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)

Present Parkinson's disease treatment strategies are far from ideal for a variety of reasons; it has therefore been suggested that partial dopamine receptor agonism might be a potential therapeutic approach with potentially fewer side effects. In the present study, we describe the in vitro characterization of the nonergot ligand SLV308 (7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolonemonohydrochloride). SLV308 binds to dopamine D(2), D(3), and D(4) receptors and 5-HT(1) (A) receptors and is a partial agonist at dopamine D(2) and D(3) receptors and a full agonist at serotonin 5-HT(1) (A) receptors. At cloned human dopamine D(2,L) receptors, SLV308 acted as a potent but partial D(2) receptor agonist (pEC(50) = 8.0 and pA(2) = 8.4) with an efficacy of 50% on forskolin stimulated cAMP accumulation. At human recombinant dopamine D(3) receptors, SLV308 acted as a partial agonist in the induction of [(35)S]GTPgammaS binding (intrinsic activity of 67%; pEC(50) = 9.2) and antagonized the dopamine induction of [(35)S]GTPgammaS binding (pA(2) = 9.0). SLV308 acted as a full 5-HT(1) (A) receptor agonist on forskolin induced cAMP accumulation at cloned human 5-HT(1) (A) receptors but with low potency (pEC(50) = 6.3). In rat striatal slices SLV308 concentration-dependently attenuated forskolin stimulated accumulation of cAMP, as expected for a dopamine D(2) and D(3) receptor agonist. SLV308 antagonized the inhibitory effect of quinpirole on K(+)-stimulated [(3)H]-dopamine release from rat striatal slices (pA(2) = 8.5). In the same paradigm, SLV308 had antagonist properties in the presence of quinpirole (pA(2) = 8.5), but the partial D(2) agonist terguride had much stronger antagonistic properties. In conclusion, SLV308 combines high potency partial agonism at dopamine D(2) and D(3) receptors with full efficacy low potency serotonin 5-HT(1) (A) receptor agonism and is worthy of profiling in in vivo models of Parkinson's disease.
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PMID:In vitro characterization of SLV308 (7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolone, monohydrochloride): a novel partial dopamine D2 and D3 receptor agonist and serotonin 5-HT1A receptor agonist. 1700 60

The correct identity and functional capacity of transplanted dopamine (DA) neurons derived in vitro from embryonic stem (ES) cells is a critical factor for the development of an ES cell-based replacement therapy for Parkinson's disease. We transplanted primate Cyno-1 ES cells differentiated in vitro for 4 (progenitor ES cells) or 6 (differentiated ES cells) weeks, or control fetal primate cells into the striatum of hemi-parkinsonian rats. Partial behavioral recovery in amphetamine-induced rotation was correlated with the number of ES-derived tyrosine hydroxylase-positive (TH+) neurons in the grafts (r=0.5, P<0.05). Post mortem analysis of ES-derived grafts revealed TH+neurons with mature morphology, similar to fetal DA neurons, and expression of midbrain transcription factors, such as Engrailed (En) and Nurr-1. While the total number of TH+neurons was not different between the two groups, TH/En co-expression was significantly higher (>90%) in grafts from differentiated ES cells than in grafts derived from progenitor cells (<50%), reflecting a more heterogeneous cellular composition. Within the grafts there was an overlap between ES-derived TH+axonal arbors and clusters of primate ES-derived striatal neurons expressing brain factor 1 (Bf-1, Foxg1) and DA and cAMP-regulated phosphoprotein (DARPP-32). Such overlap was never observed for other regional transcription factors that define neighboring forebrain domains in the developing brain, such as Nkx2.1 (medial ganglionic eminence), Nkx2.2 (pallidal and diencephalic progenitors) or Pax6 (dorsal telencephalic progenitors). Despite the heterogeneity of ES-derived graft cell composition, these results demonstrate normal phenotypic specification, conserved natural axonal target selectivity and functionality of DA neurons derived from primate ES cells.
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PMID:Transplanted dopamine neurons derived from primate ES cells preferentially innervate DARPP-32 striatal progenitors within the graft. 1706 92

