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P Riederer

Publications and source records attributed to P Riederer.

At least 163 records · Page 9Linked to original sources
PubMed1998

Peripheral-type benzodiazepine receptors in diagnostic subtypes of schizophrenic patients.

The peripheral-type benzodiazepine receptor (pBZD-R; also called the omega-3 receptor or the mitochondrial benzodiazepine receptor) seems to play a critical role in the production of neurosteroids, which are able to alter the electrical properties of neuronal membranes and thus the firing patterns of neurons. Putative endogenous ligands are the diazepam-binding inhibitor and its processing products, as well as porphyrins, some of them, in the case of porphyria, are well known to give rise to certain aspects of neuropsychiatric disorders, such as schizophrenic-like symptoms. Previous findings of altered benzodiazepine binding sites in post-mortem brain samples and platelets from small samples of schizophrenic patients have been inconclusive. Therefore we investigated characteristic binding parameters (Bmax, Kd) of the granulocytic pBZD-R by using the selective ligand PK11.195 in 53 subjects, fulfilling ICD-10 and DSM-IV criteria of schizophrenia. The binding parameters in our total group of 53 schizophrenic patients did not differ from those in healthy subjects. However, Bmax values were significantly reduced in schizophrenic patients with predominantly negative symptoms (residual type) compared to schizophrenic patients with predominantly positive symptoms, i.e. paranoid (-50%) and catatonic subtype (-38%). Moreover, only residual type schizophrenics exhibited a significantly reduced binding capacity compared to healthy subjects (-38%). More studies are warranted to clarify the functional significance of this binding site in the pathogenesis of negative symptoms.

Adult↗
PubMed1998

1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline increases extracellular serotonin and stimulates hydroxyl radical production in rats.

1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), a neurotoxin structurally similar to the dopaminergic neurotoxin MPTP, may be formed in humans treated with chloral hydrate or exposed to trichloroethylene, a widely used industrial solvent. Systemically administered TaClo (0.4 mg/kg, i.p.) induced an immediate and transient release of dopamine (DA) and serotonin (5-HT) measured using microdialysis. However, only 5-HT was increased significantly (area under the curve, AUC, for the 1-2 h-period following TaClo administration: 400% compared with the respective control value; 2-3 h-period: 326%). This was followed by a progressive increase in hydroxyl radical formation reflected by higher extracellular concentrations of the hydroxylate product of salicylic acid, 2,3-dihydroxybenzoic acid (AUC for the 1-2 h period following TaClo administration: 182% compared with the respective control value; 2-3 h period: 190%). In contrast, extracellular glutamate and GABA were increased 2-3 h post-injection by 64 and 51%, respectively. These data suggest that TaClo stimulates the generation of hydroxyl free radicals via an acute release of 5-HT and perhaps DA.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Regulation of PAX-6 gene transcription: alternate promoter usage in human brain.

We have isolated and characterized the 5'-flanking regulatory region of the human PAX-6 gene. Mapping of transcription initiation sites revealed the existence of an additional non-coding 5' exon, exon 1A. Functional analyses indicated that PAX-6 transcription is regulated by two distinct promoters, A and B, resulting in alternative transcription of exon 1A or 1B and joint transcription of exons 2 to 13. While a single initiation site was identified for exon 1A, transcription of exon 1B appears to be initiated from more than one site downstream of the promoter B-associated TATA motif. Multiple potential binding sites for transcription factors were found in the regions of promoter A and B. Although a 1.1-kb fragment of promoter A and a 1.5 kb fragment of promoter B, which had been fused to a reporter gene and transiently expressed in cell lines, displayed constitutive promoter activity, transcription of PAX-6 driven by promoter B was considerably higher than by promoter A in various regions of human postmortem brain. Transcript PAX-6B was primarily expressed in cerebellar cortex, whereas relatively low concentrations were detected in other brain areas. Functional dissection by serial deletions revealed several clusters of both activating elements and cell-selective silencers within the regulatory regions upstream of exon 1A and 1B. Coexpression of the promoter B constructs with a vector expressing PAX-6 modulated promoter B activity, thus indicating autoregulation by PAX-6 transcription. In conclusion, our findings suggest that PAX-6 transcription is regulated by alternate usage of promoter A and B, and that in adult human brain expression of PAX-6 is primarily controlled by promoter B. Alternate promoter usage and differential PAX-6 transcription are likely to play a critical role in brain development and neuroplasticity.

