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Research Interests: Biophysics, Chemistry, Biology, Calcium, Enzyme Inhibitors, and 15 moreMedicine, Animals, Male, Clinical Sciences, Experimental Neurology, Ion Transport, Membrane Potential, Interneurons, Glutamate Receptor, Choline Acetyltransferase, Depolarization, Cell Membrane, Corpus striatum, Complex I, and In Vitro Techniques
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Age-related macular degeneration is an incurable chronic neurodegenerative disease, which causes progressive loss of the central vision and even blindness. All current treatments aim at slowing down the progression of the disease. In the... more
Age-related macular degeneration is an incurable chronic neurodegenerative disease, which causes progressive loss of the central vision and even blindness. All current treatments aim at slowing down the progression of the disease. In the present paper we provide in vitro evidence for the feasibility of layered biohybrid retinas built with silk silkworm fibroin and cultures of different types of cells: retinal pigment epithelium, retinal neurons, Müller and mesenchymal stem cells. The layers of the biohybrid retina are glued together with silk fibroin hydrogel. In vitro tests show primary culture neurons grow and develop neurites on silk fibroin biofilms alone, or in presence of other cells cultivated on the same biomaterial, the organization of the cells and the cellular phenotypes, are maintained during the 7 days of the experiment.
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Research Interests: Histochemistry, Dopamine, Brain Mapping, Internal Medicine, Female, and 15 moreAnimals, Male, Gender Difference, Frontal Cortex, Animal Model, Cytochrome oxidase, Globus Pallidus, Basal ganglia, Enzyme activity, Interaction effect, Attention deficit disorder with hyperactivity, Forebrain, Attention deficit hyperactivity disorder, Medical and Health Sciences, and Male rat
Remodeling of neural networks in the anterior forebrain of an animal model of hyperactivity and attention deficits as monitored by molecular imaging probes. These studies report on the remodeling of neural networks which are likely to be... more
Remodeling of neural networks in the anterior forebrain of an animal model of hyperactivity and attention deficits as monitored by molecular imaging probes. These studies report on the remodeling of neural networks which are likely to be the consequences of the segmental defect in the anterior forebrain of an animal model of hyperactivity and attention-deficit, the juvenile prehypertensive male spontaneously hypertensive rat (SHR). Molecular biology and microscope imaging techniques were used such as: (i) dopamine (DA) D-1 and D-2 receptors by radioligand binding studies; (ii) the Ca2+/Calmodulin-dependent protein kinase II (CaMKII); (iii) transcription factors (TF) such as c-FOS by Immunocytochemistry; and (iv) the respiratory chain enzyme cytochrome-oxidase (C.O.), as markers of neuronal activity in the anterior forebrain of SHR and Wistar Kyoto normotensive (WKY) controls rats. Microcomputer-assisted high-resolution image analysis using DA receptor binding and C.O., as probes revealed by cross-correlations among different regions within brain an altered cross-talk in the anterior forebrain of the SHR as compared to the controls. In particular, an altered cross-talk was also observed within the amygdala complex in the SHR by CaMKII and c-FOS expression. Therefore, the hypothesized segmental defect in the anterior forebrain of the SHR produces network consequences leading to behavioral alteration in the attentional activity and emotional domains. Subchronic treatment with metilphenidate (MP) that is known to block the reuptake of biogenic amines (mainly DA) produced network remodeling which are known to be paralleled by behavioral modifications in the attentive activity and emotional domains. Imperspective, the results from this model system that features the main aspects of attention-deficit hyperactivity disorder (ADHD), can be useful for the understanding of the neural substrates of hyperactivity and attention deficits and possibly for an early diagnosis and appropriate treatment of ADHD children.
