Michele Papa

Michele Papa
University of Campania , Luigi Vanvitelli · Department of Mental and Physical Health and Preventive Medicine

MD

About

140
Publications
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Introduction
Pentapartite synapse, a systems biology approach to brain function and neurological diseases. In vivo models, slice, and cell culture. Morpho-molecular analysis by light and confocal microscopy, proteomics, and epigenomic analysis

Publications

Publications (140)
Article
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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 ensures the immune-escape and tumor promotion. This interplay induces metabolic, (epi)-genetic and molecular rew...
Article
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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 nerve injury (PNI). We evaluated the effects on spinal maladaptive plasticity through administration of oxidize...
Article
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Glioblastoma (GBM) are among the most common malignant central nervous system (CNS) cancers, they are relatively rare. This evidence suggests that the CNS microenvironment is naturally equipped to control proliferative cells, although, rarely, failure of this system can lead to cancer development. Moreover, the adult CNS is innately non-permissive...
Article
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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 functional/metabolic remodeling. Glial acidic fibrillary protein (GFAP), a major protein constituent of astrocyte...
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The spatial and temporal coordination of each element is a pivotal characteristic of systems, and the central nervous system (CNS) is not an exception. Glial elements and the vascular interface have been considered more recently, together with the extracellular matrix and the immune system. However, the knowledge of the single-element configuration...
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Patients with high-frequency resistant migraine and medication-overuse headache are still the main clinical challenge in tertiary headache centers. The approval of targeted antibodies against the calcitonin gene-related peptide (CGRP) and its receptor represents a powerful instrument. In this study, we observed how biological and clinical features...
Article
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...
Preprint
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The neuroglial network characterizes synaptic transmission and accounts for both cellular elements (neurons and glia) and neural extracellular matrix (nECM) roles. Glial cells, neuron, and nECMnetwork is strongly interconnected, in physiological and pathological conditions as shownin several neurodegenerative diseases. Purinergic activation and mat...
Preprint
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Different functional states determine glioblastoma (GBM) heterogeneity. Brain cancer cells coexist with the glial cells in a functional syncytium based on a continuous metabolic rewiring. However, standard glioma therapies do not account for the effects of the glial cells within the tumor microenvironment. This may be a possible reason for the lack...
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Migraine is a primary headache with high prevalence among the general population, characterized by functional hypersensitivity to both exogenous and endogenous stimuli particularly affecting the nociceptive system. The hyperresponsivity of cortical neurons could be due to a disequilibrium in the excitatory/inhibitory signaling. This study aimed to...
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Non-invasive low-intensity transcranial electrical stimulation (tES) of the brain is an evolving field that has brought remarkable attention in the past few decades for its ability to directly modulate specific brain functions. Neurobiological after-effects of tES seems to be related to changes in neuronal and synaptic excitability and plasticity,...
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How the network around ROS protects against oxidative stress and Parkinson’s disease (PD), and how processes at the minutes timescale cause disease and aging after decades, remains enigmatic. Challenging whether the ROS network is as complex as it seems, we built a fairly comprehensive version thereof which we disentangled into a hierarchy of only...
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Stroke is a major challenge in modern medicine and understanding the role of the neuronal extracellular matrix (NECM) in its pathophysiology is fundamental for promoting brain repair. Currently, stroke research is focused on the neurovascular unit (NVU). Impairment of the NVU leads to neuronal loss through post-ischemic and reperfusion injuries, as...
Article
The extracellular matrix (ECM) of the central nervous system (CNS) plays a pivotal role in the pathogenesis of several neurodegenerative and neuroinflammatory disorders. Among the major factors, matrix metalloproteinases (MMPs) are actively involved in ECM remodeling and directly affect neuro-glial interactions. Since disease-related functional alt...
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Age-related macular degeneration is an incurable chronic neurodegenerative disease, causing progressive loss of the central vision and even blindness. Up-to-date therapeutic approaches can only slow down he progression of the disease. Objective: Feasibility study for a multilayered, silk fibroin-based, 3D biohybrid retina. Approach: Fabrication...
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Background: Covid-19 is an infectious disease caused by an invasion of the alveolar epithelial cells by coronavirus 19. The most severe outcome of the disease is the Acute Respiratory Distress Syndrome (ARDS) combined with hypoxemia and cardiovascular damage. ARDS and co-morbidities are associated with inflammatory cytokine storms, sympathetic hype...
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The synaptic cleft has been vastly investigated in the last decades, leading to a novel and fascinating model of the functional and structural modifications linked to synaptic transmission and brain processing. The classic neurocentric model encompassing the neuronal pre- and post-synaptic terminals partly explains the fine-tuned plastic modificati...
