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)

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

Noradrenaline has been shown to control dopamine turnover and release in rat brain. Noradrenergic lesion with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) decreases dopamine release in the striatum and enhances catalepsy in experimental models of Parkinson's disease. However, in due course, sprouting of remaining noradrenergic axons, to compensate for the decreased noradrenaline is said to occur in specific brain regions. Though this is to some extent understood, the longstanding effects of noradrenergic lesion on dopaminergic neurons of the basal ganglia and in Parkinsonian behavior is not known. Here the question is addressed, whether locus coeruleus lesion with DSP-4 in rats alters dopamine concentration of the basal ganglia and influences Parkinsonian behavior in a long term (6 months). Parkinsonian behavior was assessed by catalepsy and activity cage after challenging with subthreshold dose of haloperidol (0.2 mg/kg), on 7, 30, 90, 120 and 180 days after DSP-4 lesion. The concentrations of noradrenaline and dopamine and its metabolites were estimated by HPLC. 6 months after DSP-4 lesion, increased concentration of noradrenaline was found in prefrontal cortex and hippocampus. Other regions remain unaffected. The concentration of dopamine remained unchanged. However, dopamine turnover appeared to be increased in prefrontal cortex and reduced in striatum and nucleus accumbens. Catalepsy and hypoactivity were observed in DSP-4 lesioned animals after haloperidol challenge on 7th, 30th and 60th day. Though dopamine turnover was reduced after 6 months in the striatum, haloperidol-induced catalepsy was not observed after 60 days. These results indicate a gradual functional recovery, perhaps hyperinnervation of noradrenergic neurons after DSP-4 treatment and the reversal of its effects on dopaminergic neurons and on Parkinsonian symptoms.
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PMID:Functional recovery of locus coeruleus noradrenergic neurons after DSP-4 lesion: effects on dopamine levels and neuroleptic induced-parkinsonian symptoms in rats. 1471 12

In previous studies, the polycyclic cage amine 8-benzylamino-8,11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane (NGP1-01) and a number of its derivatives showed positive effects in neuroprotection studies with MPTP, in vivo. In view of these findings, we examined these compounds for their effects on [(3)H]dopamine ([(3)H]DA) release and uptake inhibition in murine striatal synaptosomes, as well as for inhibition of baboon liver monoamine oxidase (MAO) B. In order to assess specificity, initial experiments focused on compounds that blocked dopamine uptake without causing appreciable release (<40% at 100 microM) of the transmitter. NGP1-01 blocked the uptake of [(3)H]DA with an IC(50) of 57 microM, while another compound, 8-phenylethyl-8,11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane, blocked uptake at an IC(50) value of 23 microM. These values were comparable to that of another polycyclic cage amine, amantadine (IC(50); 82 micro), that is used in parkinsonian therapy. Structure-activity relationships of this series of compounds support the importance of geometric and steric, rather than electronic effects, in determining biological activity. MAO-B inhibition for this group was weak, with less than 50% inhibition at 300 microM for any of the compounds in the series. The present study suggests that blockage of the dopamine transporter may underlie, at least in part, their neuroprotective effects against MPTP-induced parkinsonism. These compounds may be considered as potential lead compounds for Parkinson's Disease therapy.
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PMID:Synthesis and biological evaluation of pentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane derivatives as potential therapeutic agents in Parkinson's disease. 1502 70

Aggresomes are associated with many neurodegenerative disorders, including Parkinson's disease, and polyglutamine disorders such as Huntington's disease. These inclusions commonly contain ubiquitylated proteins. The stage at which these proteins are ubiquitylated remains unclear. A malfunction of the ubiquitin/proteasome system (UPS) may be associated with their formation. Conversely, it may reflect an unsuccessful attempt by the cell to remove them. Previously, we demonstrated that overexpression of Parkin, a ubiquitin-protein ligase associated with autosomal recessive juvenile Parkinsonism, generates aggresome-like inclusions in UPS compromised cells. Mutations in the de-ubiquitylating enzyme, UCH-L1, cause a rare form of Parkinsonism. We now demonstrate that overexpression of UCH-L1 also forms ribbon-like aggresomes in response to proteasomal inhibition. Disease-associated mutations, which affect enzymatic activities, significantly increased the number of inclusions. UCH-L1 aggresomes co-localized with ubiquitylated proteins, HSP70, gamma-tubulin and, to a lesser extent, the 20S proteasome and the chaperone BiP. Similar to Parkin inclusions, we found UCH-L1 aggresomes to be surrounded by a tubulin rather than a vimentin cage-like structure. Furthermore, UCH-L1 aggregates with Parkin and alpha-synuclein in some, but not all inclusions, suggesting the heterogeneous nature of these inclusion bodies. This study provides additional evidence that aggregation-prone proteins are likely to recruit UPS components in an attempt to clear proteins from failing proteasomes. Furthermore, UCH-L1 accumulation is likely to play a pathological role in inclusion formation in Parkinson's disease.
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PMID:UCH-L1 aggresome formation in response to proteasome impairment indicates a role in inclusion formation in Parkinson's disease. 1522 95

