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)

Dopa and carbidopa, components of the dual therapy for Parkinson's disease treatment, are both provided as single enantiomers, since their D-forms are inactive. To ensure the efficiency and safety of the therapy, these D-enantiomers, therefore, should be considered as impurities. In this paper, the enantioseparation power of different types of cyclodextrins, both neutral and charged ones, on dopa and carbidopa enantiomers was tested. Three methods of simultaneous separation of dopa and carbidopa enantiomers were developed, using highly sulfated beta-cyclodextrin and sulfated beta-cyclodextrin as chiral selector, in normal and reversed polarity mode. Two methods among these three were found sensitive enough for the quantitation of 0.1% D-enantiomers in L-forms (impurity level). After the optimization study, the best method was selected, using 16 mM sulfated beta-cyclodextrin in 15 mM sodium phosphate buffer pH 2.45, an uncoated fused-silica capillary (50 num inner diameter, 30 cm total length), and an applied voltage of -12 kV. This method is robust and efficient, with very high resolution for all peaks within a short analysis time of 10 min. Quantitatively, the method offers a limit of detection (LOD) of 0.2 nug/mL and a limit of quantitation (LOQ) of 0.5 nug/mL for both D-dopa and D-carbidopa, which is equivalent to 0.02% and 0.05% against the respective L-enantiomers. A linear relationship was found between the concentration of the analyte and the corresponding peak area in a range of 0.5-2.0 nug/mL.
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PMID:Simultaneous determination of dopa and carbidopa enantiomers by capillary zone electrophoresis. 1237 70

During the past decade, in vivo imaging of the nigrostriatal dopaminergic system has been developed as a research tool to monitor progressive dopaminergic neuron loss in Parkinson's disease (PD) and to assess the effect of medication on imaging outcomes. Recently two similar studies compared the effect of initial treatment with a dopamine agonist (pramipexole (CALM-PD CIT) or ropinirole (REAL-PET)) or levodopa on the progression of PD as measured by [123I]beta-CIT or [18F]Dopa imaging. These two clinical imaging studies targeting dopamine function with different imaging ligands and technology both demonstrate slowing in the rate of loss of [123I]beta-CIT or [18F]Dopa uptake in early PD patients treated with dopamine agonists compared with levodopa. The relative reduction in the per cent loss from baseline of [123I]beta-CIT uptake in the pramipexole versus the levodopa group was 47% at 22 months, 44% at 34 months and 37% at 46 months after initiating treatment. The relative reduction of 18F-dopa uptake in the ropinirole group versus the levodopa group was 35% at 24 months. These results should be very cautiously interpreted with regard to the effect of dopamine agonists or levodopa on clinical disease progression. These data highlight the need to compare imaging outcomes of dopamine neuronal loss with multiple meaningful clinical endpoints of disease progression in placebo controlled, larger and long-term studies.
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PMID:Do dopamine agonists or levodopa modify Parkinson's disease progression? 1246 17

Neuroprotection may be defined as measures to protect neurons from degenerative processes by use of medication, to stop or prolong cell death and to positively interfere with the underlying cell death mechanism(s) in Parkinson's disease. So far, the question whether neuroprotection exists in parkinsonian treatment was difficult to answer because we had no objective method to check for dopaminergic cell death. Imaging techniques such as beta-CIT-SPECT or F-Dopa-PET are the best methods to approach this goal. This paper critically reviews the two most recently published studies on the possible neuroprotective effect of the dopamine agonists pramipexole and ropinirole. For the first time, these two drugs have shown a significantly smaller decrease in dopamine cell function when compared to levodopa. Nonetheless, there may still be some hesitation to accept the good correlation between imaging techniques and dopamine cell function. For obvious reasons, neither study included a placebo arm, since ethical reasons forbid a period of 2 to 4 years without treatment. Thus, the question, whether these two dopamine agonists are really neuroprotective or whether levodopa increases cell death in Parkinson's disease has to stay open. A rather remarkable finding was that, in both studies, motor function was slightly better in the levodopa arm, which raises the question whether imaging techniques really reflect improvement in cell function in those patients treated with dopamine agonists. We certainly have to continue our search for even better tools to evaluate neuroprotection.
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PMID:Neuroprotection in idiopathic Parkinson's disease. 1252 67

Deep brain simulation (DBS) is a powerful new therapeutic approach for patients with Parkinson's disease. However, patient selection is critical for a valuable therapeutic result. Dopa sensitivity of the target symptoms, severe disability and low neurosurgical risks are among the major criteria for this indication. Other criteria like age or cognition must still be addressed in future prospective studies. The preferred target for DBS in PD is the subthalamic nucleus for various good reasons. However, prospective studies for this procedure are lacking and some clinical problems may be more easily solved with targeting the internal pallidum or the thalamus. Despite major progress in this field, much work remains to be done.
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PMID:Deep-brain stimulation for Parkinson's disease. 1252 71