Parkinson's disease (PD) is characterized by a selective loss of dopamine-producing neurons in the substantia nigra (SN), which in turn results in dopamine depletion in the striatum, and the presence of neuronal cytoplasmic inclusions known as Lewy bodies (LBs). Alpha-synuclein is a presynaptic protein that accumulates abnormally in LBs and is seen predominantly in cases of dementia with LBs. Although the central role of alpha-synuclein in neurodegeneration has been previously demonstrated by the discovery of missense alpha-synuclein mutations in familial PD, the specific mechanism by which alpha-synuclein contributes to these diseases remains unclear. In the present study, we examined whether alpha-synuclein affects the downstream signaling of dopamine D2 receptor (D2R). In CHO cells stably transfected with D2Rs, alpha-synuclein enhanced dopamine D2-agonist-mediated inhibition of adenylate cyclase, which consequently affected its downstream cAMP-responsive element (CRE)-mediated gene transcription, while C-terminal deletion mutant of alpha-synuclein did not. Our study suggests that the alpha-synuclein enhances the dopamine-mediated intracellular signaling pathways by D2R, thus provide a possible mechanism in presynaptic regulation of the synaptic homeostasis in the dopaminergic neurotransmission.
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PMID:Alpha-synuclein enhances dopamine D2 receptor signaling. 1708 19

Neural stem cells (NSCs) possess high potencies of self-renewal and neuronal differentiation. We explored here whether transplantation of human NSCs cloned by v-myc gene transfer, HB1.F3 cells, is a feasible therapeutic option for Parkinson's disease. In vivo, green fluorescent protein-labeled HB1.F3 cells (200,000 viable cells in 3 microl of PBS) when stereotaxically transplanted (same-day lesion-transplant paradigm) into the 6-hydroxydopamine-lesioned striatum of rats significantly ameliorated parkinsonian behavioral symptoms compared with controls (vehicle, single bolus, or continuous minipump infusion of trophic factor, or killed cell grafts). Such graft-derived functional effects were accompanied by preservation of tyrosine hydroxylase (TH) immunoreactivity along the nigrostriatal pathway. Grafted HB1.F3 cells survived in the lesioned brain with some labeled with neuronal marker mitogen-activated protein 2 and decorated with synaptophysin-positive terminals. Furthermore, endogenous neurogenesis was activated in the subventricular zone of transplanted rats. To further explore the neuroprotective mechanisms underlying HB1.F3 cell transplantation, we performed cell culture studies and found that a modest number of HB1.F3 cells were TH and dopamine and cAMP-regulated phosphoprotein 32 positive, although most cells were nestin positive, suggesting a mixed population of mature and immature cells. Administration of the HB1.F3 supernatant to human derived dopaminergic SH-SY5Y cells and fetal rat ventral mesencephalic dopaminergic neurons protected against 6-hydroxydopamine neurotoxicity by suppressing apoptosis through Bcl-2 upregulation, which was blocked by anti-stem cell factor antibody alone, the phosphatidylinositol 3-kinase/Akt inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one] alone, or a combination of both. These results suggest that HB1.F3 cell transplantation exerts neuroprotective effects against dopaminergic depletion in vitro and in vivo because of trophic factor secretion and neuronal differentiation.
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PMID:Transplantation of human neural stem cells exerts neuroprotection in a rat model of Parkinson's disease. 1713 12