Recently we identified TPPP/p25 (tubulin polymerization promoting protein/p25) as a brain-specific unstructured protein that induced aberrant microtubule assemblies and ultrastructure in vitro and as a new marker for Parkinson's disease and other synucleopathies. In this paper the structural and functional consequences of TPPP/p25 are characterized to elucidate the relationship between the in vitro and the pathological phenomena. We show that at low expression levels EGFP-TPPP/p25 specifically colocalizes with the microtubule network of HeLa and NRK cells. We found that the colocalization was dynamic (tg=5 seconds by fluorescence recovery after photobleaching) and changed during the phases of mitosis. Time-lapse and immunofluorescence experiments revealed that high levels of EGFP-TPPP/p25 inhibited cell division and promoted cell death. At high expression levels or in the presence of proteosome inhibitor, green fusion protein accumulated around centrosomes forming an aggresome-like structure protruding into the nucleus or a filamentous cage of microtubules surrounding the nucleus. These structures showed high resistance to vinblastin. We propose that a potential function of TPPP/p25 is the stabilization of physiological microtubular ultrastructures, however, its upregulation may directly or indirectly initiate the formation of aberrant protein aggregates such as pathological inclusions.
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PMID:Dynamic targeting of microtubules by TPPP/p25 affects cell survival. 1556 85

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is currently a leading neurotoxic agent used for producing Parkinsonism in laboratory animals. The MPTP neurotoxicity in humans is irreversible and the consequential clinical and neurochemical features closely resemble those of the idiopathic Parkinson's disease. Therefore, handling of MPTP in laboratory may pose neurotoxic risk among researchers and animal caretakers. While it is well recognized that systemic administration of MPTP will cause Parkinsonian-like symptoms in humans and animals, it is not known whether similar neurological toxicity is transmittable and would develop in normal subjects housed closely with the MPTP-treated animals. In the present study, we treated mice daily with MPTP hydrochloride (30mg/kg, s.c.) for 5 consecutive days. In the same cage, a non-treated mouse (cagemate) was kept allowing for close physical interaction, free contact with the excreta, and sharing of food and water. Seventy-two hours after the treatment, the MPTP-treated mice and MPTP-exposed cagemates were analyzed for dopaminergic neurotoxicity comparing with the MPTP non-exposed control animals. We detected a significant number of TUNEL-positive cells, loss of tyrosine hydroxylase immunoreactivity in the substantia nigra, and depletion of dopamine in the striatum of MPTP-treated mice. However, these neurotoxic indices were not detected in the MPTP-exposed cagemates or MPTP non-exposed controls. Following each MPTP injection, approximately 42% of the chemical was excreted within 3h through the urine largely in the form of MPTP N-oxide, which is not expected to cross the blood-brain barrier and to cause dopaminergic toxicity in the brain when administered peripherally. These observations suggest that MPTP injections in mice do not transmit and cause Parkinsonian-like dopaminergic neurotoxicity in the neighboring normal cagemates through direct physical contact and exposure from the contaminated cage, food, water, and excreta.
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PMID:MPTP treatment in mice does not transmit and cause Parkinsonian neurotoxicity in non-treated cagemates through close contact. 1593 37

Individuals with Parkinson's disease (PD) demonstrate low vocal intensity (hypophonia) which results in reduced speech intelligibility. We examined the effects of three cues to increase loudness on respiratory support in individuals with PD. Kinematic data from the rib cage and abdomen were collected using respiratory plethysmography while participants read a short passage. Individuals with PD and normal age- and sex-matched controls (OC) increased sound pressure level (SPL) to a similar extent. As compared to OC, individuals with PD used larger rib cage volume excursions in all conditions. Further, they did not slow their rate of speech in noise as OC speakers did. Respiratory strategies used to support increased loudness varied with the cue, but the two groups did not differ in the strategies used. When asked to target a specific loudness, both groups used more abdominal effort than at comfortable loudness. Speaking in background noise resulted in the largest increase in SPL with the most efficient respiratory patterns, suggesting that natural or implicit cues may be best when treating hypophonia in individuals with PD. Data demonstrate the possibility that both vocal loudness and speech rate are impacted by cognitive mechanisms (attention or self-perception) in individuals with PD.
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PMID:Effects of loudness cues on respiration in individuals with Parkinson's disease. 1726 87

