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

A number of studies have demonstrated that 17β-estradiol (E2) protects the brain from ischemia and yet the mechanism by which this hormone brings about its protective effect is unclear. Interestingly, like E2, 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 E2 treatment of cultured mammary cells increases SOD1 expression, we hypothesized that E2 might increase SOD1 expression in the brain and that this E2-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 E2, and that the E2-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, E2 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 E2 and deprived of oxygen and glucose, 8-oxoguanine levels are reduced. Taken together, these studies provide a critical link between E2 treatment, SOD1 expression, and neuroprotection and help to define a mechanism through which E2-mediated neuroprotection may be conferred.

• 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.