Protective Action of Neurotrophic Factors and Estrogen against Oxidative Stress-Mediated Neurodegeneration

Figure 3

17β-estradiol inhibits neuronal cell death under oxidative stress via reducing the series of events evoked by exposure to H₂O₂, including overactivation of the ERK signaling and overload of Ca²⁺. Upper: After H₂O₂ addition, marked phosphorylated (activated) ERK (pERK) and resultant increase in intracellular Ca²⁺ concentration were observed, resulting in cell death. Lower: Pretreatment with 17β-estradiol induced downregulation of ionotropic glutamate receptors via decreasing ERK activation, while also serving to decrease levels of Ca²⁺ influx triggered by H₂O₂. Such a decrease in glutamate receptor expression and intracellular Ca²⁺ was also confirmed in the presence of U0126, an inhibitor of ERK signaling. As expected, chronic 17β-estradiol reduced levels of pERK stimulated by H₂O₂. A blockade of glutamate receptors rescued cortical cells from H₂O₂-dependent death. Therefore, it is possible that 17β-estradiol promotes survival via suppressing glutamate receptor-mediated Ca²⁺ influx, due to downregulation of ionotropic glutamate receptors [120].