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)

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

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

The NMDA receptor complex represents a key molecular element in the pathogenesis of long-term synaptic changes and motor abnormalities in Parkinson's disease (PD). Here we show that NMDA receptor 1 (NR1) subunit and postsynaptic density (PSD)-95 protein levels are selectively reduced in the PSD of dopamine (DA)-denervated striata. These effects are accompanied by an increase in striatal levels of alphaCa2+-calmodulin-dependent protein kinase II (alphaCaMKII) autophosphorylation, along with a higher recruitment of activated alphaCaMKII to the regulatory NMDA receptor NR2A-NR2B subunits. Acute treatment of striatal slices with R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, but not with l-sulpiride, mimicked the effect of DA denervation on both alphaCaMKII autophosphorylation and corticostriatal synaptic plasticity. In addition to normalizing alphaCaMKII autophosphorylation levels as well as assembly and anchoring of the kinase to the NMDA receptor complex, intrastriatal administration of the CaMKII inhibitors KN-93 (N-[2-[[[3-(4-chlorophenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide) and antennapedia autocamtide-related inhibitory peptide II is able to reverse both the alterations in corticostriatal synaptic plasticity and the deficits in spontaneous motor behavior that are found in an animal model of PD. The same beneficial effects are produced by a regimen of l-3,4-dihydroxyphenylalanine (L-DOPA) treatment, which is able to normalize alphaCaMKII autophosphorylation. These data indicate that abnormal alphaCaMKII autophosphorylation plays a causal role in the alterations of striatal plasticity and motor behavior that follow DA denervation. Normalization of CaMKII activity may be an important underlying mechanism of the therapeutic action of L-DOPA in PD.
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PMID:Abnormal Ca2+-calmodulin-dependent protein kinase II function mediates synaptic and motor deficits in experimental parkinsonism. 1519 99

Although l-3,4-dihydroxyphenylalanine (L-dopa) is one of the most effective therapies for Parkinson's disease, continued treatment may result in excessive involuntary movements known as L-dopa-induced dyskinesias (LIDs). Because LIDs can become dose-limiting, there is great interest in finding ways to ameliorate or prevent this troubling side effect of L-dopa therapy. It was recently reported that the D3 receptor partial agonist BP897 [N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide] reduces LIDs without diminishing antiparkinsonian effects of L-dopa in macaques. In the present study, we tested the effects of BP897 on LIDs in squirrel monkeys, a nonhuman primate particularly prone to dyskinesias. Parkinsonism was induced using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Animals were then gavaged with L-dopa/carbidopa (7.5 or 15 mg/kg/dose) without and with BP897. The effects of BP897 treatment were evaluated on several components of LIDs, including time course, peak dyskinesias, and area under the curve (AUC), a measure that encompasses both peak and duration of the response. Analyses of the time course and overall dyskinetic response (AUC) showed that BP897 significantly reduced LIDs but at the expense of the antiparkinsonian effect of L-dopa. BP897 had no significant effect on peak dyskinesias. Correlation studies showed that beneficial effects of BP897 on dyskinesias were linked to a decline in the antiparkinsonian action of L-dopa. Analyses of a subgroup of animals with mild/moderate parkinsonism yielded comparable results. Thus, in squirrel monkeys in contrast to macaques, BP897 fails to exert an antidyskinetic effect without diminishing the antiparkinsonian effects of L-dopa. These results suggest that BP897 may be less effective than originally anticipated for treating LIDs in Parkinson's disease.
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PMID:Effect of the D3 dopamine receptor partial agonist BP897 [N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide] on L-3,4-dihydroxyphenylalanine-induced dyskinesias and parkinsonism in squirrel monkeys. 1522 82

The pathophysiology of Parkinson's disease and l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia are characterised by an imbalance between activity of the direct and indirect pathways regulated by dopamine D1 and D2 receptors, respectively. In this study, we investigated the effects of treatments combining adenosine A(1) and metabotropic glutamate 5 (mGlu5) receptors modulators on locomotion induced by dopamine D1 receptor activation in the reserpine-treated rats. Administration of the adenosine A(1) receptor agonist and mGlu5 receptor antagonist resulted in the significant reduction of dopamine D1 receptor agonist-induced locomotion. The combination of adenosine A(1) receptor agonist with mGlu5 receptor antagonist had no greater effect than these compounds alone. However, the adenosine A(1) receptor antagonist attenuated the inhibitory effect of mGlu5 receptor antagonist. The data suggest that the effect of mGlu5 receptor blockade on locomotion elicited by dopamine D1 receptor stimulation involves activation of adenosine A(1) receptors. This interaction can improve our understanding of pathophysiology of L-DOPA-induced dyskinesia.
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PMID:Effects of adenosine A1, dopamine D1 and metabotropic glutamate 5 receptors-modulating agents on locomotion of the reserpinised rats. 1530 4

