Psychologically Traumatic Oxidative Stress; A Comprehensive Review of Redox Mechanisms and Related Inflammatory Implications

Abstract

The organism’s energy requirements for homeostatic balance are covered by the redox mechanisms. Yet in case of psychologically traumatic stress, allostatic regulations activate both pro-oxidant and antioxidant molecules as well as respective components of the inflammatory system. Thus a new setpoint of dynamic interactions among redox elements is reached. Similarly, a multifaceted interplay between redox and inflammatory fields is activated with the mediation of major effector systems such as the immune system, Hypothalamic-Pituitary-Adrenal axis, kynurenine, and the glycaemic regulatory one. In case of sustained and/or intense traumatic stress the prophylactic antioxidant components are inadequate to provide the organism with neuroprotection finally culminating in Oxidative Stress and subsequently to cellular apoptosis. In parallel multiple inflammatory systems trigger and/or are triggered by the redox systems in tight fashion so that the causation sequence appears obscure. This exhaustive review aims at the comprehension of the interaction among components of the redox system as well as to the collection of disperse findings relative to the redox-inflammatory interplay in the context of traumatic stress so that new research strategies could be developed.

Introduction

The energy requirement for the brain is vast, with more than 20% of the total body’s consumption at resting state being spent mainly on the maintenance of resting and restoration of action potentials, signal transduction, neurotransmitters receptors regulation.¹ Ninety percent of the ATP required for the normal neuronal function is provided by mitochondria, and this supply highly depends on the aerobic oxidative phosphorylation through redox reactions.² The reliance of the brain on these redox reactions accounts for its vulnerability to toxic end byproducts such as the Reactive Oxygen Species (ROS) and the Reactive Nitrogen Species (RNS), which are generated in circumstances where the cellular energy demand elevates (i.e. stress, trauma, inflammation and ischemia).³

Life stress is known for its association with the pathological oxidative cascade, the so-called Oxidative Stress (OxS).⁴ The former can extend from minor stress, such as daily life hassles to Severe Life Stress (SLS). The SLS can happen as early as the beginning of life span and is described by the term of Early Life Stress (ELS). The ELS exerts a pathogenetic role in the generation of maladaptive allostatic load, thus reflecting links with inflammation in general as well as with psychiatric and organic disorders in particular.^5,6

As far as the association between the psychologically traumatic stress and OxS is concerned, there is substantial evidence furthering it. Namely, preclinical studies suggest that traumatic stress-related conditions (i.e. predator exposure, physical restraint, social isolation) tend to cause depletion of the antioxidants’ levels/function as well as increase in the OxS byproducts concentrations.^7,8 In addition, human studies on traumatic ELS provide evidence that Childhood Maltreatment (CM) can correlate with increased redox activity later in life as well as with increased OxS byproducts generation.^9,10 Similarly, studies on veterans showed that exposure to war-related trauma and/or PTSD diagnosis was associated with increased RNS and decreased antioxidants levels/activity.^11,12

Lately, findings from novel fields, such as Psycho-immunology and Psycho-neuro-endocrinology, have enriched the biological branch of Psychiatry. Expansion into the redox and metabolic fields has been added. The redox findings appear hitherto inconclusive regarding the formation of pathological neurobiological substrates in the trauma-related stress context. The redox cascade complexity relates to the multifaceted (i.e. pro- vs antioxidant) roles of several constituents as well as their equivocal action (i.e. constitutive vs toxic) depending on their concentration. What is more, far less is known about the redox cascade molecules’ causative association with the respective inflammatory ones, despite the fact that traumatic stress has been linked aetiologically with inflammation.¹³ Thus, the present review aims to collect 1. the disperse findings from preclinical and clinical studies on psychologically traumatic stress-related redox mechanisms, 2. the circumstantial findings indicative of the redox mechanisms’ interplay with inflammation within the traumatic stress context. In our attempt to increase the readers’ comprehension of the complex trauma-related redox mechanisms and the relevant inflammatory ones, we expanded on the literature on the redox-inflammation fields from basic research not necessarily restricted to the psychologically traumatic stress condition.

