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2. Conditioned medium from amniotic cells protects striatal degeneration and ameliorates motor deficits in the R6/2 mouse model of Huntington's disease

Author

Giampà, Carmela, Alvino, Alessandra, Magatti, Marta, Silini, Antonietta R., Cardinale, Antonella, Paldino, Emanuela, Fusco, Francesca R., Parolini, Ornella, Giampà, Carmela (ORCID:0000-0001-8037-9214), Parolini, Ornella (ORCID:0000-0002-5211-6430), Giampà, Carmela, Alvino, Alessandra, Magatti, Marta, Silini, Antonietta R., Cardinale, Antonella, Paldino, Emanuela, Fusco, Francesca R., Parolini, Ornella, Giampà, Carmela (ORCID:0000-0001-8037-9214), and Parolini, Ornella (ORCID:0000-0002-5211-6430)

Abstract

Inflammation significantly impacts the progression of Huntington's disease (HD) and the mutant HTT protein determines a pro-inflammatory activation of microglia. Mesenchymal stem/stromal cells (MSC) from the amniotic membrane (hAMSC), and their conditioned medium (CM-hAMSC), have been shown to possess protective effects in vitro and in vivo in animal models of immune-based disorders and of traumatic brain injury, which have been shown to be mediated by their immunomodulatory properties. In this study, in the R6/2 mouse model for HD we demonstrate that mice treated with CM-hAMSC display less severe signs of neurological dysfunction than saline-treated ones. CM-hAMSC treatment significantly delayed the development of the hind paw clasping response during tail suspension, reduced deficits in rotarod performance, and decreased locomotor activity in an open field test. The effects of CM-hAMSC on neurological function were reflected in a significant amelioration in brain pathology, including reduction in striatal atrophy and the formation of striatal neuronal intranuclear inclusions. In addition, while no significant increase was found in the expression of BDNF levels after CM-hAMSC treatment, a significant decrease of microglia activation and inducible nitric oxide synthase levels were observed. These results support the concept that CM-hAMSC could act by modulating inflammatory cells, and more specifically microglia.

Published
2019

11. Microglial activation and the nitric oxide/cGMP/PKG pathway underlie enhanced neuronal vulnerability to mitochondrial dysfunction in experimental multiple sclerosis

Author

Mancini, Andrea, primary, Tantucci, Michela, additional, Mazzocchetti, Petra, additional, de Iure, Antonio, additional, Durante, Valentina, additional, Macchioni, Lara, additional, Giampà, Carmela, additional, Alvino, Alessandra, additional, Gaetani, Lorenzo, additional, Costa, Cinzia, additional, Tozzi, Alessandro, additional, Calabresi, Paolo, additional, and Di Filippo, Massimiliano, additional

Published
2018
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13. Phosphodiesterase-10A Inverse Changes in Striatopallidal and Striatoentopeduncular Pathways of a Transgenic Mouse Model ofDYT1Dystonia

Author

D'Angelo, Vincenza, primary, Castelli, Valentina, additional, Giorgi, Mauro, additional, Cardarelli, Silvia, additional, Saverioni, Ilaria, additional, Palumbo, Francesca, additional, Bonsi, Paola, additional, Pisani, Antonio, additional, Giampà, Carmela, additional, Sorge, Roberto, additional, Biagioni, Stefano, additional, Fusco, Francesca R., additional, and Sancesario, Giuseppe, additional

Published
2017
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15. Erratum: Persistent activation of microglia and NADPH oxidase drive hippocampal dysfunction in experimental multiple sclerosis

Author

Di Filippo, Massimiliano, primary, de Iure, Antonio, additional, Giampà, Carmela, additional, Chiasserini, Davide, additional, Tozzi, Alessandro, additional, Orvietani, Pier Luigi, additional, Ghiglieri, Veronica, additional, Tantucci, Michela, additional, Durante, Valentina, additional, Quiroga-Varela, Ana, additional, Mancini, Andrea, additional, Costa, Cinzia, additional, Sarchielli, Paola, additional, Fusco, Francesca Romana, additional, and Calabresi, Paolo, additional

Published
2016
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16. Alpha-Synuclein Produces Early Behavioral Alterations via Striatal Cholinergic Synaptic Dysfunction by Interacting With GluN2D N -Methyl-D-Aspartate Receptor Subunit

