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Atorvastatin Prevents Cognitive Deficits Induced by Intracerebroventricular Amyloid-β1–40 Administration in Mice: Involvement of Glutamatergic and Antioxidant Systems

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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.

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Abbreviations

Aβ:

Amyloid-β

AD:

Alzheimer’s disease

EAATs:

Excitatory aminoacids transporters

GLAST, GLT-1:

Glial glutamate transporters

GPx:

Glutathione peroxidase

GR:

Glutathione reductase

GSHt:

Total glutathione

GSSG:

Oxidized glutathione

HMG-CoA reductase:

3-Hydroxyl-3-methyl-glutaryl-coenzyme A reductase

i.c.v.:

Intracerebroventricular

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Acknowledgments

The research is supported by Grants from the Brazilian funding agencies: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Conselho de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Financiadora de Estudos e Projetos – IBN-Net # 01.06.0842-00 (FINEP), and Instituto Nacional de Ciência e Tecnologia (INCT) for Excitotoxicity, and Neuroprotection. C.I.T., R.D.P. and M.F. are the recipients of CNPq productivity fellowship. W.C.M. is the recipient of CAPES Master scholarship and G.G.V. is the recipient of CAPES-PRODOC post-doctoral scholarship.

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Author notes

  1. Samuel Vandresen-Filho

    Present address: Departamento de Ciências Básicas em Saúde, Universidade Federal de Mato Grosso, Cuiabá, MT, 78060-900, Brazil

  2. Giordano Gubert Viola

    Present address: Universidade Federal de Sergipe, Campus São Cristóvão, São Cristóvão, SE, 49100-000, Brazil

  3. Vanessa Valgas dos Santos

    Present address: Department of Physiology, Monash University, Clayton, Melbourne, VIC, 3800, Australia

Authors and Affiliations

  1. Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, 88040-900, Brazil

    Wagner C. Martins, Alessandra Antunes dos Santos, Samuel Vandresen-Filho, Tharine A. Dal-Cim, Karen A. de Oliveira, Marcelo Farina & Carla I. Tasca

  2. Programa de Pós-graduação em Neurociências, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, 88040-900, Brazil

    Wagner C. Martins, Tharine A. Dal-Cim, Karen A. de Oliveira, Claudia B. N. Mendes-de-Aguiar, Marcelo Farina, Rui Daniel Prediger, Giordano Gubert Viola & Carla I. Tasca

  3. Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, 88040-900, Brazil

    Vanessa Valgas dos Santos & Rui Daniel Prediger

  4. Departamento de Biologia Celular, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, 88040-900, Brazil

    Claudia B. N. Mendes-de-Aguiar

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  1. Wagner C. Martins
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  2. Vanessa Valgas dos Santos
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  3. Alessandra Antunes dos Santos
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  4. Samuel Vandresen-Filho
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  5. Tharine A. Dal-Cim
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Correspondence to Carla I. Tasca.

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Martins, W.C., dos Santos, V.V., dos Santos, A.A. et al. Atorvastatin Prevents Cognitive Deficits Induced by Intracerebroventricular Amyloid-β1–40 Administration in Mice: Involvement of Glutamatergic and Antioxidant Systems. Neurotox Res 28, 32–42 (2015). https://doi.org/10.1007/s12640-015-9527-y

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