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)

Nitric oxide (NO) is a highly diffusible cellular mediator generated from L-arginine by the enzyme nitric oxide synthase (NOS). As little is known about the regional distribution of NOS in the human brain, we examined the distribution pattern of nitric oxide synthase activity in 28 regions of the human brain using the [(3)H]L-citrulline formation assay. To elucidate which isoforms contribute to the total NOS activity we performed Western blot analysis of neuronal, inducible and endothelial NOS. We further determined brain levels of arginine and citrulline as a potential index of NOS activity pre mortem. NOS activity appears to remain unaltered during ageing and is independent of post mortem delay, gender or sample storage time. We identified a regional pattern of NOS distribution with highest levels of NOS activity in the substantia innominata, cerebellar cortex, nucleus accumbens and subthalamicus, whereas lowest levels were measured in the corpus callosum, thalamus, occipital cortex, and dentate nucleus. nNOS was measured throughout the brain, in contrast iNOS and eNOS were not detectable. We therefore conclude that primarily nNOS is responsible for NOS activity in the human brain. Levels of citrulline were higher than those of arginine, but did not correlate with the enzyme activity, suggesting that these parameters are unsuitable for testing NOS activity premortem. The characterization and topographical pattern of NOS in the human brain during normal ageing may assist our understanding of the physiological role of NO and its relevance in Parkinson's and Alzheimer's disease, alcoholism, schizophrenia and AIDS.
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PMID:Characterization and regional distribution of nitric oxide synthase in the human brain during normal ageing. 1040 1

The neonatal destruction of the ventral hippocampus was introduced as a model to recreate features of schizophrenia in the rat. While behavioral consequences of this intervention have been studied in detail, less is known about the cellular processes underlying the deviant behavior. We studied in rats (neonatally or adult lesioned, controls) brain areas receiving or not receiving hippocampal projections. The number of neurons and the expression of the cell markers L-ornithine decarboxylase, nitric oxide synthase/NADPH diaphorase, calretinin and GFAP were estimated. Reduced numbers of neurons and increased immunostaining for ornithine decarboxylase and nitric oxide synthase in the prefrontal, perirhinal and entorhinal cortex of neonatally but not adult lesioned rats or controls demonstrate persistent cellular changes after ventral hippocampus damage.
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PMID:Cellular changes in rat brain areas associated with neonatal hippocampal damage. 1043 54

NADPH-d (nicotinamide-adenine dinucleotide phosphate-diaphorase) neurons are thought to migrate improperly during development in the brains of schizophrenic patients. This enzyme is a nitric oxide synthase (NOS). Nitric oxide (NO) is known to affect neurodevelopmental processes in the CNS. Therefore, we hypothesized that interference of NO generation during development may produce some aspects of schizophrenia symptomatology in a rat model. In these experiments, neonatal rats were challenged with a NOS inhibitor (L-nitroarginine 1-100 mg/kg s.c.) daily on post-natal days 3-5. L-Nitroarginine (L-NoArg) treated male rats developed a hypersensitivity to amphetamine in adulthood versus vehicle treated controls, whereas female rats did not. However, L-NoArg treated female rats developed a hypersensitivity to phencyclidine (PCP) at juvenile and adult ages versus vehicle treated controls, whereas male animals did not. L-NoArg treated male rats also had deficits in pre-pulse inhibition of startle whereas adult female rats did not. The results are discussed in terms of a new neurodevelopmental model of schizophrenia and male/female differences inherent in this disease.
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PMID:On the effect of neonatal nitric oxide synthase inhibition in rats: a potential neurodevelopmental model of schizophrenia. 1047 Oct 83

1. The neurodevelopmental hypothesis of schizophrenia postulates that disturbed nitric oxide (NO) function during neuronal development is one of premorbid factors for schizophrenia in later life. 2. The aim of present study is to investigate behaviorally whether neonatal inhibition of nitric oxide synthase (NOS) affects dopaminergic function, the abnormality of which may be ascribed to a major pathophysiology of schizophrenia. 3. Male rat pups were injected daily with NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), from postnatal day (PD) 1 to 14. 4. When methamphetamine (MAP) was challenged on PD42, MAP-induced stereotypy was significantly attenuated in the L-NAME treated rats. The development of sensitization to the stereotypy-inducing effect of MAP, however, was not prevented with neonatal L-NAME. 5. These results suggest that decreased NO production during neonatal period may disturb normal maturation of dopaminergic system and result in impaired dopaminergic function in adult period.
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PMID:Neonatal treatment with L-name (NG-nitro-L-arginine methyl ester) attenuates stereotyped behavior induced by acute methamphetamine but not development of behavioral sensitization to methamphetamine. 1104 41