Research Interests: Behavior Modification, Molecular Biology, Immunohistochemistry, Neural Network, Medicine, and 15 moreMolecular Imaging, Cross Correlation, Animals, Male, Animal Model, Dopamine Receptors, Cytochrome oxidase, Calmodulin, Neuronal Activity, CaMKII, Autoradiography, Methylphenidate, Attention deficit disorder with hyperactivity, Forebrain, and Medical and Health Sciences
The role of nitric oxide in learning and memory processes has been tested in the albino rat by a histochemical and a behavioral study, following behavioral habituation to spatial novelty. Histochemically, the neural consequences of... more
The role of nitric oxide in learning and memory processes has been tested in the albino rat by a histochemical and a behavioral study, following behavioral habituation to spatial novelty. Histochemically, the neural consequences of behavioral testing were mapped in the brain by staining for NADPH-d, known to be a NOS, whereas behaviorally the formation of LTH has been interfered with by posttrial NOS-inhibition. In the histochemical study, adult male Sprague-Dawley rats were tested in a Làt-maze and sacrificed at different time intervals thereafter. Handled unexposed rats served as controls. The brains were perfused with aldheide and processed for NADPH-d staining. In unexposed control rats the basal expression of NADPH-d was low and scattered. It pertained to few cells in the neostriatum, cerebral cortex, and CA1 hippocampal regions. In contrast, rats that had been exposed for the first time to the maze (spatial novelty) showed NADPH-d activity in the dorsal hippocampus (granule cells, few hilar neurons, and some CA1 pyramidal cells), the caudate-putamen complex, the cerebellum, and in all layers of somatosensory cortex. The positivity was not due to activity per se, since immediately after exposure it was not different from baseline. In contrast, it was present by 2 h and decreased significantly 24 h later. In addition, a strong neuronal discharge induced by the convulsant pentylentetrazol did not induce NADPH-d 2 h afterwards. The staining was prevented by pretreatment with the NMDA receptor antagonist CPP (5 mg/kg) or with the NOS inhibitor L-NOARG (10 mg/kg). In the behavioral study, rats were given an intraperitoneal injection of 1-10 mg/kg (L-NOARG) or vehicle immediately following exposure to a Làt-maze. The highest dose used (10 mg/kg) disrupted habituation of the vertical component only, known to be mainly of emotional meaning. Conversely, both doses disrupted emotional habituation based on defecation scores. The data indicate that the formation of LTH to novelty triggers a cascade of neurochemical events also involving NOS neurons. Further, the widespread induction of NADPH-d by exposure to novelty suggests that spatial and emotional information processing activate neural networks across different organizational levels of the CNS.
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In the central nervous system (CNS), the Na(+)-Ca(2+) exchanger plays a fundamental role in controlling the changes in the intracellular concentrations of Na(+) and Ca(2+) ions. These cations are known to regulate neurotransmitter... more
In the central nervous system (CNS), the Na(+)-Ca(2+) exchanger plays a fundamental role in controlling the changes in the intracellular concentrations of Na(+) and Ca(2+) ions. These cations are known to regulate neurotransmitter release, cell migration and differentiation, gene expression, and neurodegenerative processes. In the present study, nonradioactive in situ hybridization and light immunohistochemistry were carried out to map the regional and cellular distribution for both transcripts and proteins encoded by the three known Na(+)-Ca(2+) exchanger genes NCX1, NCX2, and NCX3. NCX1 transcripts were particularly expressed in layers III-V of the motor cortex, in the thalamus, in CA3 and the dentate gyrus of the hippocampus, in several hypothalamic nuclei, and in the cerebellum. NCX2 transcripts were strongly expressed in all hippocampal subregions, in the striatum, and in the paraventricular thalamic nucleus. NCX3 mRNAs were mainly detected in the hippocampus, in the thalamus, in the amygdala, and in the cerebellum. Immunohistochemical analysis revealed that NCX1 protein was mainly expressed in the supragranular layers of the cerebral cortex, in the hippocampus, in the hypothalamus, in the substantia nigra and ventral tegmental area, and in the granular layer of the cerebellum. The NCX2 protein was predominantly expressed in the hippocampus, in the striatum, in the thalamus, and in the hypothalamus. The NCX3 protein was particularly found in the CA3 subregion, and in the oriens, radiatum, and lacunoso-moleculare layers of the hippocampus, in the ventral striatum, and in the cerebellar molecular layer. Collectively, these results suggest that the different Na(+)-Ca(2+) exchanger isoforms appear to be selectively expressed in several CNS regions where they might underlie different functional roles.
