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)

Multiple studies implicate metals in the pathophysiology of neurodegenerative diseases. Disturbances in brain iron metabolism are linked with synucleinopathies. For example, in Parkinson's disease, iron levels are increased and magnesium levels are reduced in the brains of patients. To understand how changes in iron and magnesium might affect the pathophysiology of Parkinson's disease, we investigated binding of iron to alpha-synuclein, which accumulates in Lewy bodies. Using fluorescence of the four tyrosines in alpha-synuclein as indicators of metal-related conformational changes in alpha-synuclein, we show that iron and magnesium both interact with alpha-synuclein. alpha-Synuclein exhibits fluorescence peaks at 310 and 375 nm. Iron lowers both fluorescence peaks, while magnesium increases the fluorescence peak only at 375 nm, which suggests that magnesium affects the conformation of alpha-synuclein differently than iron. Consistent with this hypothesis, we also observe that magnesium inhibits alpha-synuclein aggregation, measured by immunoblot, cellulose acetate filtration, or thioflavine-T fluorescence. In each of these studies, iron increases alpha-synuclein aggregation, while magnesium at concentrations >0.75 mm inhibits the aggregation of alpha-synuclein induced either spontaneously or by incubation with iron. These data suggest that the conformation of alpha-synuclein can be modulated by metals, with iron promoting aggregation and magnesium inhibiting aggregation.
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PMID:Magnesium inhibits spontaneous and iron-induced aggregation of alpha-synuclein. 1185 Apr 16

Recent studies have implicated N-methyl-D-aspartate (NMDA) receptor dysfunction in the pathogenesis and treatment of Parkinson's disease (PD). The NMDA receptor is composed of several subunits, of which, the receptor 2b subunit (GRIN2B) is of particular significance for PD. This subunit is found enriched in the basal ganglia, and PD-monotherapy potential has been determined for GRIN2B antagonists. For this study of a sample population consisting of 101 PD patients and 108 controls, we tested the hypothesis that an ACC --> ACT transversion (2664(th) nucleotide of the coding sequence) affecting codon 888 (tyrosine) of GRIN2B confers susceptibility to PD, or relates to the age of onset. Comparing PD patients and controls, the distribution of the GRIN2B genotypes (p = 0.754) and alleles (p = 0.269) did not differ significantly. The onset age was not significantly different comparing the three genotypic groups (p = 0.189). Our negative findings suggest that it is unlikely that the GRIN2B C2664T polymorphism plays a substantial role in conferring susceptibility to PD in the Chinese population. Further studies with other genetic variations of NMDA subunits, relating either to PD or to the therapeutic response for PD, are suggested.
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PMID:Association analysis for genetic variants of the NMDA receptor 2b subunit (GRIN2B) and Parkinson's disease. 1195 67

A new method for quantitative measurement of brain acetylcholinesterase (AChE) activity in living human brain using positron emission tomography (PET) is described. We tested several radiolabeled lipophilic acetylcholine analogs, e.g., N-methylpiperidyl esters, which readily entered the brain via the blood-brain barrier, were hydrolyzed selectively by AChE, and were then trapped in the brain. Among them, and tested and N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) was chosen as the tracer for PET. Quantitative measurement of cortical AChE was accomplished by fitting the time course of cerebral radioactivity concentration measured by PET and the metabolite-corrected arterial plasma input function using a nonlinear least-squares fitting method. Normal control studies of subjects with a wide range in age (24-89 years) showed no decrease in AChE activity in the cerebral cortex with age. Studies on patients with Alzheimer's disease demonstrated a widespread reduction of AChE activity in the cerebral cortex (more profound in early-onset than in late-onset Alzheimer's disease). Parkinson's disease and progressive supranuclear palsy, clinically similar disorders, could be differentiated with [11C]MP4A/PET studies. Simple methods without using an arterial input function are also proposed. The method provides a quantitative measure of the cholinergic aspect of brain function and proved to be useful in diagnosis of neurodegenerative disorders including Alzheimer's disease.
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PMID:Positron emission tomography: quantitative measurement of brain acetylcholinesterase activity using radiolabeled substrates. 1218 13

