Electroretinography, immunocytochemistry, quantitative histology, RT-PCR and Western blots were used to obtain data which showed that thioredoxin overexpression prevented loss of photoreceptors and retinal function. Analysis of signal pathways showed that thioredoxin up-regulated neurotrophic factors BDNF and GDNF and activated survival signaling pathways Akt, Ras/Raf1/ and the ERKs while inhibiting the ASK1/JNK apoptosis pathway.;In this study, we showed that Trx in the submicromolar range protects neuronal SH-SY5Y cells from apoptosis caused by serum deprivation or by MPP+. Using antisense oligonucleotides and reductase inhibitors, we showed that preconditioning treatment of SH-SY5Y cells with a non-lethal serum-free stress produces a hormesis effect mediated by the induction of Trx and leads to enhanced tolerance against oxidative stress and apoptosis induced by either serum deprivation or by MPP+.; Trx mRNA transcription was inhibited by H2O2 (300 µM), which could be reversed by the pre-administration of DHEA in various concentrations (0.1–100 nM). Western blot assay confirmed that protein level of Trx could be elevated by the pre-treatment of DHEA (10–100 nM) with the exposure of H2O2. Taken together, these data suggest that DHEA may be useful in treating age-related neurodegenerative diseases based on its up-regulating effects on an antioxidant and neuroprotective protein thioredoxin, a substrate in the Trx redox system.