Neurobiological Mechanisms of Traumatic Stress-Related OxS

As said earlier, the bulk of the energy required for the neuronal function is provided by four mitochondrial respiratory chain complexes and ATP synthase, via electron donors, ending up in the generation of Nicotinamide Adenine Dinucleotide Phosphate (NADPH).¹⁴ The leakage of electrons along the respiratory chain within mitochondria and their subsequent reaction with oxygen, along with the supply of NADPH Oxidase (NOX) with molecular oxygen outside mitochondria,¹⁵ can both lead to the production of ROS [Superoxide anion (O^-;²), Hydrogen Peroxide (H₂O₂), Hydroxyl radical (OH)] and RNS [Peroxynitrite (ONOO^–), Nitric Oxide (NO)]. ROS/RNS are regulated to the optimum low levels by enzymatic [e.g., Superoxide Dismutase (SOD), Catalase (CAT), Glutathione Peroxidase (GSH-Px), Glutathione Reductase(GSH-Rd), Thioredoxin (TXN), Peroxiredoxin (PRX), Glyoxalase(GLO)] and non-enzymatic [e.g., Glutathione (GSH), Vitamins A, C, and E, Selenium, Homocysteine,Heme Oxygenase (HO)-1] antioxidants.^16,17 In case, ROS/RNS levels increase beyond the organism’s antioxidant systems repairing capacity, OxS arises,^16,18 mitochondria become dysfunctional and vital cellular constituents, such as proteins, lipids, DNA end up degraded, finally leading the cell to an apoptotic state.¹⁹ Yet the evidence regarding the (dys)function of the psychological trauma-activated redox machinery still appears inconclusive.

Role of NO in OxS

NO is produced in the brain by neurons, astrocytes, and endothelial cells. Its primary function relates to neurotransmission and neuronal protection through GSH increase.²⁰ These vital for survival functions are served when NO is synthesized in low concentrations by the neuronal isoform of NO Synthase (nNOS). Yet, in case of traumatic stress, hypoxia, inflammation, injury, where the energy demands increase, astrocytes take over, the inducible isoform of NOS (iNOS) along with Calcium (Ca) transients are upregulated and N-Methyl-D-Aspartate Receptors (NMDA-R) are activated. Subsequently, iNOS leads to NO tone dysregulation, NOX activation and consequently O^-;₂ generation, thus further causing ONOO^– production as well as GSH wear, collectively ending to mitochondrial damage.^20–22

Role of Central Glycaemic Dysregulation in OxS

Constitutively, the neuronal energy demand is served by astrocytes along with their integrated energy levels sensor, the 5-activated protein kinase (AMPK). The latter activates glycolytic cascades offering energy to adjacent neurons,²³ thus embodying the astrocyte-neuron lactate shuttle (ANLS) model.²⁴ Yet, in case of intense(traumatic)/prolonged stress, the neuronal (as opposed to the astrocytic) AMPK is activated²⁵ and catabolic processes, such as fatty acid oxidation, are further enhanced. High neuronal energy demand can be further complicated by an impaired brain insulin signalling²⁶ and a stress-related dysfunctional neuronal glucose transport.²⁷ In addition, in the context of high glycolytic demand, the glycolytic products react with amino groups in proteins, lipids, nucleic acids leading to the formation of Advanced Glycation End Products (AGEs). The accumulation of carbonyl precursors and lipoxidation products can culminate in carbonyl stress.²⁸ The latter further aggravates the OxS cascade via iNOS activation.²⁹

Role of HO-1 & 4-Hydroxynonenal (HNE) in OxS

Apart from NO, other redox components formed by lipid oxidation, such as 4-HNE and Oxidized-Low Density Lipoprotein (Ox-LDL) can serve as signaling compounds. In low constitutive concentrations, they, similar to NO, induce HO-1, TRX and GSH formation, possibly through the antioxidant bilirubin precursor’s generation and the induction of Nuclear factor erythroid 2-related factor 2- Antioxidant Response Element (Nrf2-ARE) gene expression, thus enhancing the cellular antioxidant capacity.^30–32 Yet, the effects of both 4-HNE and HO-1, appear dose-dependent; namely, a multiple-fold post-stress increase in HO-1 and/or 4-HNE tissue levels is thought to induce ROS toxic effects, senescence, apoptosis or cell death.^33–34