We evaluated the effect of cabergoline on superoxide anion production by rat microglial cells using a 2-methyl-6-(p-methoxyphenyl)-3,7-dihydroimidazo[1, 2-a]pyrazin-3-one-dependent chemiluminescence assay. Cabergoline dose-dependently inhibited superoxide anion production by microglial cells stimulated with phorbol myristate acetate or opsonized zymosan, while it had no superoxide dismutase-like activity. We also studied the effects of cabergoline and alpha-tocopherol on thiobarbituric acid reactive substances formation in homogenized brain-tissue in rats. Cabergoline was stronger than alpha-tocopherol in inhibiting auto-oxidation. While cabergoline is commonly used to treat the motor dysfunction of Parkinson's disease, it may also be effective in inhibiting oxidative stress, a possible mechanism of dopaminergic neuronal degeneration in Parkinson's disease.
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PMID:Antioxidant properties of cabergoline: inhibition of brain auto-oxidation and superoxide anion production of microglial cells in rats. 1221 20

Recently, it has been shown that rotenone, a specific inhibitor of mitochondrial complex I, is a useful tool in animal models of Parkinson's disease, but the mechanism of rotenone-induced neuronal death is not fully understood. In human neuroblastoma SH-SY5Y cells, rotenone induced the degradation of procaspases-12, -9 and -3, followed by cleavage of poly (adenosine diphosphate-ribose) polymerase, DNA fragmentation and cell death. Pretreatment with phorbol-12-myristate-13-acetate inhibited the rotenone-induced decrease in procaspases-9 and -3, but not that in procaspase-12. In contrast, benzyloxycarbonyl-Val-Ala-Asp(OCH(3))-CH(2)F inhibited the decrease in procaspase-12, but not those in procaspases-9 and -3 in this study. These results suggest that rotenone may induce activation of both mitochondria- and endoplasmic reticulum-dependent caspases in human SH-SY5Y cells.
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PMID:Possible involvement of both mitochondria- and endoplasmic reticulum-dependent caspase pathways in rotenone-induced apoptosis in human neuroblastoma SH-SY5Y cells. 1240 52

Increased sexual activity in patients with dementia is problematic for caregivers and has no proven treatment. This report describes two male patients who had dementia with pronounced sexual acting out. One patient had vascular dementia and the other patient had Parkinson's disease with associated dementia. After nonresponse to neuroleptics and sedatives, low-dose cyproterone acetate successfully reduced sexual acting out without relevant side effects in both patients.
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PMID:Low-dose cyproterone acetate treatment of sexual acting out in men with dementia. 1462 76

Salviae miltiorrhizae Radix (SMR), an eminent herb in the treatment of cardiovascular disorder (called blood stasis in traditional Chinese medicine), is widely used in China, Japan, Taiwan and Korea. SMR is also herbal medicines used in the treatment of drug addiction without scientific support for their mechanism of action. We evaluated the effect of SMR on superoxide production by rat microglias using a 2-methyl-6-(p-methoxyphenyl)-3,7-dihydroimidazo[1,2-a]pyrazin-3-one-dependent chemiluminescence assay. SMR dose-dependently inhibited superoxide production by microglias stimulated with phorbol myristate acetate or opsonized zymosan, while it had no effect on superoxide production by a hypoxanthinexanthine oxidase system. These results indicate that SMR does not have a scavenging effect, but has an inhibitory effect on superoxide generation by microglias. Although SMR is commonly used for treating chronic cerebral infarction, it may also have a protective effect on progression of Parkinson's disease or Alzheimer's disease. On the other hand, the present study investigated the effect of the medicinal plant on dopaminergic neurotransmission in comparison with amphetamine. The effect of crude water extracts (0.1 g/ml) of SMR on K+ (20 mM)-stimulated dopamine release from rat striatal slices was compared with amphetamine (10(-4) M) using high-performance liquid chromatography with electrochemical detection to measure endogenous dopamine. Amphetamine and SMR significantly increased K+-stimulated dopamine release (P<0.001) from rat striatal slices when compared with K+-stimulated alone. SMR potentiated the effect of amphetamine on K+-stimulated dopamine release (P<0.001) when compared with amphetamine alone. The results indicate that SMR may stimulate dopamine release in the same manner as amphetamine. It remains to be determined whether the effect of this extract on dopamine function is important in its therapeutic use in the treatment of drug addiction.
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PMID:Salviae miltiorrhizae radix inhibits superoxide generation by activated rat microglias and mimics the action of amphetamine on in vitro rat striatal dopamine release. 1553 39

