PubMed Health⌕ Search

Biomedical subjects

Peter Riederer

Publications and source records attributed to Peter Riederer.

At least 37 records · Page 2Linked to original sources
PubMed2005

Dolichol is the major lipid component of human substantia nigra neuromelanin.

Neuromelanin is a dark brown pigment present at high concentrations in dopaminergic neurones of the human substantia nigra (SN). Early electron microscopic examinations of neuromelanin fine structure revealed a significant neutral lipid component; however, the identity of this lipid has remained unknown. Here we show that the lipid component of neuromelanin pigment derived from human SN is the polyisoprenoid dolichol. Established methods were used to isolate the pigment from the SN of 32 brains and the lipid fraction was recovered in high purity and yield. Using reversed-phase HPLC, atmospheric pressure chemical ionization mass spectrometry, and 1H- and 13C-NMR techniques, we showed that the neuromelanin dolichol contained 17-23 isoprenoid units. Dolichol accounted for 14% of the mass of neuromelanin pigment; low levels of other hydrophobic compounds were detected (e.g. ubiquinone-10, alpha-tocopherol and cholesterol together accounted for < 0.5% of the neuromelanin lipid mass). This is the first time that dolichol has been identified in such a physiological setting and significantly advances our understanding of neuromelanin pigment structure and biosynthetic pathways. Furthermore, these studies identify a potential novel role for the isoprenoid pathway in the regulation of neuromelanin function and neurodegeneration within the SN.

Adolescent↗
PubMed2005

Gene expression profiling of sporadic Parkinson's disease substantia nigra pars compacta reveals impairment of ubiquitin-proteasome subunits, SKP1A, aldehyde dehydrogenase, and chaperone HSC-70.

Sporadic Parkinson's disease (PD) constitutes 99% of the disorder, while the remaining 1% of the cases is of familial (genetic) origin. The mutations reported to be associated with familial PD indicate impairment in protein processing and misfolding, as is handled by the ubiquitin-proteasome system (UPS), and in mitochondrial function. For these reasons, we have recently applied, for the first time, Affymetrix oligonucleotide microarray technique in the substantia nigra pars compacta of sporadic parkinsonian patients for studying global gene expression analysis and comparison to the alterations identified in inherited PD. This study identified decreased expression of 68 genes and elevation of 69 genes. Classification into functional groups revealed that the downregulated genes are related to signal transduction, protein degradation (e.g., ubiquitin-proteasome subunits), dopaminergic transmission/metabolism, iron transport, protein modification/phosphorylation, and energy pathways/glycolysis functional classes. A major finding is the decreased expressions of 5 subunits of the UPS, SKP1A, a member of the SCF (E3) ubiquitin ligase complex, and chaperone HSC-70, which can lead to a wide impairment in the function of an entire repertoire of proteins. The upregulated genes are clustered in cell adhesion/cytoskeleton, extracellular matrix components, cell cycle, protein modification/phosphorylation, protein metabolism and transcription, and inflammation/hypoxia (e.g., key iron and oxygen sensor EGLN1) classes. The study shows, for the first time, a convergence in the pathogenic processes that are observed in hereditary (familial) and sporadic PD, where abnormal iron metabolism, oxidative stress, and aggregation of proteins occur. An additional breakthrough in this research is the identification of a number of previously unsuspected crucial gene players that are also involved in the process of neurodegeneration, which can serve as specific biomarkers for PD and novel drug development.

Aldehyde Dehydrogenase↗
PubMed2005

The AGNP-TDM Expert Group Consensus Guidelines: focus on therapeutic monitoring of antidepressants.

