Biochemical integrity of the brain is vital for normal functioning of the central nervous system (CNS). One of the factors contributing to cerebral biochemical impairment is a chemical process called oxidative stress. Oxidative stress occurs upon excessive free radical production resulting from an insufficiency of the counteracting antioxidant response system. The brain, with its high oxygen consumption and lipid-rich content, is highly susceptible to oxidative stress. Therefore, oxidative stress–induced damage to the brain has a strong potential to negatively impact normal CNS functions. Although oxidative stress has historically been considered to be involved mainly in neurodegenerative disorders such as Alzheimer disease, Huntington disease, and Parkinson disease, its involvement in neuropsychiatric disorders, including anxiety disorders and depression, is beginning to be recognized. This review is a discussion of the relevance of cerebral oxidative stress to impairment of emotional and mental well-being.

https://jpet.aspetjournals.org/content/jpet/360/1/201.full.pdf

Oxidative Stress and the Central Nervous System.

https://isiarticles.com/bundles/Article/pre/pdf/29802.pdf

Is depression associated with increased oxidative stress? A systematic review and meta-analysis.

A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks. The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress. Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress. These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults. We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display. Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress. In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets. Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress. The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets. Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.

https://www.pnas.org/content/pnas/110/22/9130.full.pdf

Perineuronal nets protect fast-spiking interneurons against oxidative stress

Oxidative Stress in Schizophrenia: An Integrated Approach

Meta-analysis of oxidative stress in schizophrenia

Accruing data suggest that oxidative stress may be a factor underlying the pathophysiology of bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). Glutathione (GSH) is the major free radical scavenger in the brain. Diminished GSH levels elevate cellular vulnerability towards oxidative stress; characterized by accumulating reactive oxygen species. The aim of this study was to determine if mood disorders and SCZ are associated with abnormal GSH and its functionally related enzymes. Post-mortem prefrontal cortex from patients with BD, MDD, SCZ, and from non-psychiatric comparison controls were provided by the Stanley Foundation Neuropathology Consortium. Spectrophotometric analysis was utilized for the quantitative determination of GSH, while immunoblotting analyses were used to examine expression of glutamyl-cysteine ligase (GCL), GSH reductase (GR), and GSH peroxidase (GPx). We found that the levels of reduced, oxidized, and total GSH were significantly decreased in all psychiatric conditions compared to the control group. Although GCL and GR levels did not differ between groups, the levels of GPx were reduced in MDD and SCZ compared to control subjects. Since oxidative damage has been demonstrated in MDD, BD, and SCZ, our finding that GSH levels are reduced in post-mortem prefrontal cortex suggests that these patient groups may be more susceptible to oxidative stress.

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Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders.

Antioxidant defence systems have received increasing attention in the pathophysiology of psychiatric disorders, including: bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). Recently, we reported decreased glutathione (GSH) levels in post-mortem prefrontal cortex from patients with BD, MDD, and SCZ. To explore this further, we evaluated the levels of two glutathione S -transferase (GST) isoforms via immunoblotting: GST Pi and GST Mu. GST Pi levels were not affected in any of the patients groups vs. controls. GST Mu levels were significantly decreased in patients with MDD and SCZ but not BD. Compared to controls, GST Mu levels were not different in BD patients who had been treated with mood stabilizers at the time of death but were significantly lower in those not taking mood stabilizers at the time of death. These data suggest that GST Mu may be a target for mood stabilizers.

Prefrontal cortex glutathione S-transferase levels in patients with bipolar disorder, major depression and schizophrenia.

Signal transduction pathways and genes associated with cellular life and death have received much attention in bipolar disorder (BPD) and provide scientists with molecular targets for understanding the biological basis of BPD. In this chapter, we describe the signal transduction pathways involved in the molecular biology of BPD and the indications for the mechanisms of disease and treatment. We discuss the BPD literature with respect to the disease itself and the effects of mood stabilizer treatment on cellular receptors, including G-protein-coupled receptors, glutamate receptors, and tyrosine receptor kinase. We also discuss the intracellular alterations observed in BPD to second messenger systems, such as cyclic adenosine monophosphate (cAMP), protein kinase A, phosphoinositide pathways, glycogen synthase kinase-3, protein kinase B, Wnt, and arachidonic acid. We describe how receptor activation and modulation of second messengers occurs, and how transcription factors are activated and altered in this disease (e.g., the transcription factors ?-catenin, cAMP response element binding protein, heat shock transcription factor-1, and activator protein-1). Abnormalities in intracellular signal transduction pathways could generate a functional discrepancy in numerous neurotransmitter systems, which may explain the varied clinical symptoms observed in BPD. The influence of mood stabilizers on transcription factors may be important in connecting the regulation of gene expression to neuroplasticity and cellular resilience.

Jeremy W. Gawryluk

Papers

Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders.

Prefrontal cortex glutathione S-transferase levels in patients with bipolar disorder, major depression and schizophrenia.

Signal transduction pathways in the pathophysiology of bipolar disorder.