Antioxidants, redox signaling, and pathophysiology in schizophrenia: an integrative view.
TL;DR: The body of evidence reviewed herein provides a theoretical rationale for the development of novel treatment approaches and burgeoning evidence indicating a link among oxidative stress, membrane defects, immune dysfunction, and multineurotransmitter pathologies in SZ.
Abstract: Schizophrenia (SZ) is a brain disorder that has been intensively studied for over a century; yet, its etiology and multifactorial pathophysiology remain a puzzle. However, significant advances have been made in identifying numerous abnormalities in key biochemical systems. One among these is the antioxidant defense system (AODS) and redox signaling. This review summarizes the findings to date in human studies. The evidence can be broadly clustered into three major themes: perturbations in AODS, relationships between AODS alterations and other systems (i.e., membrane structure, immune function, and neurotransmission), and clinical implications. These domains of AODS have been examined in samples from both the central nervous system and peripheral tissues. Findings in patients with SZ include decreased nonenzymatic antioxidants, increased lipid peroxides and nitric oxides, and homeostatic imbalance of purine catabolism. Reductions of plasma antioxidant capacity are seen in patients with chronic illness as well as early in the course of SZ. Notably, these data indicate that many AODS alterations are independent of treatment effects. Moreover, there is burgeoning evidence indicating a link among oxidative stress, membrane defects, immune dysfunction, and multineurotransmitter pathologies in SZ. Finally, the body of evidence reviewed herein provides a theoretical rationale for the development of novel treatment approaches. Antioxid. Redox Signal. 15, 2011–2035.
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TL;DR: The main objective of this review is to examine the role of endogenous reactive oxygen/nitrogen species (ROS) in the aging process and proposes the "redox stress hypothesis", which proposes that aging-associated functional losses are primarily caused by a progressive pro-oxidizing shift in the redox state of the cells, which leads to the overoxidation of redox-sensitive protein thiols and the consequent disruption of theredox-regulated signaling mechanisms.
425 citations
TL;DR: Using mice carrying a genetic redox imbalance, it is demonstrated 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.
Abstract: 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.
398 citations
Cites background from "Antioxidants, redox signaling, and ..."
...Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16, 17)....
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French Institute of Health and Medical Research1, University of California, Los Angeles2, University of California, San Diego3, King's College London4, Charité5, University of Illinois at Chicago6, University of Freiburg7, Utrecht University8, University of Pittsburgh9, Medical Research Council10, Centre national de la recherche scientifique11, Heidelberg University12, University of Glasgow13, Johns Hopkins University14, Yale University15, University of Miami16
TL;DR: A broad-based consideration of the challenges and opportunities inherent in efforts to alter the course of schizophrenia is provided, including 'hybrid' strategies that both relieve presenting symptoms and reduce the risk of transition to schizophrenia or another psychiatric disorder.
Abstract: Despite a lack of recent progress in the treatment of schizophrenia, our understanding of its genetic and environmental causes has considerably improved, and their relationship to aberrant patterns of neurodevelopment has become clearer. This raises the possibility that 'disease-modifying' strategies could alter the course to — and of — this debilitating disorder, rather than simply alleviating symptoms. A promising window for course-altering intervention is around the time of the first episode of psychosis, especially in young people at risk of transition to schizophrenia. Indeed, studies performed in both individuals at risk of developing schizophrenia and rodent models for schizophrenia suggest that pre-diagnostic pharmacotherapy and psychosocial or cognitive-behavioural interventions can delay or moderate the emergence of psychosis. Of particular interest are 'hybrid' strategies that both relieve presenting symptoms and reduce the risk of transition to schizophrenia or another psychiatric disorder. This Review aims to provide a broad-based consideration of the challenges and opportunities inherent in efforts to alter the course of schizophrenia.
397 citations
TL;DR: Oxidative stress abnormalities in FEP suggest an effect that might be independent of antipsychotic medications, and oxidative stress might serve as a potential biomarker in the etiopathophysiology and clinical course of schizophrenia.
384 citations
TL;DR: The basic molecular mechanisms of free radical metabolism, the impaired antioxidant defense system and membrane pathology in schizophrenia, their interrelationships with the characteristic clinical symptoms and the implications for antipsychotic treatments are summarized.
