title: Atorvastatin Protects from Aβ1-40-Induced Cell Damage and Depressive-Like Behavior via ProBDNF Cleavage.
abstract: Intracerebroventricular (icv) amyloid-beta (Aβ)1-40infusion to mice has been demonstrated to cause neurotoxicty and depressive-like behavior and it can be used to evaluate antidepressant and neuroprotective effect of drugs. Atorvastatin is a widely used statin that has demonstrated antidepressant-like effect in predictable animal behavioral models and neuroprotective effect against Aβ1-40infusion. The purpose of this study was to determine the effect of in vivo atorvastatin treatment against Aβ1-40-induced changes in mood-related behaviors and biochemical parameters in ex vivo hippocampal slices from mice. Atorvastatin treatment (10 mg/kg, p.o., once a day for seven consecutive days) abolished depressive-like and anhedonic-like behaviors induced by Aβ1-40(400 pmol/site, icv) infusion. Aβ1-40-induced hippocampal cell damage was reversed by atorvastatin treatment. Aβ1-40infusion decreased glutamate uptake in hippocampal slices, and atorvastatin did not altered it. Glutamine synthetase activity was not altered by any treatment. Atorvastatin also increased hippocampal mature brain-derived neurotrophic factor (mBDNF)/precursor BDNF (proBDNF) ratio, suggesting an increase of proBDNF to mBDNF cleavage. Accordingly, increased tissue-type plasminogen activator (tPA) and p11 genic expression were observed in hippocampus of atorvastatin-treated mice. Atorvastatin displays antidepressant-like and neuroprotective effects against Aβ1-40-induced toxicity, and these effects may involve tPA- and p11-mediated cleavage of proBDNF to mBDNF.
authors.affiliation: Departamento de Bioquímica, CCB, UFSC Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, 88040-900, Brazil. fabianakalyne@hotmail.com.|Programa de Pós-graduação em Bioquímica, Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, 88040-900, Brazil. fabianakalyne@hotmail.com.|Curso de Farmácia, Universidade do Contestado, Canoinhas, SC, 89460-000, Brazil. fabianakalyne@hotmail.com.
authors.forename: Fabiana K
authors.initials: FK
authors.lastname: Ludka
authors.affiliation: Programa de Pós-graduação em Bioquímica, Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, 88040-900, Brazil.
authors.forename: Maurício P
authors.initials: MP
authors.lastname: Cunha
authors.affiliation: Programa de Pós-graduação em Bioquímica, Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, 88040-900, Brazil.
authors.forename: Tharine
authors.initials: T
authors.lastname: Dal-Cim
authors.affiliation: Departamento de Bioquímica, CCB, UFSC Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, 88040-900, Brazil.
authors.forename: Luisa Bandeira
authors.initials: LB
authors.lastname: Binder
authors.affiliation: Programa de Pós-graduação em Bioquímica, Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, 88040-900, Brazil.
authors.forename: Leandra C
authors.initials: LC
authors.lastname: Constantino
authors.affiliation: Programa de Pós-graduação em Bioquímica, Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, 88040-900, Brazil.
authors.forename: Caio M
authors.initials: CM
authors.lastname: Massari
authors.affiliation: Programa de Pós-graduação em Neurociências, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, 88040-900, Brazil.
authors.forename: Wagner C
authors.initials: WC
authors.lastname: Martins
authors.affiliation: Departamento de Bioquímica, CCB, UFSC Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, 88040-900, Brazil.|Programa de Pós-graduação em Bioquímica, Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, 88040-900, Brazil.|Programa de Pós-graduação em Neurociências, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, 88040-900, Brazil.
authors.forename: Ana Lúcia S
authors.initials: ALS
authors.lastname: Rodrigues
authors.affiliation: Departamento de Bioquímica, CCB, UFSC Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, 88040-900, Brazil.|Programa de Pós-graduação em Bioquímica, Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, 88040-900, Brazil.|Programa de Pós-graduação em Neurociências, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, 88040-900, Brazil.
authors.forename: Carla I
authors.initials: CI
authors.lastname: Tasca
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D000069059:Atorvastatin / Q000494:pharmacology / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects*; D003863:Depression / Q000378:metabolism / Q000517:prevention & control*; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000494:pharmacology*; D011498:Protein Precursors / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011498:Protein Precursors; C078592:amyloid beta-protein (1-40); C426674:brain-derived neurotrophic factor precursor; D000069059:Atorvastatin; D005974:Glutamate-Ammonia Ligase
keywords: Atorvastatin; Aβ1–40; BDNF; Depressive-like; Neuroprotection; p11; tPA