Publications by authors named "Michele Papa"

63 Publications

The Spatiotemporal Coupling: Regional Energy Failure and Aberrant Proteins in Neurodegenerative Diseases.

Int J Mol Sci 2021 Oct 20;22(21). Epub 2021 Oct 20.

Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, University of Campania ''Luigi Vanvitelli", 80138 Naples, Italy.

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 is not sufficient to predict physiological or pathological long-lasting changes. Ionic currents, complex molecular cascades, genomic rearrangement, and the regional energy demand can be different even in neighboring cells of the same phenotype, and their differential expression could explain the region-specific progression of the most studied neurodegenerative diseases. We here reviewed the main nodes and edges of the system, which could be studied to develop a comprehensive knowledge of CNS plasticity from the neurovascular unit to the synaptic cleft. The future goal is to redefine the modeling of synaptic plasticity and achieve a better understanding of neurological diseases, pointing out cellular, subcellular, and molecular components that couple in specific neuroanatomical and functional regions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms222111304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583302PMC
October 2021

CGRP Inhibitors and Oxidative Stress Biomarkers in Resistant Migraine: A Real-Life Study with Erenumab, Fremanezumab, and Galcanezumab.

J Clin Med 2021 Oct 4;10(19). Epub 2021 Oct 4.

Neurology Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy.

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 of resistant migraineurs responded to erenumab, fremanezumab, or galcanezumab. We found a reduction in advanced oxidation protein products (AOPP) as a biomarker of improved redox state after six months of treatment. We also found that treatment efficacy was precocious and maintained with high individual responder rates. In particular, seven out of ten patients achieved a reduction of 50% from the baseline at three months, which was maintained at six months, while about one out of our patients experienced a 75% reduction in headache frequency from the first month of treatment. The migraine disability assessment (MIDAS) and the associated fatigue, anxiety, and sleep quality also significantly improved. The allodynia symptom dropped from moderate/severe to mild/absent as a sign of central sensitization reduction. Our study confirmed the safety and efficacy of CGRP inhibition in real-life, high-challenging patients. Additional evidence is needed to understand the role of oxidative stress as a migraine biomarker.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm10194586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509234PMC
October 2021

Inhibition of plasminogen/plasmin system retrieves endogenous nerve growth factor and adaptive spinal synaptic plasticity following peripheral nerve injury.

Neurochem Int 2021 09 23;148:105113. Epub 2021 Jun 23.

Division of Human Anatomy, Laboratory of Morphology of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli, Naples, Italy. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuint.2021.105113DOI Listing
September 2021

The Italian law on body donation: A position paper of the Italian College of Anatomists.

Ann Anat 2021 Nov 15;238:151761. Epub 2021 Jun 15.

Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy.

In Italy, recent legislation (Law No. 10/2020) has tuned regulations concerning the donation of one's postmortem body and tissues for study, training, and scientific research purposes. This study discusses several specific issues to optimise the applicability and effectiveness of such an important, novel regulatory setting. Critical issues arise concerning the learners, the type of training and teaching activities that can be planned, the position of academic anatomy institutes, the role of family members in the donation process, the time frame of the donation process, the eligibility of partial donation, or the simultaneous donation of organs and tissues to patients awaiting transplantation. In particular, a universal time limit for donations (i.e., one year) makes it impossible to plan the long-term use of specific body parts, which could be effectively preserved for the advanced teaching and training of medical students and surgeons. The abovementioned conditions lead to the limited use of corpses, thus resulting in the inefficiency of the whole system of body donation. Overall, the donors' scope for the donation of their body could be best honoured by a more flexible and tuneable approach that can be used on a case-by-case basis. Furthermore, it is deemed necessary to closely monitor the events scheduled for corpses in public nonacademic institutions or private enterprises. This paper presents useful insights from Italian anatomists with the hope of providing inspiration for drafting the regulations. In conclusion, this paper focuses on the critical issues derived from the recently introduced Italian law on the donation and use of the body after death and provides suggestions to lawmakers for future implementations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.aanat.2021.151761DOI Listing
November 2021

The Glioblastoma Microenvironment: Morphology, Metabolism, and Molecular Signature of Glial Dynamics to Discover Metabolic Rewiring Sequence.

Int J Mol Sci 2021 Mar 24;22(7). Epub 2021 Mar 24.

Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, University of Campania ''Luigi Vanvitelli", 80138 Naples, Italy.