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The main pathological feature of the neurodegenerative diseases is represented by neuronal death that represents the final step of a cascade of adverse/hostile events. Early in the neurodegenerative process, glial cells (including astrocytes, microglial cells, and oligodendrocytes) activate and trigger an insidious neuroinflammatory reaction, metab...
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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 oxidative stress and limit functional repair of brain parenchyma. Dietary antioxidants may protect against neurode...
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Electrical stimulation of the auricular vagus nerve (aVNS) is an emerging technology in the field of bioelectronic medicine with applications in therapy. Modulation of the afferent vagus nerve affects a large number of physiological processes and bodily states associated with information transfer between the brain and body. These include disease mi...
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Electrical stimulation of the auricular vagus nerve (aVNS) is an emerging electroceutical technology in the field of bioelectronic medicine with applications in therapy. Artificial modulation of the afferent vagus nerve-a powerful entrance to the brain-affects a large number of physiological processes implicating interactions between the brain and...
Article
Full-text available
Electrical stimulation of the auricular vagus nerve (aVNS) is an emerging electroceutical technology in the field of bioelectronic medicine with applications in therapy. Artificial modulation of the afferent vagus nerve – a powerful entrance to the brain – affects a large number of physiological processes implicating interactions between the brain...
Preprint
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...
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Amputation of a sensory peripheral nerve induces severe anatomical and functional changes along the afferent pathway as well as perception alterations and neuropathic pain. In previous studies we showed that electrical stimulation applied to a transected infraorbital nerve protects the somatosensory cortex from the above-mentioned sensory deprivati...
Article
The recognition that neurogenesis does not stop with adolescence has spun off research towards the reduction of brain disorders by enhancing brain regeneration. Adult neurogenesis is one of the tougher problems of developmental biology as it requires the generation of complex intracellular and pericellular anatomies, amidst the danger of neuroinfla...
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Bruton’s tyrosine-kinase (BTK) is a non-receptor tyrosine kinase recently associated with glioma tumorigenesis and a novel prognostic marker for poor survival in patients with glioma. The p65BTK is a novel BTK isoform involved in different pathways of drug resistance of solid tumors, thus we aimed to investigate the expression and the putative role...
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Selective neuronal death in neurodegenerative disorders represents the final step of a cascade of events, including neuroinflammation, regional-specific reactive gliosis, changes of brain-blood barrier structure and functions, metabolic failure and mitochondrial energy impairment. Bilateral striatal necrosis is usually reported in inherited mitocho...
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Coagulation and the immune system interact in several physiological and pathological conditions, including tissue repair, host defense, and homeostatic maintenance. This network plays a key role in diseases of the central nervous system (CNS) by involving several cells (CNS resident cells, platelets, endothelium, and leukocytes) and molecular pathw...
Article
Avolition, a deficit in goal-directed behavior, is a key aspect of negative symptoms. It is highly prevalent in schizophrenia and is associated to poor functional outcome and to measures of real life motivation, indicating that central to the concept is the lack of interest and motivation. In this study we tested the hypothesis that avolition is re...
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Neuronal differentiation involves extensive modification of biochemical and morphological properties to meet novel functional requirements. Reorganization of the mitochondrial network to match the higher energy demand plays a pivotal role in this process. Mechanisms of neuronal differentiation in response to nerve growth factor (NGF) have been larg...
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Blood coagulation factors and other proteins, with modulatory effects or modulated by the coagulation cascade have been reported to affect the pathophysiology of the central nervous system (CNS). The protease-activated receptors (PARs) pathway can be considered the central hub of this regulatory network, mainly through thrombin or activated protein...
Chapter
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 m...
Article
Introduction Avolition represents an important domain of negative symptoms in schizophrenia with a strong impact on functional outcome. Primary and persistent avolition is refractory to available pharmacological and psychological treatments. A better understanding of its pathophysiological mechanisms is fundamental to promote development of new tre...
Article
Introduction Impaired motivation is considered a fundamental aspect of the Avolition domain of negative symptoms. The ventral tegmental area (VTA) contains the highest number of DA neurons projecting to the brain areas involved in motivation-related processes. Aim The aim of our study was to investigate by functional MRI the resting-state function...
Article
Background Recent advances in large datasets analysis offer new insights to modern biology allowing system-level investigation of pathologies. Here we describe a novel computational method that exploits the ever-growing amount of “omics” data to shed light on Alzheimer’s and Parkinson’s diseases. Neurological disorders exhibit a huge number of mole...
