Biomedical subjects

P Riederer

Publications and source records attributed to P Riederer.

At least 307 records · Page 17Linked to original sources

PubMed1994

The enigma of neuromelanin in Parkinson's disease substantia nigra.

The function of neuromelanin accumulation in the nigrostriatal dopamine neurons remains uncertain. Nevertheless, it is recognized that neuromelanin disappearance parallels the loss of dopamine neurons in Parkinson's disease, suggesting its participation in nigral cell death. It has been well known for some years that in systemic tissues melanin is a double-edged sword. On the one hand it can act as an antioxidant, but in the presence of transitional metals (primarily, iron) and drugs it promotes the formation of reactive oxygen free radicals. It is now apparent that synthetic dopamine-melanin and neuromelanin exhibit similar properties in vitro and nigrostriatal dopamine neuron co-culture studies. Thus, the identification of ionic iron in dopamine neurons of Parkinson's disease zona compacta and its association with neuromelanin has conferred a cytotoxic property to neuromelanin. This may explain the reported vulnerability of substantia nigra dopamine neurons in Parkinson's disease.

Antioxidants↗

PubMed1994

Influence of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, lipoic acid and L-deprenyl on the interplay between cellular redox systems.

For several years there is controversy concerning the toxic potency of reaction products catalyzed by monoamine oxidase in neurodegenerative processes. There is uncertainty whether products of catecholamine oxidation are pathogenetically relevant factors for neuronal cell death in Parkinson's disease. To date products responsible for impairment of biochemical functions essential for cell viability are not yet identified, and the primary site of damage within the cell is unknown. Ammonia, aldehydes and hydrogen peroxide are formed via monoamine oxidase catalyzed oxidations of primary amines. But which of them, if any, is damaging to the cell? We discuss some aspects of the oxidative stress theory of cell degeneration in relation to toxicity of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and to monoamine oxidation. Furthermore, we consider possible functional relationships of mitochondrial electron transfer reactions, toxicity of MPTP and MAO activity.

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

PubMed1994

Neuroprotection by dopamine agonists.

Research on Parkinson's disease has led to new hypotheses concerning the mechanisms of neurodegeneration and to the development of neuroprotective agents. Recent findings of impaired mitochondrial function, altered iron metabolism and increased lipid peroxidation in the substantia nigra of parkinsonian patients emphasize the significance of oxidative stress and free radical formation in the pathogenesis of Parkinson's disease. Present research is therefore focussing on improvements in neuroprotective therapy to prevent or slow the rate of progression of the disease. Possible neuroprotective strategies include free radical scavengers, monoamine oxidase-B inhibitors, iron chelators and glutamate antagonists. Recent studies point to the possibility of achieving neuroprotection in ageing and parkinsonism by the administration of dopamine agonists. In the rat, the dopamine agonist pergolide appears to preserve the integrity of nigrostriatal neurones with ageing. The prevention of age-related degeneration may be achieved as a result of a decreased dopamine turnover and reduced conversion of dopamine to toxic compounds. In our own study, bromocriptine treatment prevented the striatal dopamine reduction following MPTP administration in the mouse. These results suggest that the neurotoxic effects of MPTP can be prevented by bromocriptine. Monotherapy with the dopamine agonist lisuride in the early stages of Parkinson's disease delays the need for the initiation of levodopa treatment to a similar extent as has been reported for L-deprenyl. It remains to be shown whether this is due to neuroprotective efficacy of the dopamine agonist or to a direct symptomatic effect.

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

PubMed1994

The glycine binding site of the NMDA receptor: involvement in neurodegeneration and new approach for neuroprotection.

Excitatory amino acids may have a neurotoxic effect in acute and chronic neurodegenerative diseases. Glutamate mediated Ca-influx into the cell is caused by activation of the NMDA-receptor. In addition to the competitive binding site there is a glycine binding site at the NMDA-receptor, where in an agonistic function glycine leads to opening of the ion channel. Antagonists at this glycine binding site may reduce the Ca-influx and thereby have a neuroprotective effect. The affinity of HA-966 to the glycine binding site in human hippocampus brain tissue is in the low micromolar range (Ki = 8.1 +/- 1.5 microM). So HA-966 may play a role as a neuroprotective substance.

