4-hydroxy-2-nonenal and Bipolar-Disorder

4-hydroxy-2-nonenal (HNE) is considered to be a strong marker of oxidative stress; the interaction between HNE and cellular proteins leads to the formation of HNE-protein adducts able to alter cellular homeostasis and cause the development of a pathological state. By virtue of its high lipid concentration, oxygen utilization, and the presence of metal ions participating to redox reactions, the brain is highly susceptible to the formation of free radicals and HNE-related compounds. A variety of neuropsychiatric disorders have been associated with elevations of HNE concentration. For example, increased levels of HNE were found in the cortex of bipolar and schizophrenic patients, while HNE plasma concentrations resulted high in patients with major depression. On the same line, high brain concentrations of HNE were found associated with Huntington's inclusions. The incidence of high HNE levels is relevant also in the brain and cerebrospinal fluid of patients suffering from Parkinson's disease. Intriguingly, in this case the increase of HNE was associated with an accumulation of iron in the substantia nigra, a brain region highly affected by the pathology. In the present review we recapitulate the findings supporting the role of HNE in the pathogenesis of different neuropsychiatric disorders to highlight the pathogenic mechanisms ascribed to HNE accumulation. The aim of this review is to offer novel perspectives both for the understanding of etiopathogenetic mechanisms that remain still unclear and for the identification of new useful biological markers. We conclude suggesting that targeting HNE-driven cellular processes may represent a new more efficacious therapeutical intervention.

Topics: Aldehydes; Bipolar Disorder; Cerebral Cortex; Depressive Disorder, Major; Humans; Huntington Disease; Iron; Lipid Peroxidation; Mitochondria; Molecular Targeted Therapy; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Schizophrenia; Substantia Nigra

The present study evaluated the effects of AR-A014418 on behavioral and oxidative stress parameters of rats submitted to the animal model of mania induced by ouabain (OUA). Wistar rats were submitted to stereotaxic surgery and received a single intracerebroventricular (ICV) injection of artificial cerebrospinal fluid (aCSF), OUA, or AR-A014418. After 7 days, the animals were submitted to open-field test. After behavioral analysis, the brains were dissected in frontal cortex and hippocampus to the evaluation of oxidative stress. The OUA induced manic-like behavior in rats, which was reversed by AR-A014418 treatment. The ICV administration of OUA increases the levels of superoxide in submitochondrial particles, lipid hydroperoxide (LPH), 4-hydroxynonenal (4-HNE), 8-isoprostane, protein carbonyl, 3-nitrotyrosine, and activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) in both structures evaluated. In general, the treatment with AR-A014418 reversed these effects of OUA on the submitochondrial particles, LPH, 4-HNE, 8-isoprostane, protein carbonyl, 3-nitrotyrosine levels, and SOD activity. Furthermore, the injection of OUA decreased the catalase activity, and AR-A014418 promoted an increase in activity of this enzyme in the brain structures. These results suggest that GSK-3β inhibition can modulate manic-like behaviors. Also, it can be suggested that inhibition of GSK-3β can be effective against oxidative stress. However, more studies are needed to better elucidate these mechanisms. Graphical Abstract The effects of AR-A014418 on the behavioral and oxidative stress parameters in the animal model of mania induced by ouabain. Superoxide = superoxide production in submitochondrial particles; LPH = lipid hydroperoxide; 4-HNE = 4-hydroxynonenal; SOD = superoxide dismutase; GPx = glutathione peroxidase; GR = glutathione reductase.

Topics: Aldehydes; Animals; Antioxidants; Behavior, Animal; Bipolar Disorder; Catalase; Dinoprost; Disease Models, Animal; Glutathione Peroxidase; Glycogen Synthase Kinase 3 beta; Lipid Peroxidation; Male; Motor Activity; Oxidative Stress; Protein Carbonylation; Rats, Wistar; Submitochondrial Particles; Superoxide Dismutase; Superoxides; Thiazoles; Tyrosine; Urea

