Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NAD(P)H: quinone oxidoreductase (NQO1), an obligate two-electron reductase of quinones, prevents their participation in redox cycling and subsequent generation of reactive oxygen species (ROS). Reduced or negative activity of NQO1 would lead to an excess of neurotoxic compounds of cathecolamine o-quinones and ROS. Recently, there has been increasing evidence that catecholamine o-quinones and ROS might contribute to the development of schizophrenia. We investigated the genetic association between a functional polymorphism (Pro 187Ser) in the human NQO1 gene and schizophrenia (244 Japanese schizophrenic patients and 204 healthy controls). No significant differences in the allelic and genotypic distribution between patients and controls were observed. In addition, our results revealed no association between the genotypes of the polymorphism and any characteristics of patients such as gender, age at onset, family history or current neuroleptic dosage. Our results suggest that the NQO1 gene polymorphism does not confer increased susceptibility for schizophrenia in the present sample.
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PMID:NAD(P)H: quinone oxidoreductase (NQO1) gene polymorphism and schizophrenia. 1283 17

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are formed under physiological conditions in the human body and are removed by cellular antioxidant defense system. During oxidative stress their increased formation leads to tissue damage and cell death. This process may be especially important in the central nervous system (CNS) which is vulnerable to ROS and RNS damage as the result of the brain high O(2) consumption, high lipid content and the relatively low antioxidant defenses in brain, compared with other tissues. Recently there has been an increased number of reports suggesting the involvement of free radicals and their non-radical derivatives in a variety of pathological events and multistage disorders including neurotoxicity, apoptotic death of neurons and neural disorders: Alzheimer's (AD), Parkinson's disease (PD) and schizophrenia. Taking into consideration the basic molecular chemistry of ROS and RNS, their overall generation and location, in order to control or suppress their action it is essential to understand the fundamental aspects of this problem. In this presentation we review and summarize the basics of all the recently known and important properties, mechanisms, molecular targets, possible involvement in cellular (neural) degeneration and apoptotic death and in pathogenesis of AD, PD and schizophrenia. The aim of this article is to provide an overview of our current knowledge of this problem and to inspire experimental strategies for the evaluation of optimum innovative therapeutic trials. Another purpose of this work is to shed some light on one of the most exciting recent advances in our understanding of the CNS: the realisation that RNS pathway is highly relevant to normal brain metabolism and to neurologic disorders as well. The interactions of RNS and ROS, their interconversions and the ratio of RNS/ROS could be an important neural tissue injury mechanism(s) involved into etiology and pathogenesis of AD, PD and schizophrenia. It might be possible to direct therapeutic efforts at oxidative events in the pathway of neuron degeneration and apoptotic death. From reviewed data, no single substance can be recommended for use in human studies. Some of the recent therapeutic strategies and neuroprotective trials need further development particularly those of antioxidants enhancement. Such an approach should also consider using combinations of radical(s) scavengers rather than a single substance.
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PMID:Reactive oxygen species and reactive nitrogen species: relevance to cyto(neuro)toxic events and neurologic disorders. An overview. 1283 2

The fact that glutamate, dopamine, iron and reactive oxygen species are potentially individually highly neurotoxic molecules is well known. The purpose of this review is to examine the less well known complex ways in which their normal biological, as well as their neurotoxic activity, are interconnected in relation to fundamental neuronal functions. These functions include synaptic plasticity (formation and removal of synapses), endocytosis-based recycling of receptors for neurotransmitters and neuromodulators, the role of the redox balance between reactive oxygen species and antioxidants in synaptic function, and the possible role of iron-catecholamine complexes in antioxidant protection and intraneuronal iron transport. These systems are closely involved in several diseases of the nervous system including Parkinson's disease, schizophrenia and Alzheimer's disease. In all these oxidative stress and a failure of antioxidant defenses are involved. In the former two the neurotoxicity of catecholaminergic o-quinones is important. In the later excessive oxidation of neuronal membranes and excessive endocytosis and receptor recycling may be an important factor.
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PMID:The neurotoxicity of glutamate, dopamine, iron and reactive oxygen species: functional interrelationships in health and disease: a review-discussion. 1283 12