Research Interests: Biology, Calcium, Immunohistochemistry, Medicine, Gene expression, and 15 moreIn Situ Hybridization, Brain Mapping, Hippocampus, Brain, Cerebellum, Animals, Male, Medical Physiology, Neurons, Membrane transport proteins, Dentate Gyrus, Comparative Neurology, Neurosciences, Immunoblotting, and Differential expression
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The functionality and stability of the central nervous system (CNS) pabulum, called neural extracellular matrix (nECM), is paramount for the maintenance of a healthy network. The loosening or the damage of the scaffold disrupts synaptic... more
The functionality and stability of the central nervous system (CNS) pabulum, called neural extracellular matrix (nECM), is paramount for the maintenance of a healthy network. The loosening or the damage of the scaffold disrupts synaptic transmission with the consequent imbalance of the neurotransmitters, reactive cells invasion, astrocytosis, new matrix deposition, digestion of the previous structure and ultimately, maladaptive plasticity with the loss of neuronal viability. nECM is constantly affected by CNS disorders, particularly in chronic modifying such as neurodegenerative disease, or in acute/subacute with chronic sequelae, like cerebrovascular and inflammatory pathology. Matrix metalloproteinases (MMPs) are the main interfering agent of nECM, guiding the balance of degradation and new deposition of proteins such as proteoglycans and glycoproteins, or glycosaminoglycans, such as hyaluronic acid. Activation of these enzymes is modulated by their physiologic inhibitors, the tissue inhibitors of MMPs or via other proteases inhibitors, as well as genetic or epigenetic up- or downregulation through molecular interaction or receptor activation. The appropriate understanding of the pathways underlying nECM modifications in CNS pathology is probably one of the pivotal future directions to identify the healthy brain network and subsequently design new therapies to interfere with the progression of the CNS disease and eventually find appropriate therapies.
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Nell’uomo, la maggior parte della superficie mediale degli emisferi cerebrali è occupata dalla neocortex notevolmente espansa. Comunque, su questo lato dell’encefalo, sono presenti anche numerose strutture che non sono neocorticali. Due... more
Nell’uomo, la maggior parte della superficie mediale degli emisferi cerebrali è occupata dalla neocortex notevolmente espansa. Comunque, su questo lato dell’encefalo, sono presenti anche numerose strutture che non sono neocorticali. Due di queste, il sistema olfattorio centrale e il setto, occupano una posizione superficiale, mentre altre due, il complesso amigdaloideo e la formazione ippocampale, sono per la maggior parte nascoste
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Herrick [9, 10] ha diviso il diencefalo in quattro zone longitudinali: l’epitalamo, il talamo dorsale, il talamo ventrale e l’ipotalamo. Questa suddivisione è stata ampiamente condivisa dalla comunità scientifica ed è stato asserito che... more
Herrick [9, 10] ha diviso il diencefalo in quattro zone longitudinali: l’epitalamo, il talamo dorsale, il talamo ventrale e l’ipotalamo. Questa suddivisione è stata ampiamente condivisa dalla comunità scientifica ed è stato asserito che poteva essere applicata a tutte le classi di vertebrati, inclusi i mammiferi [3, 27] e l’uomo [5, 11, 12, 26]. Sebbene attualmente sia noto (vedi Cap.
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Page 1. 14 Telencefalo: gangli della base Introduzione..... 427 Nuclei ..... 429 Connessioni..... 439 Note introduttive..... ...
