Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dopamine D3 receptors may be involved in drug addiction and in disorders such as schizophrenia and Parkinson's disease. To determine the pharmacological properties of dopamine D3 receptors in the rat caudate-putamen, we have investigated R(+)-[3H]7-hydroxy-N,N-di-n-propyl-2-aminotetralin ([3H]R(+)-7-OH-DPAT) binding to membrane preparations from the rat caudate-putamen. Kinetic analyses showed that [3H]R(+)-7-OH-DPAT binding reached equilibrium in approximately 1 h and that both association and dissociation curves were composed of at least two components. Likewise, saturation curves showed at least two binding components with a combined Bmax value of about 600 fmol/mg protein, which is three times higher than what is present in the subcortical limbic area. Competition curves were performed with agonists such as R(-)-propylnorapomorphine, dopamine, PD 128907, quinpirole, and bromocriptine, and antagonists such as haloperidol, raclopride, clozapine, GR 218231x, remoxipride, and U99194A. These experiments revealed that [3H]R(+)-7-OH-DPAT binding could be resolved into three specific binding sites (R1-R3) and one nonspecific binding site, with R1-R2 probably representing D3 receptor binding and the minor R3 representing D2 receptor binding. The low affinities of (+/-)-8-OH-DPAT and 1,3-di(2-tolyl)guanidine to inhibit [3H]R(+)-7-OH-DPAT binding indicate negligible involvement of 5-HT1A or sigma binding sites, respectively. The pharmacological profile of [3H]R(+)-7-OH-DPAT (2 nM) binding in the caudate-putamen was similar to that of dopamine on [125I]iodosulpride binding in the cerebellar lobule X, which contain D3 but not D2 receptors. Mg2+ increased and GTP and Na+ decreased the binding of [3H]R(+)-7-OH-DPAT, suggesting a coupling of endogenous D3 receptors to G proteins. Taken together, these results suggest that dopamine D3 receptors display multiple agonist binding states, and that D3 receptors are present in high concentrations in the rat caudate-putamen. These results may have implications for the physiological and pathological roles of dopamine D3 receptors in the brain.
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PMID:Pharmacology of [3H]R(+)-7-OH-DPAT binding in the rat caudate-putamen. 1091 86

In the nosological viewpoint concerning diseases with a pathophysiological dysfunction of the nigro-striatal dopaminergic system, juvenile parkinsonism (JP) is discussed in this paper in relation to hereditary progressive dystonia (HPD) and Parkinson's disease (PD). Most cases of JP have dystonia with parkinsonism, which is the main symptom of HPD. In the symptomatological analysis of complication with dystonia, an interesting observation arose as regards on the anatomical and functional development of the basal ganglia through patients with childhood onset HPD and JP. Genetic analysis revealed the disease entity of HPD to be an abnormality of the GTP-CH I gene. Consequently, it has been clarified that clinical differences between HPD and JP were not merely derived from differences in developmental processes. Furthermore, the autosomal recessive type of JP (AR-JP) was confirmed to be a disease entity by the detection of an abnormality of the 'parkin' gene. The nosological controversy about JP and PD in the clinical standpoint has been clarified. However, as more than half of patients with JP do not carry a mutation in the 'parkin' gene, more investigations concerning nosological entities should be carried out. The absence of Lewy bodies in most patients with AR-JP has been confirmed to be a characteristic neorupathological finding as compared with those with typical PD pathology. In this paper, we discuss the above findings.
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PMID:Development of the nosological analysis of juvenile parkinsonism. 1098 65

