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 is released from most cells, including neurons and glial cells. Once in the extracellular space, adenosine modifies cell functioning by operating G-protein-coupled receptors. Interaction between adenosine receptors and other receptors for neuromodulators might contribute to a fine tuning of neuronal function, and therefore, to neuroprotection. Manipulation of adenosine receptors may influence sleep and arousal, cognition and memory, neuronal damage and degeneration and neuronal maturation. The therapeutic implications for neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, epilepsy and multiple sclerosis are discussed.
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PMID:Participation of adenosine receptors in neuroprotection. 1279 68

Huntington's disease (HD) is a devastating hereditary neurodegenerative disorder, the progression of which cannot be prevented by any neuroprotective approach, despite major advances in the understanding of its pathogenesis. The study of several animal models of the disease has led to the discovery of both loss-of-normal and gain-of-toxic functions of the mutated huntingtin protein and the elucidation of the mechanisms that underlie the formation of huntingtin aggregates and nuclear inclusions. Moreover, these models also provide good evidence of a role for excitotoxicity and mitochondrial metabolic impairments in striatal neuronal death. Adenosine has neuroprotective potential in both acute and chronic neurological disorders such as stroke or Parkinson's disease. Here we review experimental data on the role of A1 and A2A adenosine receptors in HD that warrant further investigation of the beneficial effects of A1 agonists and A2A antagonists in animal models of HD. Future pharmacological analysis of adenosine receptors could justify the use of A1 agonists and A2A antagonists for the treatment of HDin clinical trials.
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PMID:Adenosine receptors and Huntington's disease: implications for pathogenesis and therapeutics. 1284 53

There is strong evidence that oxidative stress participates in the etiology of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In the previous studies we have already shown that a combination of alpha-tocopherol and ascorbic acid protect neurons against tert-butyl hydroperoxide (t-BuOOH) induced neurotoxicity in different brain regions including hippocampus and mid brain. In this work, we examined the neuroprotective effect of low dose of adenosine against protein oxidation (protein carbonyls) in parallel with the level of reduced glutathione (GSH) in hippocampus and mid brain regions of mouse brain. The t-BuOOH was injected intraperitoneally in three concentrations (50, 100, 150 mg/kg b.w.) for 10 days. Results showed dose dependent increase in protein carbonyl (PC) in hippocampus and mid brain region. This increase was accompanied by a significant (p < 0.05) decline in GSH content in both brain regions of t-BuOOH treated mice. Adenosine (1 mg/kg b.w.) protected both hippocampus and mid brain neurons against protein oxidation as evidenced by reduction in protein carbonyl content. The GSH content was significantly (p < 0.05) increased after the treatment of adenosine in both brain regions. These data show that prior treatment with low dose of adenosine attenuates the oxidative protein damage with parallel increase in the GSH level in hippocampus and mid brain of t-BuOOH induced mice.
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PMID:Free radical induced increase in protein carbonyl is attenuated by low dose of adenosine in hippocampus and mid brain: implication in neurodegenerative disorders. 1287 Jun 99

Adenosine is a ubiquitous autacoid that acts on four defined receptors, named A(1), A(2A), A(2B) and A(3). Although the biological activity of adenosine has been known for more than 70 years and the existence of specific receptors for more than 25 years, it is only now that the full potential for drug development is becoming clear. Among some of the conditions for which adenosine receptor-based therapy might be used are Parkinson's disease, hypoxia/ischemia, epilepsy, kidney disease and asthma.
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PMID:Adenosine receptors as targets for drug development. 1294 59

Normal cellular metabolism produces oxidants which are neutralized within the cell by antioxidant enzymes and other antioxidants. An imbalance between oxidant and antioxidant has been postulated to lead the degeneration of dopaminergic neurons in Parkinson's disease. In this study, we examined whether adenosine, an antioxidant, can prevent or slowdown neuronal injury in 6-hydroxydopamine (6-OHDA) model of Parkinsonism. Rats were treated with adenosine (500, 250, 125 mg/kg b.wt.) once before surgery and five times after surgery (1 h interval). 2 microl 6-OHDA (12.5 microg in 0.2% ascorbic acid in normal saline) was infused in the right striatum. Two weeks after 6-OHDA infused rats were tested for neurobehavioral activity and sacrificed after 3 weeks of 6-OHDA infusion, for the estimation of glutathione peroxidase, glutathione-S-transferase, glutathione reductase, glutathione content, lipid peroxidation and dopamine and its metabolites. Adenosine was found to be successful in up-regulating the antioxidant status, lowering the dopamine loss and functional recovery returned close to the baseline dose. This study revealed that adenosine, which is an essential part of our body, might be helpful in slowing down the progression of neurodegeneration in Parkinsonism.
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PMID:Protective effect of adenosine in rat model of Parkinson's disease: neurobehavioral and neurochemical evidences. 1459 64