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Research Interests: Neuroscience, Psychology, Magnetic Resonance Imaging, Consciousness, Medicine, and 12 moreComa, Brain, Humans, Default Mode Network, Functional Magnetic Resonance Imaging, Key words, Functional Neurology, Disorders of Consciousness, resting state fMRI, Minimally conscious state, Persistent Vegetative State, and Consciousness disorders
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In questo capitolo, saranno trattati l’ippocampo e due relative strutture telencefaliche, il lobo limbico e il setto precommissurale. L’ippocampo, che si sviluppa dal pallio mediale (Figg. 2.24B, 2.25, 11.1), fa la sua comparsa durante la... more
In questo capitolo, saranno trattati l’ippocampo e due relative strutture telencefaliche, il lobo limbico e il setto precommissurale. L’ippocampo, che si sviluppa dal pallio mediale (Figg. 2.24B, 2.25, 11.1), fa la sua comparsa durante la sesta settimana di gestazione. Negli ultimi stadi della vita embrionale questa struttura occupa una considerevole parte della parete mediale dell’emisfero (Fig. 12.1A) ma, durante il
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ABSTRACT Il sistema visivo risulta costituito da un certo numero di vie parallele, ciascuna interessata a una specifica funzione. L’elaborazione parallela dell’informazione visiva è presente già a livello della retina (Figg. 19.1, 19.2).... more
ABSTRACT Il sistema visivo risulta costituito da un certo numero di vie parallele, ciascuna interessata a una specifica funzione. L’elaborazione parallela dell’informazione visiva è presente già a livello della retina (Figg. 19.1, 19.2). La struttura e la funzione della retina sono state ampiamente analizzate [54, 114, 155, 188, 189, 309]. Fig. 19.1 A–F.La retina dei primati e le sue connessioni con il corpo genicolato laterale, i nuclei del sistema ottico accessorio e il nucleo soprachiasmatico. A Strati. LCR, strato dei coni e dei bastoncelli; OLM, membrana limitante esterna; ONL, strato nucleate esterno; OPL, strato plessiforme esterno; INL, strato nucleare interno; OFF, sottostrato OFF dello strato plessiforme interno; ON, sottostrato ON dello strato plessiforme interno; GCL, strato delle cellule gangliari; LON, strato delle fibre del nervo ottico; ILM, membrana limitante interna. B Vie delle cellule gangliari nane e multipolari. I coni per le lunghezze d’onda lunga (coni L, sensibili al rosso, raffigurati in rosso) e i coni per le lunghezze d’onda medie (coni M, sensibili al verde, raffigurati in nero) hanno ciascuno una propria linea privata con gli strati parvocellulari del corpo genicolato laterale (raffigurato in nero). Ciascun cono è connesso, attraverso una cellula bipolare (piatta) OFF (6) e una bipolare (invaginante) ON (8), rispettivamente, con una cellula gangliare nana ON (7) e una cellula gangliare nana OFF (9). Le cellule bipolari diffuse ON (10) e le cellule bipolari diffuse OFF (12) ricevono informazioni da coni organizzati in maniera casuale e sono connesse, rispettivamente, con le cellule gangliari multipolari ON e OFF (11, 13). Le cellule multipolari proiettano agli strati magnocellulari del corpo genicolato laterale. Riquadro (1): la triade sinaptica tra un pedicello di un cono (2) e i dendriti basali piatti delle cellule bipolari OFF (3), i dendriti delle cellule orizzontali (cell oriz) (4), e il dendrite invaginante di una cellula bipolare ON (5). C Sistema dei coni per il blu. I coni per le lunghezze d’onda corte (cono S, sensibile al blu, raffigurato in grigio) sono connessi alle cellule gangliari bistratificate (14), che proiettano agli strati interlaminari (koniocellulari) del corpo genicolato laterale. Le cellule bipolari ON del cono S (15) si collegano ai dendriti delle cellule gangliari nello strato ON dello strato plessiforme interno. I coni L e M, responsabili per la sensibilità al giallo, sono connessi con le cellule bipolari diffuse (12) dello strato OFF. D Vie dei bastoncelli. Le bipolari dei bastoncelli (17) collegano numerosi bastoncelli con le cellule amacrine del tipo AII (18). Queste cellule amacrine stabiliscono gap junctions (16) con l’assone di cellule bipolari ON dei coni (8) e sinapsi inibitorie convenzionali (19) con cellule bipolari OFF dei coni (9). Il segnale dei bastoncelli, pertanto, è trasportato dalle vie dei coni al nucleo genicolato laterale. E Cellule gangliari contenenti melanopsina sensibili alla luce proiettano al nucleo soprachiasmatico. Queste cellule gangliari ricevono afferenze anche dai fotorecettori (20). F Un tipo di cellula gangliare sensibile alla direzione (24) è un neurone bistratificato, che riceve afferenze da cellule amacrine del tipo “starburst” (22). Il corpo cellulare di cellule “starburst” dislocate è disposto nello strato delle cellule gangliari (23). Le precise connessioni con i fotorecettori non sono note (24). Le cellule gangliari sensibili alla direzione proiettano al sistema visivo accessorio. Il riquadro raffigura una proiezione tangenziale di una cellula amacrina. del tipo “starburst” Fig. 19.2.Distribuzione dei bastoncelli e dei coni nella retina umana. Ritratta da Kolb e coll. [155]. 1, Fovea centralis; 2, Disco ottico; 3, Ora serrata
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La percezione cosciente della sensibilità cutanea e propriocettiva e del gusto dipendono dalle vie di conduzione che connettono i recettori periferici con i centri a livello del diencefalo e del telencefalo. La maggior parte di queste... more
La percezione cosciente della sensibilità cutanea e propriocettiva e del gusto dipendono dalle vie di conduzione che connettono i recettori periferici con i centri a livello del diencefalo e del telencefalo. La maggior parte di queste connessioni, a eccezione delle vie per il gusto, è crociata. L’elaborazione iniziale dell’informazione sensoriale avviene nel midollo spinale e nei nuclei delle colonne dorsali per le informazioni relative al tronco e alle estremità, e nei nuclei sensoriali del nervo trigemino per quelle della faccia. Il primo relè per il gusto è situato nel nucleo del tratto solitario nel segmento inferiore del tronco encefalico. Le vie di conduzione spinale sono costituite dal fascicolo anterolaterale e dalla via delle colonne dorsali-lemnisco mediale. Entrambi questi sistemi sono crociati. Le vie corrispondenti traggono origine dai nuclei sensoriali del nervo trigemino.