Parkinson's disease is a major neurological disorder that primarily affects the nigral dopaminergic cells. Nigral histamine innervation is altered in human postmortem Parkinson's disease brains. However, it is not known if the altered innervation is a consequence of dopamine deficiency. The aim of the present study was to investigate possible changes in the H3 receptor system in a well-characterized model of Parkinson's disease--the 6-hydroxydopamine (6-OHDA) lesioned rats. Histamine immunohistochemistry showed a minor increase of the fibre density index but we did not find any robust increase of histaminergic innervation in the ipsilateral substantia nigra on the lesioned side. In situ hybridization showed equal histidine decarboxylase mRNA expression on both sides in the posterior hypothalamus. H3 receptors were labelled with N-alpha-[3H]-methyl histamine dihydrochloride ([3H] NAMH). Upregulation of binding to H3 receptors was found in the substantia nigra and ventral aspects of striatum on the ipsilateral side. An increase of GTP-gamma-[35S] binding after H3 agonist activation was found in the striatum and substantia nigra on the lesioned side. In situ hybridization of H3 receptor mRNA demonstrated region-specific mRNA expression and an increase of H3 receptor mRNA in ipsilateral striatum. Thus, the histaminergic system is involved in the pathological process after 6-OHDA lesion of the rat brain at least through H3 receptor. On the later stages of the neurotoxic damage, less H3 receptors became functionally active. Increased H3 receptor mRNA expression and binding may, for example, modulate GABAergic neuronal activity in dopamine-depleted striatum.
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PMID:Modulation of histamine H3 receptors in the brain of 6-hydroxydopamine-lesioned rats. 1106 77

Parkinson's disease (PD) is a brain degenerative disorder with unknown etiology, and specific degeneration of mesencephalic dopaminergic cells is a morphological manifestation of the disease. The central histaminergic system appears to be activated in PD, since the histaminergic innervation is increased in the substantia nigra. The aim of the present study was to investigate the expression and function of histamine H(3) receptors in PD, using receptor mRNA in situ hybridization with oligonucleotide probes, receptor binding assay with a specific radioactive agonist, and GTP-gamma-[(35)S]-binding assay as a tool to study the activation of the receptor G-protein. H(3) receptor binding sites were detected using N-alpha-methylhistamine autoradiography in the basal ganglia and cortex, being most abundant in the substantia nigra and striatum. In PD substantia nigra we detected an increase of the receptor binding density. In situ hybridization study of the receptor mRNA revealed prominent sites of H(3) receptor synthesis in the putamen, cortex, and globus pallidus, whereas very low mRNA expression was seen in the substantia nigra. In the PD pallidum externum, H(3) receptor mRNA expression was elevated as compared with the normal brains. GTP-gamma-[(35)S]-binding assay did not reveal any significant difference between PD and normal brains, although the density values in PD substantia nigra tended to be lower than in the normal brain, and density values in PD striatum were higher. The dopaminergic neurons did not express significant amount of H(3) receptor mRNA, suggesting that the effects of H(3) receptor-mediated modulation of dopamine release are indirect. Our data indicates modulation of the histamine H(3) receptor in PD at the level of the mRNA expression in the striatum and receptor density in the substantia nigra. The receptor activity seems to be unchanged or decreased, as revealed by GTP-gamma-[(35)S]-binding assay. Modulation of the histamine H(3) receptor may influence the activity of other neurotransmitter systems, e.g., the GABAergic one, in the substantia nigra.
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PMID:Distribution and modulation of histamine H(3) receptors in basal ganglia and frontal cortex of healthy controls and patients with Parkinson's disease. 1149 35

Intrastriatal delivery of the tyrosine hydroxylase gene by viral vectors is being explored as a tool for local delivery of L-dopa in animals with lesions of the nigrostriatal pathway. The functional effects reported using this approach have been disappointing, probably because the striatal L-dopa levels attained have been too low. In the present study, we have defined a critical threshold level of L-dopa, 1.5 pmol/mg of tissue, that has to be reached to induce any significant functional effects. Using new generation high-titer recombinant adeno-associated virus vectors, we show that levels of striatal L-dopa production exceeding this threshold can be obtained provided that tyrosine hydroxylase is coexpressed with the cofactor synthetic enzyme, GTP-cyclohydrolase-1. After striatal transduction with this combination of vectors, substantial functional improvement in both drug-induced and spontaneous behavior was observed in rats with either complete or partial 6-hydroxydopamine lesions of the nigrostriatal pathway. However, complete reversal of motor deficits occurred only in animals in which part of the striatal dopamine innervation was left intact. Spared nigrostriatal fibers thus may convert L-dopa to dopamine and store and release dopamine in a more physiologically relevant manner in the denervated striatum to mediate better striatal output-dependent motor function. We conclude that intrastriatal L-dopa delivery may be a viable strategy for treatment and control of adverse side effects associated with oral L-dopa therapy such as on-off fluctuations and drug-induced dyskinesias in patients with Parkinson's disease.
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PMID:Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of L-dopa using rAAV-mediated gene transfer. 1191 5

