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- W2026366902 abstract "The cholesterol lowering drugs, statins, are neuroprotective. Bcl-2 protein is neuroprotective. Mechanistically connecting these two seemingly independent molecules is our recent discovery that simvastatin stimulated murine neuronal Bcl-2 gene expression and protein levels in vivo and in vitro. Simvastatin pretreatment resulted in a significant reduction in cytotoxicity (caspase-3 activation, LDH release) following a challenge with amyloid beta-protein compared with unchallenged neurons. G3139, an antisense oligonucleotide directed against Bcl-2, abolished the protective effects of simvastatin and eliminated simvastatin-induced upregulation of Bcl-2 protein. Effects of simvastatin on Bcl-2 stimulation occurred not only in mice but were replicated in another species, guinea pigs. We demonstrated upregulation of Bcl-2 in cerebral cortex of drug treated guinea pigs and dissociated brain cells from simvastatin treated guinea pigs were protected from neurotoxicity induced by sodium nitroprusside ex vivo. Simvastatin induced neuroprotection was reduced by inactivation of the Bcl-2 protein, similar to effects observed when Bcl-2 protein levels were reduced by G3139. Effects of simvastatin on Bcl-2 stimulation were independent of inhibition of HMG-CoA reductase and data indicated the potential role of endothelin-1 on statin-induced stimulation of Bcl-2. Here we provide novel evidence showing that simvastatin can stimulate expression of Bcl-2 both in vivo and in vitro. These innovative findings provide one of the potential mechanisms for the purported neuroprotective actions of statins. Discovering how statins are stimulating anti-apoptotic genes will offer new insight into the potential use of other cholesterol lowering and lipid related drugs which might have neuroprotective efficacy in specific neurodegenerative diseases and conditions outside of brain in which programmed cell death has been implicated. Supported in part by NIH grants AG-18357 and AG-23524." @default.
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- W2026366902 date "2009-08-01" @default.
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- W2026366902 title "Simvastatin protects neurons from cytotoxicity by up-regulating Bcl-2 mRNA and protein in vivo and in vitro" @default.
- W2026366902 doi "https://doi.org/10.1016/j.jns.2009.02.027" @default.
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