Author

Tozzi, Alessandro, primary, de Iure, Antonio, additional, Bagetta, Vincenza, additional, Tantucci, Michela, additional, Durante, Valentina, additional, Quiroga-Varela, Ana, additional, Costa, Cinzia, additional, Di Filippo, Massimiliano, additional, Ghiglieri, Veronica, additional, Latagliata, Emanuele Claudio, additional, Wegrzynowicz, Michal, additional, Decressac, Mickael, additional, Giampà, Carmela, additional, Dalley, Jeffrey W., additional, Xia, Jing, additional, Gardoni, Fabrizio, additional, Mellone, Manuela, additional, El-Agnaf, Omar Mukhtar, additional, Ardah, Mustafa Taleb, additional, Puglisi-Allegra, Stefano, additional, Björklund, Anders, additional, Spillantini, Maria Grazia, additional, Picconi, Barbara, additional, and Calabresi, Paolo, additional

Published
2016
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17. Persistent activation of microglia and NADPH oxidase drive hippocampal dysfunction in experimental multiple sclerosis

Author

Di Filippo, Massimiliano, primary, de Iure, Antonio, additional, Giampà, Carmela, additional, Chiasserini, Davide, additional, Tozzi, Alessandro, additional, Orvietani, Pier Luigi, additional, Ghiglieri, Veronica, additional, Tantucci, Michela, additional, Durante, Valentina, additional, Quiroga-Varela, Ana, additional, Mancini, Andrea, additional, Costa, Cinzia, additional, Sarchielli, Paola, additional, Fusco, Francesca Romana, additional, and Calabresi, Paolo, additional

Published
2016
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18. Rhes influences striatal cAMP/PKA-dependent signaling and synaptic plasticity in a gender-sensitive fashion.

Author

University of Naples "Federico II" - Department of Molecular Medicine and Medical Biotechnology, University of Perugia - Department of Philosophy, Human, Social, and Educational Sciences, University of Pisa - Department of Biology, Ghiglieri, Veronica, Napolitano, Francesco, Pelosi, Barbara, Schepisi, Chiara, Migliarini, Sara, Di Maio, Anna, Pendolino, Valentina, Mancini, Maria, Sciamanna, Giuseppe, Vitucci, Daniela, Maddaloni, Giacomo, Giampà, Carmela, Errico, Francesco, Nisticò, Robert, Pasqualetti, Massimo, Picconi, Barbara, Usiello, Alessandro, University of Naples "Federico II" - Department of Molecular Medicine and Medical Biotechnology, University of Perugia - Department of Philosophy, Human, Social, and Educational Sciences, University of Pisa - Department of Biology, Ghiglieri, Veronica, Napolitano, Francesco, Pelosi, Barbara, Schepisi, Chiara, Migliarini, Sara, Di Maio, Anna, Pendolino, Valentina, Mancini, Maria, Sciamanna, Giuseppe, Vitucci, Daniela, Maddaloni, Giacomo, Giampà, Carmela, Errico, Francesco, Nisticò, Robert, Pasqualetti, Massimo, Picconi, Barbara, and Usiello, Alessandro

Abstract

Mechanisms of gender-specific synaptic plasticity in the striatum, a brain region that controls motor, cognitive and psychiatric functions, remain unclear. Here we report that Rhes, a GTPase enriched in medium spiny neurons (MSNs) of striatum, alters the striatal cAMP/PKA signaling cascade in a gender-specific manner. While Rhes knockout (KO) male mice, compared to wild-type (WT) mice, had a significant basal increase of cAMP/PKA signaling pathway, the Rhes KO females exhibited a much stronger response of this pathway, selectively under the conditions of dopamine/adenosine-related drug challenge. Corticostriatal LTP defects are exclusively found in A2AR/D2R-expressing MSNs of KO females, compared to KO males, an effect that is abolished by PKA inhibitors but not by the removal of circulating estrogens. This suggests that the synaptic alterations found in KO females could be triggered by an aberrant A2AR/cAMP/PKA activity, but not due to estrogen-mediated effect. Consistent with increased cAMP signaling, D1R-mediated motor stimulation, haloperidol-induced catalepsy and caffeine-evoked hyper-activity are robustly enhanced in Rhes KO females compared to mutant males. Thus Rhes, a thyroid hormone-target gene, plays a relevant role in gender-specific synaptic and behavioral responses.