Role of Glutamate in OxS

Glutamate (GLU) represents one of the three GSH’s amino acids constituents, which participate in the redox cascade.³⁵ GLU’s effects appear in an equivocal fashion depending on its concentration. The constitutive GLU neurotransmission regulates the antioxidant defence in both neurons and astrocytes, via the transcriptional GSH-TRX/PRX increase as well as the NMDA-R-related Ca increase/Nrf-2 increased nuclear translocation, respectively.³⁶ Short-lasting acute stress requires phasic, yet within physiological limits, levels of GLU excitatory neurotransmission for a rapid, healthy, fight or flight reaction. However, in the case of long-lasting/ traumatic stress, the release of excessive amounts of GLU, combined with its decreased reuptake into astrocytes,³⁷ lead to downregulation and/or dysfunction of NMDA-R, culminating in excitotoxicity, via NOX expression upregulation. Consequently, ROS generation increases, further promoting GLU release as well as GSH decrease and NMDA-R impairment (oxidation) in a feed-forward fashion.³⁸ The latter GLU aberrations may phenotypically be expressed as cognitive deficits, behavioral disturbances and psychiatric disorders such as Depression, Psychosis, PTSD, all related to trauma.^39,40

Role of Ca in OxS

The intracellular Ca concentration constitutes another component, thought to relate closely to the redox process. Indeed, an initial low frequency synaptic (as opposed to the extra-synaptic) NMDA-R-regulated nuclear Ca signaling leads to activation of c-AMP Response Element Binding protein (CREB)(promoter of neuronal survival) and inhibition of Forkhead Box O (FOXO) (promoter of neuronal death), through potentiation of GSH, TRX, and PRX systems.⁴¹ Yet, an increased energy demand-induced intracellular Ca “overload”, such as in traumatic stress conditions, triggers iNOS activation, leading subsequently to excessive NO formation and finally to OxS.²⁰ In addition, a dysfunction of Ca regulators transfer molecules such as H₂O₂, and DISC1 at the endoplasmic reticulum-mitochondria contact sites,⁴² further aggravates Ca signalling and exerts detrimental effects on NMDA-R function, possibly via the decline of Ca/calmodulin-dependent protein kinase II activity, culminating in OxS-related excitotoxicity.^43,44

Role of N-Acetylaspartate (NAA) and Brain Derived Neurotrophic Factor (BDNF) in OxS

NAA appears to play an additional role in GLU-related OxS. It is a free amino acid produced by mitochondria during neuronal brain metabolism, consequently being used as a marker for neuronal viability⁴⁵ and a proxy for overall neuronal density.⁴⁶ Its depleted state possibly relates to GLU excitotoxicity,⁴⁰ though the causality directions remain far from being elucidated. Yet, the protective regulatory role of NAA in the context of trauma becomes more than evident as its reduced concentration has consistently been found across PTSD studies (for a meta-analysis, refer)⁴⁷. NAA’s depletion has been hypothesized that correlates with mRNA BDNF downregulation⁴⁸ and BDNF polymorphism (val66met),⁴⁹ possibly via the synaptic NMDA-R and nuclear Ca-CREB signalling cascade.⁵⁰ Herein, the reader is reminded of BDNF’s regulatory role in neuronal survival, growth, differentiation, and synapse formation; all thought to foster resiliency against PTSD.⁵¹

Role of Gamma-Aminobutyric Acid (GABA) in OxS

GABA is one of the major inhibitory neurotransmitters and it exerts its effects in multifaceted biphasic modes (tonic vs phasic, inhibitory vs stimulatory, physiological vs pathological) (for detailed review refer).⁵² In addition, GABAergic Parvalbumin Interneurons (PVI), are known for their high energy demand to support high-frequency neuronal synchronization, especially under sustained/intense (i.e., traumatic) stress conditions. This predisposition intensifies the involved redox processes,⁵³ and consequently exposes GABA_A-R to the detrimental effects of heightened ROS. Functionally speaking, pro-oxidants such as disulfide GSH (GSSG) (the oxidized GSH) inhibit the physiological inhibitory action of GABA_A-R, while antioxidants potentiate it.⁵² Moreover, upregulated NOX-induced ROS leads not only to extracellular GLU increase, GSH decrease and, NMDA-R impairment, but also to a dramatic decrease of both the inhibitory PVI and Glutamic Acid Decarboxylase (GAD)-67, the major GABA-synthesizing enzyme in the cortex.^38,54 Despite the fact that PVI functional aberration has been associated with ELS, such as prenatal maternal stress,⁵⁵ maternal separation⁵⁶ and social isolation,⁵⁷ the exact hypothesized interplay among trauma, OxS, GABA-R deficits, PVI dysfunction remains to be fully elucidated.

