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Increased secretion of adrenal glucocorticoids following physical and/or psychological stress exposure subsequently liberates glucose through gluconeogenesis, glycogenolysis, and lipolysis (Teague et al., 2007). Although increased metabolism alone generates ROS, glucocorticoids have demonstrated both direct and indirect modulatory roles in the onset of oxidative stress. Furthermore, both chronic oxidative stress and glucocorticoid exposure promote gliogenesis over neurogenesis in hippocampal neural stem cell progenitors and may be the direct result of accumulated mitochondrial oxidative stress (Wang et al., 2011; Chetty et al., 2014). Glial cells play an important but poorly understood role in the modulation of neuronal redox state. It has recently been shown that astrocyte-derived L-lactate potentiates NMDA receptor activity by modulating neuronal redox status (Yang et al., 2014). This neuron-glia interaction can also increase noradrenaline release from the locus ceruleus and hypothalamic ATP production (Cortes-Campos et al., 2011; Tang et al., 2014). Furthermore, Reyes et al. (2012) have demonstrated that neuronal NADPH oxidase-derived superoxide can traverse the extracellular space to modulate the redox state in neighboring neurons and astrocytes (Figure 1). However, in comparison to astrocytes, neurons are known to have relatively poor expression of endogenous antioxidants, making them highly susceptible to oxidative stress.
Glucocorticoids induce neuronal oxidative stress directly through enhanced mitochondrial respiration and oxidative phosphorylation. This was demonstrated clearly in a study by Du et al. (2009), showing that acute incubation of cortical neurons with corticosterone increased mitochondrial oxidation, membrane potential, and calcium-holding capacity in a dose and time-dependent manner (Figure 1). This was further clarified by You et al. (2009) using the oxidation product dichlorofluorescien as a ROS indicator in organotypic hippocampal slice cultures exposed to the synthetic glucocorticoid, dexamethasone, and the glucocorticoid receptor antagonist, RU486. The single and combination use of these compounds demonstrated that hippocampal neuronal death, marked by propidium iodide, was selectively induced by glucocorticoid exposure, while other steroid hormones had no effect. Acute incubation with dexamethasone increased the hippocampal oxidative status by approximately 200% in a dose dependent manner, an effect that was ameliorated with pre-treatment of RU486 or the ROS-scavenger, N-acetyl-L-cysteine. Furthermore, 4 h of dexamethasone incubation, induced the highest increase in oxidative status, with concurrent gene expression up-regulation of the ROS-producing enzyme NADPH-oxidase, while the antioxidant enzyme glutathione peroxidase was significantly down-regulated (You et al., 2009). This indicates that the increase in oxidative status is produced by a glucocorticoid-dependent and transcriptional increase in pro-oxidative drive, with concurrent inhibition of the antioxidant defense system, ultimately leading to increased neuronal cell death. Cortical and hippocampal neural cultures have also established that 24 h of glucocorticoid exposure increases basal ROS production and exacerbates the concomitant ROS produced by adriamycin redox cycling, which negatively affects survival in hippocampal neurons (McIntosh and Sapolsky, 1996).
This is supported by in vivo evidence that administration of exogenous corticosterone over a 14 day period increases hippocampal oxidative indicators including lipid peroxidation and protein carbonyls, while the enzymatic antioxidants SOD, catalase, and glutathione peroxidase activities are all decreased (Sato et al., 2010). This study, performed by Sato et al. (2010), also demonstrated increased apoptosis and decreased glucocorticoid receptor expression, a hallmark of chronically high glucocorticoids, in the hippocampus. Interestingly, this study also utilized a serum measurement of iron-induced superoxide formation in blood serum, establishing that this peripheral marker increased with chronic corticosterone administration. Further in vivo studies have shown that both corticosterone administration and restraint stress for 21 days induce an overall decrease in GSH in addition to SOD, catalase, glutathione transferase, and glutathione reductase activities in whole brain, liver, and heart tissues (Zafir and Banu, 2009).
This study, by Zafir and Banu (2009), also demonstrated that these treatments increased lipid peroxidation and oxidized protein carbonyl groups in the same tissues. However, in the brain, this overall oxidative increase is likely due to increases in specific subregions. For example, Mendez-Cuesta et al. (2011) used an acute immobilization stress to induce increased lipid peroxidation and decreased SOD activity in a highly oxidative-vulnerable region, the striatum. Interestingly, they found that the decrease in SOD activity was exclusively due to the mitochondrial isoform, manganese-SOD, while the copper, zinc-SOD showed little change. Furthermore, Lucca et al. (2009) used a chronic mild stress regime to show that SOD decreased and oxidized protein carbonyl groups increased in several cerebral regions including the striatum and hippocampus, while the cerebellum remained largely unaffected. We have also observed the induction of regional specific oxidative stress in the hippocampus but not the amygdala following an acute restraint stress, demonstrating that this process is not exclusive to chronic stress exposure (Spiers et al., 2013).
Recently, exposure to glucocorticoids or dexamethasone demonstrated inhibitory action over the Nrf2-dependent antioxidant pathway, causing an increase in hepatic and osteoblastic cell ROS, an effect attenuated by exogenous sulforaphane (Kratschmar et al., 2012; Lin et al., 2014).
Interestingly, ROS attenuate the glucocorticoid-induced down-regulation of pro-opiomelanocortin in pituitary corticotrophs, thereby promoting an increase in HPA axis activity via reduced negative feedback (Asaba et al., 2004). The expression and nuclear internalization of GR have also demonstrated susceptibility to highly pro-oxidative environments (Okamoto et al., 1999; Zhou et al., 2011). Using a cultured fluorescently labeled chimeric GR, Okamoto et al. (1999) demonstrated that nuclear translocation of GR following acute dexamethasone treatment is impaired in the presence of hydrogen peroxide.
This effect was reduced in the presence of exogenous antioxidants or following substitution of serine for a redox-sensitive cysteine residue. The dissociation of heat shock proteins from the cytosolic GR was also impaired in a pro-oxidative environment, indicating that there may be multiple redox regulatory roles involved in the cellular response to glucocorticoids (Okamoto et al., 1999 reviewed in Tanaka et al., 1999). These observations highlight that maintenance of a balanced redox state is critical for normal cellular homeostatic function within the neuroendocrine system.
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James Eckburg
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