Glutamate Excitotoxicity Linked to Spermine Oxidase Overexpression Stefano Pietropaoli 1 & Alessia Leonetti 1 & Chiara Cervetto 2 & Arianna Venturini 2 & Roberta Mastrantonio 1 & Giulia Baroli 1 & Tiziana Persichini 1 & Marco Colasanti 1 & Guido Maura 2,3 & Manuela Marcoli 2,3 & Paolo Mariottini 1 & Manuela Cervelli 1 Received: 28 July 2017 /Accepted: 22 December 2017 # Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Excitotoxic stress has been associated with several different neurological disorders, and it is one of the main causes of neuronal degeneration and death. To identify new potential proteins that could represent key factors in excitotoxic stress and to study the relationship between polyamine catabolism and excitotoxic damage, a novel transgenic mouse line overexpressing spermine oxidase enzyme in the neocortex (Dach-SMOX) has been engineered. These transgenic mice are more susceptible to excitotoxic injury and display a higher oxidative stress, highlighted by 8-Oxo-2′-deoxyguanosine increase and activation of defense mechanisms, as demonstrated by the increase of nuclear factor erythroid 2-related factor 2 (Nrf-2) in the nucleus. In Dach-SMOX astrocytes and neurons, an alteration of the phosphorylated and non- phosphorylated subunits of glutamate receptors increases the kainic acid response in these mice. Moreover, a decrease in excitatory amino acid transporters and an increase in the system x c - transporter, a Nrf-2 target, was observed. Sulfasalazine, a system x c - transporter inhibitor, was shown to revert the increased susceptibility of Dach-SMOX mice treated with kainic acid. We demonstrated that astrocytes play a crucial role in this process: neuronal spermine oxidase overexpression resulted in an alteration of glutamate excitability, in glutamate uptake and efflux in astrocytes involved in the synapse. Considering the involvement of oxidative stress in many neurodegenerative diseases, Dach-SMOX trans- genic mouse can be considered as a suitable in vivo genetic model to study the involvement of spermine oxidase in excitotoxicity, which can be considered as a possible therapeutic target. Keywords EAAT . Oxidative stress . Polyamine metabolism . Seizures . Sulfasalazine . System x c - transporter Pietropaoli Stefano and Leonetti Alessia equally contributed to this work. * Manuela Cervelli manuela.cervelli@uniroma3.it Stefano Pietropaoli stefano.pietropaoli@uniroma3.it Alessia Leonetti alessia.leonetti@uniroma3.it Chiara Cervetto cervetto@difar.unige.it Arianna Venturini venturini@difar.unige.it Roberta Mastrantonio roberta.mastrantonio@uniroma3.it Giulia Baroli giulia.baroli@uniroma3.it Tiziana Persichini tiziana.persichini@uniroma3.it Marco Colasanti marco.colasanti@uniroma3.it Guido Maura maura@pharmatox.unige.it Manuela Marcoli marcoli@pharmatox.unige.it Paolo Mariottini paolo.mariottini@uniroma3.it 1 Department of Sciences, University of Rome BRoma Tre^, Viale Marconi 446, 00146 Rome, Italy 2 Section of Pharmacology and Toxicology, Department of Pharmacy, University of Genova, Viale Cembrano 4, 16148 Genoa, Italy 3 Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 5, 16132 Genoa, Italy Molecular Neurobiology https://doi.org/10.1007/s12035-017-0864-0