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  • Parkinson's disease  (183)
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  • 1
    ISSN: 1435-1463
    Keywords: Parkinson's disease ; NADH ; endogenous biosynthesis of levodopa
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Exogenous application of levodopa is conventionally used to equalize the striatal dopamine deficit in idiopathic Parkinson's disease (PD). The stimulation of endogenous biosynthesis of levodopa via activation of tyrosine hydroxylase (TH) has been proposed as new therapeutic concept in PD. This may be achieved by exogenous supply with the reduced coenzyme nicotinamide adenine dinucleotide (NADH). Aim of this open prospective study was to investigate (1) the efficacy of a new developed, parenteral application form of NADH on Parkinsonian symptoms and (2) the influence of bioavailability of levodopa. 15 patients, suffering from idiopathic PD (11 male, 4 female, age: 61.40[mean] ± 10.27[SD] range: 44–74 years, Hoehn and Yahr stage: 3.03 ± 0.69, range 2–4) received intravenous infusions of NADH (10 mg a' 30 min) over a period of 7 days in addition to conventional Parkinsonian pharmacotherapy. Parkinsonian symptoms were scored before (day 1) and after NADH treatment (day 8). Levodopa plasma levels were estimated over a period of four hours on the day before and on the first day of NADH application by HPLC. Parkinsonian patients showed a significant response, evaluated by the Unified Parkinson's Disease Rating Scale Version 3.0 (p=0.025; Wilcoxon test). Moreover application of NADH significantly increased bioavailability of plasma levodopa (AUC, p=0.035; Cmax, p=0.025). In conclusion NADH in the used galenic form may be a potent stimulator of endogenous levodopa biosynthesis with clinical benefit for Parkinsonian patients.
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  • 2
    ISSN: 1435-1463
    Keywords: Parkinson's disease ; harman ; norharman ; cerebrospinal fluid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Death of dopaminergic neurons in Parkinson's disease (PD) may partially be caused by synthesis and accumulation of endogenous and exogenous toxins. Because of structural similarity to MPTP, β-carbolines, like norharman and harman, have been proposed as putative neurotoxins. In vivo they may easily be formed by cyclization of indoleamines with e.g. aldehydes. For further elucidation of the role of β-carbolines in neurodegenerative disorders harman and norharman levels in cerebrospinal fluid (CSF) were measured in 14 patients with PD and compared to an age- and sex-matched control group (n=14). CSF levels of norharman and harman in PD were significantly higher compared to controls. These results may suggest a possible role of harman and norharman or its N-methylated carbolinium ions in the pathophysiological processes initiating PD. However the origin of increased levels of these β-carbolines remains unclear. On the one hand one may speculate, that unknown metabolic processes induce the increased synthesis of harman and norharman in PD. On the other hand a possible impact of exogenous sources may also be possible.
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  • 3
    ISSN: 1435-1463
    Keywords: Parkinson's disease ; depression ; biogenic amines ; cerebrospinal fluid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Introduction. Etiology of depression in Parkinsons disease (PD) is associated with serotonergic dysfunction. Previous studies, supporting this hypothesis, were performed on patients treated with antiparkinsonian drugs. To eliminate the influence of parkinsonian drug therapy and to elucidate significance of different biochemical pathways in PD associated with depression we determined levels of biogenic amines in cerebrospinal fluid (CSF) of 26 untreated “de novo” Parkinsonian patients.Material and methods. Patients were scored with the Hamilton depression scale (HD) and subdivided into groups with HD score ≥ 18 and HD score 〈18. Diagnosis of depression was made according to DSM III R. Both groups were matched for age and motor disability.Results. In both groups no significant differences appeared between CSF levels of dopamine, noradrenaline, 3,4-dihydroxyphenylacetic acid, homovanillic acid, 3-methoxy-4-hydroxyphenylglycol and 5-hydroxyindole acetic acid, determined by high-performance liquid chromatography.Discussion. In contrast to previous studies on treated Parkinsonian patients no sign of altered serotonin metabolism especially in context with severity of depression in early stages of PD was found. Due to our results, we suggest, that biochemical markers of depression in CSF of PD may be influenced by antiparkinsonian therapy and that depression in PD may respond to serotonin reuptake inhibitors mainly in later stages of PD.
