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FASEB J. 2003 May;17(8):947-8. Epub 2003 Mar 5.

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

Author information

1
Department of Neuroscience and Anatomy, Penn State University College of Medicine, M.S. Hershey Medical Center, Hershey, Pennsylvania, USA.

Abstract

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.

PMID:
12626428
DOI:
10.1096/fj.02-0807fje
[Indexed for MEDLINE]

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