Executive dysfunction is common and impairing in youth bipolar disorder (BD), and oxidative stress (OS) and brain-derived neurotrophic factor (BDNF) have been implicated in executive deficits of adult BD. This study aimed to determine the association between OS and executive dysfunction in BD adolescents and the influence of BDNF on this association.. Serum levels of lipid hydroperoxides (LPH) and 4-hydroxy-2-nonenal (4-HNE) and BDNF levels were measured in 29 BD and 25 control adolescents. The intra-extra-dimensional (IED) set-shifting task assessed executive function. Lower IED scores indicated better performance. High and low BDNF subgroups were defined by median split.. There is a negative association between LPH and executive function in BD adolescents, which may be modulated by BDNF. LPH and BDNF may be useful biomarkers of executive function in BD. These findings highlight the importance of examining multiple peripheral biomarkers in relation to cognitive functions in BD adolescents. Future studies should explore these factors in longitudinal designs to determine the directionality of observed associations.

Topics: Adolescent; Aldehydes; Biomarkers; Bipolar Disorder; Brain-Derived Neurotrophic Factor; Cognition; Executive Function; Female; Humans; Lipid Peroxidation; Lipid Peroxides; Male; Oxidative Stress; Young Adult

Prior work suggests that adult bipolar disorder (BD) is associated with increased oxidative stress and inflammation. This exploratory study examined markers of lipid and protein oxidation and inflammation in adolescents with and at varying risk for BD type I (BD-I).. Blood was obtained from four groups of adolescents (9-20 years of age): (1) healthy comparison subjects with no personal or family history of psychiatric disorders (n=13), (2) subjects with no psychiatric diagnosis and at least one parent with BD-I ('high-risk', n=15), (3) subjects with at least one parent with BD-I and a diagnosis of depressive disorder not-otherwise-specified ('ultra-high-risk', n=20), and (4) first-episode patients exhibiting mixed or manic symptoms that received a diagnosis of BD-I (n=16). Plasma levels of lipid peroxidation (LPH, 4-HNE, 8-ISO), protein carbonyl, and inflammation (IL-1α-β, IL-6, IL-10, IFNγ, TNFα) were assessed using analysis of variance and covariance models.. LPH was lower in adolescents with fully syndromal BD than controls, while LPH levels in the at-risk groups were between healthy controls and fully syndromal BD. Post-hoc analysis showed a non-significant increase in the (4-HNE+8-ISO)/LPH ratio suggesting a potential conversion of LPH into late-stage markers of lipid peroxidation. There were no significant differences among protein carbonyl content and inflammatory markers.. In adolescents, fully syndromal BD is associated with significant reductions in LPH levels, and LPH levels decrease along the spectrum of risk for BD-I. Quantifying lipid peroxidation in longitudinal studies may help clarify the role of LPH in BD risk progression.

Topics: Adolescent; Adult; Aldehydes; Biomarkers; Bipolar Disorder; Case-Control Studies; Dinoprost; Female; Humans; Interleukin-1; Interleukin-10; Interleukin-6; Interleukins; Lipid Peroxidation; Lipid Peroxides; Male; Oxidative Stress; Protein Carbonylation; Risk Factors; Tumor Necrosis Factor-alpha

Reduced dentate gyrus volume and increased oxidative stress have emerged as potential pathophysiological mechanisms in bipolar disorder. However, the relationship between dentate gyrus volume and peripheral oxidative stress markers remains unknown. Here, we examined dentate gyrus-cornu ammonis (CA) 4 volume longitudinally in patients with bipolar II disorder (BD-II) and healthy controls and investigated whether BD-II is associated with elevated peripheral levels of oxidative stress.. We acquired high-resolution structural 3T-magnetic resonance imaging (MRI) images and quantified hippocampal subfield volumes using an automated segmentation algorithm in individuals with BD-II (n=29) and controls (n=33). The participants were scanned twice, at study inclusion and on average 2.4 years later. In addition, we measured peripheral levels of two lipid peroxidation markers (4-hydroxy-2-nonenal [4-HNE] and lipid hydroperoxides [LPH]).. First, we demonstrated that the automated hippocampal subfield segmentation technique employed in this work reliably measured dentate gyrus-CA4 volume. Second, we found a decreased left dentate gyrus-CA4 volume in patients and that a larger number of depressive episodes between T1 and T2 predicted greater volume decline. Finally, we showed that 4-HNE was elevated in BD-II and that 4-HNE was negatively associated with left and right dentate gyrus-CA4 volumes in patients.. These results are consistent with a role for the dentate gyrus in the pathophysiology of bipolar disorder and suggest that depressive episodes and elevated oxidative stress might contribute to hippocampal volume decreases. In addition, these findings provide further support for the hypothesis that peripheral lipid peroxidation markers may reflect brain alterations in bipolar disorders.

