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)

An alteration of dopaminergic transmission in the brain has been proposed for schizophrenia. To explore this, the rate constant for the intransport of L-tyrosine across the blood-brain barrier in healthy controls and in patients with schizophrenia (DSM-III-R) was determined with PET and L-[1-11C] tyrosine as the tracer. Kinetics for tyrosine transport were determined according to a two-compartment model using radioactivity data of arterial blood and brain tissue sampled between 1 and 3.5 min after a bolus injection of L-[1-11C] tyrosine. Radioactivity was measured every second in the blood and in 10-sec intervals in the brain tissue. In the normal controls the brain intransport rate constant for tyrosine was 0.052 ml/g/min with an influx rate of 2.97 nmol/g/min. The patients had a similar intransport rate constant (0.045 ml/g/min) but a lower influx rate of tyrosine 1.95 nmol/g/min (p less than 0.05). The patients' tyrosine concentrations in the blood were lower. For data sampled between 5 and 25 min, the net accumulation rate of tyrosine into the brain was 0.015 ml/g/min in the controls which did not differ to the patients' rate. However, the net utilization of tyrosine was lower in the patients (0.672 nmol/g/min) than in the controls (0.883 nmol/g/min) despite similar tissue concentrations of tyrosine.
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PMID:The transport of tyrosine into the human brain as determined with L-[1-11C]tyrosine and PET. 194 Nov 37

The ventral mesencephalons of hamster, guinea pig, cat, monkey, and several humans with and without the diagnosis of schizophrenia were analyzed with in situ hybridization and immunohistochemistry. Extensive codistribution of cholecystokinin mRNA and tyrosine hydroxylase [L-tyrosine, tetrahydropteridine: oxygen oxidoreductase (3-hydroxylating), EC 1.14.16.2] mRNA was observed in cats and monkeys as well as in all five human subjects with the diagnosis of schizophrenia and in two out of five control brains. Double labeling revealed coexistence of the two markers in cat, monkey, and human. No cholecystokinin mRNA or cholecystokinin peptide was detected in the substantia nigra/ventral tegmental area of the hamster or guinea pig, even after acute and chronic neuroleptic treatment.
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PMID:Analysis of expression of cholecystokinin in dopamine cells in the ventral mesencephalon of several species and in humans with schizophrenia. 197 24

We have determined the erythrocyte membrane uptake of the monoamine precursors L-tyrosine (L-TYR) and L-tryptophane (L-TRYP) in 72 patients with schizophrenia: 21 without neuroleptic treatment and not depressed, 15 with neuroleptic treatment and depressed, 33 without neuroleptic treatment, 27 depressed, compared to: 59 control subjects, and 54 depressed patients. We found that the ratio of L-TYR facilitated membrane diffusion to that of L-TRYP is: decreased when the patients are depressed, increased when they are untreated. When untreated patients receive neuroleptics and are depressed, the ratio tends to equal that of depressed patients'. The meaning of these anomalies is analysed, using our up-to-date knowledge of the erythrocytes's role in uptaking and dispatching the human body amino-acids, and of the role of these uptakes in regulating the functional monoamine balance. We postulate that in depressions, Parkinson's disease and schizophrenia, a change of membrane fluidity occurs, being decreased in depressions and Parkinsons's disease, and increased in schizophrenia.
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PMID:[Erythrocyte membrane transports of monoamine precursor amino acids in schizophrenia]. 204 99

The utility of L-tyrosine (10 g/day in four divided doses) as an adjuvant to molindone (150 mg/day) in the treatment of schizophrenia was investigated using a placebo-controlled, double-blind crossover design (3 weeks on L-tyrosine, 3 weeks on placebo). The objective of this inpatient study was to increase dopaminergic neural transmission along mesocortical projections in patients by increasing the precursor availability of L-tyrosine for dopamine biosynthesis. Theoretically, this approach might lessen both negative and positive symptoms of schizophrenia and improve frontal lobe-mediated neuropsychological performance. There was no evidence of statistically significant improvement conferred by L-tyrosine as measured by weekly Brief Psychiatric Rating Scale (BPRS), Schedule for the Assessment of Negative Symptoms (SANS), or Clinical Global Impressions (CGI) scales. The 12-h trough plasma level of L-tyrosine was significantly higher in all patients during the L-tyrosine phase of the study (t = -3.9, df = 20, p = 0.0009). At the end of each 3-week study period, no significant differences could be found in Wisconsin Card Sorting Test (WCST) or memory test performance. Smooth-pursuit eye movement (SPEM) performance had significantly more saccadic intrusions during the L-tyrosine supplementation phase compared to the placebo period. This increase in saccades during SPEM suggests that the tyrosine supplementation might have had some central effect.
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PMID:L-tyrosine pharmacotherapy of schizophrenia: preliminary data. 814 60