Phencyclidine (PCP) is widely used as an animal model of schizophrenia. In rats, acute PCP treatment increased locomotor activity and induced stereotyped behaviours consisting of head weaving, turning and backpedalling. PCP had differential regional effects on c-fos expression in rat brain, suggesting different patterns of neuronal activity. The most prominent immunostaining was observed in the cortical regions. To elucidate the role of nitric oxide, an important intracellular messenger, in the mechanism of action of PCP the effects of nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) were studied in PCP-treated animals. L-NAME potentiated PCP-induced behaviours and c-fos expression in many brain regions. The greatest increases were observed in the frontal, retrosplenial granular cortex, cerebellum, thalamic and subthalamic nuclei. While PCP alone induced low c-fos expression in the entorhinal cortex, with almost no expression in the rostral part of caudate putamen, animals pretreated with L-NAME showed marked activation in these brain areas. These results strongly indicate the involvement of the nitric oxide system in the mechanism of action of PCP.
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PMID:Effects of nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester on phencyclidine-induced effects in rats. 1109

This paper is a review of a recent findings on the pathology of hippocampal interneurons in schizophrenia, with specific emphasis on a protein expressed by these cells, the alpha7-nicotinic acetylcholine receptor subunit. Convergent information indicates that interneurons in the hippocampus and other forebrain structures are decreased in number and function in subjects with schizophrenia. Among the neurochemical markers that are decreased in the hippocampus are synapsin I, cholecystokinin, somatostatin, glutamic acid decarboxylase, and nitric oxide synthase. GABA uptake sites and the GABA synthetic enzyme glutamic acid decarboxylase are also diminished. Included among these findings is decreased binding of alpha-bungarotoxin, which binds to low-affinity nicotinic acetylcholine receptors, such as the alpha7-nicotinic receptor. Co-labeling experiments in rodents indicate that these markers are expressed on overlapping populations of hippocampal interneurons. Thus, the finding of decreased neurochemical function of hippocampal interneurons is a widely replicated finding, with different groups reporting markedly similar findings using independent post mortem samples and different neurochemical strategies. Decreased alpha-bungarotoxin binding or decreased alpha7-nicotinic receptor immunoreactivity has also been found in the frontal cortex and in the nucleus reticularis thalami of schizophrenic subjects. The alpha7-nicotinic receptor subunit gene on chromosome 15q14 is a site of heritability for schizophrenia and bipolar affective disorder, and in, particular, for a deficit in inhibitory neuronal function associated with these illnesses. Thus, the post mortem data are further supported by psychophysiologic and genetic investigations that indicate a deficit in inhibitory interneuronal function, involving the alpha7-nicotinic receptor. The alpha7-receptor is a ligand-gated ion channel that admits calcium ions into cells, and it has been proposed to have various developmental roles. Its malfunction may be part of the developmental pathogenesis of schizophrenia.
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PMID:The alpha7-nicotinic acetylcholine receptor and the pathology of hippocampal interneurons in schizophrenia. 1120 27

The effects of social isolation on prepulse inhibition of acoustic startle (PPI), electrophysiology and morphology of subicular pyramidal neurons and the densities of interneuronal sub-types in the hippocampal formation were examined. Wistar rats (male weanlings) were housed socially (socials, n=8) or individually (isolates, n=7). When tested eight weeks later, PPI was lower in isolates. Rats then received terminal anaesthesia before slices of hippocampal formation were made in which the electrophysiological properties of a total of 108 subicular neurons were characterized. There were no differences in neuronal sub-types recorded in socials compared with isolates. Intrinsically burst-firing and regular spiking pyramidal neurons were examined in detail. There were no differences in resting membrane potential or input resistance in isolates compared with socials but action potential height was reduced and action potential threshold raised in isolates. A limited morphological examination of Neurobiotin-filled intrinsically burst-firing neurons did not reveal differences in cell-body area or in number of primary dendrites. Sections from the contralateral hemispheres of the same rats were stained with antibodies to calretinin, parvalbumin and the neuronal isoform of nitric oxide synthase (nNOS). In isolates, the density of calretinin positive neurons was increased in the dentate gyrus but unchanged in areas CA3, CA1 and subiculum. Parvalbumin and nNOS positive neuronal densities were unchanged. Hence in rats with environmentally induced reductions in PPI there are structural and functional abnormalities in the hippocampal formation. If the reduction in PPI stems from these abnormalities, and reduced PPI in rats is relevant to schizophrenia, then drugs that correct the reported electrophysiological changes might have antipsychotic effects.
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PMID:Structural and functional abnormalities of the hippocampal formation in rats with environmentally induced reductions in prepulse inhibition of acoustic startle. 1124 47