We examined the effects of perindopril on the dopaminergic system in mice after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. The mice received four intraperitoneal injections of MPTP at 1-h intervals. Administration of perindopril showed dose-dependent neuroprotective effects against striatal dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) depletion 3 days after MPTP treatment. Our immunohistochemical study showed that MPTP can severe damage in tyrosine hydroxylase (TH)-immunoreactive neurons after MPTP treatment. The administration of perindopril significantly attenuated MPTP-induced substantia nigra and striatal damage. The present study also showed that the immunoreactivity of parvalbumin (PV)- or neuronal nitric oxide synthase (nNOS)-positive cells in the substantia nigra was decreased 7 days after MPTP treatment, whereas no significant changes were observed in these cells of the striatum throughout the experiments. The administration of perindopril significantly attenuated MPTP-induced decrease of the PV- or nNOS-immunoreactivity in the nigral cells. In double-labeled immunostaining with anti-PV and anti-nNOS antibody, PV-immunoreactive cell bodies and fibers were not double-labeled for nNOS-immunoreactive cell bodies and fibers in both the striatum and substantia nigra after MPTP treatment. Furthermore, PV- or nNOS-immunoreactive cell bodies and fibers in both the striatum and substantia nigra were not double-labeled for TH-immunoreactive cell bodies and fibers. These results demonstrate that the ACE inhibitor perindopril has a dose-dependent protective effect against MPTP-induced striatal dopamine, DOPAC and HVA depletion in mice. The present study also demonstrates that perindopril is effective against MPTP-induced degeneration of the nigral neurons and interneurons. Furthermore, our immunohistochemical study suggests that PV-immunoreactive cells and nNOS-immunoreactive cells are different interneurons in both the striatum and substantia nigra. Thus, our results provide further evidence that the ACE inhibitor perindopril may offer a novel therapeutic strategy for Parkinson's disease (PD).
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PMID:Effect of angiotensin-converting enzyme inhibitor perindopril on interneurons in MPTP-treated mice. 1557 74

Tremorine-induced tremors model is used to evaluate antiparkinsonian drugs because rest tremor is a sign that distinguishes Parkinson's disease (PD) from other diseases. The effects of crude ethanolic extract (CEE) and total acetate fraction (TAF) of Plumbago scandens were investigated at several doses. These extracts at doses of 125 and 250 mg/kg i.p. failed to reduce tremors in tremorine-treated mice. TAF showed significant effects only at a dose of 500 mg/kg. Both CEE and TAF at doses of 1000 and 2000 mg/kg i.p. suppressed the tremors in a dose-dependent fashion for 60 min. Biperiden, an anticholinergic drug, was used as standard at a dose of 3 mg/kg i.p. This study suggests that P. scandens is a plant with possible therapeutic value for PD.
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PMID:Antiparkinsonian-like effects of Plumbago scandens on tremorine-induced tremors methodology. 1558 83

The aim of this work was to explore in vivo the metabolism of the basal ganglia in a rat model of Parkinson's disease. (13)C NMR spectroscopy was used to monitor the synthesis of glutamate/glutamine from [2-(13)C] sodium acetate. (13)C label incorporation in glutamate at the carbon C4 was measured in the brain of rats in different physiopathological states and after antiparkinsonian treatment. Studies were performed in control rats (n = 6) and parkinsonian rats (n = 5) in a stable state and after acute levodopa administration (50 mg/kg iv). (13)C NMR spectra recorded using a (1)H/(13)C surface probe were acquired in the injured cerebral hemisphere. The sequence was a (13)C acquisition sequence with (1)H-decoupling during acquisition, which lasted 17 min, six spectra were obtained during the acetate infusion. Levels of glutamate C4 expressed as a percentage of the lipid resonance that appears in the same spectrum were significantly higher in parkinsonian rats than in controls after 34 min (45.1 +/- 12.8% vs. 32.0 +/- 3.7%; P < 0.05), 51 min (49.0 +/- 5.6% vs. 29.8 +/- 4.0%; P < 0.001), 68 min (61.6 +/- 12.5% vs. 43.5 +/- 13.7%; P < 0.01), and 85 min (46.8 +/- 5.8% vs. 27.4 +/- 7.4%; P < 0.05) of substrate infusion. In parkinsonian rats receiving an acute levodopa injection, the relative proportion of glutamate C4 was statistically lower than in parkinsonian rats receiving saline. Our results show that the metabolism of neuronal glutamate increases in dopamine-depleted striatum and that is restored by administration of levodopa.
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PMID:Cerebral glutamate metabolism in Parkinson's disease: an in vivo dynamic (13)C NMS study in the rat. 1564 82


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