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)

Amino acid metabolism in endogenous psychoses has been discussed in relation to monoamine synthesis. There are no consistent findings which prove altered monoamine syntheses to be the primary change. Our finding, which suggests decreased amino acid transport across the blood-brain barrier in schizophrenia, does not necessarily mean an insufficient amino acid supply to the brain. Several lines of investigation have shown the possibility of the involvement of glutamatergic dysfunction in the pathogenesis of schizophrenia. Our recent finding of decreased CSF asparagine concentration in schizophrenia and its positive correlation with the response to neuroleptics may support this hypothesis. Recently, free D-serine, an allosteric agonist on NMDA-receptor, has been reported to exist in the rat brain, suggesting that D-serine is an intrinsic ligand. The pathogeneses of endogenous psychoses might be studied in terms of disturbed metabolism of amino acid, as allosteric regulater of neuro-receptor, as well as neurotransmitter and precursor of monoamines.
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PMID:[Amino acid metabolism in endogenous psychoses: significance of amino acids as neurotransmitter, precursor of monoamines and allosteric regulator of neuro-receptors]. 135 4

We have measured the concentrations of free D-serine post-mortem in the prefrontal cortex, parietal cortex, cerebellum and spinal cord from individuals with and without (controls) neuropsychiatric diseases using high-performance liquid chromatography with fluorometric detection. The levels of D-serine were found to be high in the prefrontal and parietal cortex (around 100 nmol/g wet weight) and very low in the cerebellum and spinal cord (below 10 nmol/g wet weight). The uneven distribution of the D-amino acid in the human central nervous system (CNS) resembles that observed in rodents, suggesting that, as shown in the rat CNS, the regional variation of D-serine content in the human brain might also be closely correlated with those of the N-methyl-D-aspartate (NMDA) type excitatory amino acid receptor. In the prefrontal cortex, the gray and white matter had a similar concentration of D-serine. These findings, together with the selective action of D-serine at the NMDA-related glycine site and the non-neurogenic nature of extracellular D-serine release, add further support to the view that D-serine could be an intrinsic modulator of the NMDA receptor liberated from certain glial cells in the mammalian brain. Despite the anti-psychotogen activity of D-serine in the rat, there were no statistically significant differences between the D-serine contents in the prefrontal or parietal cortex of controls and those of patients with schizophrenia or dementia of the Alzheimer type.
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PMID:Free D-serine in post-mortem brains and spinal cords of individuals with and without neuropsychiatric diseases. 755 68

It is well known that the un-competitive N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine can induce a syndrome in humans that mimics both positive and negative symptoms of schizophrenia. In the light of this observation, it has been hypothesised that schizophrenia might be due to a hypofunction of central glutamate systems. A glycine agonist, by strengthening glutamatergic transmission, has been suggested to be useful as treatment. A crucial issue is the uncertainty regarding the degree of saturation of the glycine site associated with the NMDA receptor. The purpose of this study was to investigate if it is possible to strengthen NMDA receptor-mediated neurotransmission by modulating the associated glycine site. The effects of systemic and intraventricular administration of glycine. D-serine and L-serine on the hyperactivity induced in mice by the uncompetitive NMDA receptor antagonist MK-801 were tested. Systemically administered glycine and D-serine were found to decrease MK-801-induced hyperactivity. Intraventricularly administered D-serine in doses of 50 or 100 micrograms/side was found to decrease MK-801-induced hyperactivity during the second half hour of registration; L-serine given in the same doses did not affect the MK-801-induced hyperactivity during this period. These data may suggest that the NMDA receptor-associated glycine site is not saturated in vivo.
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PMID:Glycine and D-serine decrease MK-801-induced hyperactivity in mice. 950 65

