The compensatory antioxidant response system with a focus on neuroprogressive disorders

Highlights

• Oxidative and nitrosative stress (O&NS) are observed in neuroprogressive disorders.

• Inflammation also contributes to the pathophysiology of neuroprogressive disorders.

• Several counter-regulatory mechanisms that may protect brain cells in the context of O&NS and neuroinflammation.

• The existence of a compensatory anti-oxidant response system is proposed.

Abstract

Major antioxidant responses to increased levels of inflammatory, oxidative and nitrosative stress (ONS) are detailed. In response to increasing levels of nitric oxide, S-nitrosylation of cysteine thiol groups leads to post-transcriptional modification of many cellular proteins and thereby regulates their activity and allows cellular adaptation to increased levels of ONS. S-nitrosylation inhibits the function of nuclear factor kappa-light-chain-enhancer of activated B cells, toll-like receptor-mediated signalling and the activity of several mitogen-activated protein kinases, while activating nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2 or NFE2L2); in turn, the redox-regulated activation of Nrf2 leads to increased levels and/or activity of key enzymes and transporter systems involved in the glutathione system. The Nrf2/Kelch-like ECH-associated protein-1 axis is associated with upregulation of NAD(P)H:quinone oxidoreductase 1, which in turn has anti-inflammatory effects. Increased Nrf2 transcriptional activity also leads to activation of haem oxygenase-1, which is associated with upregulation of bilirubin, biliverdin and biliverdin reductase as well as increased carbon monoxide signalling, anti-inflammatory and antioxidant activity. Associated transcriptional responses, which may be mediated by retrograde signalling owing to elevated hydrogen peroxide, include the unfolded protein response (UPR), mitohormesis and the mitochondrial UPR; the UPR also results from increasing levels of mitochondrial and cytosolic reactive oxygen species and reactive nitrogen species leading to nitrosylation, glutathionylation, oxidation and nitration of crucial cysteine and tyrosine causing protein misfolding and the development of endoplasmic reticulum stress. It is shown how these mechanisms co-operate in forming a co-ordinated rapid and prolonged compensatory antioxidant response system.

Introduction

Prolonged cellular oxidative and nitrosative stress (ONS), as evidenced by excessive levels of reactive oxygen species (ROS) and of reactive nitrogen species (RNS), such as nitric oxide (NO or, more strictly, NO^•) and peroxynitrite (ONOO⁻), can cause profound damage to proteins, lipids and DNA resulting in structural damage, the creation of self-antigens, dysfunction of signalling pathways, disruption of the epigenetic landscape and bioenergetic failure, ultimately resulting in apoptosis or necrosis (Morris et al., 2018e, Morris et al., 2018c). Importantly, a state of chronic ONS may arise as a result of overproduction of ROS and RNS and/or failure of cellular antioxidant defences (Morris and Maes, 2014; Paladino et al., 2018) and hence the optimal performance and timely activation of the latter is an indispensable element in cellular survival and unsurprisingly has been the subject of extensive research over several decades. Such research has revealed that the cellular antioxidant system consists of an array of enzymatic and non-enzymatic effector molecules operating under the influence of several transcription factors.

Antioxidant enzymes include superoxide dismutase (SOD) and catalase (CAT), which catalyse the dismutation of superoxide radicals into hydrogen peroxide, and hydrogen peroxide into water and oxygen, respectively (Sepasi Tehrani and Moosavi-Movahedi, 2018; Younus, 2018). Other glutathione (GSH) system enzymes such as glutathione peroxidase (GPx), glutathione transferase (GST) and glutathione reductase enable the operation of the GSH system and the clearance of electrophiles, lipid peroxides and xenobiotics (Allocati et al., 2018; Cardoso et al., 2017; Morris et al., 2014). Thioredoxin reductase is another pivotal enzyme as it enables the function of the thioredoxin system and in turn the actions of the peroxidase family which are the most abundant cytosolic antioxidant enzymes (Lee et al., 2013; Rhee, 2016). The non-enzymatic components of the cellular antioxidant defences include vitamin A, uric acid, vitamin E, lipoic acid, molecular hydrogen, carbon monoxide (CO), haem oxygenase-1 (HO-1), coenzyme Q₁₀ (CoQ₁₀ - the only natural membrane bound antioxidant), thioredoxin and GSH (Morris et al., 2014, Morris et al., 2013; Paladino et al., 2018; Parfenova et al., 2012).

