Simvastatin protects neurons from cytotoxicity by up-regulating Bcl-2 mRNA and protein

Leslie N. Johnson-Anuna, Gunter P. Eckert, Cornelia Franke, Urule Igbavboa, Walter E. Müller, W. Gibson Wood

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

Statins are most commonly prescribed to reduce hypercholesterolemia; however, recent studies have shown that statins have additional benefits, including neuroprotection. Until now, the mechanism underlying statin-induced neuroprotection has been poorly understood. Recent in vivo studies from our lab reported the novel finding that simvastatin increased expression levels of a gene encoding for a major cell survival protein, bcl-2 [Johnson-Anuna et al., J. Pharmacol. Exp. Ther.312 (2005) 786]. The purpose of the present experiments was to determine if simvastatin could protect neurons from excitotoxicity by altering Bcl-2 levels. Neurons were pre-treated with simvastatin and challenged with a compound known to reduce Bcl-2 levels and induce cell death. Simvastatin pre-treatment resulted in a significant reduction in cytotoxicity (lactate dehydrogenase release and caspase 3 activation) following challenge compared with unchallenged neurons. In addition, chronic simvastatin treatment significantly increased Bcl-2 mRNA and protein levels while challenge resulted in a significant reduction in Bcl-2 protein abundance. G3139, an antisense oligonucleotide directed against Bcl-2, abolished the protective effects of simvastatin and eliminated simvastatin-induced up-regulation of Bcl-2 protein. These findings suggest that neuroprotection by simvastatin is dependent on the drug's previously unexplored and important effect of up-regulating Bcl-2.

Original languageEnglish (US)
Pages (from-to)77-86
Number of pages10
JournalJournal of Neurochemistry
Volume101
Issue number1
DOIs
StatePublished - Apr 2007

Keywords

  • Alzheimer's disease
  • Bcl-2
  • G3139
  • Neuroprotection
  • Simvastatin
  • Statin

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