title: Brain proteomics identifies potential simvastatin targets in acute phase of stroke in a rat embolic model.
abstract: Finding an efficient neuroprotectant is of urgent need in the field of stroke research. The goal of this study was to test the effect of acute simvastatin administration after stroke in a rat embolic model and to explore its mechanism of action through brain proteomics. To that end, male Wistar rats were subjected to a Middle Cerebral Arteria Occlusion and simvastatin (20 mg/kg s.c) (n = 11) or vehicle (n = 9) were administered 15 min after. To evaluate the neuroprotective mechanisms of simvastatin, brain homogenates after 48 h were analyzed by two-dimensional fluorescence Difference in Gel Electrophoresis (DIGE) technology. We confirmed that simvastatin reduced the infarct volume and improved neurological impairment at 48 h after the stroke in this model. Considering our proteomics analysis, 66 spots, which revealed significant differences between groups, were analyzed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry allowing the identification of 27 proteins. From these results, we suggest that simvastatin protective effect can be partly explained by the attenuation of the oxidative and stress response at blood-brain barrier level after cerebral ischemia. Interestingly, analyzing one of the proteins (HSP75) in plasma from stroke patients who had received simvastatin during the acute phase, we confirmed the results found in the pre-clinical model. Our aim was to study statins benefits when administered during the acute phase of stroke and to explore its mechanisms of action through brain proteomics assay. Using an embolic model, simvastatin-treated rats showed significant infarct volume reduction and neurological improvement compared to vehicle-treated group. Analyzing their homogenated brains by two-dimensional fluorescence Difference in Gel Electrophoresis (DIGE) technology, we concluded that the protective effect of simvastatin can be attributable to oxidative stress response attenuation and blood-brain barrier protection after cerebral ischemia.
authors.affiliation: Neurovascular Research Laboratory, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Campos-Martorell
authors.forename: Nelida
authors.initials: N
authors.lastname: Salvador
authors.forename: Marta
authors.initials: M
authors.lastname: Monge
authors.forename: Francesc
authors.initials: F
authors.lastname: Canals
authors.forename: Lidia
authors.initials: L
authors.lastname: García-Bonilla
authors.forename: Mar
authors.initials: M
authors.lastname: Hernández-Guillamon
authors.forename: María Irene
authors.initials: MI
authors.lastname: Ayuso
authors.forename: Pilar
authors.initials: P
authors.lastname: Chacón
authors.forename: Anna
authors.initials: A
authors.lastname: Rosell
authors.forename: Alberto
authors.initials: A
authors.lastname: Alcazar
authors.forename: Joan
authors.initials: J
authors.lastname: Montaner
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000235:genetics*; D015180:Electrophoresis, Gel, Two-Dimensional; D018841:HSP90 Heat-Shock Proteins / Q000097:blood; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000473:pathology; D020766:Intracranial Embolism / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D009460:Neurologic Examination; D040901:Proteomics / Q000379:methods*; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000494:pharmacology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D020521:Stroke / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology
chemical_list: D018841:HSP90 Heat-Shock Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C092306:TRAP1 protein, human; D019821:Simvastatin
keywords: acute phase treatment; embolic cerebral ischemia; proteomics; rat; simvastatin; stroke