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Glutamate Excitotoxicity Linked to Spermine Oxidase Overexpression

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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 xc− transporter, a Nrf-2 target, was observed. Sulfasalazine, a system xc− 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 transgenic 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.

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Acknowledgements

This work was supported by the Roma Tre University contribution to the laboratories [CAL/2016] to M.C. and P.M. and by the Ph.D. School (Department of Science) contribution 2016 to S.P. and A.L.

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  1. Pietropaoli Stefano and Leonetti Alessia equally contributed to this work.

Authors and Affiliations

  1. Department of Sciences, University of Rome “Roma Tre”, Viale Marconi 446, 00146, Rome, Italy

    Stefano Pietropaoli, Alessia Leonetti, Roberta Mastrantonio, Giulia Baroli, Tiziana Persichini, Marco Colasanti, Paolo Mariottini & Manuela Cervelli

  2. Section of Pharmacology and Toxicology, Department of Pharmacy, University of Genova, Viale Cembrano 4, 16148, Genoa, Italy

    Chiara Cervetto, Arianna Venturini, Guido Maura & Manuela Marcoli

  3. Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 5, 16132, Genoa, Italy

    Guido Maura & Manuela Marcoli

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  1. Stefano Pietropaoli
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  2. Alessia Leonetti
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  3. Chiara Cervetto
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Correspondence to Manuela Cervelli.

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Pietropaoli, S., Leonetti, A., Cervetto, C. et al. Glutamate Excitotoxicity Linked to Spermine Oxidase Overexpression. Mol Neurobiol 55, 7259–7270 (2018). https://doi.org/10.1007/s12035-017-0864-0

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