PubMed Health⌕ Search

Biomedical subjects

P Riederer

Publications and source records attributed to P Riederer.

At least 19 recordsLinked to original sources
PubMed1992

Reduced and oxidized glutathione in the substantia nigra of patients with Parkinson's disease.

Reduced and oxidized glutathione concentrations in post-mortem brain tissue from the substantia nigra of control subjects and patients with neuropathologically confirmed Parkinson's disease were measured by a coulometric method using high-pressure liquid chromatography and electrochemical detection. Reduced glutathione concentrations were decreased in the substantia nigra of parkinsonian patients compared with controls. Differences in the concentration of oxidized glutathione and in the percentage of oxidized glutathione of the total glutathione were not observed between parkinsonian and control subjects. The finding that oxidized glutathione is not decreased in Parkinson's disease suggests that the decrease in reduced glutathione is not exclusively the consequence of neuronal loss in the substantia nigra but may indicate a state of oxidative stress.

Aged↗
PubMed1992

The molecular pharmacology of L-deprenyl.

L-Deprenyl, the selective inhibitor of monoamine oxidase type B (MAO-B), has gained wide acceptance as a useful form of adjunct therapeutic drug in the treatment of Parkinson's disease. This review summarizes the molecular pharmacology of L-deprenyl, and the advances in our understanding of its possible mode of action in Parkinson's disease. L-Deprenyl belongs to the class of enzyme-activated irreversible inhibitors also described as 'suicide' inhibitors, because the compound acts as a substrate for the target enzyme, whose action on the compound results in irreversible inhibition. L-Deprenyl first of all forms a noncovalent complex with MAO as an initial, reversible step. The subsequent interaction of L-deprenyl with MAO leads to a reduction of the enzyme-bound flavin-adenine dinucleotide (FAD), and concomitant oxidation of the inhibitor. This oxidized inhibitor then reacts with FAD at the N-5-position in a covalent manner. The observed in vitro selectivity of L-deprenyl for MAO-B may be accounted for by differences in the affinities of the two MAO subtypes for reversible interaction with L-deprenyl, differences in the rates of reaction within the noncovalent complexes to form the irreversibly inhibited adduct, or a combination of both these factors. However, if selective inhibition is to be maintained in vivo, correct dosage schedules are critically important, since all selective MAO inhibitors described up to now lack selectivity at high doses. In experimental animals L-deprenyl is protective against the damaging effects of several neurotoxins, including the dopaminergic agents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) and the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). Beside MAO-B inhibition, which above all explains the prevention of neurotoxic action of MPTP by preventing its metabolism, L-deprenyl appears to exhibit other mechanisms of action which are independent of its action on MAO-B.

Animals↗
PubMed1992

Variations of monoamines and their metabolites in the human brain putamen.

The levels of the monoamines dopamine (DA), serotonin (5-HT) and norepinephrine (NE) and the monoaminergic metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were measured with HPLC-ECD in 42 samples from human brain putamen. The influence of gender and of age was investigated and correlations between the monoamines were established. The DAergic system shows a significant difference between males and females, with females having lower DA and higher DOPAC levels and a higher DOPAC/DA ratio than males. No gender-related differences of 5-HT and its metabolites were observed, nor of NE. Three different age groups (group 1: 0-9.9 years: group 2: 10-59.9 years; group 3: 60 years and older) were defined according to previous studies on ontogenesis and senescence in human brain. An increase in 5-HT levels, decrease in 5-HIAA levels and a decrease in the 5-HIAA/5-HT ratio were observed after the first decade of life. Changes in the DAergic system were seen in senescence, with decreasing DA levels and an increase in the HVA/DA ratio. DOPAC, HVA and the DOPAC/DA ratio are unaffected. NE is similar in all age groups. The analysis of the relation of the levels of the three monoamines proved a strong correlation between the DAergic and 5-HTergic systems. The nature of this relationship might have an impact on neuro-psychiatric disorders and brain function.

Adolescent↗
PubMed1992

3H-spiroperidol binding to human peripheral mononuclear cells: methodological aspects.

