title: 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.
abstract: 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.
authors.affiliation: Laboratory of Neuronal Networks, Department. of Mental and Physical Health and Preventive Medicine, Second University of Naples, 80138 Naples, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cirillo
authors.affiliation: Laboratory of Neuroscience "R. Levi-Montalcini", Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy.|SYSBIO, Centre of Systems Biology, University of Milano-Bicocca, Milano, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Colangelo
authors.affiliation: Laboratory of Neuronal Networks, Department. of Mental and Physical Health and Preventive Medicine, Second University of Naples, 80138 Naples, Italy.
authors.forename: Ciro
authors.initials: C
authors.lastname: De Luca
authors.affiliation: Laboratory of Neuronal Networks, Department. of Mental and Physical Health and Preventive Medicine, Second University of Naples, 80138 Naples, Italy.|SYSBIO, Centre of Systems Biology, University of Milano-Bicocca, Milano, Italy.
authors.forename: Leonilde
authors.initials: L
authors.lastname: Savarese
authors.affiliation: Laboratory of Neuronal Networks, Department. of Mental and Physical Health and Preventive Medicine, Second University of Naples, 80138 Naples, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Barillari
authors.affiliation: Laboratory of Neuroscience "R. Levi-Montalcini", Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy.|SYSBIO, Centre of Systems Biology, University of Milano-Bicocca, Milano, Italy.
authors.forename: Lilia
authors.initials: L
authors.lastname: Alberghina
authors.affiliation: Laboratory of Neuronal Networks, Department. of Mental and Physical Health and Preventive Medicine, Second University of Naples, 80138 Naples, Italy.|SYSBIO, Centre of Systems Biology, University of Milano-Bicocca, Milano, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Papa
mesh_terms: D000818:Animals; D000870:Anterior Horn Cells / Q000201:enzymology* / Q000473:pathology; D001253:Astrocytes / Q000201:enzymology* / Q000473:pathology; D004151:Dipeptides / Q000494:pharmacology; D018093:Gelatinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000201:enzymology* / Q000473:pathology; D059348:Peripheral Nerve Injuries / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000201:enzymology* / Q000293:injuries* / Q000473:pathology; D013116:Spinal Cord / Q000201:enzymology* / Q000473:pathology; D013569:Synapses / Q000201:enzymology* / Q000473:pathology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D004151:Dipeptides; D050491:Glutamate Plasma Membrane Transport Proteins; D050487:Glycine Plasma Membrane Transport Proteins; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; C493266:Slc6a9 protein, rat; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D018093:Gelatinases