Therapeutic drug monitoring (TDM) of psychotropic drugs such as antidepressants has been widely introduced for optimization of pharmacotherapy in psychiatric patients. The interdisciplinary TDM group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) has worked out consensus guidelines with the aim of providing psychiatrists and TDM laboratories with a tool to optimize the use of TDM. Five research-based levels of recommendation were defined with regard to routine monitoring of drug plasma concentrations: (i) strongly recommended; (ii) recommended; (iii) useful; (iv) probably useful; and (v) not recommended. In addition, a list of indications that justify the use of TDM is presented, eg, control of compliance, lack of clinical response or adverse effects at recommended doses, drug interactions, pharmacovigilance programs, presence of a genetic particularity concerning drug metabolism, and children, adolescents, and elderly patients. For some drugs, studies on therapeutic ranges are lacking, but target ranges for clinically relevant plasma concentrations are presented for most drugs, based on pharmacokinetic studies reported in the literature. For many antidepressants, a thorough analysis of the literature on studies dealing with the plasma concentration-clinical effectiveness relationship allowed inclusion of therapeutic ranges of plasma concentrations. In addition, recommendations are made with regard to the combination of pharmacogenetic (phenotyping or genotyping) tests with TDM. Finally, practical instructions are given for the laboratory practitioners and the treating physicians how to use TDM: preparation of TDM, drug analysis, reporting and interpretation of results, and adequate use of information for patient treatment TDM is a complex process that needs optimal interdisciplinary coordination of a procedure implicating patients, treating physicians, clinical pharmacologists, and clinical laboratory specialists. These consensus guidelines should be helpful for optimizing TDM of antidepressants.

Antidepressive Agents↗
PubMed2004

Entacapone increases and prolongs the central effects of l-DOPA in the 6-hydroxydopamine-lesioned rat.

Long-term palliative treatment of Parkinson's disease (PD) with the dopamine precursor l-3,4-dihydroxyphenylalanine ( l-DOPA, levodopa) is compromised by the occurrence of motor complications, most notably motor fluctuations and involuntary movements, l-DOPA-induced dyskinesias. This study was aimed at investigating the effect of adding the catechol- O-methyltransferase (COMT) inhibitor entacapone to chronic treatment with l-DOPA/benserazide. It was hoped that the administration of entacapone would prolong and smooth the central effect of l-DOPA exposure and that this would result in a reduced risk of l-DOPA-induced dyskinesia induction by lowering the l-DOPA dose. The rotational response and striatal extracellular dopamine release were assessed in rats that had undergone a unilateral 6-hydroxydopamine-induced lesion of the nigro-striatal system. Previous studies have shown that repeated treatment with l-DOPA is accompanied by a marked enhancement in behavioural responses and has pharmacological characteristics similar to l-DOPA-induced dyskinesia. In the present study, we demonstrated that rats receiving entacapone in addition to 6.50 mg/kg of l-DOPA displayed significant enhancement of the developing contralateral turning response compared with rats treated with the same dose of l-DOPA only. However, when reducing the l-DOPA dose to 4.25 mg/kg the behavioural response was comparable to that seen in rats treated with the higher dose of l-DOPA only. Voltammetry analysis suggests that the increased behavioural response in entacapone-treated rats is the result of a much larger dopamine release. In addition, we found that entacapone treatment prolonged and smoothed the striatal dopamine levels following chronic l-DOPA/benserazide treatment. From a clinical point of view, this finding suggests that administration of a COMT inhibitor should allow the frequency of l-DOPA administration to decrease and to smooth the brain delivery of the l-DOPA, which in the end should facilitate a reduction in the risk of dyskinesia induction.

Animals↗
PubMed2004

Redox imbalance.

Substantial evidence implies that redox imbalance attributable to an overproduction of reactive oxygen species or reactive nitrogen species that overwhelm the protective defense mechanism of cells contributes to all forms of Parkinson's disease. Factors such as dopamine, neuromelanin, and transition metals may, under certain circumstances, contribute to the formation of oxygen species such as H(2)O(2), superoxide radicals, and hydroxyl radicals and react with reactive nitrogen species such as nitric oxide or peroxinitrite. Mitochodrial dysfunction and excitotoxicity may be a cause and a result of oxidative stress. Consequences of this redox imbalance are lipid peroxidation, oxidation of proteins, DNA damage, and interference of reactive oxygen species with signal transduction pathways. These consequences become even more harmful when genetic variations impair the normal degradation of altered proteins. Therefore, therapeutic strategies must aim at reducing free-radical formation and scavenging free-radicals.

Animals↗
PubMed2004

Perineuronal nets potentially protect against oxidative stress.

