The accumulation of unfolded proteins in the endoplasmic reticulum (ER) represents a cellular stress induced by multiple stimuli and pathological conditions. These include hypoxia, oxidative injury, high-fat diet, hypoglycaemia, protein inclusion bodies and viral infection. ER stress triggers an evolutionarily conserved series of signal-transduction events, which constitutes the unfolded protein response. These signalling events aim to ameliorate the accumulation of unfolded proteins in the ER; however, when these events are severe or protracted they can induce cell death. With the increasing recognition of an association between ER stress and human diseases, and with the improved understanding of the diverse underlying molecular mechanisms, novel targets for drug discovery and new strategies for therapeutic intervention are beginning to emerge.

Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities

Proteins synthesized in the endoplasmic reticulum (ER) are properly folded with the assistance of ER chaperones. Malfolded proteins are disposed of by ER-associated protein degradation (ERAD). When the amount of unfolded protein exceeds the folding capacity of the ER, human cells activate a defense mechanism called the ER stress response, which induces expression of ER chaperones and ERAD components and transiently attenuates protein synthesis to decrease the burden on the ER. It has been revealed that three independent response pathways separately regulate induction of the expression of chaperones, ERAD components, and translational attenuation. A malfunction of the ER stress response caused by aging, genetic mutations, or environmental factors can result in various diseases such as diabetes, inflammation, and neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and bipolar disorder, which are collectively known as 'conformational diseases'. In this review, I will summarize recent progress in this field. Molecules that regulate the ER stress response would be potential candidates for drug targets in various conformational diseases.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1742-4658.2007.05639.x

ER stress and diseases

http://dosequis.colorado.edu/Courses/BrainWeb/papers/BP2.pdf

Pathways underlying neuroprogression in bipolar disorder : focus on inflammation, oxidative stress and neurotrophic factors

The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder. The third version is based explicitly on the available evidence and presented, like previous Clinical Practice Guidelines, as recommendations to aid clinical decision making for practitioners: it may also serve as a source of information for patients and carers, and assist audit. The recommendations are presented together with a more detailed review of the corresponding evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from these participants. The best evidence from randomized controlled trials and, where available, observational studies employing quasi-experimental designs was used to evaluate treatment options. The strength of recommendations has been described using the GRADE approach. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment. The use of medication is integrated with a coherent approach to psychoeducation and behaviour change.

/pdf/evidence-based-guidelines-for-treating-bipolar-disorder-4spyuaidig.pdf

Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology

This paper reviews the body of evidence that major depression is accompanied by a decreased antioxidant status and by induction of oxidative and nitrosative (ION and increased 8-hydroxy-2-deoxyguanosine, indicating oxidative DNA damage. There is also evidence in major depression, that ON and increased IgM-mediated immune responses against membrane fatty acids, like phosphatidyl inositol (Pi); oleic, palmitic, and myristic acid; and NO modified amino-acids, e.g. NO-tyrosine, NO-tryptophan and NO-arginine; and NO-albumin. There is a significant association between depression and polymorphisms in O&NS genes, like manganese superoxide dismutase, catalase, and myeloperoxidase. Animal models of depression very consistently show lowered antioxidant defences and activated O&NS pathways in the peripheral blood and the brain. In animal models of depression, antidepressants consistently increase lowered antioxidant levels and normalize the damage caused by O&NS processes. Antioxidants, such as N-acetyl-cysteine, compounds that mimic GPX activity, and zinc exhibit antidepressive effects. This paper reviews the pathways by which lowered antioxidants and O&NS may contribute to depression, and the (neuro)degenerative processes that accompany that illness. It is concluded that aberrations in O&NS pathways are--together with the inflammatory processes--key components of depression. All in all, the results suggest that depression belongs to the spectrum of (neuro)degenerative disorders.

A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness.

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.