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The integrity of the central nervous system (CNS) matrix is crucial for its proper function. Loss of the lattice-like structure compromise synaptic stability and can lead to the disruption of the excitatory/inhibitory balance, astrocytosis, maladaptive plasticity and neuronal death. Perineuronal nets (PNNs) in the extracellular matrix (ECM) provide...
Article
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Modulation of extracellular matrix (ECM) remodeling after peripheral nerve injury (PNI) could represent a valid therapeutic strategy to prevent maladaptive synaptic plasticity in central nervous system (CNS). Inhibition of matrix metalloproteinases (MMPs) and maintaining a neurotrophic support could represent two approaches to prevent or reduce the...
Article
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TGF-β pathway is generally associated with the processes of metastasis, angiogenesis and EMT in cancer. Very little is known, however, about the role of TGF-β in cancer drug resistance. In this work, we show a specific activation of the TGF-β pathway in consequence of chemotherapeutic treatment in in vivo and in vitro models of colorectal carcinoma...
Article
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Reactive astrocytes and activated microglia are the key players in several pathophysiologic modifications of the central nervous system. We used the spared nerve injury (SNI) of the sciatic nerve to induce glial maladaptive response in the ventral horn of lumbar spinal cord and examine its role in the remodeling of the tripartite synapse plasticity...
Article
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Modulation of spinal reactive gliosis following peripheral nerve injury (PNI) is a promising strategy to restore synaptic homeostasis. Oxidized ATP (OxATP), a nonselective antagonist of purinergic P2X receptors, was found to recover a neuropathic behavior following PNI. We investigated the role of intraperitoneal (i.p.) OxATP treatment in restoring...
Article
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Chronic neurodegenerative diseases represent major unmet needs for therapeutic interventions. Recently, the neurocentric view of brain function and disease has been challenged by a great number of evidence supporting the physiopathological potential of neuroglia. Astrocytes, in particular, play a pivotal role in brain homeostasis as they actively p...
Article
Background: Many brain areas participate to supraspinal control of nociception. In these regions, few studies have investigated the role of glial cells in supraspinal plasticity and the effect of 7-day intrathecal nerve growth factor-like (BB14®, Blueprint Biotech, Milano, Italy) treatment. Methods: In male Sprague-Dawley rats, we evaluated by i...
Article
Seizures are a common outcome of cerebrovascular events as well as of traumatic brain injuries. Thrombin, a protease-activated receptor (PAR) agonist, has been implicated in the onset of seizures in these settings, yet its mode of action is not entirely clear. In this study, the effect of Thrombin and a PAR-1 agonist on neuronal excitability and sy...
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Astrocytic Ca(2+) dynamics have been extensively studied in ex vivo models; however, the recent development of two-photon microscopy and astrocyte-specific labeling has allowed the study of Ca(2+) signaling in living central nervous system. Ca(2+) waves in astrocytes have been described in cultured cells and slice preparations, but evidence for ast...
Article
The role of the purinergic system in the modulation of pain mechanisms suggests that it might be promising target for treating neuropathic pain. In this study we evaluated the effects of two different dialdehydic compounds: a modified stable adenosine (2-[1-(6-amminopurin-9-il)-2-osso-etossi]prop-2-enale, named MED1101), and oxidized ATP (Ox-ATP),...
Article
Recent fMRI studies have shown that it is possible to reliably identify the default-mode network (DMN) in the absence of any task, by resting-state connectivity analyses in healthy volunteers. We here aimed to identify the DMN in the challenging patient population of disorders of consciousness encountered following coma. A spatial independent compo...
Article
Beside behavioral assessment of patients with disorders of consciousness, neuroimaging modalities may offer objective paraclinical markers important for diagnosis and prognosis. They provide information on the structural location and extent of brain lesions (e.g., morphometric MRI and diffusion tensor imaging (DTI-MRI) assessing structural connecti...
Article
Neuronal death has been reported to involve mitochondrial dysfunction and cell cycle reentry. In this report, we used Nerve Growth Factor (NGF)-differentiated PC12 cells to investigate mechanisms linking mitochondrial dysfunction and cell cycle activation during neuronal death induced by NGF withdrawal and/or oxidative stress. We found that loss of...
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Recent advances in the study of spontaneous brain activity have demonstrated activity patterns that emerge with no task performance or sensory stimulation; these discoveries hold promise for the study of higher-order associative network functionality. Additionally, such advances are argued to be relevant in pathological states, such as disorders of...
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Prognostic determination of patients in coma after resuscitation from cardiac arrest is a common and difficult requirement with significant ethical, social and legal implications. We set out to seek markers that can be used for the early detection of patients with a poor prognosis, so as to reduce uncertainty over treatment and non-treatment decisi...
Article
Repeated exposure to psychostimulant drugs induces complex molecular and structural modifications in discrete brain regions of the meso-cortico-limbic system. This structural remodeling is thought to underlie neurobehavioral adaptive responses. Administration to adolescent rats of methylphenidate (MPH), commonly used in attention deficit and hypera...