caa a22 4500 606203206 CHVBK 20210128100956.0 cr unu---uuuuu 210128e20150301xx s 000 0 eng 10.1007/s00429-014-0718-8 doi (NATIONALLICENCE)springer-10.1007/s00429-014-0718-8 Metalloproteinase-9 contributes to inflammatory glia activation and nigro-striatal pathway degeneration in both mouse and monkey models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism [Elektronische Daten] [V. Annese, María-Trinidad Herrero, M. Di Pentima, A. Gomez, L. Lombardi, C. Ros, V. De Pablos, E. Fernandez-Villalba, Maria De Stefano] Inflammation is a predominant aspect of neurodegenerative diseases, manifested by glia activation and expression of pro-inflammatory mediators. Studies on animal models of Parkinson's disease (PD) suggest that sustained neuroinflammation exacerbates degeneration of the dopaminergic (DA) nigro-striatal pathway. Therefore, insights into the inflammatory mechanisms of PD may help the development of novel therapeutic strategies against this disease. As extracellular matrix metalloproteinases (MMPs) could be major players in the progression of Parkinsonism, we investigated, in the substantia nigra and striatum of mice acutely injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), changes in mRNA expression, protein levels, and cell localization of MMP-9. This protease is mainly neuronal, but early after MPTP injection its mRNA and protein levels, as well as the number of MMP-9-expressing microglia and astrocytes, increase concomitantly to a prominent inflammation. Neuroinflammation and MMP-9+ glia begin to decline within 2weeks, although protein levels remain higher than control, in association with a partial recovery of DA nigro-striatal circuit. Comparable quantitative studies on MMP-9 knock-out mice, show a significant decrease in both glia activation and loss of DA neurons and fibers, with respect to wild-type. Moreover, in a parallel study on chronically MPTP-injected macaques, we observed that perpetuation of inflammation and high levels of MMP-9 are associated to DA neuron loss. Our data suggest that MMP-9 released by injured neurons favors glia activation; glial cells in turn reinforce their reactive state via autocrine MMP-9 release, contributing to nigro-striatal pathway degeneration. Specific modulation of MMP-9 activity may, therefore, be a strategy to ameliorate harmful inflammatory outcomes in Parkinsonism. Springer-Verlag Berlin Heidelberg, 2014 Metalloproteinases nationallicence Neuroinflammation nationallicence Parkinson's disease nationallicence Neurodegeneration nationallicence Annese V. Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Biologia e Biotecnologie "Charles Darwin”, Sapienza Università di Roma, P.le Aldo Moro 5, 00185, Rome, Italy aut Herrero María-Trinidad Clinical and Experimental Neuroscience (NiCE-CIBERNED), School of Medicine, University of Murcia, 30100, Murcia, Spain aut Di Pentima M. Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Biologia e Biotecnologie "Charles Darwin”, Sapienza Università di Roma, P.le Aldo Moro 5, 00185, Rome, Italy aut Gomez A. Clinical and Experimental Neuroscience (NiCE-CIBERNED), School of Medicine, University of Murcia, 30100, Murcia, Spain aut Lombardi L. Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Biologia e Biotecnologie "Charles Darwin”, Sapienza Università di Roma, P.le Aldo Moro 5, 00185, Rome, Italy aut Ros C. Clinical and Experimental Neuroscience (NiCE-CIBERNED), School of Medicine, University of Murcia, 30100, Murcia, Spain aut De Pablos V. Clinical and Experimental Neuroscience (NiCE-CIBERNED), School of Medicine, University of Murcia, 30100, Murcia, Spain aut Fernandez-Villalba E. Clinical and Experimental Neuroscience (NiCE-CIBERNED), School of Medicine, University of Murcia, 30100, Murcia, Spain aut De Stefano Maria Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Biologia e Biotecnologie "Charles Darwin”, Sapienza Università di Roma, P.le Aldo Moro 5, 00185, Rome, Italy aut Brain Structure and Function Springer Berlin Heidelberg 220/2(2015-03-01), 703-727 1863-2653 220:2<703 2015 220 429 https://doi.org/10.1007/s00429-014-0718-8 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00429-014-0718-8 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Annese V. Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Biologia e Biotecnologie "Charles Darwin”, Sapienza Università di Roma, P.le Aldo Moro 5, 00185, Rome, Italy aut NATIONALLICENCE 700 1- Herrero María-Trinidad Clinical and Experimental Neuroscience (NiCE-CIBERNED), School of Medicine, University of Murcia, 30100, Murcia, Spain aut NATIONALLICENCE 700 1- Di Pentima M. Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Biologia e Biotecnologie "Charles Darwin”, Sapienza Università di Roma, P.le Aldo Moro 5, 00185, Rome, Italy aut NATIONALLICENCE 700 1- Gomez A. Clinical and Experimental Neuroscience (NiCE-CIBERNED), School of Medicine, University of Murcia, 30100, Murcia, Spain aut NATIONALLICENCE 700 1- Lombardi L. Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Biologia e Biotecnologie "Charles Darwin”, Sapienza Università di Roma, P.le Aldo Moro 5, 00185, Rome, Italy aut NATIONALLICENCE 700 1- Ros C. Clinical and Experimental Neuroscience (NiCE-CIBERNED), School of Medicine, University of Murcia, 30100, Murcia, Spain aut NATIONALLICENCE 700 1- De Pablos V. Clinical and Experimental Neuroscience (NiCE-CIBERNED), School of Medicine, University of Murcia, 30100, Murcia, Spain aut NATIONALLICENCE 700 1- Fernandez-Villalba E. Clinical and Experimental Neuroscience (NiCE-CIBERNED), School of Medicine, University of Murcia, 30100, Murcia, Spain aut NATIONALLICENCE 700 1- De Stefano Maria Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Biologia e Biotecnologie "Charles Darwin”, Sapienza Università di Roma, P.le Aldo Moro 5, 00185, Rome, Italy aut NATIONALLICENCE 773 0- Brain Structure and Function Springer Berlin Heidelberg 220/2(2015-03-01), 703-727 1863-2653 220:2<703 2015 220 429