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Biomedical subjects

P Riederer

Publications and source records attributed to P Riederer.

At least 145 records · Page 8Linked to original sources
PubMed1999

Involvement of microglia in cerebrospinal fluid glutamate increase in SIV-infected rhesus monkeys (Macaca mulatta).

Cerebrospinal fluid (CSF) samples were collected from 24 uninfected and 24 SIV251 MPBMC-infected rhesus monkeys during early infection and from 6 animals in a longitudinal design up to 7 months postinfection to investigate excitatory and inhibitory amino acid neurotransmitter levels. During the early infection period CSF amino acid concentrations of infected animals were not significantly different from those of uninfected animals. However, long-term studies demonstrated that gamma-aminobutyric acid (GABA) concentrations were decreased while glutamate concentrations were increased late in infection compared with the preinfection values of the same animals. Moreover, we showed that the source of increased glutamate in animals with AIDS is, at least partially, microglial cells. Our data support the hypothesis that excitotoxicity is involved in immunodeficiency virus-induced neurological disease and propose microglia as a contributor to excitotoxic damage.

Animals↗
PubMed1999

Increased tissue copper and manganese content in the lentiform nucleus in primary adult-onset dystonia.

We analyzed trace metals in frozen brain tissue of several subcortical nuclei from 3 patients with primary adult-onset dystonia and 10 control subjects. Copper levels were significantly increased in the globus pallidus and putamen of patients with dystonia A slight increase in manganese content was identified in the putamen and thalamus of patients with dystonia. Our findings show for the first time an accumulation of trace metals in the lentiform nuclei in patients with primary dystonia, which may play a pathogenetic role in primary dystonia and may explain recent ultrasound and magnetic resonance imaging findings.

Age of Onset↗
PubMed1999

Pathogenesis and preclinical course of Parkinson's disease.

Idiopathic parkinsonism (IP) is defined by its classic symptomology, its responsiveness to therapies which elevate dopamine levels, and by the failure to identify a specific etiological factor. The progressive and irreversible degeneration of dopaminergic neurons projecting from the substantia nigra pars compacta (SNc) to the striatum and the presence of SNc Lewy bodies are regarded as the essential pathological bases of IP, but neither the initiator(s) nor the nature of the degeneration have been determined, nor its relationship with degenerative changes in other parts of the IP brain. This paper discusses the various hypotheses that have been proposed to explain these phenomena, arguing that IP be regarded as a multisystem disorder, both at the level of individual neurons and at the whole brain level. It is probable that IP is the result of a multifactorial process, and that a cascade of interacting and overlapping biochemical mechanisms determine the course of the disease.

Animals↗
PubMed1999

Investigations on oxidative stress and therapeutical implications in dementia.

Alzheimer's disease (AD) is a progressive dementia affecting a large proportion of the aging population. The histopathological changes in AD include neuronal cell death and formation of amyloid plaques and neurofibrillary tangles (NFTs) NFTs are composed of hyperphosphorylated tau protein, and senile plaques contain aggregates of the beta-peptide. There is also evidence that brain tissue in patients with AD is exposed to oxidative stress during the course of the disease. Advanced glycation endproducts (AGEs), which are formed by a non-enzymatic reaction of glucose with long-lived protein deposits, are potentially toxic to the cell, are present in brain plaques in AD, and its extracellular accumulation in AD may be caused by an accelerated oxidation of glycated proteins. The microtubuli-associated protein tau is also subject to intracellular AGE formation. AGEs participate in neuronal death causing direct (chemical) radical production: Glycated proteins produce nearly 50-fold more radicals than non-glycated proteins, and indirect (cellular) radical production: Interaction of AGEs with cells increases oxidative stress. During aging cellular defence mechanisms weaken and the damages to cell constituents accumulate leading to loss of function and finally cell death. The development of drugs for the treatment of AD remains at a very unsatisfying state. However, pharmacological approaches which break the vicious cycles of oxidative stress and neurodegeneration offer new opportunities for the treatment of AD. Theses approaches include AGE-inhibitors, antioxidants, and anti-inflammatory substances, which prevent radical production. AGE inhibitors might be able to stop formation of AGE-modified beta-amyloid deposits, antioxidants are likely to scavenge intracellular and extracellular superoxide radicals and hydrogen peroxide before these radicals damage cell constituents or activate microglia, and anti-inflammatory drugs attenuating microglial radical and cytokine production.

Aged↗
PubMed1999

Cell death and apoptosis regulating proteins in Parkinson's disease--a cautionary note.