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ABSTRACT
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L’amigdala, o corpo amigdaloideo, è un grande complesso nucleare situato nella parte dorsomediale del lobo temporale, dove costituisce parte delle pareti rostromediale e rostrodorsale del corno inferiore del ventricolo laterale (Fig. 5.6,... more
L’amigdala, o corpo amigdaloideo, è un grande complesso nucleare situato nella parte dorsomediale del lobo temporale, dove costituisce parte delle pareti rostromediale e rostrodorsale del corno inferiore del ventricolo laterale (Fig. 5.6, 5.7, 5.23, 5.24, 6.39–6.41). Il termine deriva dal Greco (amygdalon) o dal Latino (amygdalum) che significa mandorla, cui Burdach [28] paragonò questo complesso per la forma agli inizi del diciannovesimo secolo. Il volume dell’amigdala umana, come stabilito dagli studi condotti mediante RMN in soggetti normali, è di circa 1700 mm3 [22].
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THIS study aimed at investigating putative neural substrates of attention-deficit hyperactivity disorder in children using the spontaneously hypertensive rat (SHR) as animal model and the Ca2+/calmodulin-dependent protein kinase II... more
THIS study aimed at investigating putative neural substrates of attention-deficit hyperactivity disorder in children using the spontaneously hypertensive rat (SHR) as animal model and the Ca2+/calmodulin-dependent protein kinase II (CaMKII) as a marker in the nucleus accumbens, an interface between limbic and motor systems. In prehypertensive male SHR and Wistar-Kyoto rats image analysis of CaMKII immunocytochemistry showed more positive elements in the shell than in the core, and in the former a lower level in SHR. The data indicate a reduced number of nucleus accumbens modules available for limbic-motor integration revealing putative substrates of the altered attentional and reinforcement mechanisms demonstrated in the SHR and in children with attention-deficit hyperactivity disorder.
Research Interests: Neuroscience, Psychology, Cognitive Science, Attention, Immunohistochemistry, and 13 moreMedicine, Nucleus Accumbens, Animals, Male, Animal Model, Amygdala, Neurons, Rats, Isoenzymes, Limbic System, Neurosciences, Attention deficit disorder with hyperactivity, and Attention deficit hyperactivity disorder
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... Nel nucleo oscuro del rafe, i neuroni serotoninergici sono confinati in due lamine da entrambi i lati della linea mediana. Rostralmente, questi gruppi serotoninergici si continuano con il gruppo B3 corrispondente al nucleo magno del... more
... Nel nucleo oscuro del rafe, i neuroni serotoninergici sono confinati in due lamine da entrambi i lati della linea mediana. Rostralmente, questi gruppi serotoninergici si continuano con il gruppo B3 corrispondente al nucleo magno del rafe. ... lamine superficiali del corno dorsale. ...
