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)

Neurospectroscopy allows biochemical processes in the brain to be studied non-invasively. At magnetic field strengths of 1.5 T or higher, cerebral proton neurospectroscopy allows the ascertainment of values of myo-inositol, choline-containing compounds, creatine, glutamate, glutamine, and N-acetyl aspartate. At similar field strengths, cerebral 31-phosphorus neurospectroscopy allows the ascertainment of values of phosphomonoesters, inorganic phosphate, phosphodiesters, phosphocreatine, and the gamma, alpha and beta nucleotide triphosphate (mainly adenosine triphosphate) resonances. Since choline is a common polar head group at the Sn3 position of membrane phospholipid molecules, a raised level of free choline, as indexed by proton neurospectroscopy, can indicate relatively low anabolism of membrane phospholipid molecules. Furthermore, the choline peak includes phosphorylcholine and glycerophosphorylcholine and even ethanolamine. The phosphomonoesters peak measured using 31-phosphorus spectroscopy includes major contributions from phosphocholine, phosphoethanolamine and L-phosphoserine, which are important precursors of membrane phospholipids, while the phosphodiesters peak includes contributions from glycerophosphocholine and glycerophosphoethanolamine, which are important products of membrane phospholipid catabolism. Hence proton neurospectroscopy and 31-phosphorus neurospectroscopy can yield important information relating to the metabolism of cerebral membrane phospholipids. The application of these techniques to the investigation of membrane phospholipid metabolism in schizophrenia, depression, chronic fatigue syndrome (myalgic encephalomyelitis or M.E.) and dyslexia is described.
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PMID:Proton and 31-phosphorus neurospectroscopy in the study of membrane phospholipids and fatty acid intervention in schizophrenia, depression, chronic fatigue syndrome (myalgic encephalomyelitis) and dyslexia. 1677 68

Results from molecular and pharmacological studies point to involvement of the gene coding for the phosphatidylinositol-4-phosphate 5-kinase type II-alpha (PIP5K2A) in the development of schizophrenia and bipolar affective disorder (BPAD). The PIP5K2A gene locus, which is located on chromosomal region 10p12, has been implicated in the development of both disorders by independent linkage and association studies. On a cellular level, PIP5K2A is an enzyme component of the metabolism of inositol phosphate, which has been considered a potential target for the therapeutic action of lithium in BPAD patients. Given that the PIP5K2A gene is a promising candidate for the development of both disorders, we performed an association study between genetic variants at the PIP5K2A locus and 268 patients with schizophrenia, 260 patients with BPAD and 325 ethnically matched healthy controls. We failed to detect association to either disorder using PIP5K2A gene variants through single-marker and haplotype analysis. Therefore, our data does not support an involvement of the PIP5K2A locus in the etiology of either schizophrenia or BPAD in the German population.
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PMID:Association study between genetic variants at the PIP5K2A gene locus and schizophrenia and bipolar affective disorder. 1682 1

A chiral procedure based on EKC was developed and validated for determination of the enantiomeric purity of PHA-543613, a drug candidate that was under development for treatment of the cognitive deficits of Alzheimer's disease and schizophrenia. Separation of enantiomers is accomplished via differential, enantiospecific complexation with a single-isomer, precisely sulfated beta-CD and heptakis-6-sulfato-beta-CD (HpS-beta-CD). Both neutral and sulfated CDs were screened before selecting HpS-beta-CD as the chiral selector. The separation is conducted in a 61 cm x 50 microm uncoated fused silica capillary with 25 mM HpS-beta-CD in pH 2.50, 25 mM lithium phosphate as the separation buffer with detection at 220 nm. Application of reverse polarity at -30 kV results in an elution time of about 12 min for PHA-543613 and 13 min for the undesired S-enantiomer. Quantification is versus an authentic reference S-enantiomer as an external standard in combination with an internal standard. The procedure was validated over the range 0.1-2.0% w/w. The detection limit is 0.01-0.02%. The amount of distomer intrinsic to the drug substance is about 0.1% or less. The developed method was used to generate stability data on multiple lots: in one case for up to 3 years.
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PMID:Method for enantiomeric purity of a quinuclidine candidate drug by capillary electrophoresis. 1701 19

The human IMPA2 gene, which encodes myo-inositol monophosphatase 2 (IMPA2), is mapped onto 18p11.2, a susceptibility region for bipolar disorder. This chromosomal region has also been proposed to include a susceptibility locus for schizophrenia and febrile seizures. Here we report the crystal structures of human IMPA2 and its complex with calcium and phosphate ions. Human IMPA2 comprises an alpha-beta protein with a five-layered sandwich of alpha-helices and beta-sheets (alpha-beta-alpha-beta-alpha). The crystal structure and analytical ultracentrifugation results indicated that IMPA2 exists as a dimer in solution. The overall structure of IMPA2 is similar to that of IMPA1, except for the loop regions. In IMPA1, the loop region (31-43) is located at the entrance of the active site cavity. In the corresponding region (42-54) of IMPA2, the residues are disordered and partially form an alpha-helix. The structural difference in the opening of the active site cavity suggests that the substrate specificity differs between IMPA1 and IMPA2. The widely opened cavity of IMPA2 implies that the physiological substrate may be a larger compound than inositol monophosphate. The structure of IMPA2 complexed with Ca2+ revealed two metals and one phosphate binding sites, which were the same sites as in IMPA1 complexed with Mn2+ and phosphate, suggesting that the mechanism of the enzymatic reaction is similar to that of IMPA1. The crystal structures of human IMPA2 are useful for understanding the effect of nonsynonymous polymorphism reported in IMPA2, and will contribute to further functional analyses of IMPA2 that potentially predisposes to the vulnerabilities of bipolar disorder, schizophrenia, and febrile seizures.
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PMID:Crystal structure of human myo-inositol monophosphatase 2, the product of the putative susceptibility gene for bipolar disorder, schizophrenia, and febrile seizures. 1734 Jun 35