We studied the substantia nigra of three Parkinson's disease (PD) patients and three age-matched individuals by in situ DNA-end labeling (ISEL) and immunohistochemistry for the apoptosis regulating proteins Bcl-2, Bax and Bcl-x on 50 consecutive sections per patient. No melanin-containing cell was identified with typical apoptotic changes in either patient or control substantia nigra. With prolonged reaction-time the terminal transferase-mediated DNA-end labeling revealed a signal in 2.0 +/-1.2% melanin-containing cells in PD compared to 1.3 +/-1.1% in control. This difference did nor reach statistical significance and no condensation or margination of the chromatin was evident. No significant changes of any of the apoptosis regulating proteins were apparent in PD substantia nigra. These findings do not support the hypothesis that apoptosis plays a central role in the pathogenesis of PD.

Actins↗
PubMed1999

The N-methyl-D-aspartate receptor channel blocker amantadine does not cause histopathological alterations in human brain tissue.

Low doses of N-methyl-D-aspartate (NMDA)-type glutamate receptor antagonists induce morphological alterations in neurons of the cingulate gyrus and retrosplenial cortex of the rat. Neuronal cell death may result at higher doses. These effects are a major concern with regard to the introduction of new NMDA receptor antagonists into clinical trials. Amantadine is an uncompetitive NMDA receptor antagonist, which has been in clinical use for many years. In the present study we have looked for possible morphological alterations like necrosis in postmortem human brain tissue of patients previously treated with amantadine. Formalin-fixed tissue samples were taken from the hippocampus, cingulate gyrus, and retrosplenial cortex of 8 patients on previous amantadine medication and of 11 controls. Histopathological examination of sections was performed blind. All brains except one revealed either nonspecific age-related or cerebrovascular changes or other neurodegenerative disorders including Alzheimer's, Parkinson's or Lewy body disease. In conclusion, histopathological examination of the hippocampus, retrosplenial cortex, and cingulate gyrus of human brain did not reveal changes suggested to be specific for previous amantadine treatment.

Aged↗
PubMed1999

Parkinson's disease: a major hypokinetic basal ganglia disorder.

Disorders of the basal ganglia can be broadly divided into two: ones that manifest hypokinesia or those that elicit hyperkinesia. Parkinson's disease is the commonest form of hypokinetic disorder. The term Parkinson's disease (PD) usually encompasses idiopathic and Parkinsonian-like syndromes. PD is a chronic and progressive disease, in which the symptoms tend to appear unilateral to begin with. Subsequently subtle dysfunctions on the contralateral side may also be observed. Tremor, akinesia and rigidity are some of the classical features of the disease. Although many hypotheses have been proposed, the cause of PD largely remains obscure. Management of PD includes pharmacological treatment or/and surgical intervention.

Animals↗
PubMed1999

Mosaicism for a serotonin transporter gene promoter-associated deletion: decreased recombination in depression.

Transcriptional activity of the human serotonin transporter gene (5HTT) is modulated by complex interaction of multiple genomic and cellular factors. Variability of a polymorphic repetitive element (5HTTLPR) is associated with anxiety, depression, and aggression-related traits and may influence the risk to develop affective spectrum disorders. 5HTTLPR variants display a unique DNA secondary structure that has the potential to regulate the transcriptional activity of the associated 5HTT promoter. The structure of the 5HTTLPR is also likely to precipitate a 381-bp somatic deletion in the 5HTT's promoter region [del(17)(q11.2)] that is observed in 20-60% of genomic DNA isolated from mononuclear blood cells and postmortem brain. The localization of the deletion breakpoints adjacent to identical putative signal sequences (CAGCC) suggests a V(D)J recombinase-like rearrangement event. In comparison with healthy controls, del(17)(q11.2)/wildtype sequence ratios showed a decrease of the deleted variant in recurrent unipolar depression. Our results also suggest that mosaicism of del(17)(q11.2) is likely to be regulated by tissue-specific as well as 5HTTLPR-dependent mechanisms. The findings confirm that the pericentric region of human chromosome 17 is highly unstable and furnishs additional evidence for intricate complexity of 5HTT regulation under physiological condition and in disease.

Adult↗
PubMed1999

Postnatal ontogeny of GTP binding protein in the human frontal cortex.

The postnatal development of G protein in membrane preparations from frontal cortex regions in postmortem brains of various ages was investigated by immunoblotting with polyclonal antibodies against several specific G protein subtypes (the short and long form of Galphas(:Gs), Galphai1.2(:Gi), Galphao(:Go) and Galphaq/11(:Gq)) and tubulinbeta, and functional photoaffinity GTP binding. The amounts of Go showed steep increases at about 2 years, and there were similar tendency about Gs, Gi1.2 and Gq/11. Moreover, tubulinbeta was constant with development. The guanine nucleotide binding of Gs, Gi and Go also transiently increased at about the age of 2 years but the ratio of Gs to Gi.o was unchanged. Our results might have relevance for developmental neuroplasticity in signal transduction.