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  • 4
    ISSN: 1435-1463
    Keywords: Neurodegeneration ; substantia nigra ; Parkinson's disease ; 5-S-cysteinyl-dopamine ; 5-S-cysteinyl-DOPA ; 5-S-cysteinyl-DOPAC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The concentrations of the 5-S-cysteinyl adducts of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylalanine (DOPA) and the levels of noradrenaline (NA), DA, DOPAC and DOPA were determined in the putamen (PUT), caudate nucleus (CN) and substantia nigra (SN) of human post mortem brains with or without depigmentation and degeneration of the SN. The levels of DA, DOPAC and DOPA decreased with the degree of depigmentation and degeneration in the three brain regions while NA levels only decreased in SN and PUT. In general, the concentrations of the 5-S-cysteinyl adducts did not differ, but the ratios of 5-S-cysteinyl-DA/DA, 5-S-cysteinyl-DOPAC/DOPAC and 5-S-cysteinyl-DOPA/DOPA were higher in patients with a more depigmentated and degenerated SN, except for the 5-S-cysteinyl-DA/DA ratio in the PUT. Higher ratios were also found in the cell body areas compared to the neuron terminal areas. Thus depigmentation and degeneration of dopaminergic SN neurons, seem to be correlated to enhanced rates of autoxidation, possibly due to an impaired antioxidant capacity.
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  • 5
    ISSN: 1435-1463
    Keywords: Amyotrophic lateral sclerosis ; cerebrospinal fluid ; cyclic GMP ; nitric oxide ; Parkinson's disease ; spinocerebellar ataxia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To investigate whether nitric oxide (NO) plays a role in degenerative neurologic disease (DND), we measured nitrite, nitrate and cyclic GMP in cerebrospinal fluid (CSF) samples from patients with Parkinson's disease (PD), spinocerebellar ataxia (SCA) and amyotrophic lateral sclerosis (ALS). We found no significant change in CSF nitrite, nitrate or cyclic GMP in patients with any DND compared with control values. These results suggest that NO production is preserved in PD, SCA and ALS.
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  • 6
    ISSN: 1435-1463
    Keywords: Keywords: Chromogranin ; secretoneurin ; Parkinson's disease ; Alzheimer ; multiple sclerosis.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary. Human cerebrospinal fluid (CSF) contains chromogranin A and B and secretogranin II which represent peptides secreted from neuronal large dense core vesicles. Within these vesicles these precursor peptides are at least partly processed to smaller peptides. We analysed the CSF levels of chromogranins/secretogranin by radioimmunoassay using specific antisera. The degree of their processing was characterized by molecular sieve column chromatography followed by radioimmunoassay. As previously shown secretogranin II is fully processed to smaller peptides including the peptide secretoneurin, whereas processing of chromogranin A was more limited. For chromogranin B we found in this study a high degree of processing comparable to that of secretogranin II. An analysis of CSF from patients with multiple sclerosis, essential tremor, Alzheimer and Parkinson disease, did not reveal any differences in proteolytic processing of chromogranins/secretogranin when compared to control CSF. We conclude that in the four diseases investigated there is no change in the proteolytic processing of the chromogranins/secretogranin within the large dense core vesicles. The absolute levels of chromogranins/secretogranin varied in CSF collected in different hospitals, however their relative ratios were remarkable constant. We suggest to use this ratio as a parameter to standardise CSF levels of other peptides, e.g. neuropeptides. In Parkinson patients the chromogranin A/secretogranin II ratio was significantly increased whereas in Alzheimer patients and those with essential tremor and multiple sclerosis no change of the ratios was observed. Apparently there are only limited changes in the biosynthesis, processing, secretion and CSF clearance of these peptides in pathological conditions.
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  • 7
    ISSN: 1435-1463
    Keywords: Keywords: Nigrostriatal dopaminergic system ; vesicular storage ; Parkinson's disease ; reserpine ; tetrabenazine ; monoamine oxidase.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary. We examined the effect of L-dihydroxyphenylalanine (L-DOPA) infusion in vitro upon dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) output from superfused corpus striatum of vehicle and reserpine or tetrabenazine (TBZ) treated male rats. Specifically, we tested the effects of two 20-min infusions of L-DOPA (5 uM) upon DA and DOPAC output (pg/mg/min) in reserpine (5 mg/kg, i.p., 24 hours before sacrifice; n = 11), TBZ (30 mg/kg, i.p. 1 hour before sacrifice; n = 8) or vehicle (n = 21) treated rats. There was an overall significantly higher L-DOPA evoked DA output from the vehicle (12.22 ± 1.74) versus reserpine (4.39 ± 2.40) (p 〈 0.05), but not TBZ (9.16 ± 2.81) treated rats. In addition, the DA response to the second L-DOPA infusion was significantly increased over that of the first response in the vehicle (9.40 ± 2.11 vs. 15.04 ± 2.78) (p 〈 0.05), but not reserpine or TBZ treated rats. The overall DOPAC outputs did not achieve a statistically significant difference among all treatment groups. However, the DOPAC outputs following the second L-DOPA infusion were significantly reduced in reserpine (41.15 ± 6.10 vs. 20.27 ± 4.54) and TBZ (21.38 ± 4.41 vs. 10.87 ± 2.36) (both p 〈 0.05), but not vehicle (28.99 ± 4.00 vs. 24.91 ± 4.78) treated rats. We conclude that: 1) the storage capacity of DA neurons is one of the important elements involved in affecting L-DOPA's effects upon DA and DOPAC output, 2) the shunting of storage to metabolism may represent a common characteristic in impaired nigrostriatal dopaminergic system, and 3) TBZ may operate differently from reserpine in the nigrostriatal dopaminergic system.