Glutathione (GSH) is the main non-protein antioxidant and plays a critical role in protecting cells from damage by reactive oxygen species (ROS) generated by dopamine (DA) metabolism. We reported a decrease of GSH levels ([GSH]) in CSF and in prefrontal cortex in vivo in schizophrenics [Eur. J. Neurosci. 12 (2000) 3721]. A GSH deficit may lead to membrane peroxidation and microlesions around dopaminergic terminals, resulting in loss of connectivity. To test this hypothesis, we studied the effect of DA in cultured cortical neurons with low [GSH]. DA alone decreased [GSH] by 40%. This effect appears to result from direct conjugation of DA semiquinone/quinone with GSH. Ethacrynic acid (EA) decreased [GSH] in a concentration-dependent manner. When added to EA, DA further lowers [GSH]. As this additional decrease is blocked by superoxide dismutase (SOD) or D(1)/D(2) receptor antagonists, it likely involves the generation of superoxide via activation of DA receptors. It also reduces the mitochondrial membrane potential. Most interestingly, a significant decrease in number of neuronal processes (spines analogous) was induced by 24-h application of DA only in low [GSH]. These data, compatible with our hypothesis, is consistent with the dendritic spines reduction reported in schizophrenia and could be related to abnormalities in synaptic connectivity.
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PMID:Dopamine-induced oxidative stress in neurons with glutathione deficit: implication for schizophrenia. 1283 17

Omega-3 (omega-3) is an essential fatty acid (EFA) found in large amounts in fish oil. It contains eicosapentaenoic acid and docosahexaenoic acid (DHA). DHA is one of the building structures of membrane phospholipids of brain and necessary for continuity of neuronal functions. Evidences support the hypothesis that schizophrenia may be the result of increased reactive oxygen species mediated neuronal injury. Recent reports also suggest the protective effect of omega-3 EFA against neuropsychiatric disorders including schizophrenia. This study proposed to assess the changes in antioxidant enzyme and oxidant parameters in the corpus striatum (CS) of rats fed with omega-3 EFA diet (0.4g/kg/day) for 30 days. Eight control rats and nine rats fed with omega-3 were decapitated under ether anesthesia, and CS was removed immediately. Thiobarbituric acid-reactive substances (TBARS) and nitric oxide (NO) levels as well as total superoxide dismutase (t-SOD) and xanthine oxidase (XO) enzyme activities in the CS were measured. Rats treated with omega-3 EFA had significantly lower values of TBARS (P<0.001), NO (P<0.002) and XO (P<0.005) whereas higher values of t-SOD enzyme activity (P<0.002) than the control rats. These results indicate that omega-3 EFA rich fish oil diet reduces some oxidant parameters in CS. This may be revealed by means of reduced CS TBARS levels as an end product of lipid peroxidation of membranes in treated rats. Additionally, reduced XO activity and NO levels may support this notion. On the other hand, although the mechanism is not clear, omega-3 EFA may indirectly enhance the activity of antioxidant enzyme t-SOD. Taken together, this preliminary animal study provides strong support for a therapeutic effect of omega-3 EFA supplemented to classical neuroleptic regimen in the treatment of schizophrenic symptoms and tardive dyskinesia.
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PMID:Potential role of dietary omega-3 essential fatty acids on some oxidant/antioxidant parameters in rats' corpus striatum. 1290 35

