Glutamate Excitotoxicity Linked to Spermine Oxidase Overexpression.

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.

• Authors: Stefano Pietropaoli, Alessia Leonetti, Chiara Cervetto, Arianna Venturini, Roberta Mastrantonio, Giulia Baroli, Tiziana Persichini, Marco Colasanti, Guido Maura, Manuela Marcoli, Paolo Mariottini, Manuela Cervelli
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 55 Issue 9 Pg. 7259-7270 (Sep 2018) ISSN: 1559-1182 [Electronic] United States
• PMID: 29397558 (Publication Type: Journal Article)

Chemical References

• Amino Acid Transport System y+
• Excitatory Amino Acid Transporter 1
• Excitatory Amino Acid Transporter 2
• NF-E2-Related Factor 2
• Neurotoxins
• Nfe2l2 protein, mouse
• Protein Subunits
• Receptors, AMPA
• Slc1a2 protein, mouse
• Slc1a3 protein, mouse
• Glutamic Acid
• Sulfasalazine
• 8-Hydroxy-2'-Deoxyguanosine
• Oxidoreductases Acting on CH-NH Group Donors
• polyamine oxidase
• Deoxyguanosine
• glutamate receptor ionotropic, AMPA 1

Topics

• 8-Hydroxy-2'-Deoxyguanosine
• Amino Acid Transport System y+ (metabolism)
• Animals
• Behavior, Animal (drug effects)
• Brain (metabolism)
• Deoxyguanosine (analogs & derivatives, metabolism)
• Epilepsy (drug therapy, pathology)
• Excitatory Amino Acid Transporter 1 (metabolism)
• Excitatory Amino Acid Transporter 2 (metabolism)
• Glutamic Acid (toxicity)
• Mice, Transgenic
• Models, Biological
• NF-E2-Related Factor 2 (metabolism)
• Neuroglia (drug effects, metabolism)
• Neurotoxins (toxicity)
• Oxidoreductases Acting on CH-NH Group Donors (metabolism)
• Protein Subunits (metabolism)
• Protein Transport (drug effects)
• Receptors, AMPA (metabolism)
• Sulfasalazine (pharmacology, therapeutic use)
• Synaptosomes (drug effects, metabolism)