3H-spiroperidol binding to lymphocytes has been proposed as a vulnerability marker for schizophrenia. However, the biological significance and even existence of this "binding site" are still in controversy. Therefore, the present study reevaluated methodological details using a filtration binding assay. The results indicated that some well-known, but obviously uncontrolled pitfalls might contribute to this controversy [e.g., unspecific filter binding, which increased in the presence of (+)-butaclamol, or a variable amount of contaminating granulocytes). Moreover, due to an atypically shaped saturation curve, different mathematical methods to analyze the data were used and compared. The present data should help us to understand the biological relevance of this marker, as viewed in different laboratories.

Adult↗
PubMed1992

Role of iron and iron chelation in dopaminergic-induced neurodegeneration: implication for Parkinson's disease.

Recent studies in Parkinson's disease suggest that the degeneration of the nigrostriatal melanin-containing dopaminergic neurons results from toxic effects of free radicals, which are generated during dopamine metabolism in the substantia nigra (SN). This has been linked to the selective accumulation of iron, a known catalyst of radical formation, in the zona compacta of the SN. We have shown that interaction of iron with melanin may result in a high affinity binding of iron to melanin (KD = 13.0 +/- 0.15 nM). Indeed, x-ray analysis of melanized dopamine neurons of parkinsonian SN has shown an interaction of iron with melanin that is absent in control brains. In the presence of excess Fe3+, melanin potentiates iron-induced lipid peroxidation. Since iron chelators prevent lipid peroxidation, we have ascertained the ability of the iron chelator deferoxamine to prevent the lesion of the nigrostriatal dopamine neuron induced by 6-hydroxy dopamine (6-OHDA). Our results demonstrated that intraventricular injection of 130 ng deferoxamine to rats prior to 250 micrograms of 6-OHDA partially prevented the decrease in striatal dopamine content caused by 6-OHDA (56% reduction vs 90%, respectively). This protection was sufficient to produce normal dopamine-related behavioral responses. These results suggest that iron and iron chelators play a crucial role in the process of dopaminergic neurodegeneration and neuroprotection. The latter is further supported by our recent findings that intranigral injection of iron (50 micrograms) resulted in a substantial selective decrease of striatal dopamine (95%) and impaired dopamine-related responses.

Animals↗
PubMed1992

Bromocriptine lessens the incidence of mortality in L-dopa-treated parkinsonian patients: prado-study discontinued.

L-Dopa supplemented by a peripheral decarboxylase inhibitor is considered the most potent therapeutic regimen prolonging active life in Parkinsonian patients. The long-term benefit of therapy is limited by adverse effects, such as dyskinesia and on-off phenomena, which can be mitigated by the concomitant administration of dopamine agonists, such as bromocriptine. In order to quantify the beneficial impact of early combination therapy, a controlled clinical trial (PRADO: PRA videl1 + DO pa) in patients with early Parkinson's disease was carried out, whereby L-Dopa monotherapy (in a fixed combination with benserazide (DoBe) was being compared with the same combination plus bromocriptine (DoBeBro). Patients were recruited and treated by 101 practising neurologists in the Federal Republic of Germany and in Hungary. Twenty seven clinical university centers cross-checked the patients at regular intervals. The trial started with 3 months of DoBe monotherapy (median dose of 375 mg L-Dopa for both randomized groups) followed by gradual substitution of DoBe by bromocriptine over 3 months in one of the groups (250 mg L-Dopa/10 mg bromocriptine). The target medication was maintained from study months 6 to 54. Parkinsonian symptoms were classified according to the Webster rating scale, the Hoehn and Yahr scale and the Zung Self-Rating Depression Scale. Adverse events and life status were checked at regular intervals. Special emphasis was given to motor performance tests. 587 patients (302 in the DoBe group and 285 in the DoBeBro group) were available for intention-to-treat analysis. Both groups were homogeneous at baseline in all observed parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Cell-mediated immunity and its glucocorticoid-sensitivity after clinical recovery from severe major depressive disorder.

