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)

In the central nervous system (CNS), prostaglandin (PG) and other bioactive lipids regulate vital aspects of neural membrane biology, including protein-lipid interactions, trans-membrane and trans-synaptic signaling. However, a series of highly reactive PGs, free fatty acids, lysophospolipids, eicosanoids, platelet-activating factor, and reactive oxygen species (ROS), all generated by enhanced phospholipase A2 (PLA2) activity and arachidonic acid (AA) release, participate in cellular injury, particularly in neurodegeneration. PLA2 activation and PG production are among the earliest initiating events in triggering brain-damage pathways, which can lead to long-term neurologic deficits. Altered membrane-associated PLA2 activities have been correlated with several forms of acute and chronic brain injury, including cerebral trauma, ischemic damage, induced seizures in the brain and epilepsy, schizophrenia, and in particular, Alzheimer's disease (AD). Biochemical mechanisms of PLA2 overactivation and its pathophysiological consequences on CNS structure and function have been extensively studied using animal models and brain cells in culture triggered with PLA2 inducers, PGs, cytokines, and related lipid mediators. Moreover, the expression of both COX-2 and PLA2 appears to be strongly activated during Alzheimer's disease (AD), indicating the importance of inflammatory gene pathways as a response to brain injury. This review addresses some current ideas concerning how brain PLA2 and brain PGs are early and key players in acute neural trauma and in brain-cell damage associated with chronic neurodegenerative diseases such as AD.
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PMID:Prostaglandins and other lipid mediators in Alzheimer's disease. 1243 19

An absent response to the niacin skin test has been reported to occur in about 80% of schizophrenic patients, as compared to 20% of healthy individuals. Niacin provokes redness in skin caused by a capillary vasodilatation mediated by prostaglandins. The metabolism of prostaglandins is regulated by the enzyme phospholipase A2 (PLA2). Several studies have reported increased PLA2 activity in schizophrenia. In this study we investigated the relationship between niacin response and PLA2 activity in 38 drug-free schizophrenic patients and in 28 healthy controls. Twenty-two of these patients were reevaluated after 8 weeks under treatment with new generation antipsychotic drugs. Niacin response was absent in 23% of the schizophrenic patients and in 14% in controls (n.s.). PLA2 activity was higher in schizophrenics than in controls (344+/-115 vs. 290+/-71 pmol/ml/min; p=0.03). Patients with absent response to niacin had the highest PLA2 activity as compared to those with positive response (426+/-155 vs. 319+/-111; p=0.02). After 8 weeks on antipsychotic treatment, PLA2 activity was reduced (355+/-115 before, 267+/-39 after, p=0.001) and 4 out of 13 patients with absent response to niacin converted to positive. The reduction of PLA2 activity in these patients was higher than in patients who remained with absent response (36% vs. 23%). Our data support the findings that absent response to niacin is more frequent in schizophrenic than in healthy individuals although the magnitude of the difference was smaller than that reported in the literature. The relationship between absent response to niacin in schizophrenia and increased PLA2 activity suggests further that the skin test may be useful to easily identify a subgroup of patients with a disordered phospholipid metabolism.
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PMID:Increased phospholipase A2 activity in schizophrenia with absent response to niacin. 1264 30

The rationale of this study was to understand the complexity of kinetics of fluorogenic phospholipid substrates as well as contradictory findings of clinical papers measuring phospholipase A2 (PLA2) activity using different methodologies. The aim was to recommend to clinicians and researchers what substrate in conjunction with what assay should be used. Two methods, (i) continuous fluorometric assay and (ii) high performance thin layer chromatography (HPTLC) on microplates combined with quantitative image scanning, were studied with three different substrates (bis-BODIPY FL C11-PC, NBDC6-HPC, PED6). The study demonstrates that NBD-PC is not a suitable substrate to measure PLA2 activity using a spectrofluorometer. On the other hand, NBD-PC gives the highest and most reproducible integrated light intensities (ILls) in HPTLC studies. Slow time-dependent increases in fluorescence intensities recorded with biological samples in fluorometers, but not caused by substrate splitting, had to be classified as "perturbation kinetics". PLA2 activities in blood samples of 26 unmedicated schizophrenia patients and 26 age-matched healthy controls were measured by the spectrofluorometric method and then compared with the activity data obtained with the HPTLC method. A significant group difference was found only with the HPTLC. In order to get more reliable results, we recommend that clinicians and researchers use NBD-phosphatidylcholines as PLA2 substrates in biological samples and start with an analytical separation of reaction products followed by image analysis of the fluorescent spots.
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PMID:Fluorometric assays of phospholipase A2 activity with three different substrates in biological samples of patients with schizophrenia. 1294 May 17

