PMC

17β-estradiol prevents cortical neurons from cell death caused by H₂O₂ exposure. Dissociated cortical neurons were prepared from cerebral cortex of postnatal 2-day-old rats. At 6 days in vitro, 17β-estradiol was applied at indicated concentrations. Twenty-four hours later, H₂O₂ (final 50 μM) was added to induce cell death. Following an additional twelve-hour culture, cell survival was determined using an MTT (tetrazolium salt) assay. Data represent mean ± S.D. (n = 6). ***P < .001 versus control (no H₂O₂). ^### P < .001 versus no estradiol + H₂O₂.

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 [].

Mechanisms underlying oxidative stress-mediated neuronal apoptosis. Accumulation of oxidative stress is involved in the development/progression of neurodegenerative diseases. A number of events including excitotoxicity, mitochondrial dysfunction, Ca²⁺ overload, and endoplasmic reticulum stress are associated with excess reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation. High levels of ROS/RNS lead to oxidation of proteins, lipids, and DNA. Oxidized lipids induce damage of the ubiquitin-proteasome system (UPS). The UPS dysfunction and oxidation of proteins result in aggregation of proteins, recognized as a hallmark of several neurodegenerative diseases. Under oxidative stress, death signaling pathways (p53, mitogen-activated protein kinase (MAPK), etc.) are activated. Activation of p53 leads to induction of proapoptotic proteins such as Bax and p53-upregulated modulator of apoptosis (PUMA), followed by translocation of these proteins into mitochondria. Finally, mitochondrial cytochrome c is released, which then stimulates the activation of caspase 9/caspase 3. Alternatively, mitochondria secrete apoptosis-inducing factor (AIF), leading to caspase-independent apoptosis. As shown, recent studies suggest antioxidant effects of phytochemicals, vitamin E, estrogen, and neurotrophic factors including brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and hepatocyte growth factor (HGF), leading to increased preservation of neuronal function.