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 of improvements in patients with high-grade gliomas therapies. Cell metabolism and bioenergetic fitness depend on the availability of nutrients and interactions in the microenvironment. It is strictly related to the cell location in the tumor mass, proximity to blood vessels, biochemical gradients, and tumor evolution, underlying the influence of the context and the timeline in anti-tumor therapeutic approaches. Besides the cancer metabolic strategies, here we review the modifications found in the GBM-associated glia, focusing on morphological, molecular, and metabolic features. We propose to analyze the GBM metabolic rewiring processes from a systems biology perspective. We aim at defining the crosstalk between GBM and the glial cells as modules. The complex networking may be expressed by metabolic modules corresponding to the GBM growth and spreading phases. Variation in the oxidative phosphorylation (OXPHOS) rate and regulation appears to be the most important part of the metabolic and functional heterogeneity, correlating with glycolysis and response to hypoxia. Integrated metabolic modules along with molecular and morphological features could allow the identification of key factors for controlling the GBM-stroma metabolism in multi-targeted, time-dependent therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22073301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036663PMC
March 2021

Supersaturation of VEP in Migraine without Aura Patients Treated with Topiramate: An Anatomo-Functional Biomarker of the Disease.

J Clin Med 2021 Feb 15;10(4). Epub 2021 Feb 15.

Neurology Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy.

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 investigate the anatomo-functional pathway from the retina to the primary visual cortex using visual evoked potentials (VEP). Contrast gain protocol was used in 15 patients diagnosed with migraine without aura (at baseline and after 3 months of topiramate therapy) and 13 controls. A saturation (S) index was assessed to monitor the response of VEP's amplitude to contrast gain. Non-linear nor monotone growth of VEP (S < 0.95) was defined as supersaturation. A greater percentage of migraine patients (53%) relative to controls (7%) showed this characteristic. A strong inverse correlation was found between the S index and the number of days separating the registration of VEP from the next migraine attack. Moreover, allodynia measured through the Allodynia Symptoms Check-list (ASC-12) correlates with the S index both at baseline and after 3 months of topiramate treatment. Other clinical characteristics were not related to supersaturation. Topiramate therapy, although effective, did not influence electrophysiological parameters suggesting a non-intracortical nor retinal origin of the supersaturation (with possible involvement of relay cells from the lateral geniculate nucleus). In conclusion, the elaboration of visual stimuli and visual cortex activity is different in migraine patients compared to controls. More data are necessary to confirm the potential use of the S index as a biomarker for the migraine cycle (association with the pain-phase) and cortical sensitization (allodynia).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm10040769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918918PMC
February 2021

Neurobiological After-Effects of Low Intensity Transcranial Electric Stimulation of the Human Nervous System: From Basic Mechanisms to Metaplasticity.

Front Neurol 2021 15;12:587771. Epub 2021 Feb 15.

Division of Human Anatomy - Laboratory of Neuronal Networks, University of Campania "Luigi Vanvitelli", Naples, Italy.

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, however mechanisms are still far from being elucidated. We aim to review recent results from and studies that highlight molecular and cellular mechanisms of transcranial direct (tDCS) and alternating (tACS) current stimulation. Changes in membrane potential and neural synchronization explain the ongoing and short-lasting effects of tES, while changes induced in existing proteins and new protein synthesis is required for long-lasting plastic changes (LTP/LTD). Glial cells, for decades supporting elements, are now considered constitutive part of the synapse and might contribute to the mechanisms of synaptic plasticity. This review brings into focus the neurobiological mechanisms and after-effects of tDCS and tACS from and studies, in both animals and humans, highlighting possible pathways for the development of targeted therapeutic applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2021.587771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917202PMC
February 2021

ROS networks: designs, aging, Parkinson's disease and precision therapies.

NPJ Syst Biol Appl 2020 10 26;6(1):34. Epub 2020 Oct 26.

Infrastructure for Systems Biology Europe (ISBE.NL), Amsterdam, The Netherlands.

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 five simpler subnetworks each delivering one type of robustness. The comprehensive dynamic model described in vitro data sets from two independent laboratories. Notwithstanding its five-fold robustness, it exhibited a relatively sudden breakdown, after some 80 years of virtually steady performance: it predicted aging. PD-related conditions such as lack of DJ-1 protein or increased α-synuclein accelerated the collapse, while antioxidants or caffeine retarded it. Introducing a new concept (aging-time-control coefficient), we found that as many as 25 out of 57 molecular processes controlled aging. We identified new targets for "life-extending interventions": mitochondrial synthesis, KEAP1 degradation, and p62 metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41540-020-00150-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589522PMC
October 2020

Roadmap for Stroke: Challenging the Role of the Neuronal Extracellular Matrix.

Int J Mol Sci 2020 Oct 13;21(20). Epub 2020 Oct 13.

SYSBIO Centre of Systems Biology ISBE.ITALY, University of Milano-Bicocca, 20126 Milano, Italy.

