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Atorvastatin Prevents Hippocampal Cell Death due to Quinolinic Acid-Induced Seizures in Mice by Increasing Akt Phosphorylation and Glutamate Uptake

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Abstract

Statins are cholesterol-lowering agents due to the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Recent studies have shown statins possess pleiotropic effects, which appear to be independent from its cholesterol-lowering action. In this study, we investigated whether atorvastatin would have protective effects against hippocampal cell death promoted by quinolinic acid (QA)-induced seizures in mice. Mice were pretreated with Atorvastatin (1 or 10 mg/kg) or vehicle (saline, 0.9%), orally, once a day for 7 days before the intracerebroventricular (i.c.v.) QA infusion (36.8 nmol/site). Atorvastatin treatment with 1 mg/kg/day did not significantly prevent QA-induced seizures (13.34%). However, administration of atorvastatin 10 mg/kg/day prevented the clonic and/or tonic seizures induced by QA in 29.41% of the mice. Additionally, administration of atorvastatin 10 mg/kg/day significantly prevented QA-induced cell death in the hippocampus. Atorvastatin treatment promoted an increased Akt phosphorylation, which was sustained after QA infusion in both convulsed and non-convulsed mice. Moreover, atorvastatin pretreatment prevented the reduction in glutamate uptake into hippocampal slices induced by QA i.c.v. infusion. These results show that atorvastatin attenuated QA-induced hippocampal cellular death involving the Akt pathway and glutamate transport modulation. Therefore, atorvastatin treatment might be a useful strategy in the prevention of brain injury caused by the exacerbation of glutamatergic toxicity in neurological diseases such as epilepsy.

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Abbreviations

i.c.v.:

Intracerebroventricular

MTT:

3-(4,5-Dimethylthiazol-2-yl-diphenyltetrazolium bromide

NMDA:

N-Methyl-D-aspartate

PI:

Propidium iodide

QA:

Quinolinic acid, 2,3-pyridine dicarboxylic acid

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Acknowledgments

This work was supported by grants from CNPq, FAPESC, and FINEP-IBN(Net) # 01.06.0842-00 to C.I.Tasca. C. I. T. is recipient of CNPq productivity fellowship.

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Authors and Affiliations

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

    Tetsadê C. B. Piermartiri, Samuel Vandresen-Filho, Bruno de Araújo Herculano, Wagner C. Martins, Denis Dal’Agnolo, Ellen Stroeh, Cristiane Lima Carqueja & Carla I. Tasca

  2. Laboratório de Neurociências, Programa de Pós-graduação Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, 88806-000, Brazil

    Carina R. Boeck

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  1. Tetsadê C. B. Piermartiri
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  2. Samuel Vandresen-Filho
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  3. Bruno de Araújo Herculano
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  8. Carina R. Boeck
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  9. Carla I. Tasca
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Correspondence to Carla I. Tasca.

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Piermartiri, T.C.B., Vandresen-Filho, S., de Araújo Herculano, B. et al. Atorvastatin Prevents Hippocampal Cell Death due to Quinolinic Acid-Induced Seizures in Mice by Increasing Akt Phosphorylation and Glutamate Uptake. Neurotox Res 16, 106–115 (2009). https://doi.org/10.1007/s12640-009-9057-6

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