This was a small (approximately 50 people) focused meeting on neurodegenerative disorders, with most of the speakers being from biotechnology or major pharmaceutical companies. The meeting covered a range of topics including introductions to Alzheimer's disease and Parkinson's disease, examples of targeting particular receptors/pathways, animal models and preclinical studies, clinical trial design and the use of biomarkers and imaging modalities. The major focus in the Alzheimer's disease area was finding symptomatic treatments that are superior to acetylcholinesterase inhibitors and the extensive efforts that are ongoing to develop disease-modifying therapies. In terms of Parkinson's disease there are now several reports examining the effects of dopamine agonists versus 3,4-dihydroxyphenylalanine on disease progression, and ongoing work with growth factors (e.g., glial cell line-derived neurotrophic factor) and mixed lineage/c-Jun N-terminal kinase inhibitors, such as CEP-1347. Small molecules that enhance endogenous signalling and repair pathways were also discussed.
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PMID:SMi 4th Annual Conference on Neurodegenerative Disorders: a focus on Alzheimer's and Parkinson's disease. 1546 66

Oxidation of catecholamines may contribute to the pathogenesis of Parkinson's disease (PD). The effect of the oxidized products of catecholamines on the modification of Cu,Zn-superoxide dismutase (SOD) was investigated. When Cu,Zn-SOD was incubated with the oxidized 3,4-dihydroxyphenylalanine (DOPA) or dopamine, the protein was induced to be aggregated. The deoxyribose assay showed that hydroxyl radicals were generated during the oxidation of catecholamines in the presence of copper ion. Radical scavengers, azide, N-acetylcysteine, and catalase inhibited the oxidized catecholamine-mediated Cu,Zn-SOD aggregation. Therefore, the results indicate that free radicals may play a role in the aggregation of Cu,Zn-SOD. When Cu,Zn-SOD that had been exposed to catecholamines was subsequently analyzed by an amino acid analysis, the glycine and histidine residues were particularly sensitive. These results suggest that the modification of Cu,Zn-SOD by oxidized catecholamines might induce the perturbation of cellular antioxidant systems and led to a deleterious cell condition.
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PMID:Modification of Cu,Zn-superoxide dismutase by oxidized catecholamines. 1546 14

Long-term palliative treatment of Parkinson's disease (PD) with the dopamine precursor l-3,4-dihydroxyphenylalanine ( l-DOPA, levodopa) is compromised by the occurrence of motor complications, most notably motor fluctuations and involuntary movements, l-DOPA-induced dyskinesias. This study was aimed at investigating the effect of adding the catechol- O-methyltransferase (COMT) inhibitor entacapone to chronic treatment with l-DOPA/benserazide. It was hoped that the administration of entacapone would prolong and smooth the central effect of l-DOPA exposure and that this would result in a reduced risk of l-DOPA-induced dyskinesia induction by lowering the l-DOPA dose. The rotational response and striatal extracellular dopamine release were assessed in rats that had undergone a unilateral 6-hydroxydopamine-induced lesion of the nigro-striatal system. Previous studies have shown that repeated treatment with l-DOPA is accompanied by a marked enhancement in behavioural responses and has pharmacological characteristics similar to l-DOPA-induced dyskinesia. In the present study, we demonstrated that rats receiving entacapone in addition to 6.50 mg/kg of l-DOPA displayed significant enhancement of the developing contralateral turning response compared with rats treated with the same dose of l-DOPA only. However, when reducing the l-DOPA dose to 4.25 mg/kg the behavioural response was comparable to that seen in rats treated with the higher dose of l-DOPA only. Voltammetry analysis suggests that the increased behavioural response in entacapone-treated rats is the result of a much larger dopamine release. In addition, we found that entacapone treatment prolonged and smoothed the striatal dopamine levels following chronic l-DOPA/benserazide treatment. From a clinical point of view, this finding suggests that administration of a COMT inhibitor should allow the frequency of l-DOPA administration to decrease and to smooth the brain delivery of the l-DOPA, which in the end should facilitate a reduction in the risk of dyskinesia induction.
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PMID:Entacapone increases and prolongs the central effects of l-DOPA in the 6-hydroxydopamine-lesioned rat. 1550 70


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