title: A New Transgenic Mouse Model for Studying the Neurotoxicity of Spermine Oxidase Dosage in the Response to Excitotoxic Injury.
abstract: Spermine oxidase is a FAD-containing enzyme involved in polyamines catabolism, selectively oxidizing spermine to produce H2O2, spermidine, and 3-aminopropanal. Spermine oxidase is highly expressed in the mouse brain and plays a key role in regulating the levels of spermine, which is involved in protein synthesis, cell division and cell growth. Spermine is normally released by neurons at synaptic sites where it exerts a neuromodulatory function, by specifically interacting with different types of ion channels, and with ionotropic glutamate receptors. In order to get an insight into the neurobiological roles of spermine oxidase and spermine, we have deregulated spermine oxidase gene expression producing and characterizing the transgenic mouse model JoSMOrec, conditionally overexpressing the enzyme in the neocortex. We have investigated the effects of spermine oxidase overexpression in the mouse neocortex by transcript accumulation, immunohistochemical analysis, enzymatic assays and polyamine content in young and aged animals. Transgenic JoSMOrec mice showed in the neocortex a higher H2O2 production in respect to Wild-Type controls, indicating an increase of oxidative stress due to SMO overexpression. Moreover, the response of transgenic mice to excitotoxic brain injury, induced by kainic acid injection, was evaluated by analysing the behavioural phenotype, the immunodistribution of neural cell populations, and the ultrastructural features of neocortical neurons. Spermine oxidase overexpression and the consequently altered polyamine levels in the neocortex affects the cytoarchitecture in the adult and aging brain, as well as after neurotoxic insult. It resulted that the transgenic JoSMOrec mouse line is more sensitive to KA than Wild-Type mice, indicating an important role of spermine oxidase during excitotoxicity. These results provide novel evidences of the complex and critical functions carried out by spermine oxidase and spermine in the mammalian brain.
authors.affiliation: Dipartimento di Biologia, Università "Roma Tre," Rome, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Cervelli
authors.forename: Gabriella
authors.initials: G
authors.lastname: Bellavia
authors.forename: Marcello
authors.initials: M
authors.lastname: D'Amelio
authors.forename: Virve
authors.initials: V
authors.lastname: Cavallucci
authors.forename: Sandra
authors.initials: S
authors.lastname: Moreno
authors.forename: Joachim
authors.initials: J
authors.lastname: Berger
authors.forename: Roberta
authors.initials: R
authors.lastname: Nardacci
authors.forename: Manuela
authors.initials: M
authors.lastname: Marcoli
authors.forename: Guido
authors.initials: G
authors.lastname: Maura
authors.forename: Mauro
authors.initials: M
authors.lastname: Piacentini
authors.forename: Roberto
authors.initials: R
authors.lastname: Amendola
authors.forename: Francesco
authors.initials: F
authors.lastname: Cecconi
authors.forename: Paolo
authors.initials: P
authors.lastname: Mariottini
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000139:chemically induced / Q000235:genetics*; D004195:Disease Models, Animal; D018628:Gene Dosage; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000235:genetics*; D009498:Neurotoxins; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D013096:Spermine / Q000378:metabolism; D000097667:Polyamine Oxidase
chemical_list: D009498:Neurotoxins; D000587:Oxidoreductases Acting on CH-NH Group Donors; D013096:Spermine; D000097667:Polyamine Oxidase