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 A2 receptors were labeled and visualized by autoradiography in tissue sections of the human brain using the A2-selective agonist ligand [3H](2-p-(2-carboxyethyl)phenylamino)-5'-N-carboxamidoadenosine (CGS 21680). The binding of this ligand was of high affinity, reversible, and was blocked by adenosine A2 agents. Autoradiographic mapping of adenosine A2 sites revealed them to be exclusively restricted to the caudate nucleus, putamen, nucleus accumbens, olfactory tubercle and the lateral segment of the globus pallidus. The densities of adenosine A2 receptors in other brain areas did not differ from background levels. This selective localization prompted us to study the consequences of neurodegenerative diseases such as Parkinson's disease and Huntington's chorea on the densities and localization of these sites in the basal ganglia. In Parkinson's disease the density of adenosine A2 binding sites was comparable to that seen in control cases. In contrast, density values of A2 sites were dramatically decreased, compared to control values, in the basal ganglia of patients with Huntington's chorea. Similar losses of A2 receptors were observed in the guinea-pig striatum after local application of quinolinic acid while lesioning of the dopaminergic neurons was without effect. All these results taken together suggest that adenosine A2 receptors are localized on striatal output neurons which degenerate in Huntington's chorea.
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PMID:Adenosine A2 receptors: selective localization in the human basal ganglia and alterations with disease. 183 21

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

Adenosine receptor antagonists, DMPX, PACPX and theophylline, produce contralateral rotations in unilateral 6-hydroxydopamine-lesioned rats. DMPX and theophylline markedly increase rotations produced by bromocriptine (a dopamine D2 receptor agonist) and/or SKF38393A (a dopamine D1 receptor agonist). All of these effects are inhibited by CGS21680C (an adenosine A2 receptor agonist). These findings suggest synergistic interactions among D1, D2 and A2 receptors that may be relevant to the treatment of Parkinson's disease.
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PMID:Adenosine receptor antagonists potentiate dopamine receptor agonist-induced rotational behavior in 6-hydroxydopamine-lesioned rats. 818 90

The continuing lack of effective long-term therapies for Parkinson's disease and other disorders in which a primary symptom is involuntary tremor is leading to a search for alternative pharmacological strategies. Adenosine is a major modulator of neuronal activity and neurotransmitter release in the central nervous system, with A1 receptors inhibiting transmitter release and A2 receptors generally enhancing release of several transmitter systems relevant to the control of movement. The A2a subtype of receptor is especially concentrated in the neostriatum and is co-localised with D2 receptors for dopamine, the affinity of which are reduced by activation of the A2a population. Antagonists of adenosine, such as theophylline, have been reported to improve the tremor in cases of Parkinson's disease and essential tremor, and the development of better and more selective A2a receptor antagonists may prove of value in these disabling disorders.
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PMID:Potential role of adenosine antagonist therapy in pathological tremor disorders. 936 77

Treatment of Parkinson's disease with L-dopa therapy leads to long-term complications, including loss of drug efficacy and the onset of dyskinesia. Adenosine A2A receptors in striatum are selectively localized to GABAergic output neurons of the striato-pallidal pathway and may avoid such problems. The novel adenosine A2A receptor antagonist KW-6002 has been examined for antiparkinsonian activity in MPTP-treated primates. Oral administration of KW-6002 reversed motor disability in MPTP-treated common marmosets in a dose-dependent manner. However, KW-6002 only modestly increased overall locomotor activity and did not cause abnormal movement, such as stereotypy. The ability of KW-6002 to reverse motor disability was maintained on repeated daily administration for 21 days, and no tolerance was observed. KW-6002 induced little or no dyskinesia in MPTP-treated primates previously primed to exhibit dyskinesia by prior exposure to L-dopa. These results suggest that selective adenosine A2A receptor antagonists represent a new class of antiparkinsonian agents that improve disability without producing hyperactivity and without inducing dyskinesia.
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PMID:Adenosine A2A antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in parkinsonian monkeys. 954 33

The purinergic nucleoside adenosine effectively prevented the death of dopaminergic neurons that occurs spontaneously and progressively in cultures of rat mesencephalon. Adenosine also significantly increased dopamine uptake, attesting to the state of differentiation and functional integrity of the neurons that were rescued. The effects of adenosine were (a) specific to the dopaminergic neurons in these cultures, (b) long-lived, (c) still observed when the treatment was delayed after plating, (d) potentiated by inhibition of adenosine deaminase, and (e) abolished when this enzyme was added in excess to the culture medium. The action of adenosine was mimicked by 5'-(N-ethylcarboxamido)adenosine and dibutyryl-cyclic AMP, but not by CGS-21680, suggesting the possible involvement of A2B subtype purinergic receptors. ATP was also neuroprotective, but its action resulted principally from conversion to adenosine by ectonucleotidases. Several anticancer drugs, including cytosine arabinoside, have been shown previously to prevent apoptosis in cultured dopaminergic neurons by a mechanism that requires the inhibition of proliferating astrocytes. In the presence of adenosine, astrocytes were more differentiated, and their proliferation rate was significantly reduced, suggesting that the neurotrophic effect of the adenine nucleoside resulted also from the repression of the astroglial cells. We did not find evidence of a trophic intermediary in adenosine-treated cultures, however, leading to the hypothesis that limitation of astrocyte replication in itself and/or ensuing changes in the glial phenotype were crucial. Our results suggest that molecules that modulate adenine nucleotide/nucleoside release may be useful for the treatment of chronic neurodegenerative conditions affecting dopaminergic neurons, such as Parkinson's disease.
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PMID:Adenosine prevents the death of mesencephalic dopaminergic neurons by a mechanism that involves astrocytes. 1021 87

