Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine A(2A) receptors present in the central nervous system have been implicated in the modulation of motor functions. Accordingly, adenosine A(2A) receptor antagonists currently constitute an attractive non-dopaminergic option for use in the treatment of Parkinson's disease (PD). The highly enriched distributions of adenosine A(2A) receptors in striatopallidal neurons, and their ability to form functional heteromeric complexes with dopamine D(2) and metabotropic glutamate mGlu5 receptors, render A(2A) receptor antagonists of particular interest in the modulation of motor behavior, whilst at the same time displaying a low predisposition to inducing non-motor side effects. Furthermore, adenosine A(2A) receptor antagonists appear to exert a marked efficacy on PD tremor and in reducing the progress of underlying neurodegeneration and maladaptive neuroplasticity that complicates standard dopamine replacement treatments in PD. Finally, recent evidence has illustrated an improvement of cognitive function as well as enhancement of attention in rodents following administration of A(2A) receptor antagonists. This article is aimed at examining preclinical studies describing these findings as well as reports from clinical trials, in order to provide a comprehensive review of the evidence suggesting that this class of drugs may represent an advance in the treatment of PD.
 ...
PMID:Adenosine A2A receptor antagonists and Parkinson's disease: state of the art and future directions. 1853 71

Adenosine is an endogenous neuromodulator which alters neuronal excitability and firing rate. In recent years there has been growing interest in the manipulation of adenosine levels to understand the pathophysiology of various diseases. Dipyridamole (DPM) is a potent adenosine transport inhibitor that causes a several-fold increase in brain adenosine concentration. The present study was undertaken to investigate the effect of DPM on MPTP-induced neurotoxicity. Mice weighing 30 +/- 3 g were administered with MPTP (30 mg/kg, i.p.) daily for 5 days. DPM was given daily 1 h before MPTP in doses of 250, 500 and 1000 mg/kg body weight, (P.O.) respectively, in three different groups of mice for 7 days. Twenty four hours after the last dose of DPM, the animals were observed for neurobehavioral changes including locomotor activity and pole descending time. Immediately after behavioral studies, all the animals were sacrificed and brains were isolated for biochemical studies. The treatment of mice with MPTP or DPM individually produced no significant change in mobility or spasticity; however, the combination of these drugs produced significant bradykinesia. There was no incidence of mortality when the mice were treated with MPTP or DPM individually, though the combination of MPTP and DPM produced significant mortality which was proportional to the doses of the later drug. The treatment of mice with MPTP produced significant depletion of striatal dopamine and glutathione. Concomitant treatment of DPM with MPTP further reduced the striatal glutathione level without affecting dopamine. The result of this study shows the ability of DPM to potentiate MPTP-induced neurobehavioral toxicity and mortality in mice. Further studies are warranted to determine the role of adenosine in experimental and clinical Parkinson's disease.
 ...
PMID:Dipyridamole potentiates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced experimental Parkinsonism in mice. 1859 Oct 87

Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with selective loss of dopaminergic neurons in substantia nigra pars compacta. Among the proposed mechanisms of dopaminergic degeneration, oxidative stress is believed to play an important role. On the other hand, L-DOPA used as the main medication in PD and overproduction of dopamine (DA) in striatal neurons could elicit toxic effects due to formation of free radicals (FRs). Adenosine, an endogenous neuromodulator was shown in various experimental models to have neuroprotective properties. In our study, we investigated the role of adenosine A(1) and A(2A) receptor ligands in hydroxyl radical generation by L-DOPA in the rat striatum. The hydroxyl radical was assayed by HPLC-ED as a product of its reaction with p-hydroxybenzoic acid (PBA). Intrastriatal infusion of L-DOPA(50 microM) markedly increased dialysate level of DA and 3,4-dihydroxybenzoic acid (3,4-DHBA). An adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA, 25-50 microM), nonselectiveA(1)/A(2A) receptor agonist 2-chloroadenosine (2-CADO, 50-100 microM), and selective A(2A) receptor agonist CGS 21680 (25-50 microM) decreased the level of 3,4-DHBA. A non-selective A(1)/A(2A) adenosine receptor antagonist caffeine (100 microM) produced similar effect on 3,4-DHBA level. At the same time, CPA and 2-CADO, but not CGS 21680 or caffeine, decreased L-DOPA-induced DA release. The adenosine receptor ligands alone only weakly changed extracellular DA level and did not influence hydroxyl radical production. However, they showed scavenging activity in Fenton reaction in vitro. The primary caffeine metabolite in rodents, 1,3,7-trimethyl uric acid (1,3,7-mUA) decreased both, DA synthesis and 3,4-DHBA level. Thus, paradoxically, both agonists of A(1) receptor and agonist of A(2A) receptor as well as antagonist of A(1) and A(2A) receptors (caffeine), all decreased generation of FRs. Our study suggests that a decrease in hydroxyl radical generation caused by adenosine receptor ligands results from attenuation of L-DOPA-induced DA release or from their scavenging activity.
 ...
PMID:Paradoxical effects of adenosine receptor ligands on hydroxyl radical generation by L-DOPA in the rat striatum. 1862 56

