title: Atorvastatin Prevents Cognitive Deficits Induced by Intracerebroventricular Amyloid-β1-40 Administration in Mice: Involvement of Glutamatergic and Antioxidant Systems.
abstract: Deposition of amyloid-β (Aβ) peptides into specific encephalic structures has been pointed as an important event related to Alzheimer's disease pathogenesis and associated with activation of glial cells, neuroinflammation, oxidative responses, and cognitive deficits. Aβ-induced pro-oxidative damage may regulate the activity of glutamate transporters, leading to reduced glutamate uptake and, as a consequence, excitotoxic events. Herein, we evaluated the effects of the pretreatment of atorvastatin, a HMG-CoA reductase inhibitor, on behavioral and biochemical alterations induced by a single intracerebroventricular (i.c.v.) injection of aggregated Aβ1-40 in mice. Atorvastatin (10 mg/kg/day, p.o.) was administered through seven consecutive days before Aβ1-40 administration. Aβ1-40 caused significant cognitive impairment in the object-place recognition task (2 weeks after the i.c.v. injection) and this phenomenon was abolished by atorvastatin pretreatment. Ex vivo evaluation of glutamate uptake into hippocampal and cerebral cortices slices showed atorvastatin, and Aβ1-40 decreased hippocampal and cortical Na(+)-dependent glutamate uptake. However, Aβ1-40 increased Na(+)-independent glutamate uptake and it was prevented by atorvastatin in prefrontal cortex slices. Moreover, Aβ1-40 treatment significantly increased the cerebrocortical activities of glutathione reductase and glutathione peroxidase and these events were blunted by atorvastatin pretreatment. Reduced or oxidized glutathione levels were not altered by Aβ1-40 and/or atorvastatin treatment. These results extend the notion of the protective action of atorvastatin against neuronal toxicity induced by Aβ1-40 demonstrating that a pretreatment with atorvastatin prevents the spatial learning and memory deficits induced by Aβ in rodents and promotes changes in glutamatergic and antioxidant systems mainly in prefrontal cortex.
authors.affiliation: Departamento de Bioquímica, 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.forename: Vanessa Valgas
authors.initials: VV
authors.lastname: dos Santos
authors.forename: Alessandra Antunes
authors.initials: AA
authors.lastname: dos Santos
authors.forename: Samuel
authors.initials: S
authors.lastname: Vandresen-Filho
authors.forename: Tharine A
authors.initials: TA
authors.lastname: Dal-Cim
authors.forename: Karen A
authors.initials: KA
authors.lastname: de Oliveira
authors.forename: Claudia B N
authors.initials: CB
authors.lastname: Mendes-de-Aguiar
authors.forename: Marcelo
authors.initials: M
authors.lastname: Farina
authors.forename: Rui Daniel
authors.initials: RD
authors.lastname: Prediger
authors.forename: Giordano Gubert
authors.initials: GG
authors.lastname: Viola
authors.forename: Carla I
authors.initials: CI
authors.lastname: Tasca
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D000069059:Atorvastatin / Q000008:administration & dosage*; D003072:Cognition Disorders / Q000139:chemically induced* / Q000517:prevention & control*; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D057967:Infusions, Intraventricular; D008297:Male; D051379:Mice; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000633:toxicity*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects; D065853:Spatial Learning / Q000187:drug effects; D065852:Spatial Memory / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D018698:Glutamic Acid; D000069059:Atorvastatin; D000110:Acetylcholinesterase
references.citation: Neuroscience. 2011 Sep 29;192:631-41
references.pmid: 21756976
references.citation: Lancet. 1977 Jan 22;1(8004):189
references.pmid: 64712
references.citation: Anal Biochem. 1986 Apr;154(1):205-8
references.pmid: 3706724
references.citation: Behav Brain Res. 2004 Dec 6;155(2):185-96