A specialized form of extracellular matrix (ECM) termed perineuronal nets (PNs) consisting of large aggregating chondroitin sulfate proteoglycans (CSPGs), with hyaluronan and tenascin as main components, surrounds subpopulations of neurons. The glycosaminoglycan components of perineuronal nets form highly charged structures in the direct microenvironment of neurons and thus might be involved in local ion homeostasis. The polyanionic character suggests that perineuronal nets also potentially contribute to reduce the local oxidative potential in the neuronal microenvironment by scavenging and binding redox-active iron, thus providing some neuroprotection to net-associated neurons. Here, we show that neurons ensheathed by a perineuronal net in the human cerebral cortex are less frequently affected by lipofuscin accumulation than neurons without a net both in normal-aged brain and Alzheimer's disease (AD). As lipofuscin is an intralysosomal pigment composed of cross-linked proteins and lipids generated by iron-catalyzed oxidative processes, the present results suggest a neuroprotective function of perineuronal nets against oxidative stress, potentially involved in neurodegeneration.

Aged↗
PubMed2004

Heterotopic rat heart transplantation: severe loss of glutathione in 8-hour ischemic hearts.

BACKGROUND: Tissue damage caused by reactive oxygen species (ROS) formed during ischemia/reperfusion seems to be an important risk factor in the failure of transplanted hearts. Although endogenous anti-oxidants protect the myocardium against free radical attack under physiologic conditions, their capacity may become limited during severe oxidative stress. Thus, we investigated the effect of 8-hour cold ischemia on the myocardial anti-oxidative defense system in a heterotopic rat heart transplantation model. METHODS: Lewis rat hearts were subjected to 30 or 480 minutes of 4 degrees C cold ischemia in Bretschneider cardioplegic solution with or without transplantation and reperfusion (30 or 240 minutes) into F344 recipients. Activity levels of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione S-transferase (GST), and concentrations of glutathione (GSH), glutathione disulfide (GSSG) and lipid hydroperoxides (LOOH) were analyzed in heart homogenates. For histology, cross-sections of the ventricles were stained with hematoxylin-eosin. RESULTS: Except for GST, enzyme activities and GSSG concentration increased and the glutathione redox ratio (GSH/GSH + 2GSSG) significantly decreased in 480-minute ischemic hearts compared with those with 30-minute ischemia. Reperfusion dramatically decreased both GSH and GSSG and increased LOOH formation but without severe histopathologic findings in the transplants. Applying a tree-structured classifier technique, GSH and LOOH were identified as significant features indicative of transplantation-induced oxidative stress. CONCLUSIONS: In the present study severe loss of glutathione and formation of LOOH indicated transplantation-induced oxidative stress in the rat heart; therefore, alterations of these parameters may hint at relevant deficits in the myocardial anti-oxidative defense and may also predict subsequent tissue damage.

Animals↗
PubMed2004

GC/MS analysis of thermally degraded neuromelanin from the human substantia nigra.

Neuromelanin (NM) is a complex polymer pigment found in catecholaminergic neurons of the human brain. The structure, formation pathway, and physiological function of NM have not yet been clarified, but interest in this polymer has been sparked by the suggestion that NM is involved in cell death in Parkinson's disease. In the current study, pyrolysis-gas chromatography/mass spectrometry analysis was applied for structural investigation of NM isolated from the human substantia nigra, using synthetic eumelanin and pheomelanin-type pigments as reference materials. None of the heterocyclic, sulfur-containing compounds being characteristic thermal degradation products of cysteinyldopamine-derived units of synthetic pheomelanin standard was detected in the pyrolysates of natural NM. The results suggest that nigral pigment isolated from normal brain tissue does not contain benzothiazine-type monomer units. Pyrolytic experiments in the presence of a derivatizing agent allowed identification of high levels of saturated and monounsaturated straight-chain C14-C18 fatty acids and led to the conclusion that a part of a lipid component is chemically bound to the NM macromolecule. The nigral pigment was also shown to be tightly associated with an isoprenoid-type compound.

Gas Chromatography-Mass Spectrometry↗
PubMed2004

Monoamine oxidase-B inhibition in Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia in late life. There is still no clear-cut consensus whether this disease involves genetic or environmental factors or both. There is a great need to find a way to delay the disease, as delaying the onset of the disease will bring a great relieve on social and medical resources. The monoamine oxidase-B (MAO-B) inhibitors were shown to be effective in treating Parkinson's disease and possibly AD, with concomitant extension of life span. This article gives a short review on MAO-B inhibitors and their mechanism for neuroprotective effects in AD.