Adenosine A(2A) receptors are members of the G protein-coupled receptor family and mediate multiple physiological effects of adenosine, both at the central nervous system (CNS) and at peripheral tissues, by activating several pathways or interacting with other receptors or proteins. Increasing evidence relate A(2A) receptors with pharmacological stress testing, neurodegenerative disorders (such as Parkinson's disease) and inflammation, renewing the interest in these receptors, increasingly viewed as promising therapeutic targets. Series of agonists and antagonists have been developed by medicinal chemistry artwork either by structure activity relationship (SAR) or quantitative structure activity relationship (QSAR) studies. These studies have allowed identification of the structural and electrostatic requirements for high affinity A(2A) receptor binding and, therefore, contributing to the rational design of A(2A) receptor ligands. Additional rational chemical modifications of the existing A(2A) receptor ligands may further improve their affinity/selectivity. The purpose of this review is to analize and summarize aspects related to the medicinal chemistry of A(2A) receptor ligands, their present and potencial therapeutic applications by exploring the molecular structure and physiological and pathophysiological roles of A(2A) receptors.
 ...
PMID:Ligands and therapeutic perspectives of adenosine A(2A) receptors. 1867 94

Abnormalities of striatal function have been implicated in several major neurological and psychiatric disorders, including Parkinson's disease, schizophrenia and depression. Adenosine, via activation of A(2A) receptors, antagonizes dopamine signaling at D2 receptors and A(2A) receptor antagonists have been tested as therapeutic agents for Parkinson's disease. We found a direct physical interaction between the G protein-coupled A(2A) receptor (A(2A)R) and the receptor tyrosine kinase fibroblast growth factor receptor (FGFR). Concomitant activation of these two classes of receptors, but not individual activation of either one alone, caused a robust activation of the MAPK/ERK pathway, differentiation and neurite extension of PC12 cells, spine morphogenesis in primary neuronal cultures, and cortico-striatal plasticity that was induced by a previously unknown A(2A)R/FGFR-dependent mechanism. The discovery of a direct physical interaction between the A(2A) and FGF receptors and the robust physiological consequences of this association shed light on the mechanism underlying FGF functions as a co-transmitter and open new avenues for therapeutic interventions.
 ...
PMID:FGF acts as a co-transmitter through adenosine A(2A) receptor to regulate synaptic plasticity. 1895 46

8-(3-chlorostryryl) caffeine (CSC), a selective adenosine A(2A) receptor antagonist, has been reported to inhibit the levodopa-induced motor fluctuation in Parkinson's disease. However, the underlying mechanism of its action remains largely unknown. In our study, we investigated the signaling pathway by which CSC inhibited levodopa-induced motor fluctuation in rats with a 6-hydroxydopamine (6-OHDA)-induced lesion. We treated 6-OHDA-lesioned rats with levodopa (50 mg/kg/day, twice daily) for 22 days, followed by levodopa+CSC (5 mg/kg/day, twice daily) or levodopa+vehicle for 7 days. The sham-lesioned and 6-OHDA-lesioned rats treated with saline for 29 days served as sham and lesion control groups. We found that the treatment of CSC reversed the shortening of the rotational motor response duration induced by levodopa administration and the effect was maintained until the end of the treatment. The chronic levodopa treatment upregulated the adenosine A(2A) receptor expression and modified downstream signaling pathway including decreasing the phosphorylation of DARPP-32 at Thr75 site and increasing the phosphorylation of ERK1/2 in the lesioned striatum. However, the following CSC treatment attenuated the levodopa-induced adenosine A(2A) receptor upregulation and abolished the aberrant phosphorylation of DARPP-32 at Thr75 site and that of ERK1/2. Our results indicate that the inhibitory effect of CSC on levodopa-induced motor fluctuation may be associated with the inhibition of Adenosine A(2A) Receptor and downstream DARPP-32 and ERK1/2 signaling pathway.
 ...
PMID:Inhibitory effect of 8-(3-chlorostryryl) caffeine on levodopa-induced motor fluctuation is associated with intracellular signaling pathway in 6-OHDA-lesioned rats. 1939 28