Dopaminergic mechanisms in the subthalamic nucleus (STN) are implicated in the pathophysiology of Parkinson's disease. Here, electrophysiological responses of STN neurons to dopamine (DA) were investigated by using whole-cell patch-clamp recordings in the rat brain slice preparation. Under current-clamp, DA depolarized membrane potential and increased the frequency of spontaneous action potentials of STN neurons. Under voltage-clamp, DA (3-300 microM) produced a reversible concentration-dependent inward current (I(DA); 6-40 pA) with an EC(50) of 13 microM. This DA-induced current had a negative slope conductance which reversed at -102 mV. It was partially reduced by barium and by superfusion with an elevated concentration of extracellular K(+). Moreover, TTX and glutamate receptor antagonists (CNQX and AP5) did not significantly affect the DA responses, indicating that I(DA) is not dependent upon afferent synaptic activity in the STN. Quinpirole, a D(2) receptor agonist, mimicked the DA action more effectively than did the D(1) agonist SKF-38393. The D(2) antagonist sulpiride, but not the D(1) antagonist SCH-23390, blocked responses induced by DA. Intracellular application of G-protein inhibitor GDP-beta-S also suppressed I(DA). GTP-gamma-S, added to the pipette solution, evoked a sustained inward shift in the absence of DA. These results suggest that DA increases the activity of STN neurons via activation of G-protein-coupled D(2)-like receptors which reduce a K(+) conductance.
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PMID:Pharmacological identification of inward current evoked by dopamine in rat subthalamic neurons in vitro. 1201 3

We recently found that alternative transcripts of tissue transglutaminase (tTG or TG2) were present in hippocampal brain regions of Alzheimer's disease (AD), but not in control, non-demented, age-matched brains. Since antecedent non-severe trauma has been implicated in AD and other neurodegenerative diseases, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), we were interested in whether alternative transcripts might be detected in a model of neurotrauma, controlled-contusion spinal cord injury (SCI) in the rat. Implicated in diverse roles from growth and differentiation to apoptotic cell death, only bifunctional tTG, of the nine member TG family, has dual catalytic activities: guanine trinucleotide (GTP) hydrolyzing activity (GTPase), as well as protein cross-linking. These functions imply two physiological functions: programmed cell life and death. These may have profound roles in the nervous system since studies in cultured astrocytes found tTG short (S) mRNA transcripts induced by treatment with injury-related cytokines. In the developing rat spinal cord, tTG activity is concentrated in ventral horn alpha motoneurons, but neither studies of spinal cord tTG gene expression, nor evaluation of the GTP-regulated isoforms in tissues, have been reported. We now report increased tTG protein and gene expression occurring rapidly after SCI. In parallel, novel appearance of a second, short form transcript, in addition to the normal long (L) isoform, occurs by 8 h of injury. Up-regulation of tTG message and activity following neural injury. with appearance of a truncated GTP-unregulated S form, may represent new approaches to drug targets in neurotrauma.
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PMID:Injury-induced "switch" from GTP-regulated to novel GTP-independent isoform of tissue transglutaminase in the rat spinal cord. 1206 30