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 well as coagulatory and inflammatory processes. The ictal core is produced in a few minutes by the high metabolic demand of the central nervous system. Uncontrolled or prolonged inflammatory response is characterized by leukocyte infiltration of the injured site that is limited by astroglial reaction. The metabolic failure reshapes the NECM through matrix metalloproteinases (MMPs) and novel deposition of structural proteins continues within months of the acute event. These maladaptive reparative processes are responsible for the neurological clinical phenotype. In this review, we aim to provide a systems biology approach to stroke pathophysiology, relating the injury to the NVU with the pervasive metabolic failure, inflammatory response and modifications of the NECM. The available data will be used to build a protein-protein interaction (PPI) map starting with 38 proteins involved in stroke pathophysiology, taking into account the timeline of damage and the co-expression scores of their RNA patterns The application of the proposed network could lead to a more accurate design of translational experiments aiming at improving both the therapy and the rehabilitation processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21207554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589675PMC
October 2020

The Spinal Extracellular Matrix Modulates a Multi-level Protein Net and Epigenetic Inducers Following Peripheral Nerve Injury.

Neuroscience 2020 12 1;451:216-225. Epub 2020 Oct 1.

Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy; SYSBIO Centre of Systems Biology ISBE-IT, University of Milano-Bicocca, Milan, Italy.

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 alterations mostly rely on the proteome, modulation of MMPs activity may be a strategy to correct mechanisms behind neurological disorders. We here investigated modifications of signaling components related to the central pathways in spinal maladaptive plasticity following spared nerve injury (SNI) of the sciatic nerve, and after treatment with the MMPs inhibitor GM6001 for 3 or 8 days. We found that GM6001 reduced the massive astrocytic and microglial activation indicative of reactive gliosis. Functional activity of GM6001 was paralleled by its significant effect on expression levels of the purinergic P2X4 receptor (P2X4R), the transcription factors NFκB and RPBJ, as well as levels of the nerve growth factor (NGF) receptor TrkA. Moreover, we showed that histone deacetylases 1 and 2 (HDAC1, HDAC2) were differentially modulated after SNI and GM6001 treatments for 3 or 8 days. Our data suggest a multi-level network of interactions across ECM and the neuroglial network involving MMPs, the neurotrophin system, intracellular signaling, and epigenetic modifications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuroscience.2020.09.051DOI Listing
December 2020

First steps for the development of silk fibroin-based 3D biohybrid retina for age-related macular degeneration (AMD).

J Neural Eng 2020 10 31;17(5):055003. Epub 2020 Oct 31.

Neuro-computing & Neuro-robotics Research Group, Complutense University of Madrid, Spain. Innovation Research Group, Institute for Health Research San Carlos Clinical Hospital (IdISSC), Madrid, Spain. These authors equally contributed to this article.

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 of silk fibroin-based biofilms; culture of different types of cells: retinal pigment epithelium, retinal neurons, Müller and mesenchymal stem cells ; creation of a layered structure glued with silk fibroin hydrogel.

Main Results: In vitro evidence for the feasibility of layered 3D biohybrid retinas; primary culture neurons grow and develop neurites on silk fibroin biofilms, either alone or in presence of other cells cultivated on the same biomaterial; cell organization and cellular phenotypes are maintained in vitro for the seven days of the experiment.

Significance: 3D biohybrid retina can be built using silk silkworm fibroin films and hydrogels to be used in cell replacement therapy for AMD and similar retinal neurodegenerative diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1088/1741-2552/abb9c0DOI Listing
October 2020

Non-invasive Auricular Vagus Nerve Stimulation as a Potential Treatment for Covid19-Originated Acute Respiratory Distress Syndrome.

Front Physiol 2020 28;11:890. Epub 2020 Jul 28.

Faculty of Biology and Faculty of Optics, Complutense University of Madrid, Madrid, Spain.

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 hyperactivity, and respiratory dysfunction. In the present paper, we present and justify a novel potential treatment for Covid19-originated ARDS and associated co-morbidities, based on the non-invasive stimulation of the auricular branch of the vagus nerve. Auricular vagus nerve stimulation activates the parasympathetic system including anti-inflammatory pathways (the cholinergic anti-inflammatory pathway and the hypothalamic pituitary adrenal axis) while regulating the abnormal sympatho-vagal balance and improving respiratory control. Along the paper (1) we expose the role of the parasympathetic system and the vagus nerve in the control of inflammatory processes (2) we formulate our physiological and methodological hypotheses (3) we provide a large body of clinical and preclinical data that support the favorable effects of auricular vagus nerve stimulation in inflammation, sympatho-vagal balance as well as in respiratory and cardiac ailments, and (4) we list the (few) possible collateral effects of the treatment. Finally, we discuss auricular vagus nerve stimulation protective potential, especially in the elderly and co-morbid population with already reduced parasympathetic response. Auricular vagus nerve stimulation is a safe clinical procedure and it could be either an effective treatment for ARDS originated by Covid-19 and similar viruses or a supplementary treatment to actual ARDS therapeutic approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2020.00890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399203PMC
July 2020

Neurons, Glia, Extracellular Matrix and Neurovascular Unit: A Systems Biology Approach to the Complexity of Synaptic Plasticity in Health and Disease.

Int J Mol Sci 2020 Feb 24;21(4). Epub 2020 Feb 24.

