UMLS:C0030567 - FACTA Search

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Query: UMLS:C0030567 (Parkinson's disease)
63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dopaminergic receptors are widespread throughout the central and peripheral nervous systems, where they regulate a variety of physiological, behavioral, and endocrine functions. These receptors are also clinically important drug targets for the treatment of a number of disorders, such as Parkinson's disease, schizophrenia, and hyperprolactinemia. To date, five different dopamine receptor subtypes have been cloned and characterized. Many of these subtypes are pharmacologically similar, making it difficult to selectively stimulate or block a specific receptor subtype in vivo. Thus, the assignment of various physiological or behavioral functions to specific dopamine receptor subtypes using pharmacological tools is difficult. In view of this, a number of investigators have--in order to elucidate functional roles--begun to use highly selective genetic approaches to alter the expression of individual dopamine receptor subtypes in vivo. This review discusses recent studies involving the use of genetic approaches for the study of dopaminergic receptor function.
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PMID:New insights into dopaminergic receptor function using antisense and genetically altered animals. 1033 Oct 87

Preclinical studies have shown that quetiapine (Seroquel, AstraZeneca) is an atypical antipsychotic with many similarities to clozapine. Both placebo-controlled and comparative studies in patients with schizophrenia have demonstrated that quetiapine has long-term efficacy in both positive and negative domains, as well as beneficial effects on affective and cognitive symptoms. Comparative clinical studies confirm that quetiapine is at least as effective as the standard antipsychotics, chlorpromazine and haloperidol and response rates with quetiapine are similar to those reported with other atypical antipychotics. Quetiapine has also demonstrated superior efficacy to haloperidol in partially responsive patients, who can be particularly difficult to treat. Quetiapine has a wide clinical dosing range (150-750 mg/day), although doses of 400 mg or above should be used in patients who do not fully respond to lower doses of the drug. Quetiapine is generally well tolerated with no requirement for routine ECG or blood monitoring and it has minimal effects on weight. Uniquely among other first-line atypical antipsychotics, quetiapine is associated with a placebo-level incidence of EPS and an indistinguishable effect from placebo on plasma prolactin at all doses. Thus, clinicians can confidently increase the dose of quetiapine, without increasing the risk of EPS or hyperprolactinaemia. A number of studies have also shown that quetiapine is well-tolerated and effective in patients who are particularly susceptible to EPS, including elderly and adolescent patients and those with pre-existing dopaminergic pathology, such as Alzheimer's disease and Parkinson's disease. The consistent efficacy in treating all schizophrenic domains and good tolerability, particularly placebo-level EPS, make quetiapine acceptable to patients, as demonstrated in a survey of patient satisfaction. Thus quetiapine is a suitable first-line therapy for the treatment of schizophrenia and psychosis.
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PMID:Review of quetiapine and its clinical applications in schizophrenia. 1124 16

Dopamine is a small and relatively simple molecule that fulfills diverse functions. Within the brain, it acts as a classical neurotransmitter whose attenuation or overactivity can result in disorders such as Parkinson's disease and schizophrenia. Major advances in the cloning and characterization of biosynthetic enzymes, transporters, and receptors have increased our knowledge regarding the metabolism, release, reuptake, and mechanism of action of dopamine. Dopamine reaches the pituitary via hypophysial portal blood from several hypothalamic nerve tracts that are regulated by PRL itself, estrogens, and several neuropeptides and neurotransmitters. Dopamine binds to type-2 dopamine receptors that are functionally linked to membrane channels and G proteins and suppresses the high intrinsic secretory activity of the pituitary lactotrophs. In addition to inhibiting PRL release by controlling calcium fluxes, dopamine activates several interacting intracellular signaling pathways and suppresses PRL gene expression and lactotroph proliferation. Thus, PRL homeostasis should be viewed in the context of a fine balance between the action of dopamine as an inhibitor and the many hypothalamic, systemic, and local factors acting as stimulators, none of which has yet emerged as a primary PRL releasing factor. The generation of transgenic animals with overexpressed or mutated genes expanded our understanding of dopamine-PRL interactions and the physiological consequences of their perturbations. PRL release in humans, which differs in many respects from that in laboratory animals, is affected by several drugs used in clinical practice. Hyperprolactinemia is a major neuroendocrine-related cause of reproductive disturbances in both men and women. The treatment of hyperprolactinemia has greatly benefited from the generation of progressively more effective and selective dopaminergic drugs.
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PMID:Dopamine as a prolactin (PRL) inhibitor. 1173 29