TH is a tetrahydrobiopterin-requiring, iron-containing monooxygenase. It catalyses the conversion of L-tyrosine to L-dopa, which is the first, rate-limiting step in the biosynthesis of catecholamines (dopamine, noradrenaline and adrenaline), the central and sympathetic neurotransmitters and adrenomedullary hormones. The cofactor of TH is tetrahydrobiopterin, which is synthesized from GTP in three steps. The TH gene consists of 14 exons only in humans and 13 exons in animals. Human TH exists in four isoforms (hTH1-4) that are produced by alternative mRNA splicing from a single gene. A single mRNA and protein corresponding to hTH1 exists in non-primates. Monkey TH exists in two isoforms, corresponding to hTH1 and hTH2. TH activity is regulated in the short term by feedback inhibition of catecholamines in competition with tetrahydrobiopterin, and by activation and deactivation due to phosphorylation and dephosphorylation, mainly at Ser-19 and Ser-40 of hTH1. The multiple TH isoforms in humans and monkeys have additional phosphorylation, resulting in more subtle regulation. In long-term regulation under stress conditions, TH protein is induced. CRE and AP1 in the 5' flanking region of the TH gene may be the main functional elements for TH gene expression. TH may be closely related to the pathogenesis of neurological diseases, such as dystonia and Parkinson's disease, psychiatric diseases, such as affective disorders and schizophrenia, as well as cardiovascular diseases. The TH gene may prove useful in gene therapy to compensate for decreased levels of catecholamines in neurological diseases, for example, for supplementation of dopamine in Parkinson's disease.
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PMID:Tyrosine hydroxylase: human isoforms, structure and regulation in physiology and pathology. 882 46

Previous PET studies of tyrosine transport have suggested that the transport of tyrosine from blood to brain compartment is not dependent on its plasma concentration in patients with schizophrenia. In order to examine this relationship, the transport constant (K1) of tyrosine was determined in five patients with schizophrenia and five normals. L-[1-11C]Tyrosine was injected i.v. and arterial blood samples were taken during PET scanning. The tyrosine transport was assessed during baseline conditions and after oral administration of L-tyrosine at a dose (175 mg/kg) that significantly elevated the plasma levels. K1 was determined from tracer kinetic modelling. The transport rate dropped in the normals after tyrosine loading, which is consistent with the prevailing notion that the brain transport system for neutral amino acids works close to saturation, whereas it was virtually unchanged in the schizophrenics. The results demonstrated that tyrosine transport was not saturated in the patients with schizophrenia and thus could lead to elevated brain concentrations of tyrosine.
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PMID:Tyrosine transport is regulated differently in patients with schizophrenia. 1054 Oct 5

We studied the effects of a new dipeptide neuroleptic Dilept (N-caproyl-L-prolyl-L-tyrosine methyl ester) on activity of neurotransmitter systems in the brain. Dilept possessed antidopamine, glutamate modulatory, and cholinomimetic properties. These data indicate that Dilept is of potential efficacy in relieving positive and negative symptoms of schizophrenia.
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PMID:Neuromodulatory mechanism underlying the effect of the atypical dipeptide neuroleptic dilept. 1496 62

The effect of N-caproyl-L-prolyl-L-tyrosine methyl ester (GZR-123, Dilept), a new antipsychotic drug with a dipeptide structure, on cognitive functions was studied using the passive avoidance conditioned reflex (PACR) test. It was found that the drug improved both the acquisition and retrieval of PACR under the conditions of undertraining and prevented the amnesic effect of transcorneal electroshock. The neurotransmitter analysis of these effects using the corresponding blockers showed the ability of dilept to facilitate the central glutamatergic (NMDA type) and cholinergic (of both muscarine and nicotine types) neurotransmission. No evidence of the involvement of the GABAergic system was observed. The experimental data on the combination of antipsychotic effect with memory improving activity suggests that dilept may be effective in cases of negative symptoms of schizophrenia and psychotic manifestations in Alzheimer disease.
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PMID:[Dilept: a tripeptoid neurotensin analog combining neuroleptic activity with positive mnemotropic action]. 1578 54

Aberrant tyrosine transport across the fibroblast membrane, as measured by lower Vmax and/or lower Km is a repeated finding in patients with schizophrenia. The aim of this study was to investigate the importance of two major transporters, the L- and A-systems and tyrosine transport in fibroblast cell lines from patients with schizophrenia and healthy volunteers. Fibroblast cell lines, n=6 from healthy volunteers and n=6 from patients with schizophrenia, were included in the study. Uptake of [14-C] L-tyrosine in fibroblasts was measured using the cluster tray method in absence and presence of inhibitors. The uptake of tyrosine by the L-system was evaluated with the inhibitor 2-aminobicyclo heptane-2-carboxylic acid (BCH) and the A-system with the inhibitor nonmetabolized methyl-aminoisobutyric acid (MeAIB). Using [14-C] MeAIB the functionality of system A isoform 2, ATA2, was tested. BCH inhibited the uptake of tyrosine with 90%, showing that tyrosine transport in fibroblasts is mainly transported by the L-system. Not more than 10% could be contributed by the A-system. Excess of MeAIB did not influence tyrosine kinetics. Moreover, MeAIB kinetics did not differ between the patients and the controls. In conclusion, aberrant tyrosine transport observed in patients with schizophrenia is probably linked to the one of the L-systems and does not seem to involve the ATA2 transporter.
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PMID:Tyrosine transport in fibroblasts from healthy volunteers and patients with schizophrenia. 1627 28

Tridecapeptide neurotensin (NT) is known to exert the neuroleptic-like effects in case of its intracerebral administration. The group of systemically active dipeptides , acylprolyltyrosines, was constructed on the background of NT. Methyl ester of N-caproyl-L-prolyl-L-tyrosine (Dilept) was chosen for further development. The paper is dealing with main principles of Dilept'design and with analysis of the experimental data concerning its effect on the "translational" model of schizophrenia--the deficit of prepulse inhibition of the acoustic startle-reaction caused by either dopamine-mimetic, apomorphine, or by the uncompetitive NMDA-blocker, ketamine. Dilept was shown to attenuate these deficits both in case ofintraperitoneal and peroral administration. Dilept is considered as a potential antipsychotic.
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PMID:[The search of small molecules with antipsychotic activity on the background of neurotensin]. 2279 15


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