Laboratory of Morphology of Neuronal Network, Department of Public Medicine, University of Campania "Luigi Vanvitelli", 80138 Napoli, Italy.

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 modifications under both pathological and physiological circumstances. Recent experimental evidence has incontrovertibly added oligodendrocytes, astrocytes, and microglia as pivotal elements for synapse formation and remodeling (tripartite synapse) in both the developing and adult brain. Moreover, synaptic plasticity and its pathological counterpart (maladaptive plasticity) have shown a deep connection with other molecular elements of the extracellular matrix (ECM), once considered as a mere extracellular structural scaffold altogether with the cellular glue (i.e., glia). The ECM adds another level of complexity to the modern model of the synapse, particularly, for the long-term plasticity and circuit maintenance. This model, called tetrapartite synapse, can be further implemented by including the neurovascular unit (NVU) and the immune system. Although they were considered so far as tightly separated from the central nervous system (CNS) plasticity, at least in physiological conditions, recent evidence endorsed these elements as structural and paramount actors in synaptic plasticity. This scenario is, as far as speculations and evidence have shown, a consistent model for both adaptive and maladaptive plasticity. However, a comprehensive understanding of brain processes and circuitry complexity is still lacking. Here we propose that a better interpretation of the CNS complexity can be granted by a systems biology approach through the construction of predictive molecular models that enable to enlighten the regulatory logic of the complex molecular networks underlying brain function in health and disease, thus opening the way to more effective treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21041539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073232PMC
February 2020

Regional brain susceptibility to neurodegeneration: what is the role of glial cells?

Neural Regen Res 2020 May;15(5):838-842

Human Anatomy and Laboratory of Morphology of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli, Naples, Italy.

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, metabolic decay, blood brain barrier dysfunction and energy impairment, boosting neuronal death. How these mechanisms might induce selective neuronal death in specific brain areas are far from being elucidated. The last two decades of neurobiological studies have provided evidence of the main role of glial cells in most of the processes of the central nervous system, from development to synaptogenesis, neuronal homeostasis and integration into, highly specific neuro-glial networks. In this mini-review, we moved from in vitro and in vivo models of neurodegeneration to analyze the putative role of glial cells in the early mechanisms of neurodegeneration. We report changes of transcriptional, genetic, morphological, and metabolic activity in astrocytes and microglial cells in specific brain areas before neuronal degeneration, providing evidence in experimental models of neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. Understanding these mechanisms might increase the insight of these processes and pave the way for new specific glia-targeted therapeutic strategies for neurodegenerative disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/1673-5374.268897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990768PMC
May 2020

Differential Modulation of NF-B in Neurons and Astrocytes Underlies Neuroprotection and Antigliosis Activity of Natural Antioxidant Molecules.

Oxid Med Cell Longev 2019 14;2019:8056904. Epub 2019 Aug 14.

Laboratory of Neuroscience "R. Levi-Montalcini," Department of Biotechnology and Bioscience, University of Milano-Bicocca, Milano, Italy.

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 anti-inflammatory activity occurs through differential modulation of NF-B binding activity in neurons and astrocytes. In fact, we show that inflammatory stimuli promote a significant induction of NF-B binding activity in astrocytes and its concomitant reduction in neurons. These changes are prevented in astrocytes and neurons pretreated with the antioxidant molecules, suggesting that NF-B plays a key role in the modulation of survival and anti-inflammatory responses. Finally, we newly demonstrate that effective antigliosis and neuroprotective activity is achieved with a defined cocktail of four natural antioxidants at very low concentrations, suggesting a promising strategy to reduce inflammatory and oxidative damage in neurodegenerative diseases with limited side effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/8056904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710787PMC
January 2020

Current Directions in the Auricular Vagus Nerve Stimulation I - A Physiological Perspective.

Front Neurosci 2019 9;13:854. Epub 2019 Aug 9.

Department for Surgery, Medical University of Vienna, Vienna, Austria.

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 mitigating effects and sustainable therapeutic applications ranging from chronic pain diseases, neurodegenerative and metabolic ailments to inflammatory and cardiovascular diseases. Given the current evidence from experimental research in animal and clinical studies we discuss basic aVNS mechanisms and their potential clinical effects. Collectively, we provide a focused review on the physiological role of the vagus nerve and formulate a biology-driven rationale for aVNS. For the first time, two international workshops on aVNS have been held in Warsaw and Vienna in 2017 within the framework of EU COST Action "European network for innovative uses of EMFs in biomedical applications (BM1309)." Both workshops focused critically on the driving physiological mechanisms of aVNS, its experimental and clinical studies in animals and humans, aVNS studies, technological advancements, and regulatory barriers. The results of the workshops are covered in two reviews, covering physiological and engineering aspects. The present review summarizes on physiological aspects - a discussion of engineering aspects is provided by our accompanying article (Kaniusas et al., 2019). Both reviews build a reasonable bridge from the rationale of aVNS as a therapeutic tool to current research lines, all of them being highly relevant for the promising aVNS technology to reach the patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnins.2019.00854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697069PMC
August 2019

Current Directions in the Auricular Vagus Nerve Stimulation II - An Engineering Perspective.

