such as cognition and affective disorders. In this study we have investigated the effects of a repeated treatment with d-Asp in a long-lasting (12 months) model of neuropathic pain, the spared nerve injury (SNI), in mice. Specifically, we evaluated i) the pain sensitivity and related emotional/cognitive dysfunctions induced by SNI, ii) possible changes in the β-amyloid protein accumulation in specific brain regions involved in pain mechanisms ii) possible changes in steroids level in neuropathic animals with or without d-Asp in the same brain areas. SNI mice showed an increase of the insoluble form of Aβ1-42 at hippocampal level and displayed cognitive impairments, stereotypical and depressive-like behaviours. d-Asp treatment reduced abnormal behaviours and normalized the β-amyloid protein expression. Moreover, d-Asp dramatically increased steroids level measured in the prefrontal cortex and in the hippocampus. Our findings provide new insights into pain mechanisms and suggest a possible role of β-amyloid protein in neuropsychiatric dysfunctions associated with chronic pain.


Frontiers in Pharmacology | 2017

Palmitoylethanolamide Reduces Neuropsychiatric Behaviors by Restoring Cortical Electrophysiological Activity in a Mouse Model of Mild Traumatic Brain Injury

Francesca Guida; Serena Boccella; Monica Iannotta; Danilo De Gregorio; Catia Giordano; Carmela Belardo; Rosaria Romano; Enza Palazzo; Maria Antonietta Scafuro; Nicola Serra; Vito de Novellis; Francesco Rossi; Sabatino Maione; Livio Luongo

Traumatic brain injury (TBI) represents a major public health problem, which is associated with neurological dysfunction. In severe or moderate cases of TBI, in addition to its high mortality rate, subjects may encounter diverse behavioral dysfunctions. Previous reports suggest that an association between TBI and chronic pain syndromes tends to be more common in patients with mild forms of brain injury. Despite causing minimal brain damage, mild TBI (mTBI) often leads to persistent psychologically debilitating symptoms, which can include anxiety, various forms of memory and learning deficits, and depression. At present, no effective treatment options are available for these symptoms, and little is known about the complex cellular activity affecting neuronal activity that occurs in response to TBI during its late phase. Here, we used a mouse model to investigate the effect of Palmitoylethanolamide (PEA) on both the sensorial and neuropsychiatric dysfunctions associated with mTBI through behavioral, electrophysiological, and biomolecular approaches. Fourteen-day mTBI mice developed anxious, aggressive, and reckless behavior, whilst depressive-like behavior and impaired social interactions were observed from the 60th day onward. Altered behavior was associated with changes in interleukin 1 beta (IL-1β) expression levels and neuronal firing activity in the medial prefrontal cortex. Compared with vehicle, PEA restored the behavioral phenotype and partially normalized the biochemical and functional changes occurring at the supraspinal level. In conclusion, our findings reveal some of the supraspinal modifications responsible for the behavioral alterations associated with mTBI and suggest PEA as a pharmacological tool to ameliorate neurological dysfunction induced by the trauma.


Neurobiology of Disease | 2019

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

Serena Boccella; Claudia Cristiano; Rosaria Romano; Monica Iannotta; Carmela Belardo; Antonio Farina; Francesca Guida; Fabiana Piscitelli; Enza Palazzo; Mariacristina Mazzitelli; R. Imperatore; Lea Tunisi; Vito de Novellis; Luigia Cristino; Vincenzo Di Marzo; Antonio Calignano; Sabatino Maione; Livio Luongo

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


Molecular Brain | 2015

Palmitoylethanolamide reduces pain-related behaviors and restores glutamatergic synapses homeostasis in the medial prefrontal cortex of neuropathic mice

Francesca Guida; Livio Luongo; Federica Marmo; Rosaria Romano; Monica Iannotta; Francesco Napolitano; Carmela Belardo; Ida Marabese; Antimo D’Aniello; D. De Gregorio; Francesco Rossi; Francesco Piscitelli; Roberta Lattanzi; A. de Bartolomeis; Alessandro Usiello; V. Di Marzo; V. de Novellis; Sabatino Maione


European Journal of Medicinal Chemistry | 2016

Exploring the role of chloro and methyl substitutions in 2-phenylthiomethyl-benzoindole derivatives for 5-LOX enzyme inhibition.

Antonella Peduto; Verena Krauth; Selene Collarile; Fiederike Dehm; Marika Ambruosi; Carmela Belardo; Francesca Guida; Antonio Massa; Veronica Esposito; Sabatino Maione; Mario De Rosa; Oliver Werz; Rosanna Filosa


Inflammation Research | 2017

Preclinical evaluation of the urokinase receptor-derived peptide UPARANT as an anti-inflammatory drug

Serena Boccella; Elisabetta Panza; Liliana Lista; Carmela Belardo; Angela Ianaro; Mario De Rosa; Vito de Novellis; Vincenzo Pavone


The FASEB Journal | 2018

Ketones and pain: unexplored role of hydroxyl carboxylic acid receptor type 2 in the pathophysiology of neuropathic pain

Serena Boccella; Francesca Guida; Francesco De Logu; Danilo De Gregorio; Mariacristina Mazzitelli; Carmela Belardo; Monica Iannotta; Nicola Serra; Romina Nassini; Vito de Novellis; Pierangelo Geppetti; Sabatino Maione; Livio Luongo

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Sabatino Maione

Seconda Università degli Studi di Napoli

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Livio Luongo

Seconda Università degli Studi di Napoli

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Francesca Guida

Seconda Università degli Studi di Napoli

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Monica Iannotta

Seconda Università degli Studi di Napoli

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Serena Boccella

Seconda Università degli Studi di Napoli

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Vito de Novellis

Seconda Università degli Studi di Napoli

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Rosaria Romano

Seconda Università degli Studi di Napoli

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Alessandro Usiello

Seconda Università degli Studi di Napoli

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Antonio Lavecchia

University of Naples Federico II

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