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

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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.

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