It is well known that the nucleoside adenosine exerts a modulatory influence in the central nervous system by activating G protein coupled receptors. Adenosine A2A receptors, the subject of the present review, are predominantly expressed in striatum, the major area of the basal ganglia. Activation of A2A receptors interferes with effects mediated by most of the principal neurotransmitters in striatum. In particular, the inhibitory interactions between adenosine acting on A2A receptors and dopamine acting on D2 receptors have been well examined and there is much evidence that A2A receptors may be a possible target for future development of drugs for treatment of Parkinson's disease, schizophrenia and affective disorders. Our understanding of the role of striatal A2A receptors has increased dramatically over the last few years. New selective antibodies, antagonist radioligands and optimized in situ hybridization protocols have provided detailed information on the distribution of A2A receptors in rodent as well as primate striatum. Studies on the involvement of A2A receptors in the regulation of DARPP-32 and the expression of immediate early genes, such as nerve growth factor-induced clone A and c-fos, have pointed out an important role for these receptors in regulating striatopallidal neurotransmission. Moreover, by using novel selective antagonists for A2A receptors and transgenic mice lacking functional A2A receptors, crucial information on the behavioral role of striatal A2A receptors has been provided, especially concerning their involvement in the stimulatory action of caffeine and the anti-Parkinsonian properties of A2A receptor antagonists. In the present review, current knowledge on the distribution, biochemistry and function of striatal A2A receptors is summarized.
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PMID:Distribution, biochemistry and function of striatal adenosine A2A receptors. 1050 34

In Parkinson's disease a degeneration of dopaminergic neurons of the nigrostriatal pathway is observed. Loss of dopaminergic regulation of striatal neuron activity results in altered motor functions. Adenosine A2A (A2AR) and dopamine D2 (D2R) receptors are colocalized in striatal medium spiny neurons. It has been proposed that adenosine binding to A2AR lowers the affinity of dopamine for D2R, thus modulating the function of this receptor. Absence of D2R in knockout mice (D2R-/-) results in impaired locomotion and coordinated movements. This indicates that absence of dopamine in Parkinson's disease might principally affect D2R-mediated effects with regard to locomotor functions. A2AR-selective antagonists have been demonstrated to have anti- parkinsonian activities in various models of Parkinson's disease in rodents and nonhuman primates. In this article, D2R-/- mice were used to explore the possibility that an A2AR antagonist might reestablish their motor impairment. Interestingly, blockade of A2AR rescues the behavioral parameters altered in D2R-/- mice. In addition, the level of expression of enkephalin and substance P, which were altered in D2R-/-, were also reestablished to normal levels after A2AR antagonist treatment. These results show that A2AR and D2R have antagonistic and independent activities in controlling neuronal and motor functions in the basal ganglia. They also provide evidence that selective A2AR antagonists can exhibit their anti-parkinsonian activities through a nondopaminergic mechanism.
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PMID:Rescue of locomotor impairment in dopamine D2 receptor-deficient mice by an adenosine A2A receptor antagonist. 1090 27

The expression of the human adenosine A(2A) receptor was examined by reverse transcription polymerase chain reaction in post-mortem human brain tissue that was obtained from normal subjects and patients who died with Parkinson's disease. Adenosine A(2A) receptor mRNA was detected in both striatal (nucleus accumbens, caudate nucleus and putamen) and extrastriatal (globus pallidus and substantia nigra) brain regions. A significant decrease in the level of adenosine A(2A) receptor mRNA was found in the anterior and posterior caudate nucleus and anterior dorsal putamen, whereas a significant increase was observed in the substantia nigra pars reticulata of Parkinsonian brain when compared to age-matched controls. No change in adenosine A(2A) receptor mRNA levels was seen in any other brain region examined. This study demonstrates that A(2A) receptor mRNA expression is altered in the basal ganglia of patients who died with Parkinson's disease and who were receiving treatment with dopaminergic drugs. The adenosine A(2A) receptor appears subject to regulation by dopaminergic systems in human brain, though these data do not permit a distinction to be made between the effects of neuronal degeneration or drug treatment. The adenosine A(2A) receptor may therefore form a target for the treatment of basal ganglia disease.
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PMID:Adenosine A(2A) receptor mRNA expression in Parkinson's disease. 1096 52


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