This follow-up study investigated lymphocyte blastogenesis induced by concanavalin A, phytohemagglutinin A, and pokeweed mitogen and their sensitivity to in vitro dexamethasone administration in 12 patients clinically recovered from severe major depression. Although cortisol-levels at 4.00 p.m. decreased significantly after clinical remission, mitogen-driven lymphocyte proliferative responses were unchanged when assessed intra-individually. No impairment of in vitro glucocorticoid-sensitivity of lectin-induced lymphocyte blastogenesis could be observed in clinically recovered patients. The inhibitory potency of in vitro dexamethasone was found to be inversely correlated with in vivo adrenal cortical hormone levels. There were no correlations with age, weight, sex, antidepressant medication, severity or duration of depression. No differences from age- and sex-matched healthy individuals were found. These results indicate that reduced glucocorticoid receptor sensitivity occurs only during the acute depressive illness.

Adrenocorticotropic Hormone↗
PubMed1992

Iron-melanin complex in substantia nigra of parkinsonian brains: an x-ray microanalysis.

Using energy-dispersive x-ray analysis on an electron microscope working in the scanning transmission electron microscopy mode equipped with a microanalysis system, we studied the subcellular distribution of trace elements in neuromelanin-containing neurons of the substantia nigra zona compacta (SNZC) of three cases of idiopathic Parkinson's disease (PD) [one with Alzheimer's disease (AD)] and of three controls, in Lewy bodies of SNZC, and in synthetic dopamine-melanin chemically charged or uncharged with Fe. Weak but significant Fe peaks similar to those of a synthetic melanin-Fe3+ complex were seen only in intraneuronal highly electron-dense neuromelanin granules of SNZC cells of PD brains, with the highest levels in a case of PD plus AD, whereas a synthetic melanin-Fe2+ complex showed much lower iron peaks, indicating that neuromelanin has higher affinity for Fe3+ than for Fe2+. No detectable Fe was seen in nonmelanized cytoplasm of SNZC neurons and in the adjacent neuropil in both PD and controls, in Lewy bodies in SNZC neurons in PD, and in synthetic dopamine-melanin uncharged with iron. These findings, demonstrating for the first time a neuromelanin-iron complex in dopaminergic SNZC neurons in PD, support the assumption that an iron-melanin interaction contributes significantly to dopaminergic neurodegeneration in PD and PD plus AD.

Aged↗
PubMed1992

Glutamatergic-dopaminergic balance in the brain. Its importance in motor disorders and schizophrenia.

Dopamine appears to be of less importance in the regulation of psychomotor functions than was previously thought. A central dopaminergic-glutamatergic balance may be important for both akinetic motor disorders and psychosis. In Parkinson's disease glutamate antagonists may counteract central glutamatergic hyperactivity and may be of value as anti-parkinsonian drugs. An increase of dopaminergic activity and/or a reduction of glutamatergic activity may contribute to the development of paranoid hallucinatory psychosis in schizophrenic patients and of pharmacotoxic psychosis in Parkinson's disease. Because of possibly severe side-effects of glutamatergic antagonists and agonists in the treatment of akinesia and psychosis, the development of partial glutamate agonists/antagonists could be an alternative strategy capable of producing antipsychotic or anti-kinetic effects with only mild adverse reaction.

Animals↗
PubMed1992

Neurotoxicity and neuroprotection in Parkinson's disease.

Recent findings of impaired mitochondrial function, altered iron metabolism and increased lipid peroxidation in the substantia nigra in Parkinson's disease emphasize the significance of oxidative stress and free radical formation in the pathogenesis of the disease. Future research will focus on improvements in neuroprotective therapy to prevent or slow the rate of progression of Parkinson's disease. Possible neuroprotective strategies include free radical scavengers, monoamine oxidase-B inhibitors, iron chelators and glutamate antagonists.

Antiparkinson Agents↗
PubMed1992

Pathogenesis of Parkinson's disease.

The importance of genetic aspects, ageing, environmental factors, head trauma, defective mitochondrial respiration, altered iron metabolism, oxidative stress and glutamatergic overactivity of the basal ganglia in the pathogenesis of Parkinson's disease (PD) are considered in this review.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

MPTP mechanisms of neurotoxicity and their implications for Parkinson's disease.

Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) gives rise to motor deficits in humans and other primates which closely resemble those seen in patients with Parkinson's disease. These deficits are associated with a relatively selective loss of cells in the pars compacta of the substantia nigra and severe reductions in the concentrations of dopamine, noradrenaline and serotonin in the striatum. Similarly, in mice of various different strains the administration of MPTP also induces a marked loss of dopaminergic cells with severe depletion of biogenic amines, but higher doses of MPTP are required to produce these effects in mice than in primates. This review summarises advances made in understanding the biochemical events which underlie the remarkable neurotoxic action of MPTP. Major steps in the expression of neurotoxicity involve the conversion of MPTP to the toxic agent 1-methyl-4-phenylpyridinium ion (MPP+) by type B monoamine oxidase (MAO-B) in the glia, specific uptake of MPP+ into the nigro-striatal dopaminergic neurones, the intraneuronal accumulation of MPP+, and the neurotoxic action of MPP+. This is exerted mainly through the inhibition of the enzymes of the respiratory chain (Complex I), the disturbance of Ca2+ homeostasis, and possibly by the formation of free radicals. The relevance of the MPTP model to idiopathic Parkinson's disease is discussed.

Animals↗
PubMed1991

Disturbed glucocorticoid receptor autoregulation and corticotropin response to dexamethasone in depressives pretreated with metyrapone.

We studied glucocorticoid receptor autoregulation and corticotropin response to dexamethasone in depressed patients and controls, attempting to control for the confounding effect of endogenous glucocorticoids. After depletion of endogenous cortisol, depressed patients showed an attenuated suppressibility of corticotropin by dexamethasone in the face of unchanged dexamethasone plasma levels. Beta-endorphin levels were strongly correlated with adrenocorticotropic hormone (ACTH) concentrations. Although metyrapone administration resulted in a marked rise of glucocorticoid receptor sites per cell in controls, this effect was not present in depressives. These data support the hypothesis of a decreased glucocorticoid receptor plasticity and a partial steroid resistance in depression.

Adolescent↗
PubMed1991

Effects of the 1-amino-adamantanes at the MK-801-binding site of the NMDA-receptor-gated ion channel: a human postmortem brain study.

Recent studies from our laboratory have provided evidence that the 1-amino-adamantane derivative memantine (1-amino-3,5-dimethyl-adamantane) binds to the MK-801-binding site of the N-methyl-D-aspartate (NMDA)-receptor-gated ion channel. This action has been suggested to account for the antiparkinsonian and antispastic activity of the drug. In the present investigation we have extended our work by testing a series of 1-amino-adamantanes, including amantadine (1-amino-adamantane) and memantine, for their ability to compete with [3H]MK-801 binding in membrane homogenates of postmortem human frontal cortex. The most potent substance (1-amino-3,5-diethyl-adamantane) had a Ki-value of 0.19 +/- 0.06 microM while the weakest substance (1-N-methyl-amino-adamantane) had a Ki-value of 21.72 +/- 1.63 microM. The Ki-value of amantadine was 10.50 +/- 6.10 microM. In agreement with our earlier investigation, the Ki-value of memantine was 0.54 +/- 0.23 microM. The results indicate that 1-amino-adamantanes, in general, may produce their pharmacological effects through an interaction with the NMDA-receptor-gated ion channel. The displacement of [3H]MK-801 binding thus may provide the basis to predict the antiparkinsonian and antispastic activity of novel substituted 1-amino-adamantanes and possibly of other drugs.

Adamantane↗
PubMed1991

Neurochemical and behavioural features induced by chronic low dose treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the common marmoset: implications for Parkinson's disease?

Protracted long-term treatment of common marmosets with 15 doses (0.5-4.5 mg/kg, i.p.) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; total dose 25 mg/kg, given over 29 days) caused transitory changes in motor behaviour reminiscent of human Parkinson's disease. 16 days from the start of MPTP administration, all animals showed motor impairment, consisting of profound akinesia and a rigid posture, but in no case resting tremor. Biogenic amines were measured in nigrostriatal regions one month after finishing MPTP treatment. There was a profound loss of dopamine and serotonin in the substantia nigra and in the striatum; noradrenaline was only reduced in the putamen. Continuous analyses of the concentrations of biogenic amine metabolites in the CSF during this study revealed persistent dopaminergic disturbances and temporary alterations in serotoninergic and noradrenergic function.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