Autoradiography↗

PubMed1994

Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties.

The pharmacological inhibition of excitatory amino acid neurotransmission has evolved to be a major topic in neuropharmacology since enhanced synaptic action of glutamate and possibly other related neurotransmitters has been suggested to play a role both in acute neurological conditions such as ischemia and epilepsy and in chronic degenerative neurological diseases including Parkinson's disease, Huntington's disease and Alzheimer's disease. While antagonists at N-methyl-D-aspartate (NMDA) type glutamate receptors include psychotomimetic and neurotoxic agents such as phencyclidine and MK-801, the aminoadamantanes represent a class of drugs which may be largely free of such actions and which have already been used clinically as antiviral and antiparkinsonian agents. Multiple in vitro studies have recently delineated the neuroprotective properties of amantadine, and of its more potent congener, memantine, which appear to mediate neuroprotection via inhibition of NMDA receptor-dependent glutamate activity. Thus, neuroprotection targeting glutamate receptors does apparently not have to be associated with prominent psychotogenicity, and the development and evaluation of new neuroprotective drugs will have to performed in consideration both of the relative safety and of the good clinical effect of the already known and established aminoadamantanes.

Adamantane↗

PubMed1994

Alterations of receptor-G protein-adenylyl cyclase coupling in alcoholics.

This study investigated alterations in the receptor adenylyl cyclase system in the brain and platelets of alcoholics through the study of GTP binding (G) protein, which has a key role in the system, in the membranes of the post-mortem brain and platelets. Quantitative examination of G protein by immunoblotting showed that GsH alpha in the temporal cortex of the post-mortem alcoholic brain was significantly decreased with controls. Moreover, the extent of ethanol enhancement of functional photoaffinity GTP(azidoanilido GTP) labeling to Gs alpha and Gi alpha was decreased in all cortical regions (frontal, temporal, parietal, occipital cortex) from alcoholics. In the platelet membrane, a quantitative reduction in GsH alpha and GsL alpha levels as assessed by immunoblotting was seen in family history positive (FHP) alcoholics. A reduction in ethanol enhancement of AAGTP labeling to Gs alpha and Gi alpha was also observed in the FHP group. These alterations of G protein were not found in the platelets from family history negative (FHN) alcoholics. The dysfunctions of Gs protein occurring in platelet membranes of the FHP group are likely to parallel those that occur in the alcoholic brain. These results suggest that disturbances of G protein-mediated signal transduction may be involved in the pathophysiology of alcoholics and that platelet G protein may be used as a trait marker of alcoholics.

Adenylyl Cyclases↗

PubMed1994

Reduced sensitivity to ethanol of Gs alpha and Gi/o alpha in the cerebral cortex of alcoholic patients.

In this study, we examined the quantity and quality of G proteins in membrane preparations from cortical regions (frontal, parietal, temporal and occipital cortex) in post-mortem brains obtained from subjects with chronic alcoholism and controls matched with respect to age and post-mortem delay (PMDT). Immunoblot analysis showed that the level of GsH alpha (52 kDa) was significantly decreased in temporal cortical membranes from alcoholics compared with controls, while no differences were observed in the amount of any G protein in frontal, parietal and occipital regions. Additionally, ethanol enhanced photoaffinity guanine nucleotide binding to both G alpha and Gi/o alpha in human cortical membranes. The percentage of increase in ethanol-stimulated photoaffinity GTP labeling of Gs alpha and Gi/o alpha was decreased in alcoholic patients in all cortical regions. These observations indicated that subsensitivities to ethanol-induced stimulation in G protein may contribute to impaired trans-signaling in cortical membranes of chronic alcoholics.

Alcoholism↗

PubMed1993

Affinity of 1-aminoadamantanes for the sigma binding site in post-mortem human frontal cortex.