3T3 Cells↗
PubMed1998

A promoter-associated polymorphic repeat modulates PAX-6 expression in human brain.

The PAX-6 gene plays a critical role in neurodevelopment and brain plasticity. While transcription of human PAX-6 is regulated by alternate usage of two distinct promoters termed A and B, expression in adult human brain is primarily controlled by promoter B. We now report that a novel polymorphic dinucleotide repeat sequence with the structure (AC)m(AG)n is located approximately 1 kb upstream of the transcription initiation site associated with promoter B. PCR-based systematic screening for length variations in a caucasian population showed a skewed distribution of multiple alleles containing between 24 and 36 repeat units. In 217 unrelated individuals, the frequency of alleles in the range between 25 and 29 repeats was 90%, with the 26 repeat allele alone accounting for 50%; the heterozygosity rate was 65%. Variants of this PAX-6 gene-linked polymorphic region (PAX-6LPR) had different transcriptional efficiencies when fused to a luciferase reporter gene and transfected into Cos-7 cells. Promoter activity of variants with >/=29 repeats was 4- to 9-fold higher than that of the 26 repeat allele. The influence of the PAX-6LPR on PAX-6 expression was confirmed in postmortem cerebellum from individuals with different genotypes. mRNA levels were 2-fold higher in genotypes with long alleles compared to those with short alleles. Allelic variation in PAX-6 expression may be a determinant of interindividual differences in brain plasticity and function.

Alleles↗
PubMed1998

Advanced glycation endproducts are associated with Hirano bodies in Alzheimer's disease.

One of the structural posttranslational modifications contributing to the formation of insoluble, and protease-resistant protein deposits in Alzheimer's disease (AD), such as neurofibrillary tangles (NFT) and beta-amyloid plaques are 'advanced glycation endproducts' (AGE). Using a polyclonal antibody against AGE in frozen sections of fixed brain tissue from Alzheimer's disease patients, AGE were identified in a further characteristic protein deposit in AD, namely in Hirano bodies. AGE are localized to ovoid, spherical, and rod-like Hirano bodies in the hippocampus, particularly numerous in the stratum lacunosum-moleculare of CA1. Since Hirano bodies are known to contain mainly cytoskeletal and cytoplasmic components and are localized within the soma of neurons our study suggests that AGE formation and intracellular protein crosslinking represent early stages during neuronal degeneration.

Alzheimer Disease↗
PubMed1998

Measurement of receptor-mediated functional activation of G proteins in postmortem human brain membranes.

Guanine nucleotide-binding regulatory proteins (G proteins) play a pivotal role in receptor-mediated transmembrane signal transduction, and have been implicated in modes of action of psychotropic drugs as well as in pathogenesis of psychiatric disorders. In the present investigation, functional activation of G proteins coupled with several receptors, in particular with GABAB receptors, was assessed by agonist-induced stimulation of high-affinity GTPase, an enzyme that is intrinsic to alpha subunit of G protein, in postmortem human frontal cortical membranes. High-affinity GTPase activity was stimulated by GABA as well as (+/-)-baclofen, a selective GABAB receptor agonist, with EC50 values of 60-150 and 10-40 microM, respectively, in a Mg(2+)-dependent manner. The (+/-)-baclofen-stimulated response was antagonized by the selective GABAB receptor antagonist, 2-hydroxy-saclofen, in a competitive manner with a KB value of 59 microM. Although the maximal percent increase above basal value (% Emax) for GABAB receptor-mediated high-affinity GTPase activity was varied from subject to subject, % Emax values for both agonists were highly correlated with each other, and replicable and stable in a given subject, indicating that this measure is trustworthy as an index of functional coupling between receptors and G proteins in future studies at the aim of elucidating possible alteration of receptor/G protein interaction in psychiatric disorders. The % Emax values for GABAB receptor-mediated responses were correlated inversely with brain storage duration, which should be critically considered in postmortem studies. The increases in high-affinity GTPase activity stimulated by several agonists other than GABAB receptor agonists seemed too low to quantify for making a comparison in future studies.