Alzheimer Disease↗
PubMed2004

Iron, brain ageing and neurodegenerative disorders.

There is increasing evidence that iron is involved in the mechanisms that underlie many neurodegenerative diseases. Conditions such as neuroferritinopathy and Friedreich ataxia are associated with mutations in genes that encode proteins that are involved in iron metabolism, and as the brain ages, iron accumulates in regions that are affected by Alzheimer's disease and Parkinson's disease. High concentrations of reactive iron can increase oxidative-stress induced neuronal vulnerability, and iron accumulation might increase the toxicity of environmental or endogenous toxins. By studying the accumulation and cellular distribution of iron during ageing, we should be able to increase our understanding of these neurodegenerative disorders and develop new therapeutic strategies.

Aging↗
PubMed2004

The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood-brain barrier and exhibits anticonvulsive effects.

The functional characterization of hispidulin (4',5,7-trihydroxy-6-methoxyflavone), a potent benzodiazepine (BZD) receptor ligand, was initiated to determine its potential as a modulator of central nervous system activity. After chemical synthesis, hispidulin was investigated at recombinant GABA(A)/BZD receptors expressed by Xenopus laevis oocytes. Concentrations of 50 nm and higher stimulated the GABA-induced chloride currents at tested receptor subtypes (alpha(1-3,5,6)beta(2)gamma(2)S) indicating positive allosteric properties. Maximal stimulation at alpha(1)beta(2)gamma(2)S was observed with 10 microm hispidulin. In contrast to diazepam, hispidulin modulated the alpha(6)beta(2)gamma(2)S-GABA(A) receptor subtype. When fed to seizure-prone Mongolian gerbils (Meriones unguiculatus) in a model of epilepsy, hispidulin (10 mg kg(-1) body weight (BW) per day) and diazepam (2 mg kg(-1) BW per day) markedly reduced the number of animals suffering from seizures after 7 days of treatment (30 and 25% of animals in the respective treatment groups, vs 80% in the vehicle group). Permeability across the blood-brain barrier for the chemically synthesized, (14)C-labelled hispidulin was confirmed by a rat in situ perfusion model. With an uptake rate (K(in)) of 1.14 ml min(-1) g(-1), measurements approached the values obtained with highly penetrating compounds such as diazepam. Experiments with Caco-2 cells predict that orally administered hispidulin enters circulation in its intact form. At a concentration of 30 microm, the flavone crossed the monolayer without degradation as verified by the absence of glucuronidated metabolites.

Animals↗
PubMed2004

Caenorhabditis elegans MPP+ model of Parkinson's disease for high-throughput drug screenings.

The neurotoxin MPTP and its active metabolite MPP+ cause Parkinson's disease (PD)-like symptoms in vertebrates by selectively destroying dopaminergic neurons in the substantia nigra. MPTP/MPP+ models have been established in rodents to screen for pharmacologically active compounds. In addition to being costly and time consuming, these animal models are not suitable for large scale testings using compound libraries. We present a novel MPP+-based model for high-throughput screenings using the nematode Caenorhabditis elegans. Incubation of C. elegans with MPTP or its active metabolite MPP+ resulted in strong symptomatic defects including reduced mobility and increased lethality, and is correlated with a specific degeneration of the dopaminergic neurons. The phenotypic consequences of MPTP/MPP+ treatments were recorded using automated hardware and software for quantification. Incubation of C. elegans with a variety of pharmacologically active components used in PD treatment reduced the MPP+-induced defects. Our data suggest that the C. elegans MPTP/MPP+ model can be used for the quantitative evaluation of anti-PD drugs.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2004

The relevance of iron in the pathogenesis of Parkinson's disease.

Investigations that revealed increased levels of iron in postmortem brains from patients with Parkinson's disease (PD) as compared to those from individuals not suffering from neurological disorders are reported. The chemical natures in which iron predominates in the brain and the relevance of neuromelanin for neuronal iron binding are discussed. Major findings have been that iron levels increase with the severity of neuropathological changes in PD, presumably due to increased transport through the blood-brain barrier in late stages of parkinsonism. Glial iron is mainly stored as ferric iron in ferritin, while neuronal iron is predominantly bound to neuromelanin. Iron overload may induce progressive degeneration of nigrostriatal neurons by facilitating the formation of reactive biological intermediates, including reactive oxygen species, and the formation of cytotoxic protein aggregates. There are indications that iron-mediated neuronal death in PD proceeds retrogradely. These results are also discussed with respect to their relevance for disease progression in relation to cytotoxic alpha-synuclein protofibril formation.

