17beta-estradiol activates ICI 182,780-sensitive estrogen receptors and cyclic GMP-dependent thioredoxin expression for neuroprotection.

Sang Y. Lee, Tsugunobu Andoh, Dennis L. Murphy, Chuang C. Chiueh

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81 Scopus citations


Clinical studies suggest that estrogen may improve cognition in Alzheimer's patients. Basic experiments demonstrate that 17beta-estradiol protects against neurodegeneration in both cell and animal models. In the present study, a human SH-SY5Y cell model was used to investigate molecular mechanisms underlying the receptor-mediated neuroprotection of physiological concentrations of 17beta-estradiol. 17beta-estradiol (<10 nM) concomitantly increased neuronal nitric oxide synthase (NOS1) expression and cell viability. 17beta-estradiol-induced neuroprotection was blocked by the receptor antagonist ICI 182,780, also prevented by inhibitors of NOS1 (7-nitroindazole), guanylyl cyclase (LY 83,583), and cGMP-dependent protein kinase (PKG) (Rp-8-pCPT-cGMPs). In addition to the expression of NOS1 and MnSOD, 17beta-estradiol increased the expression of the redox protein thioredoxin (Trx), which was blocked by the inhibition of either cGMP formation or PKG activity. The expression of heme oxygenase 2 and brain-derived neurotrophic factor was not altered. Estrogen receptor-enhanced cell viability against oxidative stress may be linked to Trx expression because the Trx reductase inhibitor, 5,5'-dithio-bis(2-nitrobenzoic acid) significantly reduced the cytoprotective effect of 17beta-estradiol. Furthermore, Trx (1 microM) inhibited lipid peroxidation, proapoptotic caspase-3, and cell death during oxidative stress caused by serum deprivation. We conclude that cGMP-dependent expression of Trx--the redox protein with potent antioxidative and antiapoptotic properties--may play a pivotal role in estrogen-induced neuroprotection.

Original languageEnglish (US)
Pages (from-to)947-948
Number of pages2
JournalThe FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Issue number8
StatePublished - May 2003

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics


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