Morphological studies report reductions in the volume of medial temporal lobe structures and the prefrontal cortex in subjects with schizophrenia. The present study was performed to clarify the role of prefrontal-temporo-limbic system in the manifestation of psychosis, using entorhinal cortical lesion rats as a vulnerability animal model. Quinolinic acid (lesion group) or phosphate buffer (sham group) was infused into the left entorhinal cortex (EC) of male Wistar rats. On the 28th postoperative day, methamphetamine (MAP; 1 mg/kg, i.p.)-induced dopamine (DA) release in the nucleus accumbens (NAC) and the basolateral amygdala (BLA), as well as locomotor activity and prepulse inhibition (PPI), was measured following microinfusion of lidocaine or the cerebrospinal fluid (CSF) into the medial prefrontal cortex (mPFC). Lesions of the EC resulted in enhancement of MAP-induced DA release in the NAC and BLA. Further analysis revealed that the enhancement by EC lesions of MAP-induce DA release in the NAC was particularly evident in the lidocaine-infused rats. EC lesions also enhanced MAP-induced locomotor activity, especially in the lidocaine-treated animals. By contrast, infusion of lidocaine into mPFC attenuated MAP-induced DA release in the BLA, irrespective of the lesion status. Both EC lesions and lidocaine infusion disrupted PPI. These results indicate that inactivation of the mPFC, as well as structural abnormalities in the EC, leads to dysregulation of DAergic neurotransmissions in the limbic regions. The implications of these findings in relation to the neural basis for psychosis vulnerability are discussed.
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PMID:Effect of prefrontal cortex inactivation on behavioral and neurochemical abnormalities in rats with excitotoxic lesions of the entorhinal cortex. 1737 84

Atypical antipsychotics such as olanzapine have high affinity for multiple monoamine neurotransmitter receptors and are the mainstay of pharmacological therapy for treatment of schizophrenia. In addition to blocking monoamine receptors, these drugs also affect intracellular signaling cascades. We now report that 24-h treatment with 300 nM olanzapine causes desensitization of serotonin (5-HT)(2A) receptors in A1A1v cells, a rat cortical cell line, as indicated by a reduction in inositol phosphate accumulation following stimulation with a 5-HT(2A/2C) receptor agonist (-)-1-(2,5-dimethoxy-4-lodophenyl)-2-aminopropane HCl. Olanzapine treatment for 24 h increased the levels of 5-HT(2A) receptors in both cytosol (234 +/- 34% of control level) and membrane fractions (206 +/- 14% of control levels) and RGS7 proteins in both cytosol (193 +/- 32% of control levels) and membrane fractions (160 +/- 18% of control levels) as measured on Western blots. Increased phosphorylation of Janus tyrosine kinase (JAK) 2 and increased phosphorylation and nuclear translocation of signal transducer and activator of transcription (STAT) 3 with 24-h olanzapine treatment demonstrate activation of the JAK-STAT signaling cascade. Pretreatment with a JAK inhibitor, AG490 [alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide], prevented the olanzapine-induced increase in membrane RGS7 protein levels; AG490 alone had no effect on RGS7 protein levels. We verified that treatment with AG490 reduced phosphorylation of JAK2 and inhibited the nuclear localization of phospho-STAT3. Interestingly, treatment with the JAK inhibitor had no effect on 5-HT(2A) receptor protein levels. These data suggest that olanzapine-induced activation of the JAK-STAT signaling cascade causes increased expression of RGS7 protein, which in turn could mediate desensitization of 5-HT(2A) receptor signaling caused by olanzapine because RGS7 binds to Galpha(q) protein and accelerates GTP hydrolysis.
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PMID:Olanzapine increases RGS7 protein expression via stimulation of the Janus tyrosine kinase-signal transducer and activator of transcription signaling cascade. 1739 3

