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Epileptic seizures and oxidative stress in a mouse model over-expressing spermine oxidase

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Abstract

Several studies have demonstrated high polyamine levels in brain diseases such as epilepsy. Epilepsy is the fourth most common neurological disorder and affects people of all ages. Excitotoxic stress has been associated with epilepsy and it is considered one of the main causes of neuronal degeneration and death. The transgenic mouse line Dach-SMOX, with CD1 background, specifically overexpressing spermine oxidase in brain cortex, has been proven to be highly susceptible to epileptic seizures and excitotoxic stress induced by kainic acid. In this study, we analysed the effect of spermine oxidase over-expression in a different epileptic model, pentylenetetrazole. Behavioural evaluations of transgenic mice compared to controls showed a higher susceptibility towards pentylentetrazole. High-performance liquid chromatography analysis of transgenic brain from treated mice revealed altered polyamine content. Immunoistochemical analysis indicated a rise of 8-oxo-7,8-dihydro-2′-deoxyguanosine, demonstrating an increase in oxidative damage, and an augmentation of system x −c as a defence mechanism. This cascade of events can be initially linked to an increase in protein kinase C alpha, as shown by Western blot. This research points out the role of spermine oxidase, as a hydrogen peroxide producer, in the oxidative stress during epilepsy. Moreover, Dach-SMOX susceptibility demonstrated by two different epileptic models strongly indicates this transgenic mouse line as a potential animal model to study epilepsy.

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Acknowledgements

This work was supported by the Roma Tre University contribution to the laboratories (CAL/2017 and CAL/2018) to M.C. and P.M and by the Ph.D. School (Department of Science) contribution 2017 to A.L. and S.P and 2018 to G.B. The authors wish to thank Mrs Rosetta Ponzo for the revision of the English text and Prof. G. Maura (University of Genova, Italy) for useful discussion.

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Authors and Affiliations

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

    Alessia Leonetti, Giulia Baroli, Emiliano Fratini, Stefano Pietropaoli, Paolo Mariottini & Manuela Cervelli

  2. Interuniversity Consortium of Structural and Systems Biology, Viale Medaglie d’Oro 305, 00136, Rome, Italy

    Paolo Mariottini & Manuela Cervelli

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

    Manuela Marcoli

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

    Manuela Marcoli

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  1. Alessia Leonetti
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Correspondence to Manuela Cervelli.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. The experiments were carried out in accordance with the ethical guidelines for the conduction of animal research of the European Community’s Council Directive 2010/63/EU. Formal approval of these experiments was obtained from the Italian Ministry of Health with the approved protocol N°964/2015-PR.

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Leonetti, A., Baroli, G., Fratini, E. et al. Epileptic seizures and oxidative stress in a mouse model over-expressing spermine oxidase. Amino Acids 52, 129–139 (2020). https://doi.org/10.1007/s00726-019-02749-8

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