Atorvastatin prevents hippocampal cell death due to quinolinic acid-induced seizures in mice by increasing Akt phosphorylation and glutamate uptake.
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.
Piermartiri
Tetsadê C B
TC
Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC 88040-900, Brazil.
Vandresen-Filho
Samuel
S
de Araújo Herculano
Bruno
B
Martins
Wagner C
WC
Dal'agnolo
Denis
D
Stroeh
Ellen
E
Carqueja
Cristiane Lima
CL
Boeck
Carina R
CR
Tasca
Carla I
CI
D000704:Analysis of Variance; D000818:Animals; D000069059:Atorvastatin; D016923:Cell Death / Q000187:drug effects; D045424:Complex Mixtures / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D017378:Quinolinic Acid; D012640:Seizures / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D013778:Tetrazolium Salts; D013844:Thiazoles; D014316:Tritium / Q000378:metabolism
D045424:Complex Mixtures; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D013778:Tetrazolium Salts; D013844:Thiazoles; D014316:Tritium; C051709:glutamevit; D000069059:Atorvastatin; D051058:Oncogene Protein v-akt; C022616:thiazolyl blue; D017378:Quinolinic Acid