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Il midollo spinale con i suoi rivestimenti meningei e accolto nel canale vertebrale (Figg. 4.30–4.32). Il limite tra midollo spinale e tronco encefalico e fissato rostralmente all’origine del primo nervo cervicale, a livello della... more
Il midollo spinale con i suoi rivestimenti meningei e accolto nel canale vertebrale (Figg. 4.30–4.32). Il limite tra midollo spinale e tronco encefalico e fissato rostralmente all’origine del primo nervo cervicale, a livello della decussazione delle piramidi. Comunque, il passaggio dai nuclei motori e sensoriali del midollo alle corrispondenti strutture della parte caudale del tronco encefalico (responsabili dell’innervazione di strutture originate dai somiti occipitali, vedi Cap. 2) avviene in maniera graduale.
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Nel corso dell’ontogenesi, gli emisferi telencefalici evaginano bilateralmente dalla parte più dorsale della lamina alare del prosencefalo secondario (Figg. 2.2C, 2.3C, 2.4, 2.5B, C). Esistono due principali divisioni degli emisferi... more
Nel corso dell’ontogenesi, gli emisferi telencefalici evaginano bilateralmente dalla parte più dorsale della lamina alare del prosencefalo secondario (Figg. 2.2C, 2.3C, 2.4, 2.5B, C). Esistono due principali divisioni degli emisferi telencefalici: il tetto o pallio e la base o sub pallio. Classicamente, il pallio è diviso in tre zone longitudinali, mediale, dorsale e laterale. Durante lo sviluppo, i neuroblasti migrano verso l’esterno dalla matrice ventricolare per partecipare alla formazione delle strutture corticali in tutte le zone del pallio. Il pallio mediale si sviluppa dando origine alla formazione ippocampale, nella quale, tra i due strati plessiformi, periventricolare e subpiale, è racchiuso un compatto strato di cellule. Una struttura a tre strati si forma anche nel pallio laterale. Qui riscontriamo uno strato molecolare superficiale, contenente un relativo scarso numero di cellule sparse, uno strato intermedio a elevata densità cellulare e uno strato profondo, che mostra una moderata densità cellulare. La formazione corticale, che si sviluppa dal pallio laterale, riceve proiezioni dirette dal bulbo olfattorio.
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Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that is used against cognitive impairment in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). However, the neurobiological... more
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that is used against cognitive impairment in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). However, the neurobiological mechanisms underlying the rTMS therapeutic effects are still only partially investigated. Maladaptive plasticity, glial activation, and neuroinflammation, including metalloproteases (MMPs) activation, might represent new potential targets of the neurodegenerative process and progression from MCI to AD. In this study, we aimed to evaluate the effects of bilateral rTMS over the dorsolateral prefrontal cortex (DLPFC) on plasmatic levels of MMP1, -2, -9, and -10; MMPs-related tissue inhibitors TIMP1 and TIMP2; and cognitive performances in MCI patients. Patients received high-frequency (10 Hz) rTMS (MCI-TMS, n = 9) or sham stimulation (MCI-C, n = 9) daily for four weeks, and they were monitored for six months after TMS. The plasmatic levels of MMPs and TIMPs ...
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The maladaptive response of the central nervous system (CNS) following nerve injury is primarily linked to the activation of glial cells (reactive gliosis) that produce an inflammatory reaction and a wide cellular morpho-structural and... more
The maladaptive response of the central nervous system (CNS) following nerve injury is primarily linked to the activation of glial cells (reactive gliosis) that produce an inflammatory reaction and a wide cellular morpho-structural and functional/metabolic remodeling. Glial acidic fibrillary protein (GFAP), a major protein constituent of astrocyte intermediate filaments (IFs), is the hallmark of the reactive astrocytes, has pleiotropic functions and is significantly upregulated in the spinal cord after nerve injury. Here, we investigated the specific role of GFAP in glial reaction and maladaptive spinal cord plasticity following sciatic nerve spared nerve injury (SNI) in GFAP KO and wild-type (WT) animals. We evaluated the neuropathic behavior (thermal hyperalgesia, allodynia) and the expression of glial (vimentin, Iba1) and glutamate/GABA system markers (GLAST, GLT1, EAAC1, vGLUT, vGAT, GAD) in lumbar spinal cord sections of KO/WT animals. SNI induced neuropathic behavior in both G...