Adenosine receptors modulate dopaminergic function by regulating dopamine release in presynaptic neurons and intracellular signaling in postsynaptic striatal neurons. To investigate how adenosine impinges on the action of dopamine in feeding and locomotion, genetically altered, dopamine-deficient mice were treated with adenosine receptor antagonists. Acute administration of the nonselective adenosine receptor antagonist, caffeine (5-25 mgkg i.p.), reversed the hypophagia of mutant mice and induced hyperactivity in both control and mutant animals. However, caffeine treatment elicited much less hyperactivity in dopamine-deficient mice than did l-3,4-dihydroxyphenylalanine (l-dopa) administration, which partially restores dopamine content. Caffeine treatment enhanced feeding of l-dopa-treated mutants but, unexpectedly, it reduced their hyperlocomotion. Caffeine administration induced c-Fos expression in the cortex of dopamine-deficient mice but had no effect in the striatum by itself. Caffeine attenuated dopamine agonist-induced striatal c-Fos expression. An antagonist selective for adenosine A(2A) receptors induced feeding and locomotion in mutants much more effectively than an A(1) receptor antagonist. l-dopa-elicited feeding and hyperlocomotion were reduced in mutants treated with an A(1) receptor agonist, whereas an A(2A) receptor agonist decreased l-dopa-induced feeding without affecting locomotion. The observations suggest that the hypophagia and hypoactivity of mutants result not only because of the absence of dopamine but also because of the presence of A(2A) receptor signaling. This study of a genetic model of dopamine depletion provides evidence that A(2A) receptor antagonists could ameliorate the hypokinetic symptoms of advanced Parkinson's disease patients without inducing excessive motor activity.
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PMID:Adenosine receptor blockade reverses hypophagia and enhances locomotor activity of dopamine-deficient mice. 1253 62

Historically, 3,4-dihydroxyphenylalanine (DOPA) has been believed to be an inert amino acid that alleviates the symptoms of Parkinson's disease by its conversion to dopamine via the enzyme aromatic L-amino acid decarboxylase. In contrast to this generally accepted idea, we propose that DOPA itself is a neurotransmitter and/or neuromodulator, in addition to being a precursor of dopamine. Several criteria, such as synthesis, metabolism, active transport, existence, physiological release, competitive antagonism, and physiological or pharmacological responses, must be satisfied before a compound is accepted as a neurotransmitter. Recent evidence suggests that DOPA fulfills these criteria in its involvement mainly in baroreflex neurotransmission in the lower brainstem and in delayed neuronal death by transient ischemia in the striatum and the hippocampal CA1 region of rats.
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PMID:L-3,4-Dihydroxyphenylalanine as a neurotransmitter candidate in the central nervous system. 1255 86

Increased echogenicity of the substantia nigra (SN) on ultrasound is a typical sonographic finding in Parkinson's disease (PD). Sonographic signal intensity of the SN is related to tissue iron content with higher iron level being associated with increased echogenicity. Recent findings indicate that hyperechogenicity of the SN represents an important susceptibility factor for nigrostriatal degeneration. In this study we determined the prevalence of a characteristic ultrasound sign of Parkinson's disease in first-degree relatives of PD patients. Fourteen patients with sporadic PD and 58 of their relatives underwent neurological, neuropsychological, and ultrasound examination. In addition, four pairs of relatives (one member of each pair exhibiting increased echogenicity of the SN and the other with regular SN echogenicity) underwent (18)F-Dopa PET examination. On transcranial sonography, 26 of the 58 relatives exhibited SN hyperechogenicity. Twenty-four relatives showed minor signs of motor slowing. Relatives with SN hyperechogenicity more often showed signs of hypokinesia (16 v 8 relatives; U test, P = 0.01) and impaired executive functions (Tower of London task, problems solved with the minimum number of moves; U test, P = 0.012) than relatives without this echo pattern. In addition, (18)F-Dopa uptake (influx constants) at the putamen was reduced in subjects with SN hyperechogenicity compared to their relatives without this ultrasound sign (Wilcoxon, P = 0.03). In conclusion, approximately 45% of relatives of PD patients exhibited an increased echogenicity of the SN. This sign is associated with clinical findings and objective measurements, indicating some degree of impaired nigrostriatal function.
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PMID:Echogenicity of the substantia nigra in relatives of patients with sporadic Parkinson's disease. 1259 95

Transcranial ultrasound is a new tool allowing the detection of abnormalities in the echomorphology of the substantia nigra (SN) in patients with Parkinson's disease (PD). Several lines of evidence suggest that the changes in the echo-pattern represent a risk factor as: i) the majority of PD patients exhibit this echo-feature, ii) the presence of such changes in healthy controls is related to a reduced (18)F-Dopa-uptake and clinical signs of nigrostriatal dysfunction. The reason for the change of echogenicity is suggested to be an increased iron content in the substantia nigra causing oxidative stress and neuronal cell damage. This hypothesis of changes in SN echomorphology reflecting a risk factor of PD has to be proved in longitudinal studies.
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PMID:Does ultrasound disclose a vulnerability factor for Parkinson's disease? 1276 31