Role of Retinoid-related Orphan Receptor Alpha (RORA) in OxS

RORA system is expressed in the prefrontal cortex, hippocampus, and hypothalamus and is believed to be activated during OxS, thus protecting neurons through an increase of the antioxidant GSH-Px1 and PRX genes expression.⁵⁸ Recently, it has been shown that in psychotic patients the neurostructural impact of trauma may be regulated not only by GSH-Px activation but also through TXN/PRX mediated compensation,⁹ thus setting the RORA system as a candidate for future therapeutic interventions in trauma-related psychopathological fields.

Role of 12/15-Lipoxygenase in OxS

12/15-Lipoxygenase enzyme is another hypothesized component of the redox system. It is transcribed by ALOX-12 and ALOX-15 genes and has been proposed to account at least partly for OxS-related neurodegeneration, since it activates ROS generation and a subsequent attack against mitochondria in GSH depletion conditions.⁵⁹ Miller et al. (2015)⁶⁰ in their attempt to translate the 12/15-Lipoxygenase effect into the human PTSD paradigm, identified a novel ALOX-12 locus.

Role of GLO in OxS

GLO is an enzymatic antioxidant system, exerting detoxifying effects on the highly reactive dicarbonyl compound glycolytic byproduct Methylglyoxal (MGO), especially within astrocytes. MGO along with other AGEs, such as 3-Deoxyglycosone and Glyoxal, can be formed throughout different stages of the glycation process, i.e. the polyol pathway, the lipid peroxidation stage, other intermediate oxidative and non-oxidative glycation processes.⁶¹ The interaction of AGEs with their receptors (RAGE) induces signal transduction pathways, through the redox pathway, culminating in NOX-dependent OxS.^62,29 The latter exerts detrimental effects on GSH content, SOD activity (decrease) and Malondialdehyde (MDA), a lipid peroxidation byproduct, concentration (increase).²⁹ GLO’s role in the aforementioned cascade is the detoxification from pro-oxidant glycolytic products and GSH regeneration.⁶³ Expectedly, GLO’s brain levels and activity have been found downregulated in both preclinical studies on high Anxiety paradigms⁶⁴ and human studies on trauma-related psychiatric disorders.⁶⁵ In the latter (human) studies, the OxS-induced carbonyl byproducts levels were increased.

Role of Klotho Gene in OxS

Klotho gene is thought to exert aging suppressor effects, and its defective SNP variant exhibits close associations with PTSD severity.⁶⁶ Conversely, Klotho’s protective variant inhibits lipid oxidation, DNA damage as well as strengthens cellular antioxidant capacity through Manganese SOD or SOD-2 genes expression upregulation,⁶⁷ consequently increasing organism’s resilience to trauma-related (but not limited to) redox aberrations.

Role of Epigenetics in OxS

Findings from epigenetics have recently been added to the trauma-related redox puzzle. Namely, the alteration of acetylation of BDNF gene by H3 and H4 histones,⁶⁸ the direct modification of DNA methylation status,⁶⁹ the hydroxymethylation of Glucocorticoids-R (GCs-R) gene NR3C1,⁷⁰ and the acetylation of Lysine residue 27 of metabotropic GLU-R2,⁷¹ have been the proposed, via preclinical studies, epigenetic mechanisms acting as effectors within the wider redox contextl. Furthemore, clinical studies on holocaust survivors as well as on childhood abuse victims showed epigenetic changes of NR3C1 and FKBP-5 genes respectively, which regulate GCs-R function and hence indirectly redox mechanisms^72,73 (please refer to paragraph 3 for HPA axis-redox interplay literature).

Last but not least, parameters from other systemic domains such as HPA axis, immune system and, metabolism appear interconnected with redox mechanisms exerting multimodal effects ranging from survival to sensitization, neuro-progression, neuro-degeneration, apoptosis and death.⁷⁴ The directionality of the trauma-related redox-inflammation interaction is discussed in the following paragraph.