Exposure of food proteins to certain processing conditions induces two major chemical changes: racemization of all L-amino acids to D-isomers and concurrent formation of cross-linked amino acids such as lysinoalanine. Racemization of L-amino acids residues to their D-isomers in food and other proteins is pH-, time-, and temperature-dependent. Although racemization rates of the 18 different L-amino acid residues in a protein vary, the relative rates in different proteins are similar. The diet contains both processing-induced and naturally formed D-amino acids. The latter include those found in microorganisms, plants, and marine invertebrates. Racemization impairs digestibility and nutritional quality. The nutritional utilization of different D-amino acids varies widely in animals and humans. In addition, some D-amino acids may be both beneficial and deleterious. Thus, although D-phenylalanine in an all-amino-acid diet is utilized as a nutritional source of L-phenylalanine, high concentrations of D-tyrosine in such diets inhibit the growth of mice. Both D-serine and lysinoalanine induce histological changes in the rat kidney. The wide variation in the utilization of D-amino acids is illustrated by the fact that whereas D-methionine is largely utilized as a nutritional source of the L-isomer, D-lysine is totally devoid of any nutritional value. Similarly, although L-cysteine has a sparing effect on L-methionine when fed to mice, D-cysteine does not. Because D-amino acids are consumed by animals and humans as part of their normal diets, a need exists to develop a better understanding of their roles in nutrition, food safety, microbiology, physiology, and medicine. To contribute to this effort, this multidiscipline-oriented overview surveys our present knowledge of the chemistry, nutrition, safety, microbiology, and pharmacology of D-amino acids. Also covered are the origin and distribution of D-amino acids in the food chain and in body fluids and tissues and recommendations for future research in each of these areas. Understanding of the integrated, beneficial effects of D-amino acids against cancer, schizophrenia, and infection, and overlapping aspects of the formation, occurrence, and biological functions of D-amino should lead to better foods and improved human health.
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PMID:Chemistry, nutrition, and microbiology of D-amino acids. 1055 72

High levels of D-serine are found in mammalian brain, where it is an endogenous agonist of the strichinine-insensitive site of N-methyl D-aspartate type of glutamate receptors. D-serine is enriched in protoplasmic astrocytes that occur in gray matter areas of the brain and was shown to be synthesized from L-serine. We now report cloning and expression of human serine racemase, an enzyme that catalyses the synthesis of D-serine from L-serine. The enzyme displays a high homology to the murine serine racemase. It contains a pyridoxal 5'-phosphate attachment sequence similar to bacterial biosynthetic threonine dehydratase. Northern-blot analysis show high levels of human serine racemase in areas known to contain large amounts of endogenous D-serine, such as hippocampus and corpus callosum. Robust synthesis of D-serine was detected in cells transfected with human serine racemase, demonstrating the conservation of D-amino acid metabolism in humans. Serine racemase may be a therapeutic target in psychiatric diseases as supplementation of D-serine greatly improves schizophrenia symptoms. We identify the human serine racemase genomic structure and show that the gene encompasses seven exons and localizes to chromosome 17q13.3. Identification of the intron-exon boundaries of the human serine racemase gene will be useful to search for mutations in neuropsychiatric disorders.
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PMID:Human serine racemase: moleular cloning, genomic organization and functional analysis. 1105 47

The study of excitatory amino acids (EAA) [e.g. glutamate (Glu), aspartate] as neurotransmitters has resulted in many new and fundamental concepts in neuroscience. Much of this progress centres upon the role of N-methyl-D-aspartate (NMDA) subtype of Glu receptors in central nervous system synaptic transmission and plasticity. A leading hypothesis suggests that deficits in NMDA receptor-mediated neurotransmission may be central to the pathophysiology of schizophrenia. The conceptual foundation of this hypothesis derives from the clinical effects of NMDA receptor antagonists, such as phencyclidine (PCP) and ketamine and from post-mortem findings in brain samples of schizophrenia patients. Consequently, at present there is an intense search for pharmacological strategies capable of facilitating NMDA receptor function in this illness. During the last decade, a first generation of small clinical studies has focused on assessing the therapeutic potential of glycine-(Gly) site agonists of the NMDA receptor, such as Gly, D-serine and D-cycloserine. The results of these studies indicate that this type of compound may reduce negative symptoms and executive cognitive deficits in schizophrenia patients. Furthermore, preliminary findings suggest that patients having low serum Gly levels may represent the population of choice for treatment with Gly-site agonists. Additional potential schizophrenia treatments that may affect mainly NMDA receptor neurotransmission are : (i) other full and partial Gly-site agonists - in course of development for clinical use, and (ii) Gly transport antagonists that can inhibit Gly reuptake from neuronal synapses. Moreover, the antipsychotic action of some typical and atypical neuroleptics may be mediated by their agonistic activity at the strychnine-insensitive NMDA receptor-associated Gly site. After decades of relative neglect, the role of glutamatergic neurotransmission in the pathophysiology and therapeutics of schizophrenia is presently in process of conceptualization. In this context, it is likely that the development of NMDA receptor-based approaches for the treatment of this illness will continue. This trend is already supported by available clinical findings with Gly-site agonists and may herald an important, innovative development in the pharmacological treatment of neuropsychiatric syndromes.
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PMID:N-Methyl-D-aspartate (NMDA) receptor-based treatment approaches in schizophrenia: the first decade. 1134 2