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Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with a malignant prognosis. GBM is characterized by high cellular heterogeneity and its progression relies on the interaction with the central nervous system, which... more
Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with a malignant prognosis. GBM is characterized by high cellular heterogeneity and its progression relies on the interaction with the central nervous system, which ensures the immune-escape and tumor promotion. This interplay induces metabolic, (epi)-genetic and molecular rewiring in both domains. In the present study, we aim to characterize the time-related changes in the GBM landscape, using a syngeneic mouse model of primary GBM. GL261 glioma cells were injected in the right striatum of immuno-competent C57Bl/6 mice and animals were sacrificed after 7, 14, and 21 days (7D, 14D, 21D). The tumor development was assessed through 3D tomographic imaging and brains were processed for immunohistochemistry, immunofluorescence, and western blotting. A human transcriptomic database was inquired to support the translational value of the experimental data. Our results showed the dynamic of the tumor progression, being ...
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Activation of glial cells (reactive gliosis) and the purinergic pathway, together with metalloproteinase (MMP)-induced remodeling of the neural extracellular matrix (nECM), drive maladaptive changes in the spinal cord following peripheral... more
Activation of glial cells (reactive gliosis) and the purinergic pathway, together with metalloproteinase (MMP)-induced remodeling of the neural extracellular matrix (nECM), drive maladaptive changes in the spinal cord following peripheral nerve injury (PNI). We evaluated the effects on spinal maladaptive plasticity through administration of oxidized ATP (oxATP), an antagonist of P2X receptors (P2XR), and/or GM6001, an inhibitor of MMPs, in rats following spared nerve injury (SNI) of the sciatic nerve. With morpho-molecular techniques, we demonstrated a reduction in spinal reactive gliosis and changes in the neuro-glial-nECM crosstalk via expression remodeling of P2XR, nerve growth factor (NGF) receptors (TrkA and p75), and histone deacetylase 2 (HDAC2) after treatments with oxATP/GM6001. Altogether, our data suggest that MMPs and purinergic inhibition have a modulatory impact on key proteins in the neuro-glial-nECM network, acting at different levels from intracellular signaling to epigenetic modifications.
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Dysfunctions of the neuronal-glial crosstalk and/or impaired signaling of neurotrophic factors represent key features of the maladaptive changes in the central nervous system (CNS) in neuroinflammatory as neurodegenerative disorders.... more
Dysfunctions of the neuronal-glial crosstalk and/or impaired signaling of neurotrophic factors represent key features of the maladaptive changes in the central nervous system (CNS) in neuroinflammatory as neurodegenerative disorders. Tissue plasminogen activator (tPA)/plasminogen (PA)/plasmin system has been involved in either process of maturation and degradation of nerve growth factor (NGF), highlighting multiple potential targets for new therapeutic strategies. We here investigated the role of intrathecal (i.t.) delivery of neuroserpin (NS), an endogenous inhibitor of plasminogen activators, on neuropathic behavior and maladaptive synaptic plasticity in the rat spinal cord following spared nerve injury (SNI) of the sciatic nerve. We demonstrated that SNI reduced spinal NGF expression, induced spinal reactive gliosis, altering the expression of glial and neuronal glutamate and GABA transporters, reduced glutathione (GSH) levels and is associated to neuropathic behavior. Beside the increase of NGF expression, i.t. NS administration reduced reactive gliosis, restored synaptic homeostasis, GSH levels and reduced neuropathic behavior. Our results hereby highlight the essential role of tPA/PA system in the synaptic homeostasis and mechanisms of maladaptive plasticity, sustaining the beneficial effects of NGF-based approach in neurological disorders.
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Neuroinflammation, a hallmark of chronic neurodegenerative disorders, is characterized by sustained glial activation and the generation of an inflammatory loop, through the release of cytokines and other neurotoxic mediators that cause... more
Neuroinflammation, a hallmark of chronic neurodegenerative disorders, is characterized by sustained glial activation and the generation of an inflammatory loop, through the release of cytokines and other neurotoxic mediators that cause oxidative stress and limit functional repair of brain parenchyma. Dietary antioxidants may protect against neurodegenerative diseases by counteracting chronic neuroinflammation and reducing oxidative stress. Here, we describe the effects of a number of natural antioxidants (polyphenols, carotenoids, and thiolic molecules) in rescuing astrocytic function and neuronal viability following glial activation by reducing astrocyte proliferation and restoring astrocytic and neuronal survival and basal levels of reactive oxygen species (ROS). All antioxidant molecules are also effective under conditions of oxidative stress and glutamate toxicity, two maladaptive components of neuroinflammatory processes. Moreover, it is remarkable that their antioxidant and an...
