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* Sanders-Brown Research Center on Aging, The ability of the protein synthesis inhibitor
cycloheximide (CHX) to prevent neuronal death in different paradigms has been interpreted to indicate that
the cell death process requires synthesis of "killer"
proteins. On the other hand, data indicate that neurotrophic factors protect neurons in the same death
paradigms by inducing expression of neuroprotective
gene products. We now provide evidence that in embryonic rat hippocampal cell cultures, CHX protects neurons against oxidative insults by a mechanism involving induction of neuroprotective gene products including the antiapoptotic gene bcl-2 and antioxidant
enzymes. Neuronal survival after exposure to
glutamate, FeSO4, and amyloid
Department of Physiology, § Department of Anatomy and Neurobiology,
University of Kentucky, Lexington, Kentucky 40536
-peptide was increased in cultures pretreated with CHX at concentrations of 50-500 nM; higher and lower concentrations
were ineffective. Neuroprotective concentrations of
CHX caused only a moderate (20-40%) reduction in
overall protein synthesis, and induced an increase in
c-fos, c-jun, and bcl-2 mRNAs and protein levels as determined by reverse transcription-PCR analysis and
immunocytochemistry, respectively. At neuroprotective CHX concentrations, levels of c-fos heteronuclear
RNA increased in parallel with c-fos mRNA, indicating
that CHX acts by inducing transcription. Neuroprotective concentrations of CHX suppressed accumulation
of H2O2 induced by FeSO4, suggesting activation of antioxidant pathways. Treatment of cultures with an antisense oligodeoxynucleotide directed against bcl-2
mRNA decreased Bcl-2 protein levels and significantly
reduced the neuroprotective action of CHX, suggesting
that induction of Bcl-2 expression was mechanistically involved in the neuroprotective actions of CHX. In addition, activity levels of the antioxidant enzymes Cu/
Zn-superoxide dismutase, Mn-superoxide dismutase,
and catalase were significantly increased in cultures exposed to neuroprotective levels of CHX. Our data suggest that low concentrations of CHX can promote neuron survival by inducing increased levels of gene
products that function in antioxidant pathways, a neuroprotective mechanism similar to that used by neurotrophic factors.
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