Persistent negative symptoms are a major cause of chronic disability in schizophrenia. The primary management approach for negative symptoms is use of atypical antipsychotics. Among atypical antipsychotics, clozapine produces the most robust reductions in negative symptoms. Lesser degrees of reduction are observed with risperidone and olanzapine. However, it remains unclear whether these agents treat core negative symptoms of schizophrenia, or simply induce less secondary psychopathology. A second approach for treatment of persistent negative symptoms is the use of N-methyl-D-aspartate (NMDA) receptor-stimulating agents, such as glycine, D-serine, or D-cycloserine. Significant benefit of these agents has been observed in combination with both conventional and newer atypical antipsychotics. Whether or not these agents are effective in combination with clozapine remains an open question, and large scale multicenter clinical trials are ongoing.
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PMID:Management of negative symptoms of schizophrenia. 1155 79

N-methyl-D-aspartate (NMDA) receptor dysfunction may play a key role in the pathophysiology of schizophrenia. Recent studies have investigated the ability of NMDA/glycine-site modulators to ameliorate persistent negative and cognitive symptoms. Several full or partial glycine-site agonists, including glycine, D-serine and D-cycloserine, have shown effectiveness in small-scale clinical trials. Glycine levels in brain are regulated by GLYT1-type glycine transporters. Recently developed glycine transport inhibitors (GTI) have preclinical behavioral effects similar to those of glycine or D-serine, and may represent a 'next generation' approach to the treatment of the persistent negative and cognitive symptoms of schizophrenia.
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PMID:Glycine modulators in schizophrenia. 1218 69

The N-methyl-D-aspartate (NMDA) receptor (NMDA-R) has pivotal roles in neural development, learning, memory, and synaptic plasticity. Functional impairment of NMDA-R has been implicated in schizophrenia. NMDA-R activation requires glycine to act on the glycine-B (GlyB) site of the NMDA-R as an obligatory co-agonist with glutamate. Extracellular glycine near NMDA-R is regulated effectively by a glial glycine transporter (GlyT1). Using whole-cell voltage-clamp recordings in prefrontal cortex (PFC) slices, we have shown that exogenous GlyB site agonists glycine and D-serine, or a specific GlyT1 inhibitor N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS) in the presence of exogenous glycine (10 microM), potentiated synaptically evoked NMDA excitatory postsynaptic currents (EPSCs) in vitro. Furthermore, in urethan-anesthetized rats, microiontophoretic NMDA pulses excite single PFC neurons. When these responses were blocked by approximately 50% to approximately 90% on continuous iontophoretic application of the GlyB site, antagonist (+)HA-966, intravenous NFPS (5 mg/kg), or a GlyB site agonist D-serine (50 mg/kg iv) reversed this (+)HA-966 block. NFPS may elevate endogenous glycine levels sufficiently to displace (+)HA-966 from the GlyB sites of the NMDA-R, thus enabling reactivation of the NMDA-Rs by iontophoretic NMDA applications. D-Serine (50-100 mg/kg iv) or NFPS (1-2 mg/kg iv) alone also augmented NMDA-evoked excitatory responses. These data suggest that direct GlyB site stimulation by D-serine, or blockade of GLYT1 to elevate endogenous glycine to act on unsaturated GlyB sites on NMDA-Rs, potentiated NMDA-R-mediated firing responses in rat PFC. Hence, blockade of GlyT1 to elevate glycine near the NMDA-R may activate hypofunctional NMDA-R, which has been implicated to play a critical role in the pathophysiology of schizophrenia.
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PMID:Glycine tranporter-1 blockade potentiates NMDA-mediated responses in rat prefrontal cortical neurons in vitro and in vivo. 1257 47

Although valuable antischizophrenic drugs exist, they only partially ameliorate symptoms and elicit substantial side effects. Classic neuroleptic drugs act by blocking dopamine receptors. They can relieve some symptoms but not behavioral withdrawal features that are designated "negative" symptoms. Clozapine and related newer atypical neuroleptics may be more efficacious in relieving negative symptoms. Understandng their actions may facilitate new drug discovery. Agents influencing glutamate neurotransmission and N-methyl-D-aspartate receptors, especially the cotransmitter D-serine, are promising. Stimulation of the alpha7 subtype of nicotinic acetylcholine receptor may also be efficacious. The search for genes linked to schizophrenia has revealed several leads that may permit development of novel therapeutic agents. Promising genes include disrupted-in-schizophrenia-1, dysbindin, and neuregulin.
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PMID:Schizophrenia: neural mechanisms for novel therapies. 1276 34


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