Published
2015

20. Rhes influences striatal cAMP/PKA-dependent signaling and synaptic plasticity in a gender-sensitive fashion

Author

Ghiglieri, Veronica, primary, Napolitano, Francesco, additional, Pelosi, Barbara, additional, Schepisi, Chiara, additional, Migliarini, Sara, additional, Di Maio, Anna, additional, Pendolino, Valentina, additional, Mancini, Maria, additional, Sciamanna, Giuseppe, additional, Vitucci, Daniela, additional, Maddaloni, Giacomo, additional, Giampà, Carmela, additional, Errico, Francesco, additional, Nisticò, Robert, additional, Pasqualetti, Massimo, additional, Picconi, Barbara, additional, and Usiello, Alessandro, additional

Published
2015
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21. Derangement of Ras-Guanine Nucleotide-Releasing Factor 1 (Ras-GRF1) and Extracellular Signal-Regulated Kinase (ERK) Dependent Striatal Plasticity in L-DOPA-Induced Dyskinesia

Author

Cerovic, Milica, primary, Bagetta, Vincenza, additional, Pendolino, Valentina, additional, Ghiglieri, Veronica, additional, Fasano, Stefania, additional, Morella, Ilaria, additional, Hardingham, Neil, additional, Heuer, Andreas, additional, Papale, Alessandro, additional, Marchisella, Francesca, additional, Giampà, Carmela, additional, Calabresi, Paolo, additional, Picconi, Barbara, additional, and Brambilla, Riccardo, additional

Published
2015
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22. Tryptanthrin Suppresses the Activation of the LPS-Treated BV2 Microglial Cell Line via Nrf2/HO-1 Antioxidant Signaling.

Author

Young-Won Kwon, So Yeong Cheon, Sung Yun Park, Juhyun Song, Ju-Hee Lee, Valero, Jorge, Mongin, Alexander A., and Giampà, Carmela

Subjects
MICROGLIA, CENTRAL nervous system, MACROPHAGES, HOMEOSTASIS, NEUROLOGICAL disorders
Abstract

Microglia are the resident macrophages in the central nervous system (CNS) and play essential roles in neuronal homeostasis and neuroinflammatory pathologies. Recently, microglia have been shown to contribute decisively to neuropathologic processes after ischemic stroke. Furthermore, natural compounds have been reported to attenuate inflammation and pathologies associated with neuroinflammation. Tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione) is a phytoalkaloid with known anti-inflammatory effects in cells. In present study, the authors confirmed middle cerebral artery occlusion (MCAO) injury triggers the activation of microglia in brain tissue, and investigated whether tryptanthrin influences the function of mouse murine BV2 microglia under LPS-induced inflammatory conditions in vitro. It was found tryptanthrin protected BV2 microglia cells against LPS-induced inflammation and inhibited the induction of M1 phenotype microglia under inflammatory conditions. In addition, tryptanthrin reduced the production of pro-inflammatory cytokines in BV2 microglia cells via nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling and NF-ΚB signaling. The authors suggest that tryptanthrin might alleviate the progress of neuropathologies by controlling microglial functions under neuroinflammatory conditions. [ABSTRACT FROM AUTHOR]

Published
2017
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25. Effects of central and peripheral inflammation on hippocampal synaptic plasticity

Author

Di Filippo, Massimiliano, primary, Chiasserini, Davide, additional, Gardoni, Fabrizio, additional, Viviani, Barbara, additional, Tozzi, Alessandro, additional, Giampà, Carmela, additional, Costa, Cinzia, additional, Tantucci, Michela, additional, Zianni, Elisa, additional, Boraso, Mariaserena, additional, Siliquini, Sabrina, additional, de Iure, Antonio, additional, Ghiglieri, Veronica, additional, Colcelli, Elisa, additional, Baker, David, additional, Sarchielli, Paola, additional, Fusco, Francesca Romana, additional, Di Luca, Monica, additional, and Calabresi, Paolo, additional

Published
2013
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26. Changes in the expression of extracellular regulated kinase (ERK 1/2) in the R6/2 mouse model of Huntington's disease after phosphodiesterase IV inhibition