Trauma-Related OxS-Inflammation Interaction

Generally speaking it is known that inflammation and OxS, despite being closely interrelated, are not identical processes. The latter is considered the mechanism through which the former can generate cellular damage and eventually death. Yet, a closer look at the literature concerning the trauma-related OxS-inflammation interaction shows evidence supporting an equivocal directionality.

Evidence for Inflammation-Induced OxS Activation

Immune Factors

The inflammation-induced activation of OxS is furthered by basic research showing that inflammatory signaling stimulates the synthesis of large quantities of NO via NOS. NOS function is mediated by NOX and Nuclear Factor-kappa Beta (NF-kB) activation.^75,76 As previously said, among NOS enzymes, the iNOS isoform is notorious for its involvement in OxS state formation. Interestingly, it is induced by the pro-inflammatory cytokines Interferon (IFN)-γ and Tumor Necrosis Factor (TNF)-α.^18,76 Pro-inflammatory cytokines can be secreted in response to both local (brain included) and systemic inflammation, with the latter being associated with exposure to chronic/severe(traumatic)/repeated stress.^13,77 Indeed, recent preclinical and clinical studies provide evidence for an ELS associated/induced pro-inflammatory state, possibly via induction of NOD-like receptor protein (NLRP)-3 (i.e. inflammasome), activation of Toll-Like Receptors (TLR) as well as NF-kB and Mitogen-Activated Protein Kinase (MAPK).^78–80 Thus either/both the local (brain included via primed glial cells) and systemic inflammation, with their interplay being enhanced by a Blood Brain Barrier dysfunction/permeability increase,⁸¹ further activate not only the inflammatory signaling through activation of Phospholipase A-2, Cyclooxygenase (COX)-2 but also the NOX-mediated redox cascade.^19,82 Downstream of this sequence, Prostaglandins (PG) E2-induced GLU-dependent ROS is generated,^18,83 thus fostering the speculation about an inflammatory-driven OxS activation. Additional evidence supporting this direction comes from studies showing the Interleukin (IL)-6’s mediating role in ketamine-induced NOX upregulation⁸⁴ and the maternal immune challenge’s detrimental effects on GSH, vitamin E levels (decrease) as well as on OxS (increase).⁸⁵

Sympathetic and Parasympathetic Nervous Systems

From a neurobiological perspective, complementary systems, originating from the Central Nervous System (CNS) and exerting their actions peripherally, contribute to induction of pro-inflammatory state in the context of PTSD and other Fear and Anxiety Disorders.⁸⁶ Namely, over activity of the Sympathetic NS and decreased activity of the Parasympathetic NS, occurring in tandem with alterations of FKBP-5, a heat-shock protein 90 co-chaperone, can result in enhanced GCs-R sensitivity or GCs-R resistance, thus fostering the pro-inflammatory signalling while inhibiting the orchestration of an intact anti-inflammatory one.^87,88

HPA Axis

The HPA axis along with its downstream products, GCs, is another major system with regulatory role in stress and inflammation. GCs, at baseline, are known to exert inhibitory effects on both inflammatory molecules⁸⁹ and NOX-derived ROS production.⁹⁰ They also upregulate antioxidant defenses through genomic and non-genomic mechanisms.⁹¹ However, under conditions of chronic/repeated traumatic (but not limited to) stress, elevated levels of GCs have been suggested that finally induce an expression of pro-inflammatory cytokines within the brain (primarily microglia) in a two-step fashion. This mechanism involves the upregulation of NLRP-3 expression in microglia and other CNS innate immune cells, most likely via the TLR-4/NF-kB cascade.⁹² This immune regulatory potential of GCs along with their role in GLU induction and Ca upregulation , can equivocally increase mitochondrial respiration and oxidative phosphorylation, potentially escalating to OxS.^93,94 Evidence comes from preclinical studies showing that corticosterone injection within rats’ hippocampi was associated with increased OxS and reduced antioxidants activity.⁹⁵ Also,⁹⁶ in their meta-analysis of 19 studies on vertebrates concluded that OxS damage is analogous to the duration of GCs exposure. Herein, it is intentional to remind the reader of the HPA axis dysregulation etiopathogenetic hypothesis in the classical trauma-centred paradigm of PTSD.⁹⁷

Kynurenine Pathway

The kynurenine pathway is hypothesized to connect inflammation with OxS. Specifically, an initially generalized and subsequently localized in the brain increased pro-inflammatory signaling, associated with traumatic stress-related psychiatric nosology (i.e., Depression), can activate the Kynurenine 3-Monooxygenase (KMO) enzyme thus directing the tryptophan metabolic pathway towards Quinolinic Acid formation. The latter constitutes a potent GLU generator, resulting in NMDA-R overactivation and excitotoxicity as well as iNOS induction and intracellular NAD decrease, subsequently culminating in RNS generation and lipid peroxidation.^98,99

Evidence for OxS-Induced Inflammation

Having hitherto discussed the evidence supporting an inflammation-induced OxS direction, the reader should be minded of the piece of evidence furthering an opposite directionality; this being the OxS-induced inflammation.

