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 acts as a neuromodulator through A1 and A2 receptors. The adenosine analogs have been recognized, among other effects, as strong depressors of the locomotor activity by acting on striatal A2 receptors. Moreover, the A2a receptor subtype is exclusively expressed in the striatum. To elucidate at the cellular level the roles of adenosine in the basal ganglia, the anatomical and functional relationships of the A2 receptors with the dopamine D1 and D2 receptors were studied in the rat striatum. In situ hybridization histochemistry was used either in combination with retrograde labeling of striatonigral neurons to determine the projection site of A2a receptor expressing neurons, or on consecutive thin sections to address the putative coexpression of the A2a receptor with the D1 or D2 receptors in individual neurons. The A2a receptor is mainly expressed by neurons projecting to the globus pallidus and expressing also the dopamine D2 receptor and enkephalin, but very sparsely by neurons projecting to the substantia nigra that express the dopamine D1 receptor and substance P. We have further examined the regulatory effect of the A2 receptors on striatal gene expression using in situ hybridization histochemistry and quantitative autoradiography. Rats unilaterally depleted in dopamine by an unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal pathway used as a model of Parkinson's disease subsequently received chronic injections of saline or the adenosine receptor antagonist caffeine. Intact rats were chronically treated with either saline, caffeine alone, caffeine with N-ethyl-carboxamidoadenosine (an equipotent A1 and A2 agonist), or caffeine with cyclohexyladenosine (a more selective A1 agonist).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adenosine A2 receptors regulate the gene expression of striatopallidal and striatonigral neurons. 768 65

Adenosine is known to inhibit the release of dopamine from central synaptic terminals. The present open trial was therefore conducted to determine whether the adenosine receptor-antagonist theophylline would be of value in Parkinson's disease. Fifteen parkinsonian patients were treated for up to 12 weeks with a slow release oral theophylline preparation (150 mg day-1), yielding serum theophylline levels of 4.44 mg L-1 after one week. The patients exhibited significant improvements in mean objective disability scores and 11 reported moderate or marked subjective improvement. It is suggested that theophylline might be a useful adjunct to the routine therapy of parkinsonian patients.
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PMID:The effect of theophylline on parkinsonian symptoms. 793 51

A series of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives (10a-o,q,r), bearing alkyl and aralkyl chains on positions 7 and 8, were synthesized in the attempt to obtain potent and selective antagonists for the A(2A) adenosine receptor subtype. The compounds were tested in binding and functional assays to evaluate their potency for the A(2A) compared with the A1 adenosine receptor subtype. In binding studies in rat brain membranes, most of the compounds showed affinity for A(2A) receptors in the low nanomolar range with a different degree of A(2A) versus A1 selectivity. Comparison of N(7) (10a-d,h-o)- and N(8) (10e-g)-substituted pyrazolo derivatives indicates that N(7) substitution decreases the A1 affinity with the concomitant increase of A(2A) selectivity. Specifically, the introduction of a 3-phenylpropyl group at pyrazolo nitrogen in position 7 (101) increased significantly the A(2A) selectivity, being 210-fold, while the A(2A) receptor affinity remained high (Ki=2.4 nM). With regards to the affinity for A(2A) receptors, also the compound 10n, bearing in the 7-position a beta-morpholin-4-ylethyl group, deserves attention (Ki=5.6 nM) even though the A2A selectivity (84-fold) was not as high as that of 101. Conversely, the compound 10m (N(7)-4-phenylbutyl derivative) showed a remarkable selectivity (A1/a(2A) ratio = 129) associated with lower A(2A) affinity (Ki = 21 nM). In functional studies, most of the compounds examined reversed 5'-(N-ethylcarbamoyl) adenosine-induced inhibition of rabbit platelet aggregation inhibition which is a biological response mediated by the A2A receptor subtype. The compounds are potent and selective A2A antagonists which can be useful to elucidate the pathophysiological role of this adenosine receptor subtype. These compounds deserve to be further developed to assess their potential for treatment of neurodegenerative disorders such as Parkinson's disease.
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PMID:Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives: potent and selective A(2A) adenosine antagonists. 867 54