Author

Fusco, Francesca R., primary, Anzilotti, Serenella, additional, Giampà, Carmela, additional, Dato, Clemente, additional, Laurenti, Daunia, additional, Leuti, Alessandro, additional, Colucci D'Amato, Luca, additional, Perrone, Lorena, additional, Bernardi, Giorgio, additional, and Melone, Mariarosa A.B., additional

Published
2012
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28. Inhibition of phosphodiesterases rescues striatal long-term depression and reduces levodopa-induced dyskinesia

Author

Picconi, Barbara, primary, Bagetta, Vincenza, additional, Ghiglieri, Veronica, additional, Paillè, Vincent, additional, Di Filippo, Massimiliano, additional, Pendolino, Valentina, additional, Tozzi, Alessandro, additional, Giampà, Carmela, additional, Fusco, Francesca R., additional, Sgobio, Carmelo, additional, and Calabresi, Paolo, additional

Published
2010
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29. Distinct Levels of Dopamine Denervation Differentially Alter Striatal Synaptic Plasticity and NMDA Receptor Subunit Composition

Author

Paillé, Vincent, primary, Picconi, Barbara, additional, Bagetta, Vincenza, additional, Ghiglieri, Veronica, additional, Sgobio, Carmelo, additional, Di Filippo, Massimiliano, additional, Viscomi, Maria T., additional, Giampà, Carmela, additional, Fusco, Francesca R., additional, Gardoni, Fabrizio, additional, Bernardi, Giorgio, additional, Greengard, Paul, additional, Di Luca, Monica, additional, and Calabresi, Paolo, additional

Published
2010
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31. A Case of PANDAS Treated With Tetrabenazine and Tonsillectomy

Author

Fusco, Francesca Romana, primary, Pompa, Alessandra, additional, Bernardi, Giorgio, additional, Ottaviani, Fabrizio, additional, Giampà, Carmela, additional, Laurenti, Daunia, additional, Morello, Maria, additional, Bernardini, Sergio, additional, Nuccetelli, Marzia, additional, Sabatini, Umberto, additional, and Paolucci, Stefano, additional

Published
2010
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32. TrkB/BDNF-Dependent Striatal Plasticity and Behavior in a Genetic Model of Epilepsy: Modulation by Valproic Acid

Author

Ghiglieri, Veronica, primary, Sgobio, Carmelo, additional, Patassini, Stefano, additional, Bagetta, Vincenza, additional, Fejtova, Anna, additional, Giampà, Carmela, additional, Marinucci, Silvia, additional, Heyden, Alexandra, additional, Gundelfinger, Eckart D, additional, Fusco, Francesca R, additional, Calabresi, Paolo, additional, and Picconi, Barbara, additional

Published
2010
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39. Cellular localization of TRPC3 channel in rat brain: preferential distribution to oligodendrocytes

Author

Fusco, Francesca R, primary, Martorana, Alessandro, additional, Giampà, Carmela, additional, March, Zena De, additional, Vacca, Fabrizio, additional, Tozzi, Alessandro, additional, Longone, Patrizia, additional, Piccirilli, Silvia, additional, Paolucci, Stefano, additional, Sancesario, Giuseppe, additional, Mercuri, Nicola B, additional, and Bernardi, Giorgio, additional

Published
2004
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40. Rebalance of Striatal NMDA/AMPA Receptor Ratio Underlies the Reduced Emergence of Dyskinesia During D2-Like Dopamine Agonist Treatment in Experimental Parkinson's Disease.

Author

Bagetta, Vincenza, Sgobio, Carmelo, Pendolino, Valentina, Papa, Giulia Del, Tozzi, Alessandro, Ghiglieri, Veronica, Giampà, Carmela, Zianni, Elisa, Gardoni, Fabrizio, Calabresi, Paolo, and Picconi, Barbara

Subjects
PARKINSON'S disease treatment, METHYL aspartate receptors, MOVEMENT disorders, DOPAMINE, TREATMENT effectiveness, PREVENTIVE medicine
Abstract