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  • 8
    ISSN: 1435-1463
    Keywords: Glia ; L-DOPA ; dopamine neurons ; neurotrophic factors ; ascorbic acid ; glutathione ; Parkinson's disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Mesencephalic glia produce soluble factors that protect dopamine neurons from L-DOPA toxicity. The chemical composition of these soluble factors is unknown. We investigated the protective effect against L-DOPA neurotoxicity in midbrain dopamine neurons of fractions of different molecular size of glia conditioned medium and candidate neuroprotective agents produced by glia including neurotrophic factors and antioxidants. Protective effects were evaluated according to the number of tyrosine hydroxylase immunoreactive cells, high affinity dopamine uptake and levels of quinones. Both fractions of glia conditioned medium, smaller and larger than 10kD, protected against L-DOPA, but the fraction of smaller molecular size, that contains small free radical scanvenger molecules, was more effective than the fraction of larger molecular size, that contains large neurotrophic peptides. Among the neurotrophic factors GDNF and BDNF totally prevented L-DOPA neurotoxicity, while NGF and bFGF were less effective. However, only NGF significantly reduced the elevation of quinones induced by L-DOPA. Ascorbic acid, at the concentration found in glia conditioned medium, provided partial protective effect against L-DOPA toxicity. Glutathione, had neurotrophic effects on untreated midbrain dopamine neurons and prevented the effect of L-DOPA. In conclusion, the protective effect against L-DOPA neurotoxicity by glia conditioned medium is mediated by several compounds including neurotrophic factors and small antioxidants.
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  • 9
    ISSN: 1435-1463
    Keywords: Dopamine ; L-dopa ; 3-O-methyldopa ; norepinephrine ; serotonin ; vascular parkinsonism ; Parkinson's disease ; cerebrospinal fluid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The concentration of catecholamines and indoleamines in the cerebrospinal fluid of patients with vascular parkinsonism (VP) was compared to that in patients with Parkinson's disease (PD) and controls. Compared to the controls, the concentration of tyrosine was significantly higher, and the concentration of L-dopa and 3-O-methyldopa (3-OMD) was significantly lower in both VP and PD patients. The balance between the 3-OMD/L-dopa and dopamine (DA)/L-dopa ratios was changed in favor of 3-OMD/L-dopa in both VP patients and PD patients suggesting the preservation of a compensatory mechanism. All these changes were less marked in VP patients than in PD patients. A remarkable finding was that in contrast to PD patients the concentration of DA and norepinephrine (NE) was significantly higher in VP patients than in the controls. The decrease in the concentration of 5-hydroxytryptamine (5-HT) was significantly greater in VP patients than in PD patients. In PD patients, the concentration of DA, NE, and 5-HT showed significant correlation with the severity of motor symptoms. In VP patients, the concentration of 5-HT alone showed significant correlation with the severity of motor symptoms and cognitive dysfunction. These findings suggest that VP patients may have similar disturbances in the DA synthesis pathway as PD patients, but differ from PD patients in that the concentrations of DA and NE are elevated and the decrease in the 5-HT concentration is greater in VP patients.
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  • 10
    ISSN: 1435-1463
    Keywords: Monoamine oxidase ; catechol-O-methyltransferase ; Ro 41–1049 ; Ro 19–6327 ; Ro 40–7592 ; Parkinson's disease ; 6-hydroxydopamine ; behavior
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effect of enzyme-inhibiting adjuvants on L-DOPA + benserazide-induced contralateral turning in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats was studied. Both the number of turns and the duration of turning were examined. Inhibition of MAO-A with 10mg/kg Ro 41–1049 increased both parameters; inhibition of COMT with 10mg/kg Ro 40–7592 had a similar effect. In contrast, inhibition of MAO-B with 10mg/kg Ro 19–6327 did not change turning behavior. A further potentiation of turning behavior was observed after the combined administration of both the MAO-A and COMT inhibitor. MAO-A inhibition in conjunction with MAO-B inhibition prolonged the duration of L-DOPA-induced turning but had no effect on the number of turns. However, in conjunction with COMT inhibition, 10mg/kg of the MAO-B inhibitor, Ro 19–6327, significantly affected both the number and duration of turning behavior. An even further potentiation of turning behavior was observed after the combined administration of all three enzyme-inhibitors.
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