Calcium (Ca(2+)) release from intracellular stores plays a crucial role in many cellular functions in the brain. These intracellular signals have been shown to be transmitted within and between cells. We report a non-uniform distribution of proteins essential for Ca(2+) signaling in acutely prepared brain slice preparations and organotypic slice cultures, both made from rat hippocampus. The Type I inositol-1,4,5 trisphosphate receptor (InsP(3)R1) is the main InsP(3)R subtype in neurons. Immunohistochemistry experiments showed a prominent expression of InsP(3)R1 in the CA1 region of the hippocampus whereas the CA3 region and dentate gyrus (DG) showed only moderate immunoreactivity. In contrast, chromogranin B (CGB), a protein binding to the InsP(3)R1 on the luminal side of the endoplasmic reticular membrane was enriched in the CA3 region whereas DG and the CA1 region showed only faint CGB signals. The neuronal kinases leading to the formation of inositol-1,4,5 trisphosphate (InsP(3)), phosphatidylinositol-4-kinase (PI4K), and phosphatidylinositol-4-phosphate-5-kinase (PIPK), showed strong immunoreactivity throughout all hippocampal cell fields with differences in the subcellular distribution. Moreover, a distinct band of strong CGB and PIPK immunoreactivity was observed in the CA3 region that coincides with the mossy fiber tract (stratum lucidum). These data show differential expression of the components of the signaling toolkit leading to InsP(3)-mediated Ca(2+) release in cells of the hippocampus. The regulation of these differences may play an important role in various neuropathologic conditions such as Alzheimer's disease, epilepsy, or schizophrenia.
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PMID:Inositol 1,4,5 trisphosphate receptor and chromogranin B are concentrated in different regions of the hippocampus. 1747 56

Some behavioral symptoms and neuropathological features of schizophrenia, like alterations of local GABAergic interneurons, could be emulated in an animal model of psychosis based on prolonged low-dose exposure to N-methyl-D-aspartate (NMDA) receptor antagonists, e.g. MK-801. Employing this model, we examined distinct subpopulations of GABAergic interneurons within the hippocampus and prefrontal cortex. Compared to saline control, animals receiving MK-801 exhibited a decreased density of hippocampal parvalbumin-positive interneurons. A co-administration of the antipsychotic drug haloperidol ameliorated this effect of MK-801 on PV(+) interneurons in the hippocampus, but led to a marked reduction of PV immunoreactivity in the prefrontal cortex, when comparing with saline, MK-801 or haloperidol treatment alone. Neither calretinin immunoreactivity nor nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase staining, representing neuronal nitric oxide synthase activity mostly detectable in interneurons, was altered by either treatment. With special reference to the hippocampus, these data show that a prolonged application of low-dose NMDA receptor antagonist could, in part, mimic some neuropathologic findings in human schizophrenia, thus strengthening the idea that (sub-) chronic NMDA receptor antagonism in animals is a viable approach in mimicking aspects of schizophrenia. Moreover, this study provides further evidence for regional differences in the response of GABAergic interneurons to NMDA receptor antagonism and antipsychotic treatment.
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PMID:Alterations of hippocampal and prefrontal GABAergic interneurons in an animal model of psychosis induced by NMDA receptor antagonism. 1760 3

The aim of the study was to examine the association of arachidonic acid-related signal transduction with cerebral metabolism in patients with schizophrenia who have violently and dangerously offended while psychotic. Cerebral 31-phosphorus magnetic resonance spectroscopy was carried out in 11 male patients with schizophrenia who had violently offended (homicide, attempted murder, or wounding with intent to cause grievous bodily harm) while psychotic. Spectra were obtained from 70 x 70 x 70 mm(3) voxels using an image-selected in vivo spectroscopy pulse sequence. Niacin flush testing results were quantified as the volumetric niacin response. There was a strong, and negative, correlation between the volumetric niacin response and the metabolite concentration of inorganic phosphate expressed as a ratio of the total 31-phosphorus signal (p<0.005). Our results suggest that patients with schizophrenia who have violently offended and have poor phospholipid-related signal transduction may have higher levels of cerebral energy metabolism.
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PMID:Negative correlation between cerebral inorganic phosphate and the volumetric niacin response in male patients with schizophrenia who have seriously and dangerously violently offended: a (31)P magnetic resonance spectroscopy study. 1776 31

Accumulating evidence suggests that both homocysteine metabolism and monoaminergic neurotransmitter systems are important in schizophrenia pathology. We hypothesized that the gene PNPO (pyridoxine 5'-phosphatase oxidase gene) might be a candidate for susceptibility to schizophrenia because PNPO encodes pyridoxamine 5'-phosphate oxidase (EC 1.4.3.5), a rate-limiting enzyme in pyridoxal 5'-phosphate (PLP, vitamin B(6)) synthesis. PLP is a metabolically-active form of vitamin B(6) and thus, is required as a co-factor for enzymes involved in both homocysteine metabolism and synthesis of neurotransmitters such as catecholamine. We examined 8 single nucleotide polymorphisms (SNPs) in PNPO and its 5'-flanking regions in 359 schizophrenia patients and 582 control subjects. Four marker regions of PNPO showed significant levels of allelic associations with schizophrenia (the highest was rs2325751, P=0.004). In addition, the haplotype case-control study revealed a significant association (permutation P<0.00001) between PNPO and schizophrenia. These findings suggest that variations in PNPO may contribute to overall genetic risk for schizophrenia in the Japanese population.
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PMID:Association between PNPO and schizophrenia in the Japanese population. 1785 Oct 41


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