references.pmid: 15364477
references.citation: Free Radic Biol Med. 2002 Jun 1;32(11):1050-60
references.pmid: 12031889
references.citation: Lancet. 1976 Dec 25;2(8000):1403
references.pmid: 63862
references.citation: J Biol Chem. 2005 Oct 28;280(43):35789-92
references.pmid: 16141213
references.citation: Lancet. 2000 Nov 11;356(9242):1627-31
references.pmid: 11089820
references.citation: Am J Cardiol. 2005 Sep 5;96(5A):69F-75F
references.pmid: 16126026
references.citation: Nat Neurosci. 2006 Jan;9(1):119-26
references.pmid: 16311588
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2005 Nov 15;827(1):65-75
references.pmid: 16183338
references.citation: Neuroscience. 2008 Feb 6;151(3):631-43
references.pmid: 18191900
references.citation: Neurochem Res. 2004 Feb;29(2):371-7
references.pmid: 15002732
references.citation: Proc Natl Acad Sci U S A. 1986 Jul;83(13):4913-7
references.pmid: 3088567
references.citation: Methods Enzymol. 1981;77:325-33
references.pmid: 7329310
references.citation: Neurochem Res. 2005 Jan;30(1):83-9
references.pmid: 15756936
references.citation: Brain Res. 2009 Jul 14;1280:137-47
references.pmid: 19464276
references.citation: Biochem Biophys Res Commun. 1996 Dec 24;229(3):832-7
references.pmid: 8954980
references.citation: Fundam Clin Pharmacol. 2005 Feb;19(1):117-25
references.pmid: 15660968
references.citation: Nat Rev Mol Cell Biol. 2007 Feb;8(2):101-12
references.pmid: 17245412
references.citation: Neurology. 2000 Nov 14;55(9):1278-83
references.pmid: 11087768
references.citation: Nature. 1996 Aug 22;382(6593):716-9
references.pmid: 8751442
references.citation: J Neurosci. 2007 May 16;27(20):5394-404
references.pmid: 17507561
references.citation: Neurosci Lett. 2008 Aug 8;440(3):260-4
references.pmid: 18583044
references.citation: Behav Brain Res. 2007 Feb 27;177(2):205-13
references.pmid: 17194489
references.citation: J Neurosci Res. 2005 Jan 1-15;79(1-2):157-65
references.pmid: 15573410
references.citation: Cancer Res. 2002 Sep 15;62(18):5196-203
references.pmid: 12234984
references.citation: J Neural Transm (Vienna). 2011 Nov;118(11):1641-9
references.pmid: 21744242
references.citation: Genes Cells. 2003 Apr;8(4):379-91
references.pmid: 12653965
references.citation: Front Mol Neurosci. 2011 Sep 13;4:22
references.pmid: 21949503
references.citation: Biol Chem. 2003 Apr;384(4):505-16
references.pmid: 12751781
references.citation: Methods Enzymol. 1985;113:484-90
references.pmid: 3003504
references.citation: Exp Neurol. 2010 Dec;226(2):274-84
references.pmid: 20816828
references.citation: Arch Neurol. 2000 Oct;57(10):1439-43
references.pmid: 11030795
references.citation: Psychopharmacology (Berl). 2008 May;198(1):1-27
references.pmid: 18392810
references.citation: JAMA. 1999 Apr 21;281(15):1401-6
references.pmid: 10217056
references.citation: Prog Neurobiol. 2002 Oct;68(3):209-45
references.pmid: 12450488
references.citation: Neurobiol Dis. 2010 Aug;39(2):221-8
references.pmid: 20399861
references.citation: Pharmacol Res. 2011 Mar;63(3):172-80
references.pmid: 21193043
references.citation: Neurotox Res. 2009 Aug;16(2):106-15
references.pmid: 19526287
references.citation: Pharmacol Res. 2011 Sep;64(3):180-6
references.pmid: 21536132
references.citation: Int J Mol Med. 2008 May;21(5):531-7
references.pmid: 18425343
references.citation: J Biol Chem. 1951 Nov;193(1):265-75
references.pmid: 14907713
references.citation: Neurobiol Aging. 2012 Jun;33(6):1121.e1-12
references.pmid: 22035587
references.citation: Neurobiol Learn Mem. 2012 Feb;97(2):213-9
references.pmid: 22207008
references.citation: Curr Alzheimer Res. 2011 Jun;8(4):434-42
references.pmid: 21244355
references.citation: J Alzheimers Dis. 2011;24(1):77-84
references.pmid: 21383494
references.citation: Biochem Pharmacol. 1961 Jul;7:88-95
references.pmid: 13726518
references.citation: Cold Spring Harb Perspect Med. 2012 Jun;2(6):a006262
references.pmid: 22675658