Cabergoline is a synthetic ergoline dopamine agonist with a high affinity for D(2) receptors indicated for use in both early and advanced Parkinson's disease and in hyperprolactinaemic disorders. Following oral administration, peak plasma concentrations of cabergoline are reached within 2-3 hours. Over the 0.5-7mg dose range, cabergoline shows linear pharmacokinetics in healthy adult volunteers and parkinsonian patients. Cabergoline is moderately bound (around 40%) to human plasma proteins in a concentration-independent manner; concomitant administration of highly protein-bound drugs is unlikely to affect its disposition. The absolute bioavailability of cabergoline is unknown. Cabergoline is extensively metabolised by the liver, predominantly via hydrolysis of the acylurea bond of the urea moiety. Cytochrome P450-mediated metabolism appears to be minimal. The major metabolites identified thus far do not contribute to the therapeutic effect of cabergoline. A significant fraction of the administered dose undergoes a first-pass effect. Less than 4% is excreted unchanged in the urine. The elimination half-life of cabergoline estimated from urinary data of healthy subjects ranges between 63 and 109 hours. Mild to moderate renal and hepatic impairment, administration of food and the use of concomitant antiparkinsonian medications, such as levodopa and selegiline, have no effect on the pharmacokinetics of cabergoline.The pharmacokinetic properties of cabergoline allow once daily administration in patients with Parkinson's disease and twice weekly administration in patients with hyperprolactinaemia, making this drug advantageous over other dopaminergic agents in term of both therapeutic compliance and better symptom control.
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PMID:Clinical pharmacokinetics of cabergoline. 1284 25

Dopamine(DA), the most widely distributed in the nervous system and functionally important chemical signal, is synthesized in DA-ergic neurons from L-tyrosine by means of two enzymes, tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC). Apart from the enzymes, specific DA transporter is an attribute of DA-ergic neurons. In the mid eighties of the last century, in addition to DA-ergic neurons, those expressing only one enzyme, TH or AADC, have been discovered. These "monoenzymatic" neurons occurred to be more numerous and more widely distributed in the brain compared to DA-ergic neurons that manifests their wide involvement to the brain functioning. It has been demonstrated that the monoenzymatic neurons expressing complementary enzymes of DA synthesis produce this neurotransmitter in cooperation. In this case, L-tyrosine is transformed to L-DOPA in TH containing neurons that is followed by L-DOPA release and uptake from the intercellular space to AADC containing neurons for DA synthesis. Moreover, the L-DOPA uptake to DA-ergic or serotoninergic neurons results either in the increase or the onset of DA synthesis in addition to serotonin, respectively. The expression of the enzymes of DA synthesis in non-dopaminergic neurons is one of the adaptive reactions serving to compensate the functional insufficiency of DA-ergic neurons. For instance, hyperprolactinemia and the deficiency of DA, prolactin-inhibiting hormone, which is developed under degeneration of DA-ergic neurons of the arcuate nucleus, are compensated with time due to the increase of the number of monoenzymatic neurons and cooperative synthesis of DA in the nucleus. It is supposed that the same compensatory cooperative synthesis of DA is turned on under the degeneration of DA-ergic neurons of the nigrostriatal system that is manifested by the appearance of non-dopaminergic neurons expressing enzymes of DA synthesis in the deafferentated striatum. The expression of the enzymes of DA synthesis in non-dopaminergic neurons is under the control by intercellular signals, catecholamines, neurotrophic (growth) factors and, perhaps, hormones. Thus, non-dopaminergic monoenzymatic neurons expressing enzymes of DA synthesis produce this neurotransmitter in cooperation that is a compensatory reaction under functional insufficiency of DA-ergic neurons, in neurodegenerative diseases, hyperprolactinemia and Parkinson's disease, in particular.
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PMID:[Expression of the enzymes of dopamine synthesis in non-dopaminergic neurons: functional significance and regulation]. 1806 5