Front Neurosci 2019 24;13:772. Epub 2019 Jul 24.

Faculty of Electrical Engineering, Mechanical Engineering and Naval Architecture, University of Split, Split, Croatia.

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 body. Engineering aspects of aVNS determine its efficiency in application. The relevant safety and regulatory issues need to be appropriately addressed. In particular, modeling acts as a tool for aVNS optimization. The evolution of personalized electroceuticals using novel architectures of the closed-loop aVNS paradigms with biofeedback can be expected to optimally meet therapy needs. For the first time, two international workshops on aVNS have been held in Warsaw and Vienna in 2017 within the scope of EU COST Action "European network for innovative uses of EMFs in biomedical applications (BM1309)." Both workshops focused critically on the driving physiological mechanisms of aVNS, its experimental and clinical studies in animals and humans, aVNS studies, technological advancements, and regulatory barriers. The results of the workshops are covered in two reviews, covering physiological and engineering aspects. The present review summarizes on engineering aspects - a discussion of physiological aspects is provided by our accompanying article (Kaniusas et al., 2019). Both reviews build a reasonable bridge from the rationale of aVNS as a therapeutic tool to current research lines, all of them being highly relevant for the promising aVNS technology to reach the patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnins.2019.00772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667675PMC
July 2019

Dependence of Neuroprosthetic Stimulation on the Sensory Modality of the Trigeminal Neurons Following Nerve Injury. Implications in the Design of Future Sensory Neuroprostheses for Correct Perception and Modulation of Neuropathic Pain.

Front Neurosci 2019 1;13:389. Epub 2019 May 1.

Neuro-computing & Neuro-robotics Research Group, Universidad Complutense de Madrid, Madrid, Spain.

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 deprivation-related changes. In the present study we focus on the initial tract of the somatosensory pathway and we investigate the way weak electrical stimulation modulates the neuroprotective-neuroregenerative and functional processes of trigeminal ganglia primary sensory neurons by studying the expression of neurotrophins (NTFs) and Glia-Derived Neurotrophic Factors (GDNFs) receptors. Neurostimulation was applied to the proximal stump of a transected left infraorbitary nerve using a neuroprosthetic micro-device 12 h/day for 4 weeks in freely behaving rats. Neurons were studied by hybridization and immunohistochemistry against RET (proto-oncogene tyrosine kinase "rearranged during transfection"), tropomyosin-related kinases (TrkA, TrkB, TrkC) receptors and IB4 (Isolectin B4 from Griffonia simplicifolia). Intra-group (left vs. right ganglia) and inter-group comparisons (between Control, Axotomization and Stimulation-after-axotomization groups) were performed using the mean percentage change of the number of positive cells per section [100(left-right)/right)]. Intra-group differences were studied by paired -tests. For inter-group comparisons ANOVA test followed by LSD test (when < 0.05) were used. Significance level (α) was set to 0.05 in all cases. Results showed that (i) neurostimulation has heterogeneous effects on primary nociceptive and mechanoceptive/proprioceptive neurons; (ii) neurostimulation affects RET-expressing small and large neurons which include thermo-nociceptors and mechanoceptors, as well as on the IB4- and TrkB-positive populations, which mainly correspond to non-peptidergic thermo-nociceptive cells and mechanoceptors respectively. Our results suggest (i) electrical stimulation differentially affects modality-specific primary sensory neurons (ii) artificial input mainly acts on specific nociceptive and mechanoceptive neurons (iii) neuroprosthetic stimulation could be used to modulate peripheral nerve injuries-induced neuropathic pain. These could have important functional implications in both, the design of effective clinical neurostimulation-based protocols and the development of neuroprosthetic devices, controlling primary sensory neurons through selective neurostimulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnins.2019.00389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504809PMC
May 2019

Specific Expression of a New Bruton Tyrosine Kinase Isoform (p65BTK) in the Glioblastoma Gemistocytic Histotype.

Front Mol Neurosci 2019 24;12. Epub 2019 Jan 24.

School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.