The antioxidant defences are also under transcriptional and post-transcriptional control with the most important players being the activation and nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2 or NFE2L2), the activation of retrograde mitochondria to nuclear signalling pathways known as mitohormesis and S-nitrosylation of crucial structural and functional proteins (Miller et al., 2018; Morris et al., 2018a, Morris et al., 2018d).

The results of several published meta analyses confirm the presence of ONS in the brains and periphery of individuals suffering from major depressive disorder (MDD) (Black et al., 2015; Jiménez-Fernández et al., 2015; Liu et al., 2015). Individual authors have presented evidence of extensive lipid peroxidation as evidenced by high levels of malondialdehyde (MDA) and 4-hydroxy-2-trans-nonenal (HNE) whose levels correlate with the severity of symptoms indicating that this phenomenon has a causative role in the pathophysiology of the illness (Forlenza and Miller, 2006; Mazereeuw et al., 2015; Milaneschi et al., 2013; Yager et al., 2010). Other research teams have reported evidence of extensive DNA damage, elevated CAT and SOD levels, lowered levels of vitamin E and C and high levels of isoprostanes (Czarny et al., 2015; Forlenza and Miller, 2006; Gałecki et al., 2009; Maes et al., 2000). There is also evidence of nitrosative and oxidative mediated changes in the conformation of proteins rendering them immunogenic and hence acting as an additional source of elevated ROS and NO (Morris et al., 2015). Such evidence includes elevated levels of natural IgM autoantibodies directed at oxidatively modified epitopes and NO adducts (Maes et al., 2013, Maes et al., 2012, Maes et al., 2011). This evidence suggesting the presence of excessive levels of NO together with the presence of high levels of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide, which appears to extend to all body compartments, together with evidence of widespread dysregulation in NO signalling is consistent with the existence of hypernitrosylation in these patients (Nasyrova et al., 2015; Zhou et al., 2018). It is also noteworthy that researchers have reported a positive association between higher levels of NO and NO metabolites in patients with MDD who have committed suicide compared to patients with MDD who have not (Kim et al., 2006; Lee et al., 2006; Vargas et al., 2013).

The results of meta analyses confirm the presence of ONS in the periphery and post mortem brains of individuals with bipolar disorder (BPD) (Andreazza et al., 2008; Brown et al., 2014; Gawryluk et al., 2011). The most common observations are oxidative and peroxidative damage to proteins lipids, DNA and RNA, elevation of thiobarbituric acid reactive substances (TBARS), CAT/SOD imbalance, disturbance in the GSH system and elevated levels of NO (Andreazza et al., 2008; Brown et al., 2014; Gawryluk et al., 2011; Selek et al., 2008). Importantly the severity of stress correlates with the severity and or duration of the illness and is reduced following successful therapeutic intervention via the administration of lithium or valproate suggesting that increased levels of ROS and RNS and or compromised antioxidant defence systems plays a major role in the pathogenesis and or pathophysiology of BPD (Jornada et al., 2011; Kauer-Sant'Anna et al., 2009; Selek et al., 2008; Yumru et al., 2009). Once again the high levels of nNOS in the brains and periphery of BPD patients is consistent with the presence of hypernitrosylation (Oliveira et al., 2008). There is also evidence of a positive association between levels of NO metabolites, and markers of oxidative stress and suicide risk in individuals suffering from this illness (Vargas et al., 2013).

Recent meta-analyses have confirmed the presence of ONS in patients with schizophrenia even in patients during first episode and hence treatment naïve (Flatow et al., 2013; Fraguas et al., 2017; Sarandol et al., 2015). Importantly, levels of oxidative stress correlates with severity of positive symptoms in first episode patients (Martínez-Cengotitabengoa et al., 2012) and multiple lines of evidence suggest that increased levels of ROS and RNS and or failure of cellular antioxidant defences play a major causative role in the pathogenesis and pathophysiology of the illness (Bitanihirwe and Woo, 2011; O'Donnell et al., 2014; Wood, 2009). Individual studies report evidence of lipid peroxidation, protein carbonylation, DNA damage, disturbances in the GSH system, increased SOD, reduced serum antioxidant capacity (Bitanihirwe and Woo, 2011; O'Donnell et al., 2014; Wood, 2009). These markers of ONS have been observed in the in the brain and cerebrospinal fluid (CSF) and periphery in vivo and in the brain post mortem consistent with a state of hypernitrosylation (Akyol et al., 2002; Do et al., 2000; Prabakaran et al., 2007; Wang et al., 2009). It should be noted that while meta analyses consistently acknowledge the presence of ONS in schizophrenia there is considerable variance in the results of individual studies particularly those involving long term patients probably due at least in part to the confounding effects of anti-psychotics (Bošković et al., 2011). Increased ONS also appears to be a pathophysiological hallmark of schzophrenia but there is no evidence of a positive association between the extent of both parameters and increased suicide risk in this illness (Flatow et al., 2013).