Aged↗
PubMed1998

Loss of human hippocampal adenosine A1 receptors in dementia: evidence for lack of specificity.

The density of hippocampal adenosine A1 receptors was measured in autopsy samples of six patients with dementia with either Alzheimer (three) or sclerosis type pathology (three) in hippocampus and six control patients. Kinetic parameters (Bmax and KD) were determined by means of quantitative autoradiography using [3H]8-cyclopentyl-1 ,3-dipropylxanthine as a radioligand. A significant 50% reduction of CA1 adenosine A1 receptors was observed in patients with dementia independent of the specific pathology. These results suggest that loss of hippocampal adenosine A1 receptors in dementia is not specific for Alzheimer type pathology.

Aged↗
PubMed1998

Quantitative analysis of the structural requirements for blockade of the N-methyl-D-aspartate receptor at the phencyclidine binding site.

Blockade of the N-methyl-D-aspartate receptor by uncompetitive antagonists has implications for symptomatic and neuroprotective therapy of various neuropsychiatric diseases. Since the three-dimensional (3D) structure of this ion channel is unknown, the structural requirements for uncompetitive inhibition were investigated by application of a three-step strategy: At first, Ki values were measured for a number of structurally diverse compounds at the phencyclidine (PCP) binding site in postmortem human frontal cortex. Second, a pharmacophore model was developed for this set of molecules employing a mathematical method called graph theory. The resulting pharmacophore provided a very good explanation for the ability of structurally diverse compounds to bind to the same binding site. Using the experimental data and the pharmacophore as a basis for the third step, a three-dimensional quantitative structure-activity relationship (3D-QSAR) applying comparative molecular field analysis (CoMFA) was performed. The QSAR proved to be highly consistent and showed good predictiveness for several additional molecules. The results give a deeper insight into the structural requirements for effective NMDA receptor antagonism and offer the opportunity for improved drug design. The study represents the first quantitative 3D-QSAR model for NMDA receptor blockade, and it comprises structurally very different molecules. That the alignment for a highly consistent CoMFA is based on an automated 3D pharmacophore analysis has important methodological implications.

Binding Sites↗
PubMed1998

Advanced glycation end products in neurodegeneration: more than early markers of oxidative stress?

Oxidative stress is believed to play a decisive role in the pathogenesis of Parkinson's disease (PD). In addition, Lewy bodies, densely crosslinked intracellular protein deposits formed from cytoskeletal components, accumulate in presymptomatic stages of the disease. Recent findings indicate that "advanced glycation end products" (AGEs) are the major structural crosslinkers that cause the transformation of soluble neurofilament proteins to insoluble Lewy bodies. AGE formation is increased under conditions of oxidative stress, such as early GSH depletion, that are evident in the substantia nigra of PD patients, and is inhibited by radical scavengers and thiol antioxidants. Because AGEs not only are markers of oxidative stress but are also active participants in cell signaling by activation of glial cells to produce superoxide and nitric oxide, they can be considered part of a vicious cycle, which finally leads to neuronal cell death in the substantia nigra in PD.

Biomarkers↗
PubMed1998

Scavestrogens protect IMR 32 cells from oxidative stress-induced cell death.