Immune Factors

Indeed, as early as 1992 Schreck et al. showed that H₂O₂ could directly stimulate NF-kB. Later on,¹⁰⁰ with their laboratory work, showed evidence supporting free radicals’ activating effects on NF-kB inflammatory signaling cascade. Following the same line of evidence, studies on the inflammatogenic role of Ox-LDL demonstrated its immune-activating effect on JNK and IKKβ – NF-κB signaling cascades¹⁰¹ as well as on TLR, finally leading to an increase of TNF-α, IL-8 and Monocyte Chemoattractant Protein-1 levels.¹⁰² Similarly, a recent review on MDA and 4-HNE, extensively refers to their modulating (mostly inducing) effects on several transcription factors sensitive to stress such as Nrf2, Activator Protein (AP)-1, NF-kB, and Peroxisome-Proliferator-Activated Receptors (PPARs) as well as on immune signaling pathways such as MAPK (p38, Erk, and JNK), Akt, protein kinase B and C, receptor tyrosine kinases, and caspases.³³ The regulatory effect of redox cascade on inflammation is further evidenced by preclinical studies on cultured macrophage cells under hypoxic conditions¹⁰³ and on activated microglia cells via exposure to AGEs,²⁹ whereby pretreatment with ROS inhibitors such as N Acetyl Cysteine (NAC), led to the abrogation of their otherwise activating effect on NF-kB. Similarly, an immune regulatory action of antioxidants has been exhibited by,¹⁰⁴ studying the TRX’s effects on NF-kB, AP-1 and NLRP-3 inflammatory pathways.

NO and Nitrosylation

Another piece of evidence of an RNS-driven inflammatory process stems from the nNOS-derived NO inhibitory effect on NF-kB via iNOS downregulation. This regulatory mechanism prevails when NO is generated physiologically in a constitutive tonic fashion.^105,22 Indeed, the attachment of a NO group to a nucleophilic cysteine thiol anion in a process known as S-nitrosylation,¹⁰⁶ acts as a defensive shield to protect proteins against irreversible redox damage.¹⁰⁷ S-nitrosylation of cysteine residues in NF-kB as well as in p38/MAPK and other Janus kinases and/or tyrosine phosphatases, can respectively inhibit NF-kB gene transcription and regulate TLR activation, thus modulating immune response.^108,109 However, under chronic/intense stress conditions, a pathological (phasic) NO generation tone substitutes the physiological (tonic) one, followed by astrocytic iNOS upregulation, subsequently leading to hyper nitrosylation. The latter can culminate in irreversible functional and structural protein damage, as well as ONOO^- formation, NF-kB disinhibition and redox-based cellular loss of immune tolerance. ^105,110

Glycaemic Dysregulation

In addition to the above mentioned hyper nitrosylation cascade, repeated/chronic/intense (traumatic) stress can contribute to depleted cellular energy states. The latter, aggravated by a potential central insulin signalling deviation/glycaemic dysregulation, can lead to iNOS activation, mitochondrial O^-;₂ overproduction and neuronal AMPK overload. As a consequence, NF-kB may be disinhibited, thus embodying the combined hyper nitrosylation and glycaemic dysregulation inflammatogenic action.^105,111,22

HPA Axis

The principal action of the HPA axis to regulate inflammation is well known.⁸⁹ Hence, the evidence supporting a redox-modulated HPA axis function could reflect an indirect OxS-induced inflammatory regulation. Specifically, OxS may affect the HPA axis function via the attenuation of GCs-induced negative feedback,¹¹² the alteration of normal translocation of GCs-R to the nucleus,¹¹³ the increased stress-induced GLU toxicity,³⁹ the modulation of Protein Kinase C¹¹⁴ and the suboptimal Hypothalamic-Hypophyseal System hormone production via the formation of OxS-generated lipid peroxides-eElongation Factor 2 adducts.¹¹⁵ Not only does OxS affect the HPA axis function but also antioxidants (i.e. TXN) are involved in the GCs-R gene expression.¹¹⁶

Evidence for OxS-Inflammation Bidirectional/Parallel Interaction

Thirdly, a bidirectional type of link between oxidative and inflammatory arms could be the case in the OxS-inflammation context. In fact, this hypothesis may be the most plausible one.