Dopamine and norepinephrine are neurotransmitters which participate in various regulatory functions of the human brain. These functions are lost in neurodegenerative diseases including Parkinson's disease and Alzheimer's disease. In this study, we used SK-N-MC neuroblastoma cells to investigate the cytotoxicities of high concentrations of dopamine and norepinephrine on neuronal cells. Dopamine, norepinephrine, as well as their corresponding synthetic agonists (SKF38393 and isoproterenol, respectively) triggered SK-N-MC cell death when applied at 50-100 muM persistently for 2 days. This catecholamine-induced cell death appears to be neuronal specific, as demonstrated by their inabilities of triggering apoptosis of A549 lung carcinoma cells and Cos-7 kidney fibroblasts. By pretreating SK-N-MC cells with target-specific inhibitors before administration of catecholamine, components of G protein signaling (i.e. G( s )/cAMP/PKA), monoamine oxidases, nitric oxide synthase, c-Jun N-terminal kinase and oxidative stress were found to be involved in this dopamine/norepinephrine-induced cytotoxicity, which subsequently led to caspase-dependent and -independent apoptotic responses as well as DNA degradation. In contrast, agonists of G( i )-coupled dopamine receptors and adrenergic receptors (quinpirole and UK14,304, respectively) were incapable of triggering apoptosis of SK-N-MC cells. Our results suggest that both G protein (G( s ))-mediated signaling cascade and oxidative stress participate in the dopamine/norepinephrine-induced neuronal apoptosis.
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PMID:Dopaminergic and adrenergic toxicities on SK-N-MC human neuroblastoma cells are mediated through G protein signaling and oxidative stress. 1713 23

Intrastriatal transplantation of fetal ventral mesencephalon (VM) tissue provides the potential to alleviate motor symptoms of Parkinson's disease (PD) and levodopa-induced dyskinesia (LID). However, the degree of recovery varies among individuals with an incidence of "off-phase", graft-induced dyskinesia (GID) in some patients. We hypothesised that this variability is due to the heterogeneous nature of dopaminergic neurons in the transplant. We therefore investigated this in the unilateral 6-hydroxydopamine-lesioned rat model of PD. These animals were primed to develop LID and then transplanted with fetal VM into the caudal aspects of the striatum. No GID was observed but in a significant number of animals the transplants ameliorated LID. There was a correlation between the degree of behavioural and LID recovery with the number of A9 dopaminergic neurons in the transplant, based on their expression of a G-protein-coupled inward rectifying current potassium channel (Girk2). Furthermore, we showed that LID development is related to an abnormal expression profile of cyclin-dependent kinase 5 (Cdk5) and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) in the striatum and that intrastriatal VM transplants normalised both Cdk5 expression and DARPP-32 phosphorylation in animals exhibiting functional improvement. These results suggest that an A9 dopaminergic neuron-enriched transplant may be the key to an effective PD cell replacement therapy through normalisation of the altered striatal expression of Cdk5/DARPP-32.
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PMID:The importance of A9 dopaminergic neurons in mediating the functional benefits of fetal ventral mesencephalon transplants and levodopa-induced dyskinesias. 1718 99

We have studied the stability of the dopaminergic phenotype in a conditionally immortalized human mesencephalic cell line, MESC2.10. Even though MESC2.10 cells exhibit features of dopaminergic neurons in vitro, none of the cells expressed tyrosine hydroxylase (TH) after transplantation into a rat model of Parkinson's disease. We examined whether this is caused by cell death or loss of transmitter phenotype. Cells were cultured in differentiation medium, then harvested and replated into the same medium where they continued to express TH, whereas replated cells fed medium lacking differentiation factors (dibutyryl cAMP and glial cell line-derived neurotrophic factor) did not. Interestingly, cultures grown in the absence of differentiation factors could regain TH expression once exposed to differentiation medium. Our data suggest that TH expression in vitro is inducible in neurons derived from the MESC2.10 cell line and that the dopaminergic phenotype of these cells in vivo might be unstable.
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PMID:Tyrosine hydroxylase expression is unstable in a human immortalized mesencephalic cell line--studies in vitro and after intracerebral grafting in vivo. 1722 62