Oxidative stress is considered an important pathophysiological mechanism contributing to promote cell death in a broad variety of diseases including cardiovascular and neurodegenerative disorders. The so-called scavestrogens J811 and J861, structurally derived from 17alpha-estradiol, are potent radical scavengers and inhibitors of iron-induced cell damage in vitro. In this study the potential cytoprotective effects of the scavestrogens J811 and J861 against Fenton reagent-induced cell damage (50 microM FeSO4 plus 200 microM H2O2) were compared with those of 17alpha- and 17beta-estradiol. Cell viability studies using Trypan blue staining showed that estradiols and scavestrogens at concentrations ranging from 0.1 to 10 microM are able to protect IMR 32 neuroblastoma cells from Fenton-mediated death. In addition, these compounds decreased lipid peroxidation measured as thiobarbituric acid reactive substances and renormalize oxidative stress-increased intracellular glutathione levels. When given 6 h after the toxic stimulus, J811 and J861 rescued 60% of cells, whereas 17alpha- and 17beta-estradiol were ineffective. These results suggest that the scavestrogens J811 and J861 are powerful antioxidants capable of interfering with radical-mediated cell death in diseases known to be aggravated by reactive oxygen species. Such compounds may be useful in the development of novel treatments for stroke or neurodegenerative disorders.

Antioxidants↗
PubMed1998

Chronic TVP-1012 (rasagiline) dose--activity response of monoamine oxidases A and B in the brain of the common marmoset.

The stereospecific form of the known acetylenic mechanism-based MAO-inhibitor AGN1135 (Rasagiline, TVP-1012) is devoid of sympathomimetic amphetamine-like properties. To evaluate the efficiency and selectivity of subcutaneous injections of TVP-1012 (dose range from 0.01 up to 10 mg/kg for 7 days) the activities of monoamine oxidases A and B (MAO-A,-B) were determined in different brain regions of the common marmoset. At a dose of 0.1 mg/kg TVP-1012, almost 80% of MAO-B activity is inhibited in all brain regions investigated (prefrontal and occipital cortex, cerebellum, caudate nucleus, putamen, nucleus accumbens). In contrast, MAO-A is not inhibited in putamen and nucleus accumbens. However, by increasing the TVP-1012 dose to 0.5 mg/kg, MAO-A is inhibited to a significant extent as well, concomitant to total inhibition of MAO-B. The results obtained indicate that TVP-1012 irreversibly inhibits both types of MAO in the common marmoset with selectivity for MAO-B at doses less than 0.5 mg/kg. TVP-1012 could be useful in studies requiring selective MAO-B inhibition without concomitant sympathomimetic amphetamine-like effects and could thus be of therapeutic interest for Parkinson's disease and retarded depression.

Animals↗
PubMed1998

Free radicals in Alzheimer's dementia: currently available therapeutic strategies.

Substantial evidence now exists that oxidative stress may play an important role in the etiopathogenesis of DAT. The different sources of oxidative stress in DAT are suggesting several pharmacological opportunities for influencing the disease. It is possible to distinguish 2 major types of possible therapeutic agents according to their pharmacological point of attack. 1. Radical scavengers, agents directly interacting with free radicals. Candidates of this type are gingko biloba, vitamins A, C, E and estrogen. 2. Antioxidants, which are able to prevent or decrease the production of free radicals by use of specific neuropharmacological properties. Candidates are selegiline, a MAO-B inhibitor well established in the therapy of Parkinson's disease, and tenilsetam, which is believed to be an AGE-inhibitor. Recent in vitro studies have demonstrated the efficacy of both types of therapeutic agents by preventing or delaying oxidative neural damage. Some clinical data exist regarding the antidementive properties particularly in terms of gingko biloba, selegiline and vitamin E. The efficacy studies about these compounds seem to indicate a promising future strategy in the therapy of DAT. But it is too early to draw definite conclusions since it is well known that all of our candidate substances do not act specifically as radical scavengers or antioxidants.

Alzheimer Disease↗
PubMed1998

Free radicals in Alzheimer's disease.