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The eminently complex regulatory network protecting the cell against oxidative stress, surfaces in several disease maps, including that of Parkinson’s disease (PD). How this molecular networking achieves its various functionalities and... more
The eminently complex regulatory network protecting the cell against oxidative stress, surfaces in several disease maps, including that of Parkinson’s disease (PD). How this molecular networking achieves its various functionalities and how processes operating at the seconds-minutes time scale cause a disease at a time scale of multiple decennia is enigmatic.By computational analysis, we here disentangle the reactive oxygen species (ROS) regulatory network into a hierarchy of subnetworks that each correspond to a different functionality. The detailed dynamic model of ROS management obtained integrates these functionalities and fitsin vitrodata sets from two different laboratories.The model shows effective ROS-management for a century, followed by a sudden system’s collapse due to the loss of p62 protein. PD related conditions such as lack of DJ-1 protein or increased α-synuclein accelerated the system’s collapse. Variousin-silicointerventions (e.g. addition of antioxidants or caffein...
Research Interests:
Research Interests:
Neurodegeneration is a multifactorial process that involves multiple mechanisms. Examples of neurodegenerative diseases are Parkinson’s disease, multiple sclerosis, Alzheimer’s disease, prion diseases such as Creutzfeldt–Jakob’s disease,... more
Neurodegeneration is a multifactorial process that involves multiple mechanisms. Examples of neurodegenerative diseases are Parkinson’s disease, multiple sclerosis, Alzheimer’s disease, prion diseases such as Creutzfeldt–Jakob’s disease, and amyotrophic lateral sclerosis. These are progressive and irreversible pathologies, characterized by neuron vulnerability, loss of structure or function of neurons, and even neuron demise in the brain, leading to clinical, functional, and cognitive dysfunction and movement disorders. However, iron overload can cause neurodegeneration. Dysregulation of iron metabolism associated with cellular damage and oxidative stress is reported as a common event in several neurodegenerative diseases. Uncontrolled oxidation of membrane fatty acids triggers a programmed cell death involving iron, ROS, and ferroptosis, promoting cell death. In Alzheimer’s disease, the iron content in the brain is significantly increased in vulnerable regions, resulting in a lack ...
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Alzheimer’s disease (AD) is a progressive and degenerative disease producing the most common type of dementia worldwide. The main pathogenetic hypothesis in recent decades has been the well-known amyloidogenic hypothesis based on the... more
Alzheimer’s disease (AD) is a progressive and degenerative disease producing the most common type of dementia worldwide. The main pathogenetic hypothesis in recent decades has been the well-known amyloidogenic hypothesis based on the involvement of two proteins in AD pathogenesis: amyloid β (Aβ) and tau. Amyloid deposition reported in all AD patients is nowadays considered an independent risk factor for cognitive decline. Vascular damage and blood–brain barrier (BBB) failure in AD is considered a pivotal mechanism for brain injury, with increased deposition of both immunoglobulins and fibrin. Furthermore, BBB dysfunction could be an early sign of cognitive decline and the early stages of clinical AD. Vascular damage generates hypoperfusion and relative hypoxia in areas with high energy demand. Long-term hypoxia and the accumulation within the brain parenchyma of neurotoxic molecules could be seeds of a self-sustaining pathological progression. Cellular dysfunction comprises all the ...
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Inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, are incurable autoimmune diseases characterized by chronic inflammation of the gastrointestinal tract. There is increasing evidence that inappropriate... more
Inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, are incurable autoimmune diseases characterized by chronic inflammation of the gastrointestinal tract. There is increasing evidence that inappropriate interaction between the enteric nervous system and central nervous system and/or low activity of the vagus nerve, which connects the enteric and central nervous systems, could play a crucial role in their pathogenesis. Therefore, it has been suggested that appropriate neuroprosthetic stimulation of the vagus nerve could lead to the modulation of the inflammation of the gastrointestinal tract and consequent long-term control of these autoimmune diseases. In the present paper, we provide a comprehensive overview of (1) the cellular and molecular bases of the immune system, (2) the way central and enteric nervous systems interact and contribute to the immune responses, (3) the pathogenesis of the inflammatory bowel disease, and (4) the therapeutic use of vagus...