Topics: Adult; Aldehydes; Biomarkers; Bipolar Disorder; Cross-Sectional Studies; Dentate Gyrus; Depression; Female; Humans; Lipid Peroxidation; Magnetic Resonance Imaging; Male; Organ Size; Oxidative Stress; Statistics as Topic

Increases in oxidative stress have been consistently reported in younger patients with bipolar disorder (BD) in postmortem brain and blood samples studies. Changes in oxidative stress are also associated with the natural aging process. Thus, the investigation of oxidative stress across the life span of patients with BD is crucial.. We compared the levels of oxidative damage to proteins and lipids in plasma from 110 euthymic older patients with BD I or II (mean±SD age: 63.9±9.7 years) and 75 older healthy individuals (66.0±9.6 years). To assess protein oxidation, we measured the plasma levels of protein carbonyl (PC) and 3-nitrotyrosine (3-NT) using the ELISA technique. To assess lipid peroxidation, we measured plasma levels of lipid hydroperoxide (LPH) and 4-hydroxynonenal (4-HNE) using spectrophotometric assays.. LPH levels were higher in patients than in the comparison healthy individuals, whereas there were no significant differences for PC, 3-NT, and 4-HNE between the two groups.. The increased levels of an early component of the peroxidation chain (LPH) in euthymic older patients with BD support the hypothesis of a persistent effect of reactive species of oxygen in patients with BD into late life.

Topics: Aged; Aldehydes; Bipolar Disorder; Case-Control Studies; Female; Humans; Lipid Peroxides; Male; Middle Aged; Oxidative Stress; Protein Carbonylation; Tyrosine

Bipolar disorder (BD) is a severe psychiatric disorder associated with social and functional impairment. Some studies have strongly suggested the involvement of oxidative stress in the pathophysiology of BD. Paradoxal sleep deprivation (PSD) in mice has been considered a good animal model of mania because it induces similar manic-like behavior, as well as producing the neurochemical alterations which have been observed in bipolar patients. Thus, the objective of the present study was to evaluate the effects of the antioxidant agent's n-acetylcysteine (Nac) and/or deferoxamine (DFX) on behavior and the oxidative stress parameters in the brains of mice submitted to the animal model of mania induced by PSD. The mice were treated for a period of seven days with saline solution (SAL), Nac, DFX or Nac plus DFX. The animals were subject to the PSD protocol for 36 h. Locomotor activity was then evaluated using the open-field test, and the oxidative stress parameters were subsequently evaluated in the hippocampus and frontal cortex of mice. The results showed PSD induced hyperactivity in mice, which is considered a manic-like behavior. In addition to this, PSD increased lipid peroxidation and oxidative damage to proteins, as well as causing alterations to antioxidant enzymes in the frontal cortex and hippocampus of mice. The Nac plus DFX adjunctive treatment prevented both the manic-like behavior and oxidative damage induced by PSD. Improving our understanding relating to oxidative damage in biomolecules, and the antioxidant mechanisms presented in the animal models of mania are important in helping to improve our knowledge concerning the pathophysiology and development of new therapeutical treatments for BD.

