4-hydroxy-2-nonenal and Schizophrenia

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

Oxidative stress is the condition arising from imbalance between toxic reactive oxygen species and antioxidant systems. It is believed that increased oxidative stress may be relevant to the pathophysiology of schizophrenia. In this way, the main markers of the lipid peroxidation processes include 4-hydroxynonenal and malondialdehyde. On the other side, the potential toxicity of free radicals is counteracted by a number of cytoprotective antioxidant enzymes that limit the damage, such as superoxide dismutase and glutathione peroxidase. However, the reports regarding the status of oxidative stress markers schizophrenia are very inconsistent, with various authors stating both increased and decreased activities of the main antioxidant enzymes, while others did not observe any significant modifications, as compared to control groups. Similar aspects were also reported in the case of the lipid peroxidation markers, although in here the contradictions are much more reduced than in the case of the antioxidant defences. It is generally believed that the equivocal results mentioned above may be due to different tissues studies, different species or the administrated treatment and the duration of the disease/treatment. In this context, in the present paper we were interested to review some studies regarding the oxidative stress status in patients and animal models of schizophrenia, by referring mainly to antioxidant enzymes and lipid peroxidation markers.

Topics: Aldehydes; Animals; Antioxidants; Antipsychotic Agents; Biomarkers; Catalase; Free Radicals; Glutathione Peroxidase; Humans; Lipid Peroxidation; Malondialdehyde; Oxidation-Reduction; Oxidative Stress; Rats; Reactive Oxygen Species; Schizophrenia; Superoxide Dismutase

Sex differences in the symptomatology and course of illness have been reported among schizophrenic patients. Hence, the principal objective of the present study was to investigate sex differences in the concentrations of the lipid peroxidation metabolites MDA and 4-HNE, and in the membrane phospholipid levels of ARA, EPA and DHA in patients with schizophrenia. A total of 46 paranoid schizophrenics (25 women) with short-term evolution who were in an acute psychotic stage and 40 healthy controls (23 women) participated in the study. Psychopathology was evaluated by BPRS and PANSS. Lipid peroxidation sub-products (MDA, 4-HNE) and fatty acid levels (ARA, EPA, DHA) were determined in erythrocyte membranes. The men in both groups showed higher lipid peroxidation levels and those values were higher in schizophrenic patients than controls, with only EPA fatty acid concentrations found to be lower in the former than the latter. These results suggest that men may suffer greater oxidative neuronal damage than women, and that this could worsen the course of illness and result in greater disease severity.

Topics: Adolescent; Adult; Aldehydes; Analysis of Variance; Arachidonic Acid; Chromatography; Docosahexaenoic Acids; Eicosapentaenoic Acid; Erythrocyte Membrane; Erythrocytes; Fatty Acids; Female; Humans; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenia, Paranoid; Sex Characteristics; Young Adult

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

It is well-known that increased lipid peroxidation and failure of antioxidant mechanisms leads to neuronal damage in schizophrenic patients. However, this neurodegenerative mechanism has not been studied in treatment refractory schizophrenics (TRS). Therefore, the main purpose of this study was to determine neuronal damage in TRS in comparison to non-refractory schizophrenics (NRS) by means of quantitative analysis of lipid peroxidation and neuron specific enolase (NSE) related to the psychopathology severity. Two groups of paranoid schizophrenics, TRS and NRS, and a group of healthy controls (CO) were assembled (n=13). Lipid peroxidation was analyzed through spectrophotometry for quantification of malonaldehyde (MDA) and 4-hydroxynonenal (4-HNE) serum concentrations. As well, serum NSE was quantified by radioimmunoassay (ELSA). Psychopathology was evaluated using the brief psychiatric rating scale (BPRS) and the positive and negative symptoms scale (PANSS). TRS showed significant higher concentrations of lipoperoxides by-products and NSE, than NRS and CO. Clinical scores also revealed a more severe pathology in TRS, than in NRS. Raised lipoperoxidation correlated with higher delusions and emotional withdrawal symptoms, and increased NSE correlated with a lower flow of the conversation and lack of spontaneity. All these results together suggest that TRS patients suffer a greater lipid peroxidation and neuronal damage than NRS, apparently related to worsening of some of the psychiatric symptoms.

Topics: Adult; Aldehydes; Antipsychotic Agents; Brief Psychiatric Rating Scale; Drug Resistance; Female; Humans; Lipid Peroxidation; Male; Malondialdehyde; Neurons; Oxidative Stress; Phosphopyruvate Hydratase; Schizophrenia; Schizophrenic Psychology