A variety of biochemical, clinical and genetic evidence suggests that phospholipid metabolism may play an aetiological role in schizophrenia. A key piece of evidence is the reduced vasodilatory response of patients with schizophrenia to nicotinic acid (NA). NA causes vasodilation via the activation of phospholipase A2 (PLA2) leading to the release of free fatty acids from membrane phospholipids and the subsequent production of prostaglandins. Insensitivity to NA may be due to a 'block' in the downstream signaling pathway used by the drug to evoke its response. It can be argued that if such an abnormality occurs in neurons, impaired PLA2-dependent signaling could result in altered glutamateric and dopaminergic transmission in such a way as to produce or exacerbate psychotic symptoms. The complimentary finding of increased PLA2 activity in schizophrenia may be an attempt to overcome the signaling block. It is suggested that intervention aimed at increasing the activity of PLA2-dependent signaling systems may be therapeutically useful in the treatment of the illness.
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PMID:Phospholipid and eicosanoid signaling disturbances in schizophrenia. 1462 94

Findings to date provide evidence that altered membrane structure and function are present in patients with either first-episode or chronic schizophrenia, suggesting defects in phospholipid metabolism and cell signaling in schizophrenia. The purpose of this investigation is to test whether decreased membrane polyunsaturated fatty acids (PUFAs) were associated with an increased secretion of proinflammatory cytokines. Thus, we measured interleukin 6 (IL-6) and interleukin 10 (IL-10) in cerebrospinal fluid (CSF) of patients with chronic schizophrenia as well as PUFAs of red blood cell (RBC) membranes from the same individuals. A significant and inverse correlation was found between CSF IL-6 (not IL-10) and RBC membrane PUFAs levels in both haloperidol-treated and medication-free patients with schizophrenia. Specifically, such an association was found in the n-6 (18:2, 20:4, and 22:4) and, to a lesser extent, the n-3 fatty acids. Taken together, the present findings suggest that decreased membrane PUFAs may be related to an immune disturbance in schizophrenia, possibly resulting from an increased phospholipase A2 activity mediated through the proinflammatory cytokines.
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PMID:Membrane polyunsaturated fatty acids and CSF cytokines in patients with schizophrenia. 1462 97

It has been hypothesised that polyunsaturated fatty acids (PUFA) play an important role in the aetiology of schizophrenia and depression. Evidence supporting this hypothesis for schizophrenia includes abnormal brain phospholipid turnover shown by 31P Magnetic Resonance Spectroscopy, increased levels of phospholipase A2, reduced niacin skin flush response, abnormal electroretinogram, and reduced cell membrane levels of n-3 and n-6 PUFA. In depression, there is strong epidemiological evidence that fish consumption reduces risk of becoming depressed and evidence that cell membrane levels of n-3 PUFA are reduced. Four out of five placebo-controlled double- blind trials of eicosapentaenoic acid (EPA) in the treatment of schizophrenia have given positive findings. In depression, two placebo-controlled trials have shown a strong therapeutic effect of ethyl-EPA added to existing medication. The mode of action of EPA is currently not known, but recent evidence suggests that arachidonic acid (AA) if of particular importance in schizophrenia and that clinical improvement in schizophrenic patients using EPA treatment correlates with changes in AA.
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PMID:Eicosapentaenoic acid in the treatment of schizophrenia and depression: rationale and preliminary double-blind clinical trial results. 1462 2

Retinoic acid modulates a wide variety of biological processes including proliferation, differentiation, and apoptosis. It interacts with specific receptors in the nucleus, the retinoic acid receptors (RARs). The molecular mechanism by which retinoic acid mediates cellular differentiation and growth suppression in neural cells remains unknown. However, retinoic acid-induced release of arachidonic acid and its metabolites may play an important role in cell proliferation, differentiation, and apoptosis. In brain tissue, arachidonic acid is mainly released by the action of phospholipase A2 (PLA2) and phospholipase C (PLC)/diacylglycerol lipase pathways. We have used the model of differentiation in LA-N-1 cells induced by retinoic acid. The treatment of LA-N-1 cells with retinoic acid produces an increase in phospholipase A2 activity in the nuclear fraction. The pan retinoic acid receptor antagonist, BMS493, can prevent this increase in phospholipase A2 activity. This suggests that retinoic acid-induced stimulation of phospholipase A2 activity is a retinoic acid receptor-mediated process. LA-N-1 cell nuclei also have phospholipase C and phospholipase D (PLD) activities that are stimulated by retinoic acid. Selective phospholipase C and phospholipase D inhibitors block the stimulation of phospholipase C and phospholipase D activities. Thus, both direct and indirect mechanisms of arachidonic acid release exist in LA-N-1 cell nuclei. Arachidonic acid and its metabolites markedly affect the neurite outgrowth and neurotransmitter release in cells of neuronal and glial origin. We propose that retinoic acid receptors coupled with phospholipases A2, C and D in the nuclear membrane play an important role in the redistribution of arachidonic acid in neuronal and non-nuclear neuronal membranes during differentiation and growth suppression. Abnormal retinoid metabolism may be involved in the downstream transcriptional regulation of phospholipase A2-mediated signal transduction in schizophrenia and Alzheimer disease (AD). The development of new retinoid analogs with diminished toxicity that can cross the blood-brain barrier without harm and can normalize phospholipase A2-mediated signaling will be important in developing pharmacological interventions for these neurological disorders.
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PMID:Retinoic acid-mediated phospholipase A2 signaling in the nucleus. 1521 Mar 3