Tremor, akinesia, rigidity and postual instability are key signs of Parkinson's disease. The most important one is akinesia, which includes decreased spontaneous locomotor activity, slowness of movement, awkwardness and freezing. On the other hand, an electrical focal lesion in the brain, neurotoxin to dopaminergic neurons such as 6-hydroxydopamine (6-OHDA) or I-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), cholinomimetic tremorogenic agents such as oxotremorine or tremorine, monoamine depleting agents such as reserpine or tetrabenazine, or dopamine receptor antagonists such as haloperidol are applied to render animal parkinsonism. The estimation of locomotor activity can be done accurately in animal models. Tremor can be studied using the animals treated by cerebral focal lesion, neurotoxins or cholinomimetics. Skillfulness is hard to estimate in animals, however, it can be done in primates. Freezing appeared in patients with levodopa treatment over a long period. This is a specific motor sign in Parkinson's disease, and cannot be observed in animals. Supplementing dopamine by levodopa administration, retarding the metabolism of levodopa or dopamine by dopa decarboxylase inhibitor (DCI), monoamine oxidase inhibitor type B (MAO-B) inhibitor or catechol-O-methyltransferase (COMT) inhibitor, dopamine receptor agonists, anticholinergic agents, dopamine release enhancer/ uptake inhibitor, N-methyl-D-aspartate (NMDA) receptor antagonists, adenosine receptor antagonists, neurotrophic factors, GM1-ganglioside and nicotinic receptor agonists have been applied in the treatment of Parkinson's disease or are under investigation for patients. Agents to facilitate nerve growth or to inhibit the degeneration of nerves will be developed in the future.
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PMID:[Recent progress in development of psychotropic drugs (3)--Antiparkinsonian agents applied in the treatment of Parkinson's disease or are under investigation for patients or model animals]. 890

The effect of adenosine A1 and A2 receptor agonists and antagonists was investigated on haloperidol-induced catalepsy in rats. Pretreatment (i.p.) with the non-selective adenosine receptor antagonist, theophylline, or the selective adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX), significantly reversed haloperidol-induced catalepsy, whereas the selective adenosine A1 receptor antagonists, 8-phenyltheophylline and 8-cyclopentyl-1,3-dipropylxanthine produced no effect. Similar administration of the adenosine A2 receptor agonists, 5'-(N-cyclopropyl)-carboxamidoadenosine and 5'-N-ethylcarboxamidoadenosine (NECA), and the mixed agonists with predominantly A1 site of action, N6-(2-phenylisopropyl) adenosine or 2-chloroadenosine, potentiated haloperidol-induced catalepsy. Higher doses of the adenosine agonists produced catalepsy when given alone. However, N6-cyclopentyladenosine, a highly selective adenosine A1 receptor agonist, was ineffective in these respects. The per se cataleptic effect of adenosine agonists was blocked by DMPX and the centrally acting anticholinergic agent, scopolamine. Scopolamine also attenuated the potentiation of haloperidol-induced catalepsy by adenosine agonists. Further, i.c.v. administration of NECA and DMPX produced a similar effect as that produced after their systemic administration. These findings demonstrate the differential influence of adenosine A1 and A2 receptors on haloperidol-induced catalepsy and support the hypothesis that the functional interaction between adenosine and dopamine mechanisms might occur through adenosine A2 receptors at the level of cholinergic neurons. The results suggest that adenosine A2, but not A1, receptor antagonists may be of potential use in the treatment of Parkinson's disease.
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PMID:Adenosine A2 receptors modulate haloperidol-induced catalepsy in rats. 921 95

New A2A adenosine receptor antagonists in the series of pyrazolo[4, 3-e]-1,2,4-triazolo[1,5-c]pyrimidines, bearing oxygenated substituents on the phenylalkyl chains on the 7-position, have been synthesized. The compounds were tested in binding and functional assays to evaluate affinity, potency, and selectivity for rat A2A compared to rat A1 and human A3 receptor subtypes. The most interesting compounds (5d,e,h) were tested also in binding to human A1 and A2A adenosine receptors. They showed very good affinity (Ki = 0.94 nM for compound 5h) and interesting selectivity with respect to both rA1 and hA3 (compound 5h: rA1/rA2A = 787, hA3/rA2A > 10 000). These important findings make this new series of compounds the first really selective for A2A adenosine receptors. Thermodynamic parameters were evaluated; all the tested compounds displayed an enthalpy-driven binding as expected for antagonists. Moreover, compound 5h showed a negative entropy value. The highly negative enthalpic and entropic contributions could mean that 5h fits very well in the binding site where, probably, an electrostatic interaction is present associated to a scarce solvent reorganization around the receptor binding site. These compounds deserve to be further developed to assess their potential for treatment of neurodegenerative disorders such as Parkinson's disease.
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PMID:Design, synthesis, and biological evaluation of a second generation of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as potent and selective A2A adenosine receptor antagonists. 962 54

Adenosine A2A receptors are present on enkephalinergic medium sized striatal neurons in the rat and have an important function in the modulation of striatal output. In order to establish more accurately whether adenosine transmission is a generalized phenomenon in mammalian striatum we compared the A2A R expression in the mouse, rat, cat and human striatum. Secondly we compared the modulation of enkephalin gene expression and A2A receptor gene expression in rat striatal neurons after 6-OH-dopamine lesion of the substantia nigra. Hybridization histochemistry was performed with a 35S-labelled radioactive oligonucleotide probe. The results showed high expression of A2A adenosine receptor genes only in the medium-sized cells of the striatum in all examined species. In the rat striatum, expression of A2A receptors was not significantly altered after lesion of the dopaminergic pathways with 6-OH-dopamine even though enkephalin gene expression was up-regulated. The absence of a change in A2A receptor gene expression after 6-OH-dopamine treatment speaks against a dependency on dopaminergic innervation. The maintained inhibitory function of A2A R on motor activity in spite of dopamine depletion could be partly responsible for the depression of locomotor activity observed in basal ganglia disorders such as Parkinson's disease.
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PMID:Adenosine A2A receptor gene expression in the normal striatum and after 6-OH-dopamine lesion. 1104 Dec 67