Plasma membranes are fluid structures and the maintenance of fluidity is a prerequisite for function, viability, growth and reproduction of cells. Membrane fluidity is the reciprocal of membrane microviscosity, which in turn is inversely proportional to rotational and lateral diffusion rates of membrane components. In the absence of constraints most lipids and unrestrained integral proteins freely diffuse in the plane of the membrane with high diffusion coefficients. The fluid mosaic model of plasma membrane structure is essentially still valid but this model is by its nature a macroscopic one. At present, attention is focused on molecular structural details of protein-lipid interactions and on the static and dynamic structure of membrane proteins. Highly potent new macroscopic and microscopic methods have been developed to measure translational diffusion of membrane lipids and proteins. The microscopic methods can reveal diffusion via encounters between labeled molecules. Fluorescence anisotropy measurements are the most widely used techniques in biological research. The use of different permeant and non-permeant fluorophores have contributed much to a better understanding of the changes in the ordered states and motional freedom of the membrane phospholipids in different cells during development, aging and physiological functions as well as in pathological conditions. The application of fluorophores with non-random distribution have shed light on the asymmetrical changes between the outer and inner domain of the lipid bilayer and on the dynamics of 'flip-flop' in signal transduction. Membrane fluidity was shown to have a decisive role in the efficiency of ligand binding, in the outcome of direct cell to cell contacts and in the modulation of the activity of membrane enzymes. Cell filtrability reflects whole cell viscosity that can not always be correlated with the fine changes in membrane fluidity. Cell viscosity depends inter alia on the size and shape of the cells as well as on membrane rigidity. In contrast to this, membrane fluidity is only dependent on the freedom of mobility of the membrane constituents. Increased release of free radicals and reactive oxygen specie (ROS) affect membrane fluidity, cellular Ca2+ homeostasis, induce lipid peroxidation and finally cell death. Investigation of membrane fluidity proved to be a useful and sensitive additional method to obtain a better insight into the mechanisms by which different compounds, drugs and contact with foreign surfaces are affecting cellular functions. The measurements of membrane fluidity may gain more widespread use for monitoring the safety and efficacy of these actions. During the last few years, changes in membrane fluidity of blood cells have been reported during development and aging and as a result of physiological cell functions. Membrane fluidity changes have been described in thrombocythaemia, hyperlipidaemia, hypercholesterolaemia, hypertension, diabetes mellitus, obesity, septic conditions and in allergic and burnt patients, in alcoholics, in Alzheimer's disease and in schizophrenia. A short summary is given on red cell membrane fluidity changes in a Hungarian triosephosphate isomerase (TPI)-deficient family, reflecting how the very subtle changes in membrane fluidity can help to establish underlying biological differences between the clinical phenotypes of a severe enzyme (TPI) deficiency caused by the defect of a single gene in two brothers one with and one without neurological symptoms.
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PMID:Membrane fluidity of blood cells. 1465 48

Defective neutrophil function in schizophrenic patients has recently been reported. There are several lines of evidence to support the contribution of oxygen free radicals in schizophrenia, including increased lipid peroxidation, fatty acids and alterations in blood levels of anti-oxidant enzymes. Eighteen schizophrenic patients (DSM-IV) and 15 healthy controls were studied. Neutrophil chemotaxis, superoxide production and bactericidal activity were investigated. A statistically significant increase of superoxide anion release was found in schizophrenic patients compared with controls (mean+/-S.E.M., patients: 6.89+/-0.30 nmol O2-/10(6) cells/min, controls: 5.13+/-0.55 nmol O2-/10(6) cells/min). Moreover, a significant positive correlation between superoxide production and negative symptoms as assessed by the Positive and Negative Syndrome Scale was demonstrated. No differences were detected in chemotaxis and phagocytosis between schizophrenic patients and healthy controls. The present findings of a positive correlation between superoxide generation and negative symptoms in schizophrenic patients support the hypothesis that superoxide anion may participate in the pathogenesis of schizophrenia, as an excess of free radicals could contribute to the deterioration phase of the disease. Further studies are required to establish the role of oxidative stress in the ethiopathogenesis of schizophrenia.
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PMID:Overproduction of neutrophil radical oxygen species correlates with negative symptoms in schizophrenic patients: parallel studies on neutrophil chemotaxis, superoxide production and bactericidal activity. 1465 47

