17β-Estradiol-mediated increase in Cu/Zn superoxide dismutase expression in the brain: A mechanism to protect neurons from ischemia

• Estrogen treatment increases expression of the oxidative response protein superoxide dismutase (SOD1) in cortical neurons. • Estrogen treatment decreases superoxide-induced damage to cellular proteins and DNA in cortical neurons. • Estrogen treatment also reduces ischemia-induced protein damage. •...

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Published in:The Journal of steroid biochemistry and molecular biology 2011-11, Vol.127 (3), p.382-389
Main Authors: Rao, Abhi K., Dietrich, Alicia K., Ziegler, Yvonne S., Nardulli, Ann M.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Brain - drug effects
Brain - enzymology
Brain - metabolism
Brain - pathology
DNA Damage
Estradiol - pharmacology
Estrogen
Estrogen receptor
Estrogen Receptor alpha - metabolism
Fundamental and applied biological sciences. Psychology
Immunohistochemistry
Ischemia
Ischemia - prevention & control
Mice
Mice, Inbred C57BL
Neurons - pathology
Neuroprotection
Oxidative Stress
Reactive oxygen species
Reactive Oxygen Species - metabolism
Superoxide dismutase
Superoxide Dismutase - metabolism
Vertebrates: endocrinology
Vertebrates: reproduction
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Summary:• Estrogen treatment increases expression of the oxidative response protein superoxide dismutase (SOD1) in cortical neurons. • Estrogen treatment decreases superoxide-induced damage to cellular proteins and DNA in cortical neurons. • Estrogen treatment also reduces ischemia-induced protein damage. • These studies identify a critical link between estrogen treatment, SOD1 expression, and neuroprotection. • We have uncovered a novel mechanism through which estrogen-mediated neuroprotection may be conferred. A number of studies have demonstrated that 17β-estradiol (E 2) protects the brain from ischemia and yet the mechanism by which this hormone brings about its protective effect is unclear. Interestingly, like E 2, overexpression of the oxidative stress response protein Cu/Zn superoxide dismutase (SOD1), which plays a critical role in regulating reactive oxygen species, also protects the brain from ischemia. Because we previously showed that E 2 treatment of cultured mammary cells increases SOD1 expression, we hypothesized that E 2 might increase SOD1 expression in the brain and that this E 2-mediated increase in SOD1 expression might help to protect the brain from ischemia. We now show that SOD1 is expressed in cortical neurons, that SOD1 expression is increased by exposure of brain slice cultures to E 2, and that the E 2-mediated increase in SOD1 expression is further augmented by exposure of brain slice cultures to increased superoxide levels or oxygen and glucose deprivation. Importantly, when cortical neurons are exposed to increased superoxide levels and markers of protein and DNA damage, nitrotyrosine and 8-oxoguanine, respectively, are measured, both protein and DNA damage are reduced. In fact, E 2 reduces nitrotyrosine and 8-oxoguanine levels in brain slice cultures regardless of whether they have or have not been exposed to increased superoxide levels. Likewise, when brain slice cultures are treated with E 2 and deprived of oxygen and glucose, 8-oxoguanine levels are reduced. Taken together, these studies provide a critical link between E 2 treatment, SOD1 expression, and neuroprotection and help to define a mechanism through which E 2-mediated neuroprotection may be conferred.
ISSN:0960-0760
1879-1220
DOI:10.1016/j.jsbmb.2011.06.008