/pdf/decreased-levels-of-glutathione-the-major-brain-antioxidant-3cwrpop3hd.pdf

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

Context Accumulating evidence suggests that mitochondrial dysfunction and oxidative stress contribute to the pathogenesis of bipolar disorder and schizophrenia. It remains unclear whether mitochondrial dysfunction, specifically complex I impairment, is associated with increased oxidative damage and, if so, whether this relationship is specific to bipolar disorder. Objective To evaluate whether decreased levels of the electron transport chain complex I subunit NDUFS7 are associated with complex I activity and increased oxidative damage to mitochondrial proteins in the prefrontal cortex of patients with bipolar disorder, schizophrenia, or major depressive disorder. Design Postmortem prefrontal cortex from patients and controls were assessed using immunoblotting, spectrophotometric, competitive enzyme immunoassay to identify group differences in expression and activity of complex I, and in oxidative damage in mitochondria. Setting University of British Columbia, Vancouver, Canada. Patients Forty-five patients with a psychiatric disorder (15 each with bipolar disorder, schizophrenia, and major depressive disorder) and 15 nonpsychiatric control subjects were studied. Main Outcome Measures Oxidative damage to proteins and mitochondrial complex I activity. Results Levels of NDUFS7 and complex I activity were decreased significantly in patients with bipolar disorder but were unchanged in those with depression and schizophrenia compared with controls. Protein oxidation, as measured by protein carbonylation, was increased significantly in the bipolar group but not in the depressed or schizophrenic groups compared with controls. We observed increased levels of 3-nitrotyrosine in the bipolar disorder and schizophrenia groups. Conclusions Impairment of complex I may be associated with increased protein oxidation and nitration in the prefrontal cortex of patients with bipolar disorder. Therefore, complex I activity and mitochondrial dysfunction may be potential therapeutic targets for bipolar disorder.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/210694/yoa90086_360_368.pdf

Mitochondrial complex I activity and oxidative damage to mitochondrial proteins in the prefrontal cortex of patients with bipolar disorder.

Background: Recent studies indicate the presence of mitochondrial dysfunction in brains of subjects with bipolar disorder (BD). Because the mitochondrial electron transport chain is a major source for production of reactive oxygen species that cause oxidative stress, we sought to determine in the present study if BD is associated with oxidative stress.

Methods:  Postmortem anterior cingulate brain sections from subjects with BD, major depressive disorder (MDD), or schizophrenia, and from nonpsychiatric, non-neurologic comparison controls were generously provided by the Stanley Foundation Neuropathology Consortium. Oxidative stress was determined by analyzing 4-hydroxynonenal (4-HNE), a major product of lipid peroxidation. The level of 4-HNE was determined by measuring 4-HNE protein adducts using immunohistochemistry.

Results:  We found that 4-HNE levels were significantly increased by 59% in BD subjects and by 47% in schizophrenia subjects, but not in MDD subjects, when compared with controls. Levels of 4-HNE were negatively correlated with pH in all 60 subjects. When pH was used as covariate, 4-HNE levels were still significantly increased in BD subjects when compared with controls. Further, 4-HNE levels were significantly correlated with pH values only in BD subjects, but not in MDD, schizophrenia, or control subjects.

Conclusions:  Oxidative damage in the brain may contribute in part to the pathological process in BD and schizophrenia. This finding also suggests antioxidative stress as a probable alternative approach to the pharmacological treatment of these psychiatric disorders.

Li Shao

Papers

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

Mitochondrial complex I activity and oxidative damage to mitochondrial proteins in the prefrontal cortex of patients with bipolar disorder.

Increased oxidative stress in the anterior cingulate cortex of subjects with bipolar disorder and schizophrenia.

Chronic Treatment with Mood Stabilizers Lithium and Valproate Prevents Excitotoxicity by Inhibiting Oxidative Stress in Rat Cerebral Cortical Cells

Role of glutathione in neuroprotective effects of mood stabilizing drugs lithium and valproate.