Dopamine replacement with levodopa (Ɩ-DOPA) represents the mainstay of Parkinson's disease (PD) therapy. Nevertheless, this well established therapeutic intervention loses efficacy with the progression of the disease and patients develop invalidating side effects, known in their complex as Ɩ-DOPA-induced dyskinesia (LID). Unfortunately, existing therapies fail to prevent LID and very few drugs are available to lessen its severity, thus representing a major clinical problem in PD treatment. D2-like receptor (D2R) agonists are a powerful clinical option as an alternative to Ɩ-DOPA, especially in the early stages of the disease, being associated to a reduced risk of dyskinesia development. D2R agonists also find considerable application in the advanced stages of PD, in conjunction with Ɩ-DOPA, which is used in this context at lower dosages, to delay the appearance and the extent of the motor complications. In advanced stages of PD, D2R agonists are often effective in delaying the appearance and the extent of motor complications. Despite the great attention paid to the family of D2R agonists, the main reasons underlying the reduced risk of dyskinesia have not yet been fully characterized. Here we show that the striatal NMDA/AMPA receptor ratio and the AMPA receptor subunit composition are altered in experimental parkinsonism in rats. Surprisingly, while Ɩ-DOPA fails to restore these critical synaptic alterations, chronic treatment with pramipexole is associated not only with a reduced risk of dyskinesia development but is also able to rebalance, in a dose-dependent fashion, the physiological synaptic parameters, thus providing new insights into the mechanisms of dyskinesia. [ABSTRACT FROM AUTHOR]

Published
2012
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42. Rhes influences striatal cAMP/PKA-dependent signaling and synaptic plasticity in a gender-sensitive fashion

Author

Valentina Pendolino, Maria Luisa Mancini, Massimo Pasqualetti, Carmela Giampà, Francesco Errico, Sara Migliarini, Chiara Schepisi, Robert Nisticò, Veronica Ghiglieri, Barbara Pelosi, Giacomo Maddaloni, Francesco Napolitano, Giuseppe Sciamanna, Alessandro Usiello, Anna Di Maio, Barbara Picconi, Daniela Vitucci, Ghiglieri, V, Napolitano, F, Pelosi, B, Schepisi, C, Migliarini, S, Di Maio, A, Pendolino, V, Mancini, M, Sciamanna, G, Vitucci, D, Maddaloni, G, Giampà, C, Errico, F, Nisticò, R, Pasqualetti, M, Picconi, B, Usiello, Alessandro, Ghiglieri, Veronica, Napolitano, Francesco, Pelosi, Barbara, Schepisi, Chiara, Migliarini, Sara, Di Maio, Anna, Pendolino, Valentina, Mancini, Maria, Sciamanna, Giuseppe, Vitucci, Daniela, Maddaloni, Giacomo, Giampà, Carmela, Errico, Francesco, Nisticò, Robert, Pasqualetti, Massimo, and Picconi, Barbara

Subjects
Male, Dopamine, Long-Term Potentiation, Messenger, Gene Expression, Hippocampus, Striatum, Mice, Receptors, Cyclic AMP, GABAergic Neurons, Mice, Knockout, Neuronal Plasticity, Multidisciplinary, Cortical Spreading Depression, Settore BIO/14, Long-term potentiation, Settore MED/26 - NEUROLOGIA, Female, Receptor, Signal Transduction, medicine.drug, medicine.medical_specialty, Receptor, Adenosine A2A, Knockout, Motor Activity, Biology, Medium spiny neuron, Article, Adenosine A2A, Sex Factors, GTP-Binding Proteins, Dopamine receptor D2, Internal medicine, Dopamine D2, Neuroplasticity, medicine, Animals, Humans, RNA, Messenger, Corpus Striatum, Cyclic AMP-Dependent Protein Kinases, Mutation, Receptors, Dopamine D2, Endocrinology, Rhes, Synaptic plasticity, RNA
Abstract

Mechanisms of gender-specific synaptic plasticity in the striatum, a brain region that controls motor, cognitive and psychiatric functions, remain unclear. Here we report that Rhes, a GTPase enriched in medium spiny neurons (MSNs) of striatum, alters the striatal cAMP/PKA signaling cascade in a gender-specific manner. While Rhes knockout (KO) male mice, compared to wild-type (WT) mice, had a significant basal increase of cAMP/PKA signaling pathway, the Rhes KO females exhibited a much stronger response of this pathway, selectively under the conditions of dopamine/adenosine-related drug challenge. Corticostriatal LTP defects are exclusively found in A2AR/D2R-expressing MSNs of KO females, compared to KO males, an effect that is abolished by PKA inhibitors but not by the removal of circulating estrogens. This suggests that the synaptic alterations found in KO females could be triggered by an aberrant A2AR/cAMP/PKA activity, but not due to estrogen-mediated effect. Consistent with increased cAMP signaling, D1R-mediated motor stimulation, haloperidol-induced catalepsy and caffeine-evoked hyper-activity are robustly enhanced in Rhes KO females compared to mutant males. Thus Rhes, a thyroid hormone-target gene, plays a relevant role in gender-specific synaptic and behavioral responses.