Mutation of genes encoding for various components of a metabolic pathway named the ubiquitin-proteasome system (UP) leads to inherited forms of Parkinson's disease (PD), whereas various components of the UP are constantly present within neuronal inclusions, Lewy bodies, that characterize most genetic and sporadic forms of PD. It has been hypothesized that impairment of this metabolic pathway might be a common mechanism for the onset of PD, and a recent study demonstrated a dysfunction of the UP system within the substantia nigra of patients affected by sporadic PD. In search for the mechanisms underlying the selective toxicity for nigral neurons after inhibition of the UP system, we explored the selective effects after striatal microinfusions of lactacystin or epoxomycin and potential retrograde changes within the ipsilateral substantia nigra. We found that neurotoxicity was selective for striatal dopamine (DA) components and led to retrograde apoptosis within nigral DA cells, which developed neuronal inclusions staining for antigens of the UP system. We found the same ultrastructural features characterizing inclusions obtained in vivo and in vitro after UP inhibition. In vivo, lactacystin-epoxomycin-induced toxicity was suppressed by inhibiting DA synthesis. Similarly, in vitro inclusions and apoptosis were prevented by reducing endogenous DA. On the other hand, toxicity of proteasome inhibition was enhanced by drugs augmenting DA availability: l-3,4-dihydroxyphenylalanine, monoamine oxidase blockers, and DA beta-hydroxylase blockers. These findings demonstrate that impairment of the UP system produces cell death and neuronal inclusions selectively for DA-containing neurons that depend on the occurrence of endogenous DA.
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PMID:Fine structure and biochemical mechanisms underlying nigrostriatal inclusions and cell death after proteasome inhibition. 1452 98

The present experiments investigated the effects of the specific alpha(2)-adrenoceptor antagonist atipamezole, alone and in combination with a dopamine agonist, on motor function in rats with a unilateral 6-hydroxydopamine lesion of the nigro-striatal pathway and on exploratory behaviour and cardiovascular function in rats equipped with telemetry transmitters. Dexmedetomidine, an alpha(2)-adrenoceptor agonist and the alpha(2)-adrenoceptor antagonists idazoxan and yohimbine were used as reference compounds. In the unilaterally lesioned animals, direct dopamine agonists, such as apomorphine, induce contralateral turning behaviour. Indirect agonists, such as amphetamine, induce ipsilateral circling in the animals. Atipamezole (0.3 mg/kg s.c) potentiated and dexmedetomidine (10 micro g/kg s.c.) decreased contralateral circling evoked by apomorphine (50 micro g/kg s.c.) and by l-3,4-dihydroxyphenylalanine (L-DOPA, 5 mg/kg i.p.). Atipamezole also prolonged the duration of action of L-DOPA. Atipamezole dose-dependently induced ipsilateral turning behaviour and potentiated turning induced by amphetamine (1 mg/kg i.p.). The alpha(1)-adrenoceptor antagonist prazosin (0.1 mg/kg i.p.) partially antagonised the effect of amphetamine and had a strong inhibitory effect on the atipamezole-induced potentiation of the amphetamine response. Prazosin did not have any major effect on either the apomorphine response itself or on the potentiation of the apomorphine response by atipamezole. This suggests that atipamezole can modulate motor function both indirectly, by stimulating the release of noradrenaline and directly, by blocking postsynaptic alpha(2)-adrenoceptors in neurones other than noradrenergic nerves. The alpha(2)-adrenoceptor antagonists, when tested at comparably effective central alpha(2)-adrenoceptor antagonising doses in a rat mydriasis model: atipamezole 0.3 mg/kg s.c., idazoxan 1 mg/kg s.c. and yohimbine 3 mg/kg s.c., all induced ipsilateral turning behaviour and potentiated apomorphine-induced contralateral circling. The effects of the alpha(2)-adrenoceptor antagonists were in general similar in these experiments. In habituated non-lesioned rats equipped with telemetry transmitters, apomorphine (50 micro g/kg s.c.) decreased blood pressure in the home cage and in an open-field test. It also decreased spontaneous motor activity in the open field. Neither atipamezole (0.3 mg/kg s.c.) nor idazoxan (1 mg/kg s.c.) had any effect on blood pressure when given alone, but reversed the apomorphine-induced decrease in blood pressure. Atipamezole also diminished apomorphine-induced sedation in the open-field test. In conclusion, atipamezole improved the efficacy of L-DOPA and apomorphine in an animal model of Parkinson's disease and also reduced adverse dopaminergic effects on vigilance and on cardiovascular function. These results suggest that an investigation of the effects of specific alpha(2)-adrenoceptor antagonists in Parkinson's disease patients is warranted.
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PMID:The alpha 2-adrenoceptor antagonist atipamezole potentiates anti-Parkinsonian effects and can reduce the adverse cardiovascular effects of dopaminergic drugs in rats. 1456 51


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