Adolescent↗
PubMed1999

Iron accumulation in the substantia nigra in rats visualized by ultrasound.

In recent studies, we have found a marked increase in substantia nigra (SN) echogenicity in patients with Parkinson's disease (PD) using transcranial ultrasound. Because a substantial body of evidence has accumulated indicating a selective elevation of iron in the SN from patients with PD, we set out to test the hypothesis that trace metals like iron could lead to the observed increase of SN echogenicity in PD. Rat brains were scanned after stereotactic injection of iron in different concentrations into the SN and after injecting ferritin, zinc and 6-OHDA alone, and after the addition of desferrioxamine. The amount of iron in the SN was measured spectroscopically. For iron, and partly for 6-OHDA, in different concentrations, a dose-dependent increase of SN echogenicity could be visualized, corresponding to an increase of iron measured by spectroscopy. No increase of echogenicity was visualized after the injection of ferritin and the addition of desferrioxamine to 6-OHDA, though an increase of iron was measured by spectroscopy. Therefore, we conclude that iron not bound to these proteins may lead to an increase of echogenicity of the SN.

Animals↗
PubMed1999

Amino acid specificity of glycation and protein-AGE crosslinking reactivities determined with a dipeptide SPOT library.

Advanced glycation end products (AGEs) contribute to changes in protein conformation, loss of function, and irreversible crosslinking. Using a library of dipeptides on cellulose membranes (SPOT library), we have developed an approach to systematically assay the relative reactivities of amino acid side chains and the N-terminal amino group to sugars and protein-AGEs. The sugars react preferentially with cysteine or tryptophan when both the alpha-amino group and the side chains are free. In peptides with blocked N-terminus and free side chains, cysteine, lysine, and histidine were preferred. Crosslinking of protein-AGEs to dipeptides with free side chains and blocked N termini occurred preferentially to arginine and tryptophan. Dipeptide SPOT libraries are excellent tools for comparing individual reactivities of amino acids for nonenzymatic modifications, and could be extended to other chemically reactive molecules.

Amino Acid Sequence↗
PubMed1999

Borna disease virus in human brains with a rare form of hippocampal degeneration but not in brains of patients with common neuropsychiatric disorders.

To estimate the frequency of persistent Borna disease virus (BDV) infections of the human central nervous system and to determine which neuropsychiatric disorders might be associated with this viral infection, reverse transcription-nested polymerase chain reaction was used to screen a large collection of autopsy brain samples for the presence of BDV-specific nucleic acids. The presence of BDV RNA was found in 3 brains of persons with psychiatric symptoms and prominent hippocampal degeneration previously reported to be positive by others. However, no BDV RNA was detected in 86 randomly collected brains from persons with various psychiatric disorders, including schizophrenia, affective disorders, and Alzheimer's disease, or from suicide victims or in 52 brains from healthy controls. Furthermore, no BDV-RNA was detected in 16 surgical brain samples from persons with epilepsy-associated hippocampal sclerosis. These results indicate that life-long persistent BDV infections are rare in humans and that such infections may be associated with certain forms of hippocampal degeneration.

Adult↗
PubMed1999

Dopamine D3 receptor gene polymorphism and alcohol dependence: relation to personality rating.

Hereditary dopaminergic mechanisms have been implicated in the aetiology of alcoholism. For this study, the distribution of a dopamine D3 receptor gene polymorphism (Ball) has been investigated in patients suffering from alcohol dependence, and compared with non-dependent controls. The allele A1 occurred significantly more frequently among patients compared to controls. Patients with the genotype A1/A2 showed significantly higher novelty seeking (NS) scores in the tridimensional personality questionnaire (TPQ) than patients with the genotype A1/A1. The distribution of patients with high and low NS scores in heterozygotes (A1/A2) did not follow a random distribution. There were significantly more individuals with higher NS scores, and fewer individuals with lower NS scores than expected. The results of this study support the hypothesis of a genetically determined involvement of the dopaminergic system in alcohol dependence. This is probably related to the modulation of personality traits. The observed effects are relatively small, but statistically significant. Thus, the genetics of the dopaminergic neurotransmitter system alone cannot explain the aetiopathogenesis of alcoholism.

Adult↗
PubMed1999

A disturbance in the neuronal insulin receptor signal transduction in sporadic Alzheimer's disease.

Disturbances of glucose and energy metabolism are hypothesized as pathogenetic factors in sporadic dementia of Alzheimer type (SDAT). Insulin and is receptors play an important role in the regulation of brain glucose metabolism and neuronal growth. In postmortem brain cortex in SDAT, the densities of brain insulin receptors were decreased compared to adult controls, but were increased in relation to aged controls. Tyrosine kinase activity, a signal transduction mechanism common to insulin and IGF-1 receptors, was reduced in SDAT in comparison to middle-aged and age-matched control groups. The data are consistent with a neurotrophic role of insulin in the human brain and an upregulation of insulin receptors is SDAT brain as a compensatory mechanism, possibly due to impaired signal transduction mechanism.