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 of p65BTK in tumors of the central nervous system (CNS). We selected a large cohort of patients with glial tumors ( = 71) and analyzed the expression of p65BTK in different histotypes and correlation with clinical parameters. Sections were stained with glial fibrillary acidic protein (GFAP), p53, epidermal growth factor receptor (EGFR), S100, vimentin, and epithelial membrane antigen (EMA) antibodies. Glioma stem cell (GSC) lines, isolated from glioblastoma multiforme (GBM), were treated with different concentrations of ibrutinib, a specific inhibitor of BTK, in order to evaluate their metabolic activity, mitotic index and mortality. Moreover, an orthotopic xenotransplant of GSC from human GBM was used to evaluate the expression of p65BTK in the brain of immunodeficient mice. p65BTK was expressed in GSC and in gemistocytes in human gliomas at different histological grade. We found a significant correlation between BTK expression and low-grade (LG) tumors ( ≤ 0.05) and overall survival (OS) of patients with grade III gliomas ( ≤ 0.05), suggestive of worst prognosis. Interestingly, the expression of p65BTK remained restricted exclusively to gemistocytic cells in the xenograft mouse model. Ibrutinib administration significantly reduced metabolic activity and mitotic index and increased mortality in GSC, highlighting the specific role of p65BTK in cell proliferation and survival. In conclusion, our data demonstrated that p65BTK is expressed in glioma tumors, restricted to gemistocytic cells, has a key role in GSC and has a bad prognostic value, thus highlighting the importance of future research for targeted therapy of human gliomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnmol.2019.00002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353843PMC
January 2019

Selective Vulnerability of Basal Ganglia: Insights into the Mechanisms of Bilateral Striatal Necrosis.

J Neuropathol Exp Neurol 2019 02;78(2):123-129

Division of Human Anatomy - Neuronal Networks Morphology Lab, Department of Mental, Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli".

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 mitochondrial disorders, suggesting a pathogenetic role of the energy impairment by mitochondrial dysfunction. We investigated mechanisms of the selective striatal degeneration, comparing clinical findings of a patient with an acquired bilateral striatal necrosis and experimental data of a selective basal ganglia degenerative model in rats. In a 70-year-old patient affected by severe parkinsonian syndrome triggered by persistent metabolic acidosis, brain MRI revealed bilateral cystic-lacunar necrosis of basal ganglia. Immunohistochemistry of rat brain sections after single intraperitoneal administration (60 mg/kg) of the mitochondrial toxin 3-nitropropionic acid (3-NP) revealed (i) selective bilateral striatal necrotic/cavitary lesions, (ii) degeneration of striatal medium spiny neurons, (iii) evidence of synaptic and transcriptional dysfunction, and (iv) reactive gliosis (activated microglia and astrocytes) in the striatum. Our data provide an intriguing hypothesis for the selective neuronal degeneration in the striatum, claiming that selective mitochondrial energy impairment associated to loco-regional neuroinflammation and reactive gliosis might contribute to synaptic dysfunction and excitotoxicity that ultimately lead to neuronal degeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnen/nly123DOI Listing
February 2019

Neuro-Immune Hemostasis: Homeostasis and Diseases in the Central Nervous System.

Front Cell Neurosci 2018 26;12:459. Epub 2018 Nov 26.

Laboratory of Morphology of Neuronal Network, Department of Public Medicine, University of Campania-Luigi Vanvitelli, Naples, Italy.

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 pathways (protease activity, complement factors, platelet granule content). Endothelial damage prompts platelet activation and the coagulation cascade as the first physiological step to support the rescue of damaged tissues, a flawed rescuing system ultimately producing neuroinflammation. Leukocytes, platelets, and endothelial cells are sensitive to the damage and indeed can release or respond to chemokines and cytokines (platelet factor 4, CXCL4, TNF, interleukins), and growth factors (including platelet-derived growth factor, vascular endothelial growth factor, and brain-derived neurotrophic factor) with platelet activation, change in capillary permeability, migration or differentiation of leukocytes. Thrombin, plasmin, activated complement factors and matrix metalloproteinase-1 (MMP-1), furthermore, activate intracellular transduction through complement or protease-activated receptors. Impairment of the neuro-immune hemostasis network induces acute or chronic CNS pathologies related to the neurovascular unit, either directly or by the systemic activation of its main steps. Neurons, glial cells (astrocytes and microglia) and the extracellular matrix play a crucial function in a "tetrapartite" synaptic model. Taking into account the neurovascular unit, in this review we thoroughly analyzed the influence of neuro-immune hemostasis on these five elements acting as a functional unit ("pentapartite" synapse) in the adaptive and maladaptive plasticity and discuss the relevance of these events in inflammatory, cerebrovascular, Alzheimer, neoplastic and psychiatric diseases. Finally, based on the solid reviewed data, we hypothesize a model of neuro-immune hemostatic network based on protein-protein interactions. In addition, we propose that, to better understand and favor the maintenance of adaptive plasticity, it would be useful to construct predictive molecular models, able to enlighten the regulating logic of the complex molecular network, which belongs to different cellular domains. A modeling approach would help to define how nodes of the network interact with basic cellular functions, such as mitochondrial metabolism, autophagy or apoptosis. It is expected that dynamic systems biology models might help to elucidate the fine structure of molecular events generated by blood coagulation and neuro-immune responses in several CNS diseases, thereby opening the way to more effective treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fncel.2018.00459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275309PMC
November 2018

Neural plasticity and adult neurogenesis: the deep biology perspective.

