title: Astrocyte-Dependent Vulnerability to Excitotoxicity in Spermine Oxidase-Overexpressing Mouse.
abstract: Transgenic mice overexpressing spermine oxidase (SMO) in the cerebral cortex (Dach-SMO mice) showed increased vulnerability to excitotoxic brain injury and kainate-induced epileptic seizures. To investigate the mechanisms by which SMO overexpression leads to increased susceptibility to kainate excitotoxicity and seizure, in the cerebral cortex of Dach-SMO and control mice we assessed markers for astrocyte proliferation and neuron loss, and the ability of kainate to evoke glutamate release from nerve terminals and astrocyte processes. Moreover, we assessed a possible role of astrocytes in an in vitro model of epileptic-like activity in combined cortico-hippocampal slices recorded with a multi-electrode array device. In parallel, as the brain is a major metabolizer of oxygen and yet has relatively feeble protective antioxidant mechanisms, we analyzed the oxidative status of the cerebral cortex of both SMO-overexpressing and control mice by evaluating enzymatic and non-enzymatic scavengers such as metallothioneins. The main findings in the cerebral cortex of Dach-SMO mice as compared to controls are the following: astrocyte activation and neuron loss; increased oxidative stress and activation of defense mechanisms involving both neurons and astrocytes; increased susceptibility to kainate-evoked cortical epileptogenic activity, dependent on astrocyte function; appearance of a glutamate-releasing response to kainate from astrocyte processes due to activation of Ca(2+)-permeable AMPA receptors in Dach-SMO mice. We conclude that reactive astrocytosis and activation of glutamate release from astrocyte processes might contribute, together with increased reactive oxygen species production, to the vulnerability to kainate excitotoxicity in Dach-SMO mice. This mouse model with a deregulated polyamine metabolism would shed light on roles for astrocytes in increasing vulnerability to excitotoxic neuron injury.
authors.affiliation: Section of Pharmacology and Toxicology, Department of Pharmacy, University of Genova, Viale Cembrano 4, 16148, Genoa, Italy.|Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 5, 16132, Genoa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cervetto
authors.affiliation: Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Corso Europa 26, 16132, Genoa, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Vergani
authors.affiliation: Department of Experimental Medicine, University of Genova, Via L. B. Alberti 2, 16132, Genoa, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Passalacqua
authors.affiliation: Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Corso Europa 26, 16132, Genoa, Italy.
authors.forename: Milena
authors.initials: M
authors.lastname: Ragazzoni
authors.affiliation: Section of Pharmacology and Toxicology, Department of Pharmacy, University of Genova, Viale Cembrano 4, 16148, Genoa, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Venturini
authors.affiliation: Department of Biology, University of Rome 'Tor Vergata', Via della Ricerca Scientifica, 00133, Rome, Italy.|Department of Experimental Neurosciences, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano 64, 00143, Rome, Italy.|Unit of Cell Stress and Survival, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cecconi
authors.affiliation: Department of Experimental Neurosciences, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano 64, 00143, Rome, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Berretta
authors.affiliation: Department of Experimental Neurosciences, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano 64, 00143, Rome, Italy.|Department of Systems Medicine, University of Rome 'Tor Vergata', Viale Oxford 81, 00133, Rome, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Mercuri
authors.affiliation: Department of Experimental Neurosciences, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano 64, 00143, Rome, Italy.|Medical School Campus, Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128, Rome, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: D'Amelio
authors.affiliation: Section of Pharmacology and Toxicology, Department of Pharmacy, University of Genova, Viale Cembrano 4, 16148, Genoa, Italy.|Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 5, 16132, Genoa, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Maura
authors.affiliation: Department of Sciences, University of Rome "Roma Tre", Viale Marconi 446, 00146, Rome, Italy.|Interuniversity Consortium of Structural and Systems Biology, Viale Medaglie d'Oro 305, 00136, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Mariottini
authors.affiliation: Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Corso Europa 26, 16132, Genoa, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Voci
authors.affiliation: Section of Pharmacology and Toxicology, Department of Pharmacy, University of Genova, Viale Cembrano 4, 16148, Genoa, Italy. marcoli@pharmatox.unige.it.|Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 5, 16132, Genoa, Italy. marcoli@pharmatox.unige.it.
authors.forename: Manuela
authors.initials: M
authors.lastname: Marcoli
authors.affiliation: Department of Sciences, University of Rome "Roma Tre", Viale Marconi 446, 00146, Rome, Italy. manuela.cervelli@uniroma3.it.|Interuniversity Consortium of Structural and Systems Biology, Viale Medaglie d'Oro 305, 00136, Rome, Italy. manuela.cervelli@uniroma3.it.
authors.forename: Manuela
authors.initials: M
authors.lastname: Cervelli
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects* / Q000473:pathology; D001569:Benzodiazepines / Q000494:pharmacology; D015317:Biogenic Polyamines / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002540:Cerebral Cortex / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D004790:Enzyme Induction; D020022:Genetic Predisposition to Disease; D005911:Gliosis / Q000235:genetics; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D008668:Metallothionein / Q000502:physiology; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000473:pathology; D009498:Neurotoxins / Q000494:pharmacology*; D018384:Oxidative Stress; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018091:Receptors, AMPA / Q000187:drug effects / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012640:Seizures / Q000139:chemically induced* / Q000235:genetics / Q000503:physiopathology; D013574:Synaptosomes / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation; D000097667:Polyamine Oxidase
chemical_list: D001224:Aspartic Acid; D001569:Benzodiazepines; D015317:Biogenic Polyamines; D002118:Calcium; D007608:Kainic Acid; D008668:Metallothionein; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D000587:Oxidoreductases Acting on CH-NH Group Donors; D018091:Receptors, AMPA; D011993:Recombinant Fusion Proteins; D000097667:Polyamine Oxidase; C061950:GYKI 52466
keywords: Astrocyte processes; Cerebral cortex; Epileptic-like activity; Excitotoxicity; Glutamate release; Kainate; Metallothioneins; Oxidative stress; Polyamines; Spermine oxidase