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Induction of antioxidative and antiapoptotic thioredoxin supports neuroprotective hypothesis of estrogen

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Abstract

The original neuroprotective hypothesis of estrogen was based on the gender difference in brain response to the ischemia-reperfusion injury. Additional clinical reports also suggest that estrogen may improve cognition in patients with Alzheimer disease. 17β-Estradiol is the most potent endogenous ligand of estrogen, which protects against neurodegeneration in both cell and animal models. Estrogen-mediated neuroprotection is probably mediated by both receptor-dependent and -independent mechanisms. Binding of estrogen such as 17β-estradiol to estrogen receptors (ERs) activates the homodimers of ER-DNA and its binding to estrogen response elements in the promoter region of genes such as neuronal nitric oxide synthase (NOS1) for regulating gene expression in target brain cells. In addition to the induction of NOS1, estrogen increases the expression of antiapoptotic protein such as bcl-2. Furthermore, our recent observations provide new molecular biologic and pharmacologic evidence suggesting that physiologic concentrations of 17β-estradiol (<10 nM) activate ERs (ERβ >ERα) and upregulate a cyclic guanosine 5′-monophosphate (cGMP)-dependent thioredoxin (Trx) and MnSOD expression following the induction of NOS1 in human brain-derived SH-SY5Y cells. We thus proposed that the estrogen-mediated gene induction of Trx plays a pivotal role in the promotion of neuroprotection because Trx is a multifunctional antioxidative and antiapoptotic protein. For managing progressive neurodegeneration such as Alzheimer dementia, our estrogen proposal of the signaling pathway of cGMP-dependent protein kinase (PKG) in mediating estrogen-induced cytoprotective genes thus fosters research and development of the new estrogen ligands devoid of female hormonal side effects such as carcinogenesis.

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Authors and Affiliations

  1. LCS, NIMH, NIH 10/3D-41, 20892-1264, Bethesda, MD

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

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  1. Chuang C. Chiueh
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  2. Sang Y. Lee
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  4. Dennis L. Murphy
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Correspondence to Chuang C. Chiueh.

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Chiueh, C.C., Lee, S.Y., Andoh, T. et al. Induction of antioxidative and antiapoptotic thioredoxin supports neuroprotective hypothesis of estrogen. Endocr 21, 27–31 (2003). https://doi.org/10.1385/ENDO:21:1:27

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  • DOI: https://doi.org/10.1385/ENDO:21:1:27

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