The 1-aminoadamantanes memantine (1-amino-3,5-dimethyl-adamantane) and amantadine (1-amino-adamantane) are clinically used as anti-parkinsonian, anti-spasticity, anti-dementia and antiviral drugs. In the present investigation we have tested a series of 1-aminoadamantane derivatives including memantine and amantadine for their ability to compete with [3H](+)-pentazocine in homogenates of post-mortem human frontal cortex. The Ki values ranged from 0.237 +/- 0.019 microM for 1-N-dimethyl-amino-3,5-dimethyl-adamantane to 20.25 +/- 16.48 microM for amantadine. The Ki value of memantine was 19.98 +/- 3.08 microM and was thus very similar to that of amantadine. Memantine, at therapeutic concentrations, probably does not interact with the sigma binding site. Amantadine, at therapeutic concentrations, probably binds both to the sigma site and to the phencyclidine (PCP) binding site of the N-methyl-D-aspartate (NMDA) receptor.

Adult↗

PubMed1993

Alterations of guanine nucleotide-binding proteins in post-mortem human brain in alcoholics.

Qualitative and quantitative alterations of G proteins in membrane preparations from parietal and temporal cortex regions in post-mortem brains obtained from alcoholics and controls matched with respect to age and post-mortem delay were investigated by Western-blotting with polyclonal antibodies against specific G protein subunits and functional photoaffinity GTP binding. Quantitative immunoblotting showed that only Gs alpha (52 kDa species) in temporal cortex was significantly decreased (30%, P < 0.05) in alcoholics compared with controls. Moreover, ethanol-stimulated photoaffinity GTP labeling of Gs alpha and Gi/o alpha was decreased in alcoholics in both cortex regions. These results suggest that disturbances of G protein-mediated signal transduction may be involved in the pathophysiology of alcoholics.

Aged↗

PubMed1993

Nimodipine inhibits [3H]nitrobenzylthioinosine binding to the adenosine transporter in human brain.

The inhibition of [3H]nitrobenzylthioinosine ([3H]NBI) binding to human parietal cortex membranes by adenosine transport inhibitors, adenosine receptor agonists and antagonists and dihydropyridines was investigated. While the adenosine transport inhibitors inhibited [3H]NBI binding with Ki values in the low nanomolar range and the adenosine A1 receptor agonist, cyclopentyladenosine, with a Ki in the low micromolar range, no IC50 values could be obtained for the adenosine receptor antagonists at concentrations up to 100,000 nM. Among the dihydropyridines (+)-nimodipine was the most potent with a Ki of 201 +/- 55 nM. Inhibition of adenosine transport thus may contribute to the clinical effects of nimodipine in the central nervous system.

Dihydropyridines↗

PubMed1993

3H-spiroperidol binding to peripheral mononuclear cells in schizophrenic and healthy subjects.

3H-spiroperidol binding to peripheral blood mononuclear cells was measured in 28 patients, who fulfilled DSM-III-R-criteria for schizophrenia and 17 healthy subjects. There were no significant differences in characteristic binding parameters (Kd, Bmax) between schizophrenic and healthy subjects. Moreover, there was no relation of binding parameters to any of the subtypes of schizophrenia or to the course of illness according to DSM-III-R-criteria. However, some patients exhibited higher Bmax values without having a unique clinical symptomatology according to known diagnostic criteria. Neuroleptic treatment had no consistent effect on binding parameters intraindividually. Kd and Bmax values were not related to age or gender. In conclusion, despite our previously reported improved methodology, we were not able to corroborate the clinical importance of this "peripheral marker" as a tool for diagnosing schizophrenia or for predicting the response to neuroleptic treatment in our sample of schizophrenic patients.

Adult↗

PubMed1993

Adenosine A1 receptors in human hippocampus: inhibition of [3H]8-cyclopentyl-1,3-dipropylxanthine binding by antagonist drugs.