Several studies suggest increased activity of phospholipase A2 in schizophrenic patients. In the present study, variants of four genes coding for phospholipase A2 enzyme groups (sPLA2, cPLA2, iPLA2 and PAFAH) were analysed in a case-control sample using 240 schizophrenic patients and 312 healthy controls. No difference was observed on the allelic and genotypic distribution of cPLA2 and sPLA2 gene polymorphisms among the groups. The PAFAH variant was very rare in our population and therefore not informative. A significant allelic (chi2=5.86, P=0.0085, odds ratio=1.38, 95% confidence interval, 1.08-1.77) and genotypic (chi2=5.4, P=0.02) association with the iPLA2 gene polymorphism was found. In conclusion, our data suggested that iPLA2 may play a role as a susceptibility gene for schizophrenia in our sample; however, confirmatory studies in independent samples are needed.
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PMID:Allelic association analysis of phospholipase A2 genes with schizophrenia. 1531 30

A range of neurotransmitter systems have been implicated in the pathogenesis of schizophrenia based on the antidopaminergic activities of antipsychotic medications, and chemicals that can induce psychotic-like symptoms, such as ketamine or PCP. Such neurotransmitter systems often mediate their cellular response via G-protein-coupled release of arachidonic acid (AA) via the activation of phospholipases A2 (PLA2s). The interaction of three PLA2s are important for the regulation of the release of AA--phospholipase A2 Group 2 A, phospholipase A2 Group 4A and phospholipase A2 Group 6A. Gene variations of these three key enzymes have been associated with schizophrenia with conflicting results. Preclinical data suggest that the activity of these three enzymes are associated with monoaminergic neurotransmission, and may contribute to the differential efficacy of antipsychotic medications, as well as other biological changes thought to underlie schizophrenia, such as altered neurodevelopment and synaptic remodelling. We review the evidence and discuss the potential roles of these three key enzymes for schizophrenia with particular emphasis on published association studies.
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PMID:The role of phospholipases A2 in schizophrenia. 1658 43

The dopamine hypothesis of schizophrenia has been most influential since the 1970s. Normally, the prefrontal dopamine system suppressively controls the limbic dopamine system. Since the activities of prefrontal dopaminergic neurons are reduced in schizophrenia, the suppressive effect of the prefrontal area on the limbic system is reduced, and activities of the limbic dopamine system are enhanced. Reduced activities of the prefrontal dopamine system cause negative symptoms and cognitive disorders, and the increased activity of the limbic dopamine system induces positive symptoms. While the dopamine hypothesis explains the relationship between intracranial dopamine kinetics and psychiatric symptoms in schizophrenia, it is not a direct explanation of its etiology. The cause of the activities of dopaminergic neurons in schizophrenia and the resultant symptoms are unknown. n-3 Fatty acids are not synthesized in the human body and are called "essential fatty acids". Since the late 1980s, it has been revealed that the n-3 fatty acid concentration is reduced in the plasma and erythrocyte membranes of schizophrenic patients, and that the administration of n-3 fatty acids is effective for the treatment of schizophrenia. However, how n-3 fatty acid deficiency induces psychiatric symptoms remains unclear, and the mechanism of the therapeutic effect of n-3 fatty acids has not been clarified. Recently, the dopamine hypothesis and n-3 fatty acid hypothesis have been suggested to represent different aspects of the same pathology of schizophrenia. In schizophrenia, the inactivation of phospholipase A2 causes an excessive depletion of essential fatty acids from the Sn2 position of cell membrane phospholipids, and the brain concentrations of essential fatty acids decrease. This causes decreases in dopamine vesicles, dopamine concentration, and D2-receptors at prefrontal presynaptic terminals. The reduced activity of dopaminergic neurons in the prefrontal area induce negative symptoms and cognitive disorders. Furthermore, as the suppression of activities in the limbic dopamine system by the prefrontal area is reduced, the dopamine concentration and D2-receptors increase in the striate body. As a result, the hyperactivity of the limbic dopamine system induces positive symptoms. The administration of antipsychotics and n-3 fatty acids act on different points in this etiological cascade.
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PMID:[The n-3 fatty acid/dopamine hypothesis in schizophrenia]. 1702 Jan 31


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