Adenosine A(2A) receptors, abundantly expressed on striatal medium spiny neurons, appear to activate signaling cascades implicated in the regulation of coexpressed ionotropic glutamatergic receptors. To evaluate the contribution of adenosinergic mechanisms to the pathogenesis of the response alterations induced by dopaminergic treatment, we studied the ability of the selective adenosine A(2A) receptor antagonist KW-6002 to prevent as well as palliate these syndromes in rodent and primate models of Parkinson's disease. In rats, KW-6002 reversed the shortened motor response produced by chronic levodopa treatment while reducing levodopa-induced hyperphosphorylation at S845 residues on AMPA receptor GluR1 subunits. In primates, KW-6002 evidenced modest antiparkinsonian activity when given alone. Once-daily coadministration of KW-6002 with apomorphine prevented the development of dyskinesias, which appeared in control animals 7-10 days after initiating apomorphine treatment. Animals initially given apomorphine plus KW-6002 for 3 weeks did not begin to manifest apomorphine-induced dyskinesias until 10-12 days after discontinuing the A(2A) antagonist. These results suggest that KW-6002 can attenuate the induction as well as the expression of motor response alterations to chronic dopaminergic stimulation in parkinsonian animals, possibly by blocking A(2A) receptor-stimulated signaling pathways. Our findings strengthen the rationale for developing A(2A) antagonists as an early treatment strategy for Parkinson's disease.
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PMID:A2A antagonist prevents dopamine agonist-induced motor complications in animal models of Parkinson's disease. 1463 73

The principal therapeutic agents used in the management of Parkinson's disease (PD) enhance nigrostriatal dopaminergic flux through either replenishment of depleted dopamine stores or the action of dopaminergic agonists. Adenosine A2A receptor antagonists (e.g., KW-6002) may provide symptomatic relief in PD and perhaps also may display neuroprotective properties based on studies in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of nigrostriatal neurodegeneration. A second class of compounds that is neuroprotective in the MPTP model comprises inhibitors of the outer mitochondrial flavoenzyme monoamine oxidase B (MAO B), one of the two forms of MAO that regulate levels of brain neurotransmitter substances, including dopamine. In this article, data are presented that document the overlapping A2A antagonist and MAO B inhibitory properties of several 2-styrylxanthinyl derivatives. A limited structure-activity analysis of these compounds and structurally related analogs is provided. The results raise the possibility that a single structure may offer the combined benefits of two pharmacologic strategies, each with symptomatic and potential neuroprotective benefits, for the management of PD.
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PMID:Monoamine oxidase B inhibition and neuroprotection: studies on selective adenosine A2A receptor antagonists. 1466 13

Improving the translation of novel findings from basic laboratory research to better therapies for neurologic disease constitutes a major challenge for the neurosciences. This brief review of aspects of the development of an adenosine A2A antagonist for use in the management of Parkinson's disease (PD) illustrates approaches to some of the relevant issues. Adenosine A2A receptors, highly expressed on striatal medium spiny neurons, signal via kinases whose aberrant activation has been linked to the appearance of parkinsonian signs after dopaminergic denervation and to the motor response complications produced by dopaminomimetic therapy. To assess the ability of A2A receptor blockade to normalize certain of these kinases and thus benefit motor dysfunction, the palliative and prophylactic effects of the selective antagonist KW6002 were first evaluated in rodent and primate models. In hemiparkinsonian rats, KW6002 reversed the intermittent L-dopa treatment-induced, protein kinase A-mediated hyperphosphorylation of striatal alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid receptor GluR1 S845 residues and the concomitant shortening in motor response duration. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys, coadministration of KW6002 with daily apomorphine injections acted prophylactically to prevent dyskinesia onset. These and related preclinical observations guided the design of a limited, randomized, controlled, proof-of-concept study of the A2A antagonist in patients with moderately advanced PD. Although KW6002 alone or in combination with a steady-state IV infusion of optimal-dose L-dopa had no effect on parkinsonian severity, the drug potentiated the antiparkinsonian response to low-dose L-dopa with fewer dyskinesias than produced by optimal-dose L-dopa alone. KW6002 also safely prolonged the efficacy half-time of L-dopa. The results suggest that drugs capable of selectively blocking adenosine A2A receptors could confer therapeutic benefit to L-dopa-treated parkinsonian patients and warrant further evaluation in phase II studies. They also illustrate a strategy for successfully bridging a novel approach to PD therapy from an evolving research concept to pivotal clinical trials.
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PMID:Translating A2A antagonist KW6002 from animal models to parkinsonian patients. 1466 22