Drugs targeting dopamine receptors have been the focus of much research over the past 30 years, in large part because of their role in treating multiple pathological conditions including Parkinson's disease, schizophrenia, Tourette's syndrome, and hyperprolactinemia. Missense mutations in G protein-coupled receptors (GPCRs) can alter basal and/or ligand-induced signaling, which in turn can affect individuals' susceptibility to disease and/or response to therapeutics. To date, five coding variants in the human D1 receptor (hD1R; T37P, T37R, R50S, S199A, and A229T) and three in the human D2 receptor (hD2R; P310S, S311C, and T351A) have been reported in the NCBI single nucleotide polymorphism database. We utilized site-directed mutagenesis to generate cDNAs encoding these receptor isoforms. After expression in either HEK293 or neuronal GT1 cells, basal and ligand-induced signaling of each of these receptors was determined and compared to wild type. In addition, we investigated expression levels of each recombinant receptor and the effect of inverse agonist administration. Our data demonstrate that naturally occurring amino acid substitutions in the hD1R can lead to alterations in expression levels as well as in basal and ligand-induced signaling. The potency and efficacy of dopamine, synthetic agonists (i.e., fenoldopam, SKF-38393, SKF-82958, and SCH23390), and inverse agonists [i.e., flupenthixol and (+)butaclamol] were reduced at selected hD1R variants. Furthermore, inverse agonist induced effects on expression levels were sensitive to selected amino acid substitutions. In contrast to the hD1R variants, hD2R polymorphisms did not affect ligand function or receptor expression. The observation that the hD1R mutations induce significant alterations in pharmacologic properties may have implications both for disease susceptibility and/or therapeutic response to dopaminergic ligands.
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PMID:Pharmacological analysis of human D1 AND D2 dopamine receptor missense variants. 1821 Feb 31

Dopamine agonists have been associated with increased risk of cardiac valve regurgitation in patients with Parkinson's disease. Whether these drugs might be harmful for patients with hyperprolactinemia is still unsettled. Occasional case reports and 7 studies on the relationship between cabergoline and cardiac valve regurgitation have been published so far. Overall, cabergoline has been considered a safe therapy, although some studies suggested an increased prevalence of cardiac valve regurgitation. The aim of this meta-analysis was to assess the effects of cabergoline on cardiac valve regurgitation. Eligible studies were all trials using cabergoline in patients with either tumor or non-tumor hyperprolactinemia. Our search was updated to October 2008. Pooled data from the 6 selected studies showed that treatment with cabergoline was associated with increased risk of tricuspid valve regurgitation (fixed effects: prevalence ratio=1.40; 95% confidence interval: 1.17-1.67); on the contrary, patients treated with cabergoline and control subjects did not differ in prevalence of aortic or mitral valve regurgitation. This meta-analysis shows that patients with hyperprolactinemia treated with cabergoline are at increased risk of regurgitation of the tricuspid valve. However, regurgitation was only an echocardiographic finding since no patient had symptoms of valvular disease. This meta-analysis underscores that echocardiography is recommended in all patients with hyperprolactinemia who are candidate to be treated with or are under cabergoline therapy; monitoring cardiac valves is also recommended although precise follow- up for these patients will be likely provided by future longitudinal studies.
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PMID:Cabergoline therapy and the risk of cardiac valve regurgitation in patients with hyperprolactinemia: a meta-analysis from clinical studies. 1924 80

In contrast to monoaminergic (MA-ergic) neurons possessing the whole set of the enzymes for MA synthesis from the precursor amino-acid, some, mostly peptidergic, neurons co-express only one of the enzymes of monoamine synthesis. They are widely distributed in the brain, being particularly numerous in ontogenesis and, in adulthood, under certain physiological conditions. Most monoenzymatic neurons possess one of the enzymes for dopamine (DA) synthesis, tyrosine hydroxylase (TH) or aromatic L-amino acid decarboxylase (AADC). TH and AADC are enzymatically active in a substantial number of monoenzymatic neurons, where they are capable of converting L-tyrosine to L-3,4-dihydroxy-phenylalanine (L-DOPA) and L-DOPA to dopamine (DA) (or 5-hydroxy-tryptophan, 5-HTP to serotonin), respectively. According to our data L-DOPA synthesized in monoenzymatic TH-neurons is released and taken up by monoenzymatic AADC-neurons for DA synthesis. Moreover, L-DOPA captured by dopaminergic neurons and serotoninergic neurons serves to stimulate dopamine synthesis in the former and to start DA synthesis in the latter. Cooperative synthesis of MAs is considered as a compensatory reaction under a failure of MA-ergic neurons, e.g. in neurodegenerative diseases like hyperprolactinemia and Parkinson's disease, which are developed primarily because of degeneration of DA-ergic neurons of the tuberoinfundibular system and the nigrostriatal system, respectively. Noteworthy, the neurotoxin-induced increase of prolactin secretion returns with time to a normal level due to the stimulation of DA synthesis by the tuberoinfundibular most probably monoenzymatic neurons. The same compensatory mechanism is supposed to be used under the failure of the nigrostriatal DA-ergic system that is manifested by an increased number of monoenzymatic neurons in the striatum of animals with neurotoxin-induced parkinsonism and in humans with Parkinson's disease. Expression of the enzymes of MA synthesis in non-monoaminergic neurons is controlled by intercellular signals such as classical neurotransmitters (catecholamines), etc. Thus, a substantial number of brain neurons express partly the monoaminergic phenotype, namely individual complementary enzymes of MA synthesis, serving to produce MAs in cooperation, which is considered as a compensatory reaction under the failure of MA-ergic neurons.
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PMID:[Synthesis of monoamines by non-monoaminergic neurons: illusion or reality?]. 1935 13