Neural Regen Res 2019 Feb;14(2):201-205

Synthetic Systems Biology and Nuclear Organization, University of Amsterdam, Molecular Cell Physiology, VU University Amsterdam, and Infrastructure Systems Biology at NL (ISBE.NL), Amsterdam, NL, and Systems Biology, School for Chemical Engineering and Analytical Science, University of Manchester, UK.

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 neuroinflammation. We here review how a multitude of regulatory pathways optimized for early neurogenesis has to be revamped into a new choreography of time dependencies. Distinct pathways need to be regulated, ranging from neural growth factor induced differentiation to mitochondrial bioenergetics, reactive oxygen metabolism, and apoptosis. Requiring much Gibbs energy consumption, brain depends on aerobic energy metabolism, hence on mitochondrial activity. Mitochondrial fission and fusion, movement and perhaps even mitoptosis, thereby come into play. All these network processes are interlinked and involve a plethora of molecules. We recommend a deep thinking approach to adult neurobiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/1673-5374.244775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301164PMC
February 2019

Functional connectivity of the ventral tegmental area and avolition in subjects with schizophrenia: a resting state functional MRI study.

Eur Neuropsychopharmacol 2018 05 10;28(5):589-602. Epub 2018 Apr 10.

Department of Psychiatry, University of Campania "Luigi Vanvitelli", Largo Madonna delle Grazie 1, 80138 Naples, Italy.

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 related to altered connectivity within dopaminergic cortico-striatal circuits involved in motivation processes. Since dopamine input to these circuits derives mostly from the ventro-tegmental area (VTA), we investigated the relationships between the resting-state functional connectivity (RS-FC) of the VTA and avolition in twenty-six subjects with schizophrenia (SCZ), treated with second-generation antipsychotics only, compared to twenty-two healthy controls (HC). SCZ, in comparison to HC, showed significantly reduced RS-FC of the VTA with bilateral ventro-lateral prefrontal cortex (VLPFC), bilateral insular cortex (IC) and right (R) lateral occipital complex (LOC) and increased RS-FC of the VTA with bilateral dorso-lateral prefrontal cortex (DLPFC). Significant negative correlations were found between avolition and RS-FC of the VTA with the bilateral IC, R VLPFC and R LOC. According to our findings, avolition is linked to a disconnectivity of the VTA from several key cortical regions involved in the integration of value information with action selection. These findings are in line with translational animal models of "auto-activation apathy".
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.euroneuro.2018.03.013DOI Listing
May 2018

Differentiation by nerve growth factor (NGF) involves mechanisms of crosstalk between energy homeostasis and mitochondrial remodeling.

Cell Death Dis 2018 03 9;9(3):391. Epub 2018 Mar 9.

Laboratory of Neuroscience "R. Levi-Montalcini", Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126, Milano, Italy.

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 largely characterized in terms of signaling, however, little is known about its impact on mitochondrial remodeling and metabolic function. In this work, we show that NGF-induced differentiation requires the activation of autophagy mediated by Atg9b and Ambra1, as it is disrupted by their genetic knockdown and by autophagy blockers. NGF differentiation involves the induction of P-AMPK and P-CaMK, and is prevented by their pharmacological inhibition. These molecular events correlate with modifications of energy and redox homeostasis, as determined by ATP and NADPH changes, higher oxygen consumption (OCR) and ROS production. Our data indicate that autophagy aims to clear out exhausted mitochondria, as determined by enhanced localization of p62 and Lysotracker-red to mitochondria. In addition, we newly demonstrate that NGF differentiation is accompanied by increased mitochondrial remodeling involving higher levels of fission (P-Drp1) and fusion proteins (Opa1 and Mfn2), as well as induction of Sirt3 and the transcription factors mtTFA and PPARγ, which regulate mitochondria biogenesis and metabolism to sustain increased mitochondrial mass, potential, and bioenergetics. Overall, our data indicate a new NGF-dependent mechanism involving mitophagy and extensive mitochondrial remodeling, which plays a key role in both neurogenesis and nerve regeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-018-0429-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844953PMC
March 2018

Neuro-Coagulopathy: Blood Coagulation Factors in Central Nervous System Diseases.

Int J Mol Sci 2017 Oct 12;18(10). Epub 2017 Oct 12.

Laboratory of Neuronal Networks, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy.

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 C (aPC). These proteins, in fact, showed peculiar properties, being able to interfere with synaptic homeostasis other than coagulation itself. These specific functions modulate neuronal networks, acting both on resident (neurons, astrocytes, and microglia) as well as circulating immune system cells and the extracellular matrix. The pleiotropy of these effects is produced through different receptors, expressed in various cell types, in a dose- and time-dependent pattern. We reviewed how these pathways may be involved in neurodegenerative diseases (amyotrophic lateral sclerosis, Alzheimer's and Parkinson's diseases), multiple sclerosis, ischemic stroke and post-ischemic epilepsy, CNS cancer, addiction, and mental health. These data open up a new path for the potential therapeutic use of the agonist/antagonist of these proteins in the management of several central nervous system diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms18102128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666810PMC
October 2017

Matrix Metalloproteinases, Neural Extracellular Matrix, and Central Nervous System Pathology.