Parkinson's disease is a neurodegenerative disorder of the substantia nigra accompanied by the depletion of dopamine levels. Symptoms of Parkinson's disease involve motor disorders, including dysphagia and aspiration. In this study, rats were injected with 6-hydroxydopamine (6-OHDA) in order to assess the eating disorder and evaluate the effect of transplantation of neural progenitor cells (NPCs). The administration of 6-OHDA resulted in an extension of feeding time and a marked increase in the amount of feed powder on the cage floor after feeding at 2 and 4 weeks after 6-OHDA. These rats had NPCs obtained from the brains of newborn rats transplanted into their striata 2 weeks after 6-OHDA injection. The treatment shortened the feeding time and decreased the amount of feed powder on the cage floor after feeding. The 6-OHDA injection decreased the number of tyrosine hydroxylase-positive cells in the striatum and substantia nigra, and NeuN in the solitary tract. A greater number of tyrosine hydroxylase-positive cells in the substantia nigra and NeuN-positive cells in the solitary tract were detected in the animals transplanted with NPCs than the 6-OHDA injected control. The NPCs labeled with 5-bromo-2'-deoxyuridine were detected in the striatum, but not in the substantia nigra and solitary tract. These results may suggest that the eating disorder induced by 6-OHDA may be related to neural damage to the substantia nigra and/or solitary tract. Transplantation of NPCs may cure 6-OHDA-induced eating disorders accompanied by the protection of neurons from the toxin.
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PMID:Assessing an eating disorder induced by 6-OHDA and the possibility of nerve regeneration therapy by transplantation of neural progenitor cells in rats. 1763 22

Deficiency of the meso-diencephalic dopamine (mdDA) neuron specific transcription factor Pitx3 in aphakia (ak) mice results in the loss of the substantia nigra compacta (SNc). Concomitantly, reduced spontaneous locomotor behavior, symptoms reminiscent to those in Parkinson's disease, has been reported. However, the ak mouse line originates from the 1960s and has been compared to C57BL/6J inbred controls. Therefore, to define Pitx3 gene function in baseline and novelty-induced locomotor behavior and mdDA neuronal activity, we analyzed Pitx3-deficiency in a controlled genetic and epigenetic background. The analysis implicated that, in contrast to the controversial and previously reported hypo-activity in ak mice, Pitx3-/- mice showed normal dark phase motor activity levels. Our data also revealed that ak and Pitx3-/- mice both display a similar neuro-anatomical and physiological phenotype, and, interestingly, showed increased spontaneous home cage activity levels during their habitual sleep phase. Further behavioral analysis revealed that both ak and Pitx3-/- mice have reduced transitions but increased consolidation of specific locomotor behaviors, such as rearing and horizontal movement. Thus, Pitx3 is not involved in the expression of nighttime motor activity levels, but is critical for selective mdDA neuronal activity and associated with increased consolidation of movement.
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PMID:Phenotypic segregation of aphakia and Pitx3-null mutants reveals that Pitx3 deficiency increases consolidation of specific movement components. 1791 45

Collaborative pooled analyses demonstrated that allele length variability of the dinucleotide repeat sequence within the alpha-synuclein gene promoter (SNCA REP1) is associated with Parkinson disease (PD) worldwide. Other studies demonstrated that variability in the SNCA promoter is also associated with alcohol use disorders, but not consistently. Yet other studies demonstrated that alcohol use disorders are inversely associated with PD, but not consistently. The aim of this study was to clarify the patterns of association between REP1 genotype, alcohol use disorders, and PD. Cases were recruited from the Department of Neurology of the Mayo Clinic in Rochester, MN. The controls included unaffected siblings and unrelated controls. We assessed alcohol use via a structured telephone interview and screened for alcohol use disorders using the CAGE questionnaire. REP1 genotyping was performed using an ABI 3730XL platform. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined using conditional logistic regression models. We recruited 893 case-control pairs. There was an increasing risk of PD with increasing SNCA REP1 allele length (OR 1.18 for each REP1 genotype score unit, 95% CI 1.02-1.35; p=0.02). There was a decreasing risk of PD with increasing CAGE score (p=0.01). The association of REP1 score with PD remained significant after adjusting for CAGE score, and the association of CAGE score with PD remained significant after adjusting for REP1 score. There were no pairwise interactions. Our findings suggest that SNCA REP1 genotype and alcohol use disorders are independently associated with PD.
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PMID:Alpha-synuclein, alcohol use disorders, and Parkinson disease: a case-control study. 1919 39


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