Immune Factors

The tight interdependency of redox and inflammatory fields is furthered by evidence showing that a pro-inflammatory state can be orchestrated by either/both cytokines/NF-kB and/or ROS/GLU. ^33,117 Furthermore, components of both fields (i.e. redox-inflammatory) can activate AP-1, which in turn exerts its immunogenic and/or antioxidant effects, depending on the cell type, metabolic circumstances or DNA damage/repair capacity.¹¹⁸ Having spoken about DNA, Czarny et al. recently (2018)¹²⁶ reviewed the synergistic effects of mitochondrial ROS with NLRP3 on DNA integrity/repair capacity. Conversely viewing, there is evidence showing that both redox and inflammatory cascades can be activated by common stimuli.¹¹⁹ Furthermore,¹²⁰ have described a norm of reciprocity between the antioxidant gene Nrf2 and the pro-inflammatory genes inducing NF-kB.

TLR

Studies on TLR provide evidence favouring a redox-inflammatory arms concurrent involvement. The genetic ablation of TLR-4 led to a parallel inhibition of both pro-inflammatory (JNK, p-38 kinases, TNF-a levels) and redox signalling (iNOS formation, NO production). ^121,122 Additional findings from activation of complex anti inflammatory pathways, driven by the gamma isoform of PPAR, suggest repression of both inflammatory elements (proinflammatory cytokines, COX-2) and redox ones (iNOS).¹²³ Conversely viewing, reviews of laboratory studies have shown that activation of intact TLR-4 could lead to parallel activation of both NF-kB and ROS/RNS.^124,125 The self propagating and self amplifying properties of the TLR cycle, whereby the redox-derived Damage Associated Molecular Patterns such as MDA, activate the TLR complex, and subsequently the latter generates protein carbonyls, free radicals and the associated lipid peroxidation products (i.e. MDA, Ox-LDL, 4 HNE), is suggestive of the close interconnection between inflammatory and redox arms within a vicious cycle.¹¹⁰

HPA Axis

The aforementioned review by Czarny et al. (2018)¹²⁶ makes a particular reference to the HPA axis field, as a representative component of the general inflammatory system, and to its close interplay with the redox system. Similarly, a recent human gene expression study on Veterans with PTSD has supported an indirect HPA axis–OxS interplay by showing both differential expressions and significant associations of NR3C1 and TXN-Rd1 genes with PTSD.¹²⁷

Kynurenine Pathway

The kynurenine pathway and its consequent activation by the effects of both inflammatory and nitrosative regulators as well as its potential to function by itself as an effector to further induce both endogenous antioxidants depletion and free radicals generation, all constitute another neurobiological pathway evidencing the multileveled redox-inflammatory interaction.^128,129

Glycaemic Dysregulation

The evidence from the carbonyl stress and AGEs-RAGE complex formation-subsequent to amino groups glycation- fields, suggests a potential activation of both the inflammatory (COX-2, PGE2, IL-1, TNF-a upregulation, NF-kB translocation) and the redox arms (GSH content, SOD activity decrease, MDA increase, Nrf2, OH-1 alteration).²⁹

GLU

Intense(traumatic) and/or repeated stress are known to lead to excessive GLU generation.³⁷ This can trigger IL-6 production¹³⁰ upregulating both NOX expression and ROS generation. The latter further promotes GLU release as well as GSH decrease and NMDA-R impairment (oxidation) in a feed-forward fashion.³⁸ Thus, both redox-inflammatory cascades appear to be activated in parallel. The medication field provides additional evidence for parallel changes in the redox-inflammatory systems functions. In particular, the antibiotic minocycline and the antioxidant NAC were used separately in different studies. The findings suggest improvement in both inflammatory and redox indexes; namely, decrease of microglial activation, pro-inflammatory cytokines, pro-oxidative molecules, synaptic GLU release; increase of GSH levels, astrocytic cystine/glutamate antiporter activity; enhancement of NMDA-R function and myelination.^131,132 For a detailed review of the tightly synergistic interaction of redox dysregulation, neuroinflammation and NMDA-R hypofunction in the context of a trauma-related psychiatric disorder, please refer.⁵⁴