The structural and functional organization of the cerebral dopaminergic system is considered. The synthesis of dopamine, distribution of dopaminergic structures, structure and classification of dopamin receptors in the brain, and functions of dopamine are discussed. Dopamin among the main catecholamine neurotransmitters participating in the control of locomotor activity, cognition, emotion, positive reinforcement, food intake, and endocrine regulation. Moreover, several neurological diseases such as Parkinson's disease, schizophrenia, and hyperprolactinemia are associated with dysregulation of dopaminergic neurotransmission. Therefore, the search for and development of new dopaminergic drugs is of great interest.
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PMID:[Structural and functional organization of the cerebral dopaminergic system]. 1964 93

Besides the dopaminergic (DA-ergic) neurons possessing the whole set of enzymes of DA synthesis from l-tyrosine and the DA membrane transporter (DAT), the neurons partly expressing the DA-ergic phenotype have been first discovered two decades ago. Most of the neurons express individual enzymes of DA synthesis, tyrosine hydroxylase (TH) or aromatic l-amino acid decarboxylase (AADC) and lack the DAT. A list of the neurons partly expressing the DA-ergic phenotype is not restricted to so-called monoenzymatic neurons, e.g. it includes some neurons co-expressing both enzymes of DA synthesis but lacking the DAT. In contrast to true DA-ergic neurons, monoenzymatic neurons and bienzymatic non-dopaminergic neurons lack the vesicular monoamine transporter 2 (VMAT2) that raises a question about the mechanisms of storing and release of their final synthetic products. Monoenzymatic neurons are widely distributed all through the brain in adulthood being in some brain regions even more numerous than DA-ergic neurons. Individual enzymes of DA synthesis are expressed in these neurons continuously or transiently in norm or under certain physiological conditions. Monoenzymatic neurons, particularly those expressing TH, appear to be even more numerous and more widely distributed in the brain during ontogenesis than in adulthood. Most populations of monoenzymatic TH neurons decrease in number or even disappear by puberty. Functional significance of monoenzymatic neurons remained uncertain for a long time after their discovery. Nevertheless, it has been shown that most monoenzymatic TH neurons and AADC neurons are capable to produce l-3,4-dihydroxyphenylalanine (L-DOPA) from l-tyrosine and DA from L-DOPA, respectively. L-DOPA produced in monoenzymatic TH neurons is assumed to play a role of a neurotransmitter or neuromodulator acting on target neurons via catecholamine receptors. Moreover, according to our hypothesis L-DOPA released from monoenzymatic TH neurons is captured by monoenzymatic AADC neurons for DA synthesis. Such cooperative synthesis of DA is considered as a compensatory reaction under a failure of DA-ergic neurons, e.g. in neurodegenerative diseases like hyperprolactinemia and Parkinson's disease.Thus, a substantial number of the brain neurons express partly the DA-ergic phenotype, mostly individual complementary enzymes of DA synthesis, serving to produce DA in cooperation that is supposed to be a compensatory reaction under the failure of DA-ergic neurons.
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PMID:Non-dopaminergic neurons partly expressing dopaminergic phenotype: distribution in the brain, development and functional significance. 1969 80

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