Adenosine A1 receptors were visualized in human hippocampus using [3H]8-cyclopentyl-1,3-dipropylxanthine (DPCPX) as a radioactive ligand probe. The receptor antagonists caffeine, the xanthine derivative KFM 19 and the carbamazepine analogue oxcarbazepine displaced [3H]DPCPX binding homogeneously without any marked difference between the individual layers in the investigated hippocampal subregions (n = 4). Ki's in the individual layers were in a range between 8.5 +/- 6.5 microM and 18.9 +/- 16.0 microM for caffeine and 11.5 +/- 2.8 nM and 18.1 +/- 14.1 nM for KFM 19. Ki's could not be calculated for oxcarbazepine as the IC50's were greater than 100 microM with estimated IC25's varying between 51.2 +/- 53.3 microM and 179.9 +/- 89.9 microM. Antagonism of endogenous adenosine at A1 receptors may thus explain part of the clinical effects of caffeine in humans and possibly exclusively the behavioral effects of KFM 19 in non-human primates.

Aged↗

PubMed1993

The possible role of iron in the etiopathology of Parkinson's disease.

The identification of 6-hydroxydopamine (6-OHDA) and N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as dopaminergic neurotoxins that can induce parkinsonism in humans and animals has contributed to a better understanding of Parkinson's disease (PD). Although the involvement of similar neurotoxins has been implicated in PD, the etiology of the disease remains obscure. However, the recently described pathology of PD supports the view for a state of oxidative stress in the substantia nigra (SN), resulting as a consequence of the selective accumulation of iron in SN zona compacta and within the melanized dopamine neurons. Whether iron is directly involved cannot be ascertained. Nevertheless, the biochemical changes due to oxidative stress resulting from tissue iron overload (siderosis) are similar to those now being identified in parkinsonian SN. These include the reduction of mitochondrial electron transport, complex I and III activities, glutathione peroxidase activity, glutathione (GSH) ascorbate, calcium-binding protein, and superoxide dismutase and increase of basal lipid peroxidation and deposition of iron. The participation of iron-induced oxygen free radicals in the process of nigrostriatal dopamine neuron degeneration is strengthened by recent studies in which the neurotoxicity of 6-OHDA has been linked to the release of iron from its binding sites in ferritin. This is further supported by experiments with the prototype iron chelator, desferrioxamine (Desferal), a free-radical inhibitor, which protects against 6-OHDA-induced lesions in the rat. Indeed, intranigral iron injection in rats produces a selective lesioning of dopamine neurons, resulting in a behavioral and biochemical parkinsonism.

Animals↗

PubMed1993

The relevance of glial monoamine oxidase-B and polyamines to the action of selegiline in Parkinson's disease.

Dopamine and 2-phenylethylamine levels in striatal tissue are known to be increased after administration of selegiline (L-deprenyl), but it is still difficult to explain why this treatment induces longevity or dopaminergic neuroprotection in Parkinson's disease. In the absence of significant polyamine or diamine oxidase activities in human brain, polyamines and histamine are detoxified by N-acetylation and methylation, respectively. Methylhistamine as well as N-acetylated polyamine derivatives are selective substrates for monoamine oxidase type B (MAO-B). Theoretically at least, MAO-B inhibition by selegiline could result in the increase in the levels of polyamines and their N-acetyl derivatives. This could have significance for the action of selegiline in Parkinson's disease, as overactive corticostriatal glutaminergic function has been implicated in the degeneration of nigrostriatal dopamine neurons, and polyamines are potent modulators of the excitotoxic NMDA (N-methyl-D-aspartate)-glutamate subtype receptor.

Corpus Striatum↗

PubMed1993

The competitive NMDA antagonist CPP protects substantia nigra neurons from MPTP-induced degeneration in primates.