Klotho Gene

Klotho gene is known for its antioxidant-based anti-aging properties. Apart from the protective effects against lipid oxidation and DNA damage via Manganese SOD upregulation,⁶⁷ it suppresses the TNF-a-induced expression of Intracellular Adhesion Molecule-1, Vascular Cell Adhesion Molecule-1 as well as the NF-kB activation.¹³³ Thus, Klotho provides evidence for a parallel genetic regulation of both redox and inflammatory components, without hitherto having been feasible to discern the exact cause-effect sequence.

Discussion

The energy requirement of the brain to preserve its homeostasis is enormous.¹ The vast majority of this energy is provided by mitochondria, whose normal function depends on aerobic oxidative phosphorylation.² Yet, under conditions of psychological stress (the traumatic type included) the energy demand increases further and the allostatic regulations lead to redox activation and subsequently to OxS generation. Throughout this process the redox equilibrium is at risk and given the intensity and/or the chronicity of the imposed trauma, mitochondria will become dysfunctional and vital constituents of the cell such as protein, lipids, DNA will end up degraded. In parallel, the trauma-related type of stress (but not limited to it) can activate pillars of the inflammatory process such as the immune system and the HPA axis. In case of homeostatic mechanisms’ exhaustion, the allostatic load increases^134,135 with consequent effect on immune senescence acceleration, neuroprogression and neurodegeneration.^136,137 This current comprehensive review aims at the collection of findings in relation to the traumatic stress-induced redox machinery activation as well as at the synthesis of findings relative to the redox components’ interaction with effectors of the inflammatory system. All in all, it emerges that the inflammation-OxS interaction is highly complex. There is growing evidence favoring either cause-effect directionality between these fields. Thus, the OxS disentanglement from inflammation may be scientifically erroneous as most of the evidence suggests their tight interplay and their almost parallel activation in the context of stress. Besides, most of the reviewed studies did not principally aim at the causation, but rather the interaction per se no matter the directionality.

Apart from the above described complexity regarding both the modulating parameters of each one of the redox and the inflammatory systems and their in-between interplay, the reader should have in mind additional confounders. Namely, the small sample size, sociodemographics, lifestyle factors, differential type of the trauma, duration, frequency, timing of application as well as the subjectivity of retrospective reports on trauma and the inherent difficulty in translation of animal studies findings in human experience and in generalization/applicability of peripheral findings to CNS processes can all contribute to the liability of outcomes to errors.^138,139 Similarly, the antioxidants’ levels variation in brain topography as well as their potential asymmetry between levels and activity hamper the enlightenment on the redox puzzle. The cross-sectional design impedes the elucidation of the causality direction. It is, indeed, unclear from human studies whether high inflammation/OxS levels in victimized children reflect the effects of victimization per se rather than the genetic liability or vice versa.¹⁴⁰ Last but not least, the psychological and biological parameters (i.e. comorbid depression, anxiety, sleep disruption, other organic inflammatory disorders/states), common in trauma-related nosological entities, share common redox as well as inflammatory pathways,^{141,142,18,74,31,34,143} further obscuring the research field.

Conclusive Remarks

Oxidative mechanisms constitutively serve the organism’s homeostasis and survival. It is the intensity, chronicity, pattern, and nature of traumatic stress that may activate various neurobiological pathways, finally leading to loss of balance between not only the pro- and antioxidant components but also the pro- and antiinflammatory ones. The consequent redox imbalance, and the activation of related inflammatory cascades generate increased allostatic load, thus orchestrating the neurobiological substrate on to which both psychiatric and organic disorders develop. Yet, the exact interplay among redox parameters and between redox- inflammation arms in the context of trauma needs more research to be elucidated. We encourage researchers to take into consideration the many confounding parameters reviewed analytically in this review so that we increase our comprehension of the trauma-related neurobiological redox substrate and finally come closer to a breakthrough in therapy of several psychiatric and organic conditions.