Changes in the interaction between dopaminergic and GABAergic systems in the striatum have been suggested to be important in the pathology of schizophrenia. If that hypothesis is correct, these changes could produce inter-related changes in the dopaminergic and GABAergic systems in the striatum from schizophrenic subjects. To test this proposition we measured important markers on dopaminergic and GABAergic neurons in striatum obtained post-mortem from schizophrenic and non-schizophrenic subjects. There was a significant decrease in the density of the dopamine transporter (mean+/-SEM: 230+/-31 vs. 334+/-22fmol/mg ETE; P=0.01), but not nitric oxide synthase, dopamine D(2)-like, D(1)-like, D(3) or GABA(A) receptors in subjects with schizophrenia. There were no inter-related changes in the dopaminergic or GABAergic markers. In the schizophrenic subjects, the density of dopamine D(1)-like receptors decreased with age and was positively correlated with the density of dopamine D(2)-like receptors. This study does not readily add weight to the hypothesis that changes in the interaction between dopamine and GABA in the striatum are important in the pathology of schizophrenia. However, our findings could indicate that changes in the dopamine transporter within the striatum, either because of decreased transporter numbers per se or as a result of innervating neuronal loss, may be involved in the pathology of the illness.
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PMID:Studies on dopaminergic and GABAergic markers in striatum reveals a decrease in the dopamine transporter in schizophrenia. 1159 97

Nitric oxide (NO), a molecular messenger synthesized by nitric oxide synthase (NOS) from L-arginine and molecular oxygen, is involved in a number of physiological and pathological processes in mammalians. Three structurally distinct isoforms of NOS have been identified: neuronal (nNOS), endothelial (eNOS) and inducible (iNOS). Although NO mediates several physiological functions, overproduction of NO by nNOS has been reported in a number of clinical disorders including acute (stroke) and chronic (schizophrenia, Alzheimer s, Parkinson s and AIDS dementia) neurodegenerative diseases, convulsions and pain; overproduction of NO by iNOS has been implicated in various pathological processes including septic shock, tissue damage following inflammation and rheumatoid arthritis. On the contrary, NO produced by eNOS has only physiological roles such as maintaining physiological vascular tone. Accordingly, selective inhibition of nNOS or iNOS vs eNOS may provide a novel therapeutic approach to various diseases; in addition selective inhibitors may represent useful tools for investigating other biological functions of NO. For these reasons, after the identification of N-methyl-L-arginine (L-NMA) as the first inhibitor of NO biosynthesis, design of selective NOS inhibitors has received much attention. In this article the recent developments of new molecules endowed with inhibitory properties against the various isoforms of NOS are reviewed. Major focus is placed on structure-activity-selectivity relationships especially concerning compounds belonging to the non-amino acid-based inhibitors.
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PMID:Progress in the development of selective nitric oxide synthase (NOS) inhibitors. 1181 67

There is growing interest in the cerebellum as a site of neuropathological changes in schizophrenia. Reports showing that schizophrenics have higher nitric oxide synthase (NOS) activity and MAPKinase levels in the vermis, point to possible aberrations in the cerebellar signal transduction of schizophrenics. It has been speculated that Ca(2+)-dependent extracellular to intracellular signal transduction may be disrupted in the cerebellum of schizophrenics. We decided to test this hypothesis by studying the nitrergic system and markers of the Ca(2+)-triggered signal cascade in the cerebellum of schizophrenics, depressives and controls. The cellular distribution of two calcium sensor proteins (VILIP-1 and VILIP-3) and of neuronal NOS immunoreactivity was studied morphometrically in the flocculonodulus, the inferior vermis and the dentate nucleus of 9 schizophrenics, 7 depressive patients and 9 matched controls. In comparison to controls and depressed patients there were fewer Nissl-stained neurons in the dentate nucleus of schizophrenics. The number of NOS-expressing Purkinje neurons was however strongly increased. In the flocculonodulus and the vermis no differences between the groups were found with regard to the density of Nissl-stained Purkinje cells. The number of NOS-expressing Purkinje neurons was increased in schizophrenics, however. No differences between schizophrenics, depressives and controls were found in the number of VILIP-1 immunoreactive dentate nucleus neurons and VILIP-3 immunoreactive vermal and flocculonodular Purkinje cells. Our data provide further histochemical evidence in favor of structural abnormalities in discrete cerebellar regions of schizophrenics. They confirm and extend earlier reports of increased cerebellar NOS immunoreactivity in schizophrenia and point to possible neurodevelopmental disturbances. Our failure to show an altered expression of two calcium sensor proteins possibly points to a less important role of calcium signaling in cerebellar pathology of the disease.
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PMID:Increased number of nitric oxide synthase immunoreactive Purkinje cells and dentate nucleus neurons in schizophrenia. 1211 54


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