Whereas dopamine agonists are known to provide symptomatic benefits for Parkinson's disease, recent clinical trials suggest that they might also be neuroprotective. Laboratory studies demonstrate that dopamine agonists can provide neuroprotective effects in a number of model systems, but the role of receptor-mediated signalling in these effects is controversial. We find that dopamine agonists have robust, concentration-dependent anti-apoptotic activity in PC12 cells that stably express human D(2L) receptors from cell death due to H(2)O(2) or trophic withdrawal and that the protective effects are abolished in the presence of D(2)-receptor antagonists. D(2) agonists are also neuroprotective in the nigral dopamine cell line SN4741, which express endogenous D(2) receptors, whereas no anti-apoptotic activity is observed in native PC12 cells, which do not express detectable D(2) receptors. Notably, the agonists studied differ in their relative efficacy to mediate anti-apoptotic effects and in their capacity to stimulate [(35)S]guanosine 5'-[gamma-thio]triphosphate ([(35)S]GTP[S]) binding, an indicator of G-protein activation. Studies with inhibitors of phosphoinositide 3-kinase (PI 3-kinase), extracellular-signal-regulated kinase or p38 mitogen-activated protein kinase indicate that the PI 3-kinase pathway is required for D(2) receptor-mediated cell survival. These studies indicate that certain dopamine agonists can complex with D(2) receptors to preferentially transactivate neuroprotective signalling pathways and to mediate increased cell survival.
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PMID:Activation of phosphoinositide 3-kinase by D2 receptor prevents apoptosis in dopaminergic cell lines. 1268 52

Parkinson's disease (PD) is a neurodegenerative disease characterized by loss of nigra dopaminergic neurons. Lewy bodies (LBs) are a characteristic neuronal inclusion in PD brains. In this study, we report that Dorfin, a RING finger-type ubiquityl ligase for mutant superoxide dismutase-1, was localized with ubiquitin in LBs. Recently, synphilin-1 was identified to associate with alpha-synuclein and to be a major component of LBs. We found that overexpression of synphilin-1 in cultured cells led to the formation of large juxtanuclear inclusions, but showed no cytotoxicity. Dorfin colocalized in these large inclusions with ubiquitin and proteasomal components. In contrast to full-length synphilin-1, overexpression of the central portion of synphilin-1, including ankyrin-like repeats, a coiled-coil domain, and an ATP/GTP-binding domain, predominantly led to the formation of small punctate aggregates scattered throughout the cytoplasm and showed cytotoxic effects. Dorfin and ubiquitin did not localize in these small aggregates. Overexpression of the N or C terminus of synphilin-1 did not lead to the formation of any aggregates. Dorfin physically bound and ubiquitylated synphilin-1 through its central portion, but did not ubiquitylate wild-type or mutant alpha-synuclein. These results suggest that the central domain of synphilin-1 has an important role in the formation of aggregates and cytotoxicity and that Dorfin may be involved in the pathogenic process of PD and LB formation by ubiquitylation of synphilin-1.
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PMID:Dorfin localizes to Lewy bodies and ubiquitylates synphilin-1. 1275 Mar 86

The glial cell line-derived neurotrophic factor (GDNF) is involved in the development and maintenance of neural tissues. Mutations in components of its signaling pathway lead to severe migration deficits of neuronal crest stem cells, tumor formation, or ablation of the urinary system. In animal models of Parkinson's disease, GDNF has been recognized to be neuroprotective and to improve motor function when delivered into the cerebral ventricles or into the substantia nigra. Here, we characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and alpha-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization. Axonal guidance depends on cell-surface molecules and extracellular matrix proteins. Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. Moreover, we found four key enzymes of the cholesterol-synthesis pathway to be down-regulated leading to decreased farnesyl-pyrophospate production. Many proteins are anchored by farnesyl-derivates at the cell membrane. The identification of these GDNF-regulated genes may open new opportunities for directly influencing differentiation and developmental processes of neurons.
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PMID:Overexpression of glial cell line-derived neurotrophic factor induces genes regulating migration and differentiation of neuronal progenitor cells. 1521 50


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