Both simple attention tasks (e.g. letter cancellation) and most tasks of higher cognitive processing (e.g. word generation) are known to activate the dorsolateral prefrontal cortex (PFC). While attention and higher cognitive processing differ phenomenologically, with attention tasks requiring great subjective effort despite their simplicity, possible physiological differences in the activation of the PFC between the two types of cognitive processing have remained uninvestigated. Hemodynamic changes in the PFC during activation due to tasks of attention and those of higher cognitive processing were examined using near-infrared spectroscopy in 10 Japanese and 10 American healthy adults. In tasks of higher cognitive processing, which included both verbal and non-verbal tasks, the concentration of oxygenated hemoglobin ([HbO2]) increased, and that of deoxygenated hemoglobin ([HbR]) decreased, with an increase in the tissue hemoglobin saturation (THS). In tasks of attention, which consisted of the letter cancellation and continuous performance test, both [HbO2] and [HbR] increased, with no significant changes in the THS observed. The distinctive patterns of hemodynamic changes were not affected by the factors of task difficulty or language. The change in [HbR] may be a physiological marker of the prefrontal lobe activation that discriminates between attention and higher cognitive processing. The increase in [HbR] suggests increased oxygen consumption of the PFC during tasks of attention, which might be related to the disproportionately great subjective effort associated with sustained attention. The physiological alteration in hemodynamic patterns according to changes in cognition needs to be examined in subjects with prefrontal lobe dysfunction, such as schizophrenia and mood disorder.
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PMID:Hemodynamic differences in the activation of the prefrontal cortex: attention vs. higher cognitive processing. 1472 6

The conceptualization of schizophrenia as a disorder of connectivity, i.e., of neuronal?synaptic plasticity, suggests abnormal synaptic modeling and neuronal signaling, possibly as a consequence of flawed interactions with the environment, as at least a secondary mechanism underlying the pathophysiology of this disorder. Indeed, deficits in episodic memory and malfunction of hippocampal circuitry, as well as anomalies of axonal sprouting and synapse formation, are all suggestive of diminished neuronal plasticity in schizophrenia. Evidence supports a dysfunction of mitochondria in schizophrenia, including mitochondrial hypoplasia, and a dysfunction of the oxidative phosphorylation system, as well as altered mitochondrial-related gene expression. Mitochondrial dysfunction leads to alterations in ATP production and cytoplasmatic calcium concentrations, as well as reactive oxygen species and nitric oxide production. All of the latter processes have been well established as leading to altered synaptic strength or plasticity. Moreover, mitochondria have been shown to play a role in plasticity of neuronal polarity, and studies in the visual cortex show an association between mitochondria and synaptogenesis. Finally, mitochondrial gene upregulation has been observed following synaptic and neuronal activity. This review proposes that mitochondrial dysfunction in schizophrenia could cause, or arise from, anomalies in processes of plasticity in this disorder.
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PMID:Mitochondria, synaptic plasticity, and schizophrenia. 1500 92

Possible involvement of oxidative stress in the pathophysiology of tardive dyskinesia (TD) has been proposed. Long-term administration of neuroleptics alters dopaminergic turnover, yielding the increase of the formation of reactive oxygen species (ROS), which may lead to TD through neuronal toxicity as a consequence of oxidative stress. In the present study, the relationship between TD and a polymorphism of the neuronal nitric oxide synthase (NOS1) gene whose reaction product, nitric oxide (NO), is involved in oxidative stress was studied in 171 Japanese patients with schizophrenia, including 41 patients meeting TD criteria. The C/T polymorphism in exon 29 of the NOS1 gene was genotyped using polymerase chain reaction (PCR) amplification followed by restriction enzyme digestion. No significant difference in genotype frequencies was detected between subjects with and without TD (chi2 = 1.54, df = 2, p = 0.46). In addition, there was no difference in allele frequencies (chi2 = 0.42, df = 1, p = 0.51). These results suggest that the NOS1 gene polymorphism may not confer increased susceptibility to TD, although more investigations on other populations are warranted.
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PMID:Genetic association analysis of neuronal nitric oxide synthase gene polymorphism with tardive dyskinesia. 1507 42


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