Alzheimer's disease is a neurodegenerative disorder comprising multisystem atrophies probably caused by multifactorial processes. The disease is characterized by typical neuropathology, impaired synaptic function and massive cell loss. The pathobiochemistry of this disorder involves oxidative stress, which accumulates free radicals leading to excessive lipid peroxidation and neuronal degeneration in certain brain regions. Moreover, radical induced disturbances of DNA, proteins and lipid membranes have been measured. The hypothesis has been proposed that cellular events involving oxidative stress may be one basic pathway leading to neurodegeneration in Alzheimer's disease. In this work we report evidence for increased oxidative stress and disturbed defense mechanisms in Alzheimer's disease, which may result in a self-propagating cascade of neurodegenerative events. Furthermore it is evident from experimental data, that aggregation of beta-amyloid and beta-amyloid toxicity is favourably caused by oxidative stress. Therefore, oxidative stress plays a key role in the conversion of soluble to unsoluble beta-amyloid, suggesting that oxidative stress is primary to the beta-amyloid cascade.

Alzheimer Disease↗
PubMed1998

A novel technique for the isolation of Lewy bodies in brain.

Previously, immunohistochemical methods were primarily used to detect and provide indirect evidence on the composition of Lewy bodies, the pathological hallmark of Parkinson's disease. This was chiefly because there are very few procedures that describe the isolation of these structures. We report here a relatively simple method that we have developed for the exclusive isolation of Lewy bodies from brain tissue. The isolation of the Lewy bodies and subsequent evaluation of their components may furnish an insight into their role in the neurodegenerative mechanism(s) operating in the spectrum of Lewy body disorders.

Aged↗
PubMed1998

Distribution of the B33 CTG repeat polymorphism in a subtype of schizophrenia.

Clinical evidence for a dominant mode of inheritance and anticipation in periodic catatonia, a distinct subtype of schizophrenia, suggests that trinucleotide repeat expansions may be involved in the aetiology of this disorder. Since genes with triplet repeats are putative canditates for causing schizophrenia, we have analysed the polymorphic B33 CTG repeat locus on chromosome 3 in 45 patients with periodic catatonia and 43 control subjects. The B33 CTG repeat locus was highly polymorphic, but all alleles in both the patient and control groups had repeat lengths within the normal range. We conclude that susceptibility to periodic catatonia is not influenced by variation at the B33 CTG repeat locus. Nevertheless, that periodic catatonia displays dominant inheritance and anticipation, characteristic of genetic disorders involving trinucleotide repeats, justifies further screening for triplet repeat expansions in this illness.

Adult↗
PubMed1998

Susceptibility for schizophrenia is not influenced by a functional insertion/deletion variant in the promoter of the serotonin transporter gene.

A possible dysregulation of serotonergic neurotransmission has been implicated in the aetiology of schizophrenic psychoses. In the present study we analysed allelic and genotypic variations of a recently described functional polymorphic region in the promoter of the human serotonin transporter gene (5-HTTLPR) and a variable tandem repeat (VNTR) in intron 2 of the 5-HTT gene. We investigated 413 unrelated individuals, 180 schizophrenic patients and 233 blood donors as controls. With regard to the 5-HTTLPR, both the schizophrenic and the control group did not significantly differ between genotype frequencies (chi2, p = 0.920) and allele frequencies (chi2, p = 0.836). The odds ratio for subjects with schizophrenia who were homozygous for the short allele was 1.04 (95% CI 0.59-1.84). No evidence of allelic association to specific schizophrenia subtypes was found. The 5-HTT associated VNTR also showed no significant differences between either the allelic or the genotypic distributions. Haplotype analysis revealed a significant overall linkage disequilibrium at a level of p = 0.00004. Our findings indicate that both polymorphisms are unlikely to play a substantial role in the genetic predisposition to schizophrenic disorders.

Adolescent↗
PubMed1998

Levels and proteolytic processing of chromogranin A and B and secretogranin II in cerebrospinal fluid in neurological diseases.

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.

Adult↗