Adenosine A2A receptor has emerged as an attractive non-dopaminergic target in the experimental pharmacological therapy for Parkinson's disease (PD). Moreover, it has been postulated that A2A adenosine receptor antagonists exert neuroprotective effects in experimental models of PD and progressive supranuclear palsy (PSP). Interestingly, in both these pathological conditions a deficit of mitochondrial complex I has been found. Thus, utilizing extracellular and intracellular recordings from corticostriatal brain slices, we have tested the possible neuroprotective action of two A2A receptor antagonists, ST1535 and ZM241385, on the irreversible electrophysiological effects induced by the acute application of rotenone, a pesticide acting as a selective inhibitor of mitochondrial complex I activity. Both these antagonists reduced the rotenone-induced loss of corticostriatal field potential amplitude as well as the membrane depolarization caused by this toxin on striatal spiny neurons. The use of A2A receptor antagonists might represent a promising neuroprotective strategy in basal ganglia disorders involving a deficit of mitochondrial complex I activity.
 ...
PMID:A2A adenosine receptor antagonists protect the striatum against rotenone-induced neurotoxicity. 1941 78

Loss of dopaminergic nigrostriatal neurons in the substantia nigra leads to Parkinson's disease (PD). Adenosine A(2A) receptors (A(2A)Rs) have been anticipated as novel therapeutic target for PD. A(2A)Rs potentiate locomotor behavior and are predominantly expressed in striatum. Naphtha [1, 2-d] thiazol-2-amine (NATA), a tricyclic thiazole have been studied as new anti-Parkinsonian compound. AutoDock analysis and pharmacophore study of NATA with known A(2A)R antagonists explicit its efficacy as a possible adenosine receptor antagonist. In vivo pharmacology of NATA showed reduction of haloperidol (HAL)-induced motor impairments in Swiss albino male mice. Relatively elevated levels of dopamine in NATA pre-treated mice are suggestive of its possible role as neuromodulator in PD.
 ...
PMID:In silico study of naphtha [1, 2-d] thiazol-2-amine with adenosine A 2A receptor and its role in antagonism of haloperidol-induced motor impairments in mice. 1965 38

Adenosine A(2A) (A(2A)R) and dopamine D(2) (D(2)R) receptors mediate the antagonism between adenosinergic and dopaminergic transmission in striatopallidal GABAergic neurons and are pharmacological targets for the treatment of Parkinson's disease. Here, a family of heterobivalent ligands containing a D(2)R agonist and an A(2A)R antagonist linked through a spacer of variable size was designed and synthesized to study A(2A)R-D(2)R heteromers. Bivalent ligands with shorter linkers bound to D(2)R or A(2A)R with higher affinity than the corresponding monovalent controls in membranes from brain striatum and from cells coexpressing both receptors. In contrast, no differences in affinity of bivalent versus monovalent ligands were detected in experiments using membranes from cells expressing only one receptor. These findings indicate the existence of A(2A)R-D(2)R heteromers and of a simultaneous interaction of heterobivalent ligands with both receptors. The cooperative effect derived from the simultaneous interaction suggests the occurrence of A(2A)R-D(2)R heteromers in cotransfected cells and in brain striatum. The dopamine/adenosine bivalent action could constitute a novel concept in Parkinson's disease pharmacotherapy.
 ...
PMID:Adenosine A2A receptor-antagonist/dopamine D2 receptor-agonist bivalent ligands as pharmacological tools to detect A2A-D2 receptor heteromers. 1971 95

The antagonistic interaction between adenosine and dopamine receptors could have important pathophysiological and therapeutic implications in Parkinson's disease (PD). The primary aim of this study was to investigate the expression, affinity, and density of A(1), A(2A), A(2B), and A(3) adenosine receptors (ARs) and D(2) dopamine receptors (D(2)Rs) in PD. An increase in A(2A)AR density in putamen was found. The presence and functionality of ARs in human lymphocyte and neutrophil membranes from patients with PD revealed a specific A(2A)AR alteration compared with healthy subjects. A statistically significant linear correlation among the A(2A)AR density, functionality, or tumor necrosis factor-alpha (TNF-alpha) levels and Unified Parkinson's Disease Rating Scale (UPDRS) motor score was reported. Adenosine concentration and TNF-alpha levels were increased in plasma of patients with PD. In rat adrenal pheochromocytoma (PC12) cells, a widely useful model, adenosine antagonists decreased dopamine uptake, and an opposite effect was mediated by A(2A) agonists. This is the first report showing the presence of an A(2A)AR alteration in putamen in PD that mirrors a similar up-regulation in human peripheral blood cells. Moreover, the correlation found between A(2A)AR density or A(2A) agonist potency and UPDRS motor score highlights the central role of A(2A)ARs in the pharmacological treatment of PD.
 ...
PMID:A2A adenosine receptor overexpression and functionality, as well as TNF-alpha levels, correlate with motor symptoms in Parkinson's disease. 1977 36


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>