Parkinson's disease (PD) is the only neurodegenerative disorder in which pharmacological intervention has resulted in a marked decrease in morbidity and a significant delay in mortality. The discovery of striatal dopamine deficiency as the neurochemical basis of PD in 1960 was a pivotal event that led to the era of levodopa therapy. Although levodopa produces dramatic improvements in patients' symptoms, it is also associated with adverse effects that can be disabling. Some of these are felt to be related to fluctuating levels of levodopa in the plasma and brain, and as a result, research has focused on drugs that can provide more continuous dopamine receptor stimulation. Dopamine agonists and catechol-O-methyl-transferase (COMT) inhibitors have been valuable adjuncts to levodopa, but until now levodopa has remained the cornerstone of therapy. Recent studies indicate that the newer dopamine agonists may be assuming greater importance in the control of symptoms. Other drugs, such as nicotinic acetylcholine receptor agonists, neurotrophic factors and adenosine receptor antagonists are under investigation. Efforts are being concentrated on understanding the causes and mechanisms involved in the death of dopaminergic neurones in the substantia nigra. Overactivity of the subthalamic nucleus and glutamate-mediated excitotoxicity might play key roles in the genesis of the disease. Therapeutic approaches aimed at correcting these abnormalities may lead to neuroprotective therapy that can inhibit or prevent the relentless progression of nigral neuronal loss. Well- controlled clinical trials using positron emission tomography (PET) and single photon emission computerised tomography (SPECT) will assist in assessing the putative neuroprotective properties attributed to various agents.
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PMID:Therapeutic advances in idiopathic Parkinsonism. 1113 11

Antiparkinsonian agents applied or under the investigation for the treatment of patients with Parkinson's disease were reviewed. Tremor, akinesia, rigidity and postual instability are key signs of Parkinson's disease. The most important one is akinesia, which includes decreased spontaneous locomotor activity, slowness of movement, awkwardness and freezing. The main pathophysiology of Parkinson's disease is neurodegeneration of nigrostriatal dopaminergic neurons. Neurotoxins or oxidative stress to the dopaminergic neurons have been discussed as one of the etiologies of degeneration. Antioxidant or neuroprotective agents will be the future drugs for Parkinson's disease. At present, supplement of dopamine by levodopa administration, retarding the metabolism of levodopa or dopamine by a dopa decarboxylase inhibitor (DCI), MAO-B (monoamine oxidase inhibitor type B) inhibitor or catechol-O-methyltransferase (COMT) inhibitor, dopamine receptor agonists, anticholinergic agents, dopamine release enhancer/uptake inhibitor, N-methyl-D-aspartate (NMDA) receptor antagonists are applied for the treatment of Parkinson's disease. New agents such as adenosine receptor antagonists, serotonergic agents and nicotinic receptor agonists are under investigation. Agents to facilitate the growth of nerves or to inhibit degeneration of nerves are also studied and will be developed for the treatment of Parkinson's disease in the future. In the case of familial Parkinson's disease, abnormal genes were identified. Gene therapy might be another future treatment for these cases.
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PMID:[Pharmacological treatments of Parkinson's disease]. 1123 2

Recent epidemiological studies have established an association between the common consumption of coffee or other caffeinated beverages and a reduced risk of developing Parkinson's disease (PD). To explore the possibility that caffeine helps prevent the dopaminergic deficits characteristic of PD, we investigated the effects of caffeine and the adenosine receptor subtypes through which it may act in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin model of PD. Caffeine, at doses comparable to those of typical human exposure, attenuated MPTP-induced loss of striatal dopamine and dopamine transporter binding sites. The effects of caffeine were mimicked by several A(2A) antagonists (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH 58261), 3,7-dimethyl-1-propargylxanthine, and (E)-1,3-diethyl-8 (KW-6002)-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione) (KW-6002) and by genetic inactivation of the A(2A) receptor, but not by A(1) receptor blockade with 8-cyclopentyl-1,3-dipropylxanthine, suggesting that caffeine attenuates MPTP toxicity by A(2A) receptor blockade. These data establish a potential neural basis for the inverse association of caffeine with the development of PD, and they enhance the potential of A(2A) antagonists as a novel treatment for this neurodegenerative disease.
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PMID:Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson's disease. 1131 41


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