Published
2015

43. Correction: Systemic Delivery of Recombinant Brain Derived Neurotrophic Factor (BDNF) in the R6/2 Mouse Model of Huntington's Disease

Author

Carmela Giampà, Elena Montagna, Clemente Dato, Mariarosa A. B. Melone, Giorgio Bernardi, Francesca Romana Fusco, Giampà, Carmela, Montagna, Elena, Dato, Clemente, Melone, Mariarosa Anna Beatrice, Bernardi, Giorgio, and Fusco, Francesca Romana

Subjects
Multidisciplinary, lcsh:R, lcsh:Medicine, lcsh:Q, lcsh:Science
Abstract

[This corrects the article DOI: 10.1371/journal.pone.0064037.].

Published
2016

44. Conditioned medium from amniotic cells protects striatal degeneration and ameliorates motor deficits in the R6/2 mouse model of Huntington's disease.

Author

Giampà C, Alvino A, Magatti M, Silini AR, Cardinale A, Paldino E, Fusco FR, and Parolini O

Subjects
Amnion metabolism, Animals, Brain Injuries, Traumatic genetics, Brain Injuries, Traumatic metabolism, Brain Injuries, Traumatic pathology, Brain-Derived Neurotrophic Factor genetics, Corpus Striatum drug effects, Corpus Striatum metabolism, Disease Models, Animal, Humans, Huntington Disease genetics, Huntington Disease metabolism, Huntington Disease pathology, Mesenchymal Stem Cells metabolism, Mice, Mice, Transgenic, Protective Agents pharmacology, Brain Injuries, Traumatic drug therapy, Culture Media, Conditioned pharmacology, Huntington Disease drug therapy, Motor Disorders drug therapy
Abstract

Inflammation significantly impacts the progression of Huntington's disease (HD) and the mutant HTT protein determines a pro-inflammatory activation of microglia. Mesenchymal stem/stromal cells (MSC) from the amniotic membrane (hAMSC), and their conditioned medium (CM-hAMSC), have been shown to possess protective effects in vitro and in vivo in animal models of immune-based disorders and of traumatic brain injury, which have been shown to be mediated by their immunomodulatory properties. In this study, in the R6/2 mouse model for HD we demonstrate that mice treated with CM-hAMSC display less severe signs of neurological dysfunction than saline-treated ones. CM-hAMSC treatment significantly delayed the development of the hind paw clasping response during tail suspension, reduced deficits in rotarod performance, and decreased locomotor activity in an open field test. The effects of CM-hAMSC on neurological function were reflected in a significant amelioration in brain pathology, including reduction in striatal atrophy and the formation of striatal neuronal intranuclear inclusions. In addition, while no significant increase was found in the expression of BDNF levels after CM-hAMSC treatment, a significant decrease of microglia activation and inducible nitric oxide synthase levels were observed. These results support the concept that CM-hAMSC could act by modulating inflammatory cells, and more specifically microglia., (© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Published
2019
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45. Persistent activation of microglia and NADPH oxidase [corrected] drive hippocampal dysfunction in experimental multiple sclerosis.