Antagonists of adenosine A2A receptors (A2A -antagonists) with different chemical structures have been developed by several pharmaceutical companies for the potential treatment of Parkinson's disease. Pharmacological characterization of these antagonists was incomplete, and different assay conditions were used in different labs. Therefore, we characterized the potencies, selectivities, and pharmacokinetic profiles of six prototypical A2A -antagonists. Displacements of [3H]MSX-2 and of [3H]CGS21680 binding to the human cloned and rat A2A receptors were performed. The rank order of potency of antagonists to displace [(3)H]MSX-2 binding to the human A2A was SCH58261 > or = Biogen-34 > or = Ver-6623 > or = MSX-2 > KW-6002 > > DMPX. For the rat striatal A2A, the order of potency was Biogen-34 > or = SCH58261 > or = Ver-6623 > or = MSX-2 > or = KW-6002 > > DMPX. SCH58261 was the most potent antagonist of the human A2A with a K(i) value of 4 nM, whereas Biogen-34 was the most potent antagonist of the rat A2A with a K(i) value of 1.2 nM. Similar results were obtained from cAMP assays. Selectivities of A2A-antagonists were determined using radioligands [3H]DPCPX, [3H]ZM241385, and [125I]-AB-MECA for A1, A2B, and A3 receptors, respectively. KW-6002 and Biogen-34 exhibited the highest selectivity for A2A vs A1 (human and rat), respectively. The pharmacokinetic profiles of antagonists were evaluated in vivo in rats. DMPX and KW-6002 had the greatest oral bioavailability. In contrast, SCH58261, MSX-2, and Ver-6623 had low or poor oral bioavailability. In summary, SCH58261, Biogen-34, MSX-2, and Ver-6623 had high affinities for both human and rat A2A receptors, with reasonable selectivity for A2A over A1 and A2B receptors. They are suitable as A2A -antagonists for in vitro pharmacological studies. Among the six A2A-antagonists, KW-6002 is the best for use in in vivo animal studies, particularly for a CNS target, based on its bioavailability, half life, and brain penetration.
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PMID:Characterization of the potency, selectivity, and pharmacokinetic profile for six adenosine A2A receptor antagonists. 1731 Feb 64

Multivalent ligands are promising pharmacological tools that may be more efficacious for several diseases than highly selective single-target drugs. A combined therapy using dopaminergic agonists and adenosinergic antagonists is currently being evaluated for the treatment of Parkinson's disease. [(a) Kanda, T.; et al. Exp. Neurol. 2000, 162, 321-327. (b) Jenner, P. Expert Opin. Invest. Drugs 2005, 14, 729-738. (c) Kase, H.; et al. Neurology 2003, 61 (Suppl 6), S97-S100.] Here we prepared dual ligands acting on adenosine and dopamine receptors by applying a combinatorial approach based on the ergolene privileged structure. The potency and efficacy of these novel compounds were determined by radioligand binding studies and intracellular cAMP production assays in cells expressing adenosine and dopamine receptors. Selected compounds displayed dual dopamine agonist and adenosine antagonist activity. Molecules with this pharmacological profile are potentially useful for studying dopamine-adenosine cross-talk in the central nervous system and for testing the therapeutic potential of multivalent drugs for Parkinson's disease.
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PMID:Novel ergopeptides as dual ligands for adenosine and dopamine receptors. 1753 20

The molecular basis of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID), one of the major hindrances in the current therapy for Parkinson's disease, is still unclear. We show that attenuation of cAMP signaling in the medium spiny neurons of the striatum, achieved by genetic inactivation of the dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), reduces LID. We also show that, in dyskinetic mice, sensitized cAMP/cAMP-dependent protein kinase/DARPP-32 signaling leads to phosphorylation/activation of the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). The increase in ERK1/2 phosphorylation associated with dyskinesia results in activation of mitogen- and stress-activated kinase-1 (MSK-1) and phosphorylation of histone H3, two downstream targets of ERK involved in transcriptional regulation. In line with these observations, we found that c-Fos expression is abnormally elevated in the striata of mice affected by LID. Persistent enhancement of the ERK signaling cascade is implicated in the generation of LID. Thus, pharmacological inactivation of ERK1/2 achieved using SL327 (alpha-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile), an inhibitor of the mitogen-activated kinase/ERK kinase, MEK, during chronic L-DOPA treatment counteracts the induction dyskinesia. Together, these results indicate that a significant proportion of the abnormal involuntary movements developed in response to chronic L-DOPA are attributable to hyperactivation in striatal medium spiny neurons of a signaling pathway including sequential phosphorylation of DARPP-32, ERK1/2, MSK-1, and histone H3.
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PMID:Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia. 1759 48


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