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Activation of the hypothalamic-pituitary-adrenal stress axis induces cellular oxidative stress
Glucocorticoids released from the adrenal gland in response to stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis induce activity in the cellular reduction-oxidation (redox) system. The redox system is a ubiquitous chemical mechanism allowing the transfer of electrons between donor/acceptors and target molecules during oxidative phosphorylation while simultaneously maintaining the overall cellular environment in a reduced state. The objective of this review is to present an overview of the current literature discussing the link between HPA axis-derived glucocorticoids and increased oxidative stress, particularly focussing on the redox changes observed in the hippocampus following glucocorticoid exposure.
Introduction
The acute neuroendocrine response to adverse stress stimuli is characterized by the tripartite activation of the three stress axes including the autonomic sympathetic nervous system, the direct neural innervation of the adrenal cortex, and a cascade of hypothalamic hormonal messengers. Both the sympathetic system and the hypothalamic spinal adrenal axis utilize direct neural innervations of the adrenal medulla and cortex respectively to release adrenal catecholamines and prime the adrenal cortex for subsequent hormonal activation (Jansen et al., 1995; Buijs et al., 1999). This is initiated by neurosecretory neurons in the paraventricular nucleus of the hypothalamus, which release both corticotropin-releasing hormone and arginine vasopressin into the portal circulation of the pituitary gland. These two factors synergistically act on pituitary corticotroph cells to stimulate the release of the pro-opiomelanocortin peptide fragment, adrenocorticotropic hormone, into the circulation. Adrenocorticotropic hormone activates the melanocortin 2 receptor in the zona fasciculata of the adrenal cortex to initiate de novo synthesis and release of glucocorticoids, primarily cortisol in humans and corticosterone in rodents (Spiga et al., 2011). Together, this hormone cascade constitutes the hypothalamic-pituitary-adrenal (HPA) axis and is the primary system underlying stress physiology.
The physiological effects of corticosterone in the brain are canonically mediated through a near-ubiquitously expressed (with the exception of the suprachiasmatic nucleus of the hypothalamus) low affinity (KD ≈ 5.0 nM) glucocorticoid receptor (GR), and a regionally specific high affinity (KD ≈ 0.5 nM) mineralocorticoid receptor (MR) (Reul and de Kloet, 1985; Rose et al., 2012). Typically, these receptors reside in the cytoplasm heterocomplexed with heat shock proteins and immunophilins, which maintain the affinity of the hormone-binding domain (Pratt and Toft, 1997). The lipophilic steroid hormones are cell membrane permeable and bind these receptors, causing the dissociation of the chaperone proteins and translocation into the nucleus where the activated receptor complex forms GR and MR homo- or hetero-dimers that interact with specific glucocorticoid responsive elements in the promoter regions of genomic DNA. Both GR and MR elicit equivalent activity at glucocorticoid responsive elements and these interactions can result in transcriptional activation or repression of target genes depending on the cellular context (De Kloet et al., 1998).
Transcriptional repression can also be mediated through protein-protein interactions specifically with activated GR and transcription factors such as NFκ B, offering a possible mechanism through which delineation of receptor function occurs between the GR and MR (van der Burg and van der Saag, 1996; De Kloet et al., 1998). Termination of the HPA response to stress is mediated through multiple negative feedback loops and utilizes both genomic and non-genomic actions of the GR (Calogero et al., 1988; Groeneweg et al., 2011). In circulation, adrenal glucocorticoids reach peak total plasma concentrations approximately 30 min after activation of the HPA axis (Qian et al., 2011). At the cellular level, these hormones act in conjunction with catecholamines to facilitate glucose availability and increase metabolic rate, which in turn increases spontaneous production of free radicals (Teague et al., 2007; Du et al., 2009).
Free Radical Production
The process of aerobic metabolism utilizes oxygen to generate ATP in the mitochondrial electron transport chain (Halliwell and Gutteridge, 1989). During this process, 1–3% of all electrons “leak” from the electron transport chain to react with oxygen, generating superoxide radicals instead of being reduced to water (Liu et al., 2002; Muller et al., 2004; Cash et al., 2007). Although this occurs at both complex I and complex III of the electron transfer chain, the majority occurs at complex I where it is facilitated by succinate (Liu et al., 2002)
Most of the cellular superoxide is produced inside the inner mitochondrial membrane where the mitochondrial concentration of superoxide can be between 5–10 times that of the cytosol or nucleus (Cadenas and Davies, 2000). The remainder of mitochondrial superoxide is primarily formed by complex III on both sides of the mitochondrial membrane and by extra-mitochondrial flavoenzymes (Zimmerman and Granger, 1994; Cadenas and Sies, 1998; Brand et al., 2004). Superoxide then undergoes spontaneous or enzymatic dismutation via superoxide dismutase (SOD) to generate hydrogen peroxide. Although hydrogen peroxide is relatively stable, subsequent interactions with superoxide radicals and/or transition metals such as Fe2+ or Cu2+ induce production of the highly toxic hydroxyl radical by Haber-Weiss and Fenton chemistry.
This radical has been suggested to cause more damage to biological systems than any other reactive oxygen species (ROS) due to the extreme reactivity and very short in vivo half-life of ≈9–10 ms (Pastor et al., 2000).
Outside the mitochondrion, there are three major processes responsible for the production of free radicals, principally in the form of reactive oxygen and nitrogen species.
The first process involves the production of hydrogen peroxide as a by-product of fatty acid catabolism by peroxisomes (Ames et al., 1993; Wanders and Waterham, 2006). Although technically not a free radical, hydrogen peroxide is still classed as a ROS for its role in Fenton and Haber-Weiss chemistry (Cimen, 2008). Within the peroxisome, the majority of hydrogen peroxide is neutralized via canonical catalase activity or peroxidation to another catalase substrate (Wanders and Waterham, 2006; Valko et al., 2007).
However, under some conditions hydrogen peroxide can avoid degradation and escape the peroxisome, ultimately leading to cellular and nucleic acid damage (Kasai et al., 1989). The second process involves the reliance of the innate immune system on the ability of phagocytic cells such as neutrophils to engulf and digest foreign pathogens. Following the encapsulation of the foreign body into a phagosome, neutrophils increase their oxygen consumption specifically to supply the dormant NADPH-oxidase with molecular oxygen (Dahlgren and Karlsson, 1999).
This enzyme catalyzes the oxidation of NADPH to form two superoxide radicals which, together with reactive metabolites of superoxide including hydrogen peroxide and hypochlorite, constitutes the respiratory burst responsible for killing the pathogen (Ames et al., 1993; Dahlgren and Karlsson, 1999; Stadtman et al., 2007; Valko et al., 2007). Hayashi et al. (2008) have also demonstrated that NADPH-oxidase derived ROS can also be produced via a non-genomic mechanism following aldosterone administration in rat cardiac myocytes. The third process involves redox metals such as Fe2/3+, Cu2+, and Mn2+ which are essential for electron transfer in many enzymatic reactions, including the antioxidant enzymes of the oxidative cascade.
However, these transitional metal ions can also undergo reactions resulting in the production of hydroxyl radicals (Rovira et al., 2007).
Jereme G. Spiers*, Hsiao-Jou Cortina Chen, Conrad Sernia and Nickolas A. Lavidis
School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia
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Reposted by:
James Eckburg