Adult↗
PubMed1999

Persistence of haloperidol in human brain tissue.

OBJECTIVE: After discontinuation of neuroleptic drugs, their antipsychotic and antiparkinsonian effects are still present for a prolonged period. It is not known whether the extended effects of neuroleptic drugs in humans are due to the continued presence of drug in brain tissue or to long-lasting drug-induced physiologic changes. The aim of this study was to directly examine haloperidol concentrations in human brain tissue in relation to drug-free time. METHOD: Haloperidol concentrations were measured in five regions (temporal cortex, cingulate gyrus, caudate nucleus, dentate nucleus, corpus callosum) of the postmortem brains of 11 patients previously treated with haloperidol. Haloperidol was analyzed by means of high-performance liquid chromatography with ultraviolet detection. The half-life in brain tissue was estimated by a population kinetic analysis. RESULTS: Haloperidol concentrations in the human brain tissue were 10-30 times higher than optimal serum concentrations used in the treatment of schizophrenia. Haloperidol concentrations appeared to be homogeneously distributed across different brain areas within a single patient. There was no apparent relation between duration of treatment and mean haloperidol concentration. Higher doses of haloperidol seemed to be related to higher concentrations in brain tissue. The elimination half-life from brain tissue was calculated to be 6.8 days. CONCLUSIONS: The results may have implications for clinical treatment decisions and the design of clinical research protocols. Patients exposed to haloperidol cannot be considered to be free of residual effects of the drug for a number of weeks after withdrawal.

Antipsychotic Agents↗
PubMed1999

Effects of Selegiline in a retroviral rat model for neurodegenerative disease.

Upon inoculation into neonatal rats, murine leukemia virus (MuLV) NT40 causes a non-inflammatory degeneration of the central nervous system. While microglia cells appear to be the major target cells within the brain parenchyma for neurovirulent MuLV, degenerating neurons do not express retroviral gene products. In order to protect rats from neuronal damage we treated retrovirally infected rats once with monoamine oxidase (MAO) B inhibitor Selegiline which--under different conditions--exerts neuroprotective effects. Unexpectedly, when administered at 17 days post-infection (d.p.i.) a single intraperitoneal dose of Selegilin (1 mg/kg bodyweight) significantly shortened the incubation period for neurological disease. In contrast, Selegiline given in a lower dosage (0.05 mg/kg bodyweight) and/or at a different time point (13 d.p.i.) at the low (0.05 mg/kg bodyweight) and the high dose (1.0 mg/kg bodyweight) had no effect on the outcome of neurological disease. Animals treated with Selegiline (1.0 mg/kg bodyweight at 17 d.p.i.) contained higher amounts of viral loads in the CNS, higher numbers of brain cells expressing major histocompatibility complex class II molecules, and exhibited inhibition of MAO-B in comparison to untreated yet infected (control) animals. Supposedly, Selegiline activated the major target cell population of the CNS for MuLV-NT40, microglia, with the consequence of enhanced susceptibility for retroviral infection and triggered endogenous mechanism(s) involved in the pathogenesis of retroviral neurodegeneration.

Animals↗
PubMed1999

Age-dependent changes in memory and mushroom bodies in the Drosophila mutant vermilion deficient in the kynurenine pathway of tryptophan metabolism.

Evolutionary conservation of homologous genes that cause related phenotypes in humans and Drosophila help to unravel genes implicated in polygenic human diseases. Among them are neurodegenerative disorders, such as Huntington, Parkinson, Alzheimer and HIV-induced diseases. They are characterized by a late onset disturbances of memory, changes in volumetric indices of the brain structures involved in memory formation, synaptic and glial pathology, and altered content of the intermediates of the kynurenine pathway, the endogenous modulators of the NMDA receptors. This pathway in conserved in insects, rodents and humans. We, therefore, studied the effects of aberrant tryptophan metabolism on memory, brain plasticity, synaptic and glial immunoreactivity in the Drosophila mutants vermilion (no kynurenines) and cinnabar (excess of neuroprotective kynurenic acid) over the life time. The mutant vermilion demonstrated gradual decline of 3-th memory performance and complete memory failure on the 28th day of life in a paradigm of conditioned courtship suppression. A drastic increase in the volume of the calyces of the mushroom bodies, and a decay in immunochemical staining of this brain structure with antibodies to synaptic protein csp and glia, precede the age-dependent memory defect and develop from the 12th day of adult life.

Aging↗