Animals↗
PubMed2004

Functional neurochemistry of Alzheimer's disease.

A review of neurochemical research on classical neurotransmitters, i.e. acetylcholine, serotonin, noradrenaline, dopamine, glutamate, and GABA in Alzheimer's disease is presented. Findings are linked to the information processing system of the human brain to establish a more functional neurochemistry. On this basis, different pharmacotherapeutic strategies are discussed. Our conclusion is that current symptomatic therapy of Alzheimer's disease is insufficient. Besides therapy with acetylcholinesterase inhibitors, comedication to act on imbalances between serotonin and noradrenaline on the one site, and dopamine, glutamate and GABA on the other site should should be considered.

Alzheimer Disease↗
PubMed2003

Iron-binding characteristics of neuromelanin of the human substantia nigra.

The vulnerability of the dopaminergic neurons of the substantia nigra (SN) in Parkinson's disease has been related to the presence of the pigment neuromelanin (NM) in these neurons. It is hypothesised that NM may act as an endogenous storage molecule for iron, an interaction suggested to influence free radical production. The current study quantified and characterised the interaction between NM and iron. Iron-binding studies demonstrated that both NM and synthetically-produced dopamine melanin contain equivalent numbers of high and low-affinity binding sites for iron but that the affinity of NM for iron is higher than that of synthetic melanin. Quantification of the total iron content in iron-loaded NM and synthetic melanin demonstrated that the iron-binding capacity of NM is 10-fold greater than that of the model melanin. This data was in agreement with the larger iron cluster size demonstrated by Mössbauer spectroscopy in the native pigment compared with the synthetic melanin. These findings are consistent with the hypothesis that NM may act as an endogenous iron-binding molecule in dopaminergic neurons of the SN in the human brain. The interaction between NM and iron has implications for disorders such as Parkinson's disease where an increase in iron in the SN is associated with increased indices of oxidative stress.

Humans↗
PubMed2003

NADPH-diaphorase staining reveals new types of interneurons in human putamen.

Neurons in the human striatum have been divided into five or seven different types, respectively. To further characterize these interneurons, we investigated the putamen of five brains by means of NADPH-diaphorase staining and compared our results to previous classifications in man. The NADPH-diaphorase method is selective for nitric oxide synthase (NOS); in the human striatum, predominantly interneurons were stained. NADPH-diaphorase positive neurons were then further examined. They showed clear morphological differences and could be classified into 12 different types, which only partially corresponded to previously described neuron types. Thus, we suggest at least three novel types of neostriatal interneurons. Furthermore, a special class of large neurons thought to be efferent in nature, stained NOS-positive.

Adult↗
PubMed2003

Microglial activation induces cell death, inhibits neurite outgrowth and causes neurite retraction of differentiated neuroblastoma cells.

Activation of glial cells has been proposed to contribute to neuronal dysfunction and neuronal cell death in Alzheimer's disease. In this study, we attempt to determine some of the effects of secreted factors from activated murine N-11 microglia on viability and morphology of neurons using the differentiated neuroblastoma cell line Neuro2a. Microglia were activated either by lipopolysaccharide (LPS), bacterial cell wall proteoglycans, or advanced glycation endproducts (AGEs), protein-bound sugar oxidation products. At high LPS or AGE concentrations, conditioned medium from microglia caused neuronal cell death in a dose-dependent manner. At sublethal LPS or AGE concentrations, conditioned media inhibited retinoic acid-induced neurite outgrowth and stimulated retraction of already extended neurites. Among the many possible secreted factors, the contribution of NO or NO metabolites in the cytotoxicity of conditioned medium was investigated. Cell death and changes in neurite morphology were partly reduced when NO production was inhibited by nitric oxide synthase inhibitors. The results suggest that even in the absence of significant cell death, inflammatory processes, which are partly transmitted via NO metabolites, may affect intrinsic functions of neurons such as neurite extension that are essential components of neuronal morphology and thus may contribute to degenerative changes in Alzheimer's disease.

Alzheimer Disease↗