title: Atorvastatin prevents cell damage via modulation of oxidative stress, glutamate uptake and glutamine synthetase activity in hippocampal slices subjected to oxygen/glucose deprivation.
abstract: Oxygen-glucose deprivation (OGD) in brain cells increases extracellular glutamate concentration leading to excitotoxicity. Glutamate uptake from the synaptic cleft is carried out by glutamate transporters, which are likely to be modulated by oxidative stress. Therefore, oxidative stress is associated with reduced activity of glutamate transporters and glutamine synthetase, thus increasing extracellular glutamate levels that may aggravate damage to brain cells. Atorvastatin, a cholesterol-lowering agent, has been shown to exert neuroprotective effects. The aim of this study was to investigate if in vivo atorvastatin treatment would have protective effects against hippocampal slices subjected to OGD, ex vivo. Atorvastatin pretreatment promoted increased cell viability after OGD and reoxygenation of hippocampal slices. Atorvastatin-induced neuroprotection may be related to diminished oxidative stress, since it prevented OGD-induced decrement of non-proteic thiols (NPSH) levels and increase in the production of reactive oxygen species (ROS). Atorvastatin pretreatment also prevented the OGD-induced decrease in glutamate uptake and glutamine synthetase activity, although it had no effect on OGD-induced excitatory aminoacids release. Addition of cholesterol before OGD and reoxygenation, abolished the protective effect of atorvastatin on cellular viability as well as on glutamate uptake and glutamine synthetase activity. Therefore, atorvastatin is capable of preventing OGD-induced cell death, an effect achieved due to modulation of glutamate uptake and glutamine synthetase activity, and associated with diminished oxidative stress. Additionally, atorvastatin effects were dependent on its action on cholesterol synthesis inhibition. Thus, atorvastatin might be a useful strategy in the prevention of glutamate exitotoxicity involved in brain injuries such as vascular disorders.
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, 88040-900 Florianópolis, SC, Brazil.
authors.forename: Samuel
authors.initials: S
authors.lastname: Vandresen-Filho
authors.forename: Wagner C
authors.initials: WC
authors.lastname: Martins
authors.forename: Daniela B
authors.initials: DB
authors.lastname: Bertoldo
authors.forename: Gianni
authors.initials: G
authors.lastname: Mancini
authors.forename: Bruno A
authors.initials: BA
authors.lastname: Herculano
authors.forename: Andreza F
authors.initials: AF
authors.lastname: de Bem
authors.forename: Carla I
authors.initials: CI
authors.lastname: Tasca
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D016923:Cell Death / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism*; D018698:Glutamic Acid / Q000187:drug effects / Q000378:metabolism*; D006538:Heptanoic Acids / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D010100:Oxygen / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D006538:Heptanoic Acids; D018696:Neuroprotective Agents; D011758:Pyrroles; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; D000069059:Atorvastatin; D005974:Glutamate-Ammonia Ligase; D005947:Glucose; D010100:Oxygen