Author

Di Filippo M, de Iure A, Giampà C, Chiasserini D, Tozzi A, Orvietani PL, Ghiglieri V, Tantucci M, Durante V, Quiroga-Varela A, Mancini A, Costa C, Sarchielli P, Fusco FR, and Calabresi P

Subjects
Animals, Encephalomyelitis, Autoimmune, Experimental enzymology, Encephalomyelitis, Autoimmune, Experimental pathology, Encephalomyelitis, Autoimmune, Experimental physiopathology, Enzyme Activation, Female, Mice, Behavior, Animal, CA1 Region, Hippocampal enzymology, CA1 Region, Hippocampal pathology, CA1 Region, Hippocampal physiopathology, Cognition, Long-Term Potentiation, Microglia enzymology, Microglia pathology, Multiple Sclerosis enzymology, Multiple Sclerosis pathology, Multiple Sclerosis physiopathology, NADPH Oxidases metabolism
Abstract

Cognitive impairment is common in multiple sclerosis (MS). Unfortunately, the synaptic and molecular mechanisms underlying MS-associated cognitive dysfunction are largely unknown. We explored the presence and the underlying mechanism of cognitive and synaptic hippocampal dysfunction during the remission phase of experimental MS. Experiments were performed in a chronic-relapsing experimental autoimmune encephalomyelitis (EAE) model of MS, after the resolution of motor deficits. Immunohistochemistry and patch-clamp recordings were performed in the CA1 hippocampal area. The hole-board was utilized as cognitive/behavioural test. In the remission phase of experimental MS, hippocampal microglial cells showed signs of activation, CA1 hippocampal synapses presented an impaired long-term potentiation (LTP) and an alteration of spatial tests became evident. The activation of hippocampal microglia mediated synaptic and cognitive/behavioural alterations during EAE. Specifically, LTP blockade was found to be caused by the reactive oxygen species (ROS)-producing enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. We suggest that in the remission phase of experimental MS microglia remains activated, causing synaptic dysfunctions mediated by NADPH oxidase. Inhibition of microglial activation and NADPH oxidase may represent a promising strategy to prevent neuroplasticity impairment associated with active neuro-inflammation, with the aim to improve cognition and counteract MS disease progression.

Published
2016
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46. Endogenous 17β-estradiol is required for activity-dependent long-term potentiation in the striatum: interaction with the dopaminergic system.

Author

Tozzi A, de Iure A, Tantucci M, Durante V, Quiroga-Varela A, Giampà C, Di Mauro M, Mazzocchetti P, Costa C, Di Filippo M, Grassi S, Pettorossi VE, and Calabresi P

Abstract

17β-estradiol (E2), a neurosteroid synthesized by P450-aromatase (ARO), modulates various brain functions. We characterized the role of the locally synthesized E2 on striatal long-term synaptic plasticity and explored possible interactions between E2 receptors (ERs) and dopamine (DA) receptors in the dorsal striatum of adult male rats. Inhibition of E2 synthesis or antagonism of ERs prevented the induction of long-term potentiation (LTP) in both medium spiny neurons (MSNs) and cholinergic interneurons (ChIs). Activation of a D1-like DA receptor/cAMP/PKA-dependent pathway restored LTP. In MSNs exogenous E2 reversed the effect of ARO inhibition. Also antagonism of M1 muscarinic receptors prevented the D1-like receptor-mediated restoration of LTP confirming a role for ChIs in controlling the E2-mediated LTP of MSNs. A novel striatal interaction, occurring between ERs and D1-like receptors in both MSNs and ChIs, might be critical to regulate basal ganglia physiology and to compensate synaptic alterations in Parkinson's disease.

Published
2015
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47. Phosphodiesterases as therapeutic targets for Huntington's disease.

Author

Fusco FR and Giampà C

Subjects
Animals, Humans, Huntington Disease drug therapy, Huntington Disease enzymology, Phosphodiesterase Inhibitors therapeutic use, Phosphoric Diester Hydrolases chemistry
Abstract

Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder characterized by motor dysfunction, cognitive decline, and emotional and psychiatric disturbances. The genetic mutation is characterized by a CAG expansion, resulting in the formation of a mutant huntingtin protein with an expanded polyglutamine repeat region. Mutated huntingtin has been shown to impair a number of physiological activities by interacting with several factors. In particular, cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) are severely affected by mutant huntingtin. In this view, drugs targeted at counteracting CREB loss of function and BDNF decrease have been considered as powerful tools to treat HD. Recently, cyclic nucleotide phosphodiesterase (PDE) inhibitors have been used successfully to increase levels of CREB and BDNF in HD models. Indeed, PDE4, 5 or 10 inhibitors have been shown to afford neuroprotection and modulation of CREB and BDNF. In this review, we will summarize the data supporting the use of PDE inhibitors as the therapeutical approach to fight HD and we will discuss the possible mechanisms of action underlying these effects.

Published
2015
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