Topics: Acetylcysteine; Aldehydes; Analysis of Variance; Animals; Antimanic Agents; Bipolar Disorder; Brain; Deferoxamine; Disease Models, Animal; Glutathione Peroxidase; Glutathione Reductase; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Sleep Deprivation; Tyrosine

Diffusion tensor imaging (DTI) studies consistently reported abnormalities in fractional anisotropy (FA) and radial diffusivity (RD), measures of the integrity of white matter (WM), in bipolar disorder (BD), that may reflect underlying pathophysiologic processes. There is, however, a pressing need to identify peripheral measures that are related to these WM measures, to help identify easily obtainable peripheral biomarkers of BD. Given the high lipid content of axonal membranes and myelin sheaths, and that elevated serum levels of lipid peroxidation are reported in BD, these serum measures may be promising peripheral biomarkers of underlying WM abnormalities in BD. We used DTI and probabilistic tractography to compare FA and RD in ten prefrontal-centered WM tracts, 8 of which are consistently shown to have abnormal FA (and/or RD) in BD, and also examined serum lipid peroxidation (lipid hydroperoxides, LPH and 4-hydroxy-2-nonenal, 4-HNE), in 24 currently euthymic BD adults (BDE) and 19 age- and gender-matched healthy adults (CONT). There was a significant effect of group upon FA in these a priori WM tracts (BDECONT: F[1,41]=10.3; P=0.003), and a significant between-group difference in LPH (BDE>CONT: t[40]=2.4; P=0.022), but not in 4-HNE. Multivariate multiple regression analyses revealed that LPH variance explained, respectively, 59 and 51% of the variance of FA and RD across all study participants. This is the first study to examine relationships between measures of WM integrity and peripheral measures of lipid peroxidation. Our findings suggest that serum LPH may be useful in the development of a clinically relevant, yet easily obtainable and inexpensive, peripheral biomarkers of BD.

Topics: Adult; Aldehydes; Anisotropy; Biomarkers; Bipolar Disorder; Brain; Diffusion Tensor Imaging; Female; Humans; Lipid Peroxidation; Lipid Peroxides; Male; Models, Statistical; Multivariate Analysis; Nerve Fibers, Myelinated; Neural Pathways; Prefrontal Cortex; Signal Processing, Computer-Assisted

Recent studies indicate that bipolar disorder is associated with mitochondrial dysfunction and oxidative stress. Previous studies in our laboratory have shown that the mood stabilizer lithium inhibits oxidative stress. The α,β-unsaturated aldehyde 4-hydroxy-2-nonenal (4-HNE), a major product of lipid peroxidation, is able to exert cytotoxicity and disturb cellular function by forming protein adducts. The purpose of this study is to determine whether chronic lithium treatment prevents 4-HNE-protein adduction in an amphetamine-induced hyperactive mania-like model. We found that repeated amphetamine stimulation significantly induced hyperactive behaviour, decreased activities of mitochondrial complexes I and III, and increased 4-HNE-protein adducts in rat frontal cortex, and that chronic lithium treatment inhibited both amphetamine-induced hyperactivity and 4-HNE-protein adduction. Monoamine neurotransmitters are involved in the aetiology and pathology of bipolar disorder and other psychiatric diseases, and also contribute significantly to amphetamine-induced behavioural effects. Vesicular monoamine transporter 2 (VMAT2) is critical in packaging monoamine neurotransmitters. We found that 4-HNE can form protein adducts with VMAT2. Repeated amphetamine stimulation significantly increased 4-HNE-VMAT2 adducts, while chronic lithium treatment reduced amphetamine-increased 4-HNE-VMAT2 adducts in rat frontal cortex. Our findings suggest that chronic lithium treatment may inhibit amphetamine-induced hyperactive mania-like behaviour by preventing 4-HNE-VMAT2 adduction. This finding also indicates that prevention of 4-HNE-VMAT2 adduction may contribute in part to the pharmacological action of lithium for the treatment of bipolar disorder.

Topics: Aldehydes; Amphetamine; Animals; Antimanic Agents; Bipolar Disorder; Blotting, Western; Central Nervous System Stimulants; Electron Transport Complex I; Electron Transport Complex III; Immunohistochemistry; Immunoprecipitation; Lithium; Male; Motor Activity; Nerve Tissue Proteins; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Vesicular Monoamine Transport Proteins

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.. 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.. 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.. 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.

Topics: Aldehydes; Analysis of Variance; Bipolar Disorder; Case-Control Studies; Depressive Disorder, Major; Female; Gyrus Cinguli; Humans; Lipid Peroxidation; Male; Oxidative Stress; Postmortem Changes; Schizophrenia; Statistics as Topic