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

Abstract

Oxidative stress is involved in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Low levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important for maintenance of neuronal function, though elevated levels lead to neuronal cell death. A complex series of events including excitotoxicity, Ca(2+) overload, and mitochondrial dysfunction contributes to oxidative stress-mediated neurodegeneration. As expected, many antioxidants like phytochemicals and vitamins are known to reduce oxidative toxicity. Additionally, growing evidence indicates that neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and estrogens significantly prevent neuronal damage caused by oxidative stress. Here, we review and discuss recent studies addressing the protective mechanisms of neurotrophic factors and estrogen within this system.

Figure 1

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.

Figure 2

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.

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].