Several authors have reported decreased Nrf-2 activity and nuclear translocation in brains of individuals with MDD and BPD (Hashimoto, 2018; Martín-Hernández et al., 2018; Zhang et al., 2018). There is also some suggestion that this might be true in the case of schizophrenia (Genc and Genc, 2009). Higher levels of kynurenine 3-monooxygenase (KMO) observed in patients with MDD and BPD with a resulting increase in quinolinic acid (QUIN) appear to restrict the activity of Nrf-2 (Parrott and O'Connor, 2015). Chronically upregulated KMO secondary to the presence of neuroinflammation is also increasingly recognised as a source of self-amplifying oxidative stress and mitochondrial dysfunction (Castellano-Gonzalez et al., 2019) and hence may inhibit the activity of Nrf-2 by the oxidation of functional cysteine residues residing within DJ-1 which acts as the “master activator” of the Nrf-2 system (Morris et al., 2018a). It should be noted that there is limited evidence of increased KMO activity in schizophrenia. However, the production of kynurenic acid (KYNA) appears to far outweigh the production of QUIN in the brains of individuals suffering from this disease (Morris et al., 2016). Furthermore, the high levels of ONS seen in the brains of patients with schizophrenia might well be sufficient to inactivate DJ-1 and thus downregulate Nrf-2 activity in these individuals. In any event decreased Nrf-2 activity may be a cause downregulated or dysregulated HO-1 expression in neuroprogressive illnesses as the activity of the OH-1/Bilirubin system is regulated the kelch-like ECH-associated protein-1 (KEAP1)/Nrf-2 system (Neis et al., 2018). The effect of reduced HO-1 activity has been emphasised in MDD where the extent of such reduction correlates with symptom severity and increases in markers of oxidative stress (Robaczewska et al., 2016). Compromised Nrf-2 activity can also exacerbate ROS mediated endoplasmic reticulum (ER) stress and compromise the ER stress mediated cellular survival systems as part of the unfolded protein response (Cullinan and Diehl, 2004; Digaleh et al., 2013) and the mitochondrial unfolded protein response (Morris et al., 2018b). This phenomenon is of clinical relevance as unopposed ER stress also appears to be an element driving the pathophysiology of neuroprogressive disorders (Muneer and Shamsher Khan, 2019). For example, ER stress leading to a compromised mitochondrial UPR (mtUPR) would appear to be one of the major drivers of neuronal apoptosis in schizophrenia (Drechsel and Patel, 2010). This phenomenon is also associated with the dysfunctional pattern of mitochondrial dynamics seen in individuals with this illness (Barksdale et al., 2014; Flippo and Strack, 2017). The presence of ER stress and activation of the UPR has also been reported in patients with schizophrenia and is thought to play a major role in the pathophysiology of this illness (Bengesser et al., 2016; Pfaffenseller et al., 2014). Perhaps predictably given the presence of ER stress there is also evidence of a dysfunctional mtUPR in BPD as revealed by compromised mitochondrial dynamics and an imbalance between mitochondrial fusion and fission protein levels (Kim et al., 2017b; Scaini et al., 2017). There is limited evidence of ER stress in patients with MDD although one team of authors have reported increased levels of proteins involved in the UPR post mortem (Ii Timberlake and Dwivedi, 2019).

Finally compromised Nrf-2 activity also exerts a detrimental effect on another branch of the cellular antioxidant defence network referred to as mitohormensis (Coleman et al., 2018).

The objective of this paper is to discuss the antioxidant responses instigated by activation of Nrf2, mitohormesis and S-nitrosylation and how they co-operate in forming a co-ordinated rapid and prolonged compensatory antioxidant response system in the face of increasing levels of RNS and ROS and how they may be bolstered by selective therapeutic interventions.