The most effective treatment of Parkinson's disease (PD) is, at present, the dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA), however a number of disadvantages such as a loss of drug efficacy and severe side-effects (psychoses, dyskinesias and on-off phenomena) limit long-term effective utilisation of this drug. Recent experimental studies in which selective antagonists of adenosine A(2A) receptors were used, have shown an improvement in motor disabilities in animal models of PD. The A(2A) antagonist [7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-(4,3-e)-1,2,4-triazolo(1,5-c) pyrimidine] (SCH 58261) potentiated the contralateral turning behavior induced by a threshold dose of L-DOPA or direct dopamine receptor agonists in unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, an effect accompanied by an increase in Fos-like-immunoreactivity in neurons of the lesioned striatum. Likewise, other A(2A) receptor antagonists such as (3,7-dimethyl-1-propargylxanthine) (DMPX), [E-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine] (KF 17837) and [E-1,3-diethyl-8(3,4-dimethoxystyryl-7-methyl-3,7-dihydro-1H-purine-2,6-dione] (KW 6002) antagonized catalepsy induced by haloperidol or reserpine in the rat, whereas in non-human primate models of PD, KW 6002 reduced the rigidity and improved the disability score of MPTP-treated marmosets and cynomolgus monkeys. Moreover, in contrast to L-DOPA, selective A(2A) receptor antagonists administered chronically did not produce dyskinesias and did not evoke tolerance in 6-OHDA and MPTP models of PD. An additional therapeutic potential of adenosine A(2A) antagonists emerged from studies showing neuroprotective properties of these compounds in animal models of cerebral ischemia and excitotoxicity, as well as in the MPTP model of PD. Adenosine A(2A) receptor antagonists by reversing motor impairments in animal models of PD and by contrasting cell degeneration are some of the most promising compounds for the treatment of PD.
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PMID:Adenosine A(2a) receptor antagonists: potential therapeutic and neuroprotective effects in Parkinson's disease. 1511 Dec 44

Adenosine A2A receptors are a new target for drug development in Parkinson's disease. Some experimental and clinical data suggest that A2A receptor antagonists can provide symptomatic improvement by potentiating the effects of L-DOPA as well as a decrease in secondary effects such as L-DOPA-induced dyskinesia. L-DOPA-induced behavioral sensitization in unilateral 6-hydroxydopamine-lesioned rats is frequently used as an experimental model of L-DOPA-induced dyskinesia. In the present work this model was used to evaluate the effect of the A2A receptor agonist CGS 21680 and the A2A receptor antagonist MSX-3 on L-DOPA-induced behavioral sensitization and 6-hydroxydopamine-induced striatal dopamine denervation. L-DOPA-induced behavioral sensitization was determined as an increase in L-DOPA-induced abnormal involuntary movements and enhancement of apomorphine-induced turning behavior. Striatal dopamine innervation was determined by measuring tyrosine-hydroxylase immunoreactivity. Chronic administration of MSX-3 was not found to be effective at counteracting L-DOPA-induced behavioral sensitization. On the other hand, CGS 21680 completely avoided the development of L-DOPA-induced behavioral sensitization. The analysis of the striatal dopamine innervation showed that L-DOPA-CGS 21680 co-treatment conferred neuroprotection to the toxic effects of 6-hydroxydopamine. This neuroprotective effect was dependent on A2A and D2 receptor stimulation, since it was counteracted by MSX-3 and by the D2 receptor antagonist haloperidol. These results open new therapeutic avenues in early events in Parkinson's disease.
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PMID:Neuroprotective effect of L-DOPA co-administered with the adenosine A2A receptor agonist CGS 21680 in an animal model of Parkinson's disease. 1534 3


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