Prog Mol Biol Transl Sci 2017 4;148:167-202. Epub 2017 May 4.

Laboratory of Neuronal Networks, University of Campania "Luigi Vanvitelli", Naples, Italy; SYSBIO, Centre for Systems Biology, University of Milano-Bicocca, Milano, Italy. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/bs.pmbts.2017.04.002DOI Listing
March 2018

Beyond peripheral nerve injury: spinal gliopathy and maladaptive synaptic plasticity.

Neural Regen Res 2016 Sep;11(9):1422-1423

Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, Second University of Naples, Naples, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/1673-5374.191214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5090842PMC
September 2016

Modulation of Matrix Metalloproteinases Activity in the Ventral Horn of the Spinal Cord Re-stores Neuroglial Synaptic Homeostasis and Neurotrophic Support following Peripheral Nerve Injury.

PLoS One 2016 30;11(3):e0152750. Epub 2016 Mar 30.

Laboratory of Neuronal Networks, Department. of Mental and Physical Health and Preventive Medicine, Second University of Naples, 80138 Naples, Italy.

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 maladaptive plastic changes in the ventral horn of spinal cord following PNI. The purpose of our study was to analyze changes in the ventral horn produced by gliopathy determined by the suffering of motor neurons following spared nerve injury (SNI) of the sciatic nerve and how the intrathecal (i.t.) administration of GM6001 (a MMPs inhibitor) or the NGF mimetic peptide BB14 modulate these events. Immunohistochemical analysis of spinal cord sections revealed that motor neuron disease following SNI was associated with increased microglial (Iba1) and astrocytic (GFAP) response in the ventral horn of the spinal cord, indicative of reactive gliosis. These changes were paralleled by decreased glial aminoacid transporters (glutamate GLT1 and glycine GlyT1), increased levels of the neuronal glutamate transporter EAAC1, and a net increase of the Glutamate/GABA ratio, as measured by HPLC analysis. These molecular changes correlated to a significant reduction of mature NGF levels in the ventral horn. Continuous i.t. infusion of both GM6001 and BB14 reduced reactive astrogliosis, recovered the expression of neuronal and glial transporters, lowering the Glutamate/GABA ratio. Inhibition of MMPs by GM6001 significantly increased mature NGF levels, but it was absolutely ineffective in modifying the reactivity of microglia cells. Therefore, MMPs inhibition, although supplies neurotrophic support to ECM components and restores neuro-glial transporters expression, differently modulates astrocytic and microglial response after PNI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152750PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814041PMC
August 2016

The TGF-β pathway is activated by 5-fluorouracil treatment in drug resistant colorectal carcinoma cells.

Oncotarget 2016 Apr;7(16):22077-91

Department of Surgery and Translational Medicine, University of Milano-Bicocca, 20900, Monza, Italy.

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. 5-Fluorouracil (5FU) was able to stimulate the activation of SMAD3 and the transcription of specific genes such as ACVRL1, FN1 and TGFB1. On the other hand, the specific inhibition of TGF-βRI was able to repress the 5FU-induced genes transcription and to restore the sensitivity of chemoresistant cells to the toxic action of the drug, by decreasing the expression of BCL2L1 and ID1 genes. The role of the TGF-β molecule in the chemoresistant colon carcinoma cells' response to 5FU was further demonstrated by conditioned medium (CM) experiments: CM from 5FU-treated chemoresistant cells was able to protect chemosensitive cells against the toxic action of 5FU. In conclusion, these findings showed the pivotal role of TGF-β pathway in colon cancer mechanisms of drug resistance suggesting new possible approaches in diagnosis and treatment of colon cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.7895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008345PMC
April 2016

Looking Inside the Matrix: Perineuronal Nets in Plasticity, Maladaptive Plasticity and Neurological Disorders.

Neurochem Res 2016 Jul 2;41(7):1507-15. Epub 2016 Mar 2.

Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, Second University of Naples, 80138, Naples, Italy.

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 synaptic integration and control the functional wiring between neurons. These nets are significantly modified during CNS disorders, such as neurodegenerative, cerebrovascular and inflammatory diseases. The breakdown or the modification of PNNs could be due to the activity of matrix metalloproteinases (MMPs) or to the deposition of proteoglycans, glycoproteins, and hyaluronic acid. The expression and the activity of ECM-degrading enzymes can be regulated with tissue inhibitors of MMPs or via transcriptional and epigenetic silencing or enhancement (i.e. via histone deacetylases). The identification of molecules and mechanisms able to modify these processes will be essential for a new perspective on brain functioning in health and disease, leading to a target-directed approach with drugs directly interfering with the molecular mechanism underlying neurological disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11064-016-1876-2DOI Listing
July 2016
-->