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J Biol Chem. 2002 Mar 22;277(12):9655-60. Epub 2001 Dec 19.

The roles of thioredoxin in protection against oxidative stress-induced apoptosis in SH-SY5Y cells.

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Laboratory of Biochemistry, National Heart, Lung, and Blood Institute and the Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland 20892, USA.


Using models of serum deprivation and 1-methyl-4-phenylpyridinium (MPP(+)), we investigated the mechanism by which thioredoxin (Trx) exerts its antiapoptotic protection in human neuroblastoma cells (SH-SY5Y) and preconditioning-induced neuroprotection. We showed that SH-SY5Y cells are highly sensitive to oxidative stress and responsive to both extracellularly administered and preconditioning-induced Trx. Serum deprivation and MPP(+) produced an elevation in the hydroxyl radicals, malondialdehyde and 4-hydroxy-2,3-nonenal (HNE), causing the cells to undergo mitochondria-mediated apoptosis. Trx in the submicromolar range blocked the observed apoptosis via a multiphasic protection mechanism that includes the suppression of cytochrome c release (most likely via the induction of Bcl-2), the inhibition of procaspase-9 and procaspase-3 activation, and the elevated level of Mn-SOD. The reduced form of Trx suppresses the serum-free-induced hydroxyl radicals, lipid peroxidation, and apoptosis, indicating that H(2)O(2) is removed by Trx peroxidase. The participation of Trx in preconditioning-induced neuroprotection is supported by the observation that inhibition of Trx synthesis with antisense oligonucleotides or of Trx reductase drastically reduced the hormesis effect. This effect of Trx-mediated hormesis against oxidative stress-induced apoptosis is striking. It induced a 30-fold shift in LD(50) in the MPP(+)-induced neurotoxicity.

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