Abstract: The etiopathogenic mechanisms of schizophrenia are to date unknown, although several hypotheses have been suggested. Accumulating evidence suggests that excessive free radical production or oxidative stress may be involved in the pathophysiology of schizophrenia as evidenced by increased production of reactive oxygen or decreased antioxidant protection in schizophrenic patients. This review aims to summarize the basic molecular mechanisms of free radical metabolism, the impaired antioxidant defense system and membrane pathology in schizophrenia, their interrelationships with the characteristic clinical symptoms and the implications for antipsychotic treatments. In schizophrenia, there is accumulating evidence of altered antioxidant enzyme activities and increased levels of lipid peroxidation, as well as altered levels of plasma antioxidants. Moreover, free radical-mediated abnormalities may contribute to specific aspects of schizophrenic symptomatology and complications of its treatment with antipsychotic drugs, as well as the development of tardive dyskinesia (TD). Finally, the potential therapeutic strategies implicated by the accumulating data on oxidative stress mechanisms for the treatment of schizophrenia are discussed.
304 citations
References
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Journal Article•
15,827 citations
"Antioxidants, redox signaling, and ..." refers background in this paper
...However, NO is a unique second messenger molecule that mediates a number of cellular functions, including neurotransmission, neurotoxicity and plasticity, vasodilation, regulation of blood flow, and inhibition of platelet aggregation (22, 105, 174)....
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TL;DR: There is growing evidence that aging involves, in addition, progressive changes in free radical-mediated regulatory processes that result in altered gene expression.
Abstract: At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...
9,131 citations
"Antioxidants, redox signaling, and ..." refers background in this paper
...The inflammatory response is intimately connected with oxidative stress via free radical generation (57)....
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TL;DR: Current evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion, which is presented in detail in this review.
Abstract: The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.
5,514 citations
"Antioxidants, redox signaling, and ..." refers background in this paper
...UA can also neutralize peroxynitrite (125) and hydroxyl radicals (12, 46) to inhibit protein nitration (192) and lipid peroxidation (181), respectively....
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TL;DR: It is demonstrated that NO can be synthesized from L-arginine by porcine aortic endothelial cells in culture and the strict substrate specificity of this reaction suggests that L- arginine is the precursor for NO synthesis in vascular endothelium cells.
Abstract: Nitric oxide (NO) released by vascular endothelial cells accounts for the relaxation of strips of vascular tissue1 and for the inhibition of platelet aggregation2 and platelet adhesion3 attributed to endothelium-derived relaxing factor4. We now demonstrate that NO can be synthesized from L-arginine by porcine aortic endothelial cells in culture. Nitric oxide was detected by bioassay5, chemiluminescence1 or by mass spectrometry. Release of NO from the endothelial cells induced by bradykinin and the calcium ionophore A23187 was reversibly enhanced by infusions of L-arginine and L-citrulline, but not D-arginine or other close structural analogues. Mass spectrometry studies using 15N-labelled L-arginine indicated that this enhancement was due to the formation of NO from the terminal guanidino nitrogen atom(s) of L-arginine. The strict substrate specificity of this reaction suggests that L-arginine is the precursor for NO synthesis in vascular endothelial cells.
4,803 citations
"Antioxidants, redox signaling, and ..." refers background in this paper
...Later, Xing et al. (277) demonstrated decreased constitutive NOS activity but normal nNOS protein in the cerebral cortex of SZ patients....
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...In human brain, nNOS is primarily responsible for the synthesis of NO (18)....
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...There are three isoforms of the NOS family: neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) (70)....
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...Changes in cellular expression of brain-associated NOS/ nicotinamide adenine dinucleotide phosphate diaphorase have been variable in SZ (2)....
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...NO is the product of a five-electron oxidation of the amino acid L-arginine by nitric oxide synthase (NOS) (195)....
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TL;DR: Two broad mechanisms--oxidative stress and excessive activation of glutamate receptors--are converging and represent sequential as well as interacting processes that provide a final common pathway for cell vulnerability in the brain.
Abstract: There is an increasing amount of experimental evidence that oxidative stress is a causal, or at least an ancillary, factor in the neuropathology of several adult neurodegenerative disorders, as well as in stroke, trauma, and seizures. At the same time, excessive or persistent activation of glutamate-gated ion channels may cause neuronal degeneration in these same conditions. Glutamate and related acidic amino acids are thought to be the major excitatory neurotransmitters in brain and may be utilized by 40 percent of the synapses. Thus, two broad mechanisms--oxidative stress and excessive activation of glutamate receptors--are converging and represent sequential as well as interacting processes that provide a final common pathway for cell vulnerability in the brain. The broad distribution in brain of the processes regulating oxidative stress and mediating glutamatergic neurotransmission may explain the wide range of disorders in which both have been implicated. Yet differential expression of components of the processes in particular neuronal systems may account for selective neurodegeneration in certain disorders.
3,844 citations
"Antioxidants, redox signaling, and ..." refers background in this paper
...There is accumulating evidence that NMDA-mediated excitotoxicity involves free radicals such as superoxide and nitric oxide (42, 197)....
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