Degeneration of nigrostriatal dopaminergic neurons is the primary histopathological feature of Parkinson's disease. The neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces a neurological syndrome in man and non-human primates very similar to idiopathic Parkinson's disease by selectively destroying dopaminergic nigrostriatal neurons. This gives rise to the hypothesis that Parkinson's disease may be caused by endogenous or environmental toxins. Endogenous excitatory amino acids (EAAs) such as L-glutamate could be involved in neurodegenerative disorders including Parkinson's disease. We report in this study that the competitive NMDA antagonist CPP (3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) protects nigral tyrosine hydroxylase (TH) positive neurons from degeneration induced by systemic treatment with MPTP in common marmosets. This indicates that EAAs are involved in the pathophysiological cascade of MPTP-induced neuronal cell death and that EAA antagonists may offer a neuroprotective therapy for Parkinson's disease.

Animals↗

PubMed1993

Analyses of energy metabolism and mitochondrial genome in post-mortem brain from patients with Alzheimer's disease.

Biochemical and mitochondrial DNA analyses were performed in post-mortem brain tissue from seven patients with dementia of Alzheimer's type and age- and sex-matched controls. We analysed all complexes of the respiratory chain in four regions, i.e. temporal, parietal, entorhinal cortex and hippocampus. Although enzymes representing complex II, III and IV were reduced in activity, succinate cytochrome c reductase was significantly reduced only in the parietal and temporal cortex. However, Southern blot analyses with two restriction enzymes excluded any deletions larger than 500 bp in parietal and entorhinal cortex. It is concluded that there seems to be no specific respiratory chain defect in Alzheimer's disease.

Aged↗

PubMed1993

Effects of long-term recovery from transient cerebral ischemia in rat brain: tissue levels of acetylcholine, monoamines, and their metabolites.

Concentrations of acetylcholine and the monoaminergic neurotransmitters dopamine, serotonin and their respective metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), 4-hydroxy-3-methoxy-phenylacetic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA) and choline were simultaneously determined in the corpus striatum of rats after 15 min. complete cerebral ischemia (CCI) and in different intervals (1, 24, 48, 72, 96 hours) of postischemic cerebral reperfusion. Results were compared to respective sham-operated control animals. After 15 min. CCI acetylcholine concentration decreased to 15%, and dopamine concentration to 56% of the control values. The metabolite levels of DOPAC decreased to 40% and HVA to 64% of the control values. Acetylcholine, dopamine, serotonin and choline concentrations were not changed significantly after reperfusion. The metabolites HVA and 5-HIAA showed their maximum increases after 1 and 24 hours of reperfusion, additionally HVA was decreased both, after 72 and 96 hours of reperfusion. The data indicate that surprisingly little permanent damage could be caused by a 15 min. ischemia in the striatum. Tissue levels of the neurotransmitters appeared differentially altered but similarly regulated during ischemia and subsequent recirculation. Acetylcholine and dopamine levels decreased profoundly during ischemia. However, acetylcholine levels could be compensated rapidly during reperfusion, whereas the dopaminergic system showed a long-lasting change in its turnover rate. Although serotonin levels were unaffected by CCI, there was an increase of its presumed turnover rate during reperfusion.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1993

Binding of the ligand [3H]MK-801 to the MK-801 binding site of the N-methyl-D-aspartate receptor during experimental encephalopathy from acute liver failure and from acute hyperammonemia in the rabbit.

Binding of the ligand [3H]MK-801 to the MK-801 binding site of the N-methyl-D-aspartate (NMDA) receptor population on brain homogenates in rabbits was studied during experimental encephalopathy from acute liver failure and from acute hyperammonemia in the rabbit. Homogenates were prepared from brain cortex, hippocampus and striatum. Hepatic encephalopathy was induced by a two-stage liver devascularization procedure and acute hyperammonemia by a prolonged ammonium-acetate infusion; rabbits receiving a sodium-potassium-acetate infusion served as controls. In these animal models extracellular brain glutamate levels are known to be elevated. However no significant alterations in the number nor the affinity of the MK-801 binding sites of the NMDA receptors were found during acute liver failure and acute hyperammonemia. These findings suggest that the NMDA receptor population remains unaltered in experimental encephalopathy from acute liver failure and acute hyperammonemia, despite alterations in extracellular brain glutamate levels.

Acute Disease↗