Biomedical subjects

W D Rausch

Publications and source records attributed to W D Rausch.

At least 19 recordsLinked to original sources

PubMed2006

Glutamate-induced cell death and formation of radicals can be reduced by lisuride in mesencephalic primary cell culture.

Oxidative stress evoked by excitotoxicity is considered an important factor for the loss of dopaminergic neurons in Parkinson's disease. In vitro, protective effects of the dopamine agonist lisuride on complex I inhibition in primary dopaminergic cell culture have been reported. However, little is known about the effects of lisuride on glutamate-induced radical formation. Here, effects of lisuride on the formation of nitric oxide (NO) and superoxide radicals following glutamate exposure were studied on primary cell cultures prepared from mouse mesencephala. Glutamate treatment resulted in doubling of NO and superoxide radical formation, increased dopaminergic cell degeneration and extensively altered neuronal appearance. Pretreatment with lisuride significantly lowered the levels of either reactive species and increased the survival of dopaminergic neurons compared to glutamate-treated cultures. Moreover, the beneficial effect of lisuride could be completely inhibited by the D2/D3 receptor antagonist sulpiride when co-treated in cultures.

Animals↗

PubMed2002

Protection of dopaminergic neurons in primary culture by lisuride.

Dopamine agonists play an important role in the treatment of Parkinson's disease by reducing the administration of L-3,4-dihydroxyphenylalanine (L-DOPA). The enzymatic and non-enzymatic conversion of L-DOPA is suspected to increase oxidative stress, which leads to the degeneration of dopaminergic neurons in Parkinson's disease. In primary mouse mesencephalic cultures we show that the dopamine D1/D2 receptor agonist lisuride, in a concentration range of 0.001-1 microM, enhances the survival of dopaminergic neurons, protects against toxicity induced by L-DOPA or 1-methyl-4-phenylpyridinium ion (MPP+) and stimulates 3H-dopamine uptake. Lisuride also reduces anaerobic metabolism during incubation with L-DOPA. The present findings suggest that lisuride may have trophic/survival-promoting properties and potentially reduces oxidative stress.

1-Methyl-4-phenylpyridinium↗

PubMed2001

Reduction of Menkes mRNA and copper in leukocytes of patients with primary adult-onset dystonia.

Studies on postmortem tissue of patients with primary adult-onset dystonia revealed a significant increase in copper levels and a reduction of copper transporting Menkes protein of the lentiform nuclei. Here we demonstrate that patients with idiopathic adult-onset cervical dystonia (n = 14) have reduced Menkes mRNA copies and lower copper levels in leukocytes compared to controls (n = 17; U test, p < 0.05). Changes were less distinct in patients with blepharospasm. Therefore, disturbances of copper metabolism in focal dystonia may not be restricted to the basal ganglia.

Adenosine Triphosphatases↗

PubMed2000

The industrial chemical Tinuvin 123 does not induce dopaminergic neurotoxicity in C57Bl/6 mice.

We have investigated the acute effects of systemic administration of Tinuvin 123 on nigro-striatal dopaminergic neurons in the C57Bl/6 mouse. Tinuvin 123 was administered subcutaneously (s.c.) twice, 16 h apart, at doses of 0, 2, 20 or 200 mg/kg body weight to a total of 48 male C57Bl/6 mice (12 animals/group). Seven days following the last dose the animals were decapitated and the brains removed. No deaths occurred during the study. There were no differences between the mean body weights of any of the experimental groups prior to or following Tinuvin 123 treatment. Animals treated s.c. with 2 mg/kg Tinuvin 123 exhibited no changes in striatal dopamine or metabolite concentrations compared with vehicle-treated animals. Higher doses of Tinuvin 123 (20 and 200 mg/kg) resulted in a moderate loss of striatal dopamine (31 and 38%) but concentrations of the dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid and the neurotransmitters serotonin, aspartate, gamma aminobutyric acid and glutamate were unchanged. The total number of tyrosine hydroxylase-immunoreactive neurons in the entire substantia nigra were equivalent in the vehicle- and Tinuvin 123-treated animals at all doses, thus no neuronal loss was demonstrated. In conclusion, this study demonstrates no evidence that systemic administered Tinuvin 123 induces dopaminergic neurotoxicity in C57Bl/6 mice.

3,4-Dihydroxyphenylacetic Acid↗

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

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↗

PubMed1998

Comparison of substance P concentration in acupuncture points in different tissues in dogs.

Histologically, acupuncture points show neuronal innervation. One hundred seventy-seven tissue samples of acupuncture points and control points from 4 dogs were collected. Concentrations of substance P, a neurotransmitter, in the skin, muscle and subcutis of acupuncture points and control points were measured by means of enzyme immunoassay. The determined tissue concentrations of substance P (mean +/- SEM) in acupuncture points and control points were 1.81 +/- 0.13 and 1.51 +/- 0.1 ng/g in the muscle, 3.33 +/- 0.29 and 2.63 +/- 0.28 ng/g in the skin and 1.59 +/- 0.22 and 1.32 +/- 0.16 ng/g in the subcutis, respectively. The results indicate that there is a difference in the neurochemical profile between acupuncture points and control points.

Acupuncture Points↗

PubMed1998

Inverse hierarchy of vimentin epitope expression in primary cultures of chicken and rat astrocytes: a double-immunofluorescence study.

Vimentin contributes to the cytoskeleton of different cell-types, among them glial cells. We report here that different forms of this protein, distinguishable by the monoclonal antibodies Vim3B4 and V9, are species-specifically expressed in cultures of glial fibrillary acidic protein (GFAP) positive, primary astrocytes of the chicken and rat. Most cells in the cultures co-expressed GFAP and one of the two vimentin epitopes. The Vim3B4 positive epitope was present in chicken astrocytes, while the V9 positive was not. Inverse situation was found in the astrocytes of rat. In vitro age of the cells did not influence the hierarchy of vimentin epitope expression with respect to species-specificity. Our result shows that the different vimentin expression program of cultured astrocytes of the chicken and rat is preserved under in vitro conditions. The presented data support the concept of the species-specific regulation of vimentin forms in glial cells of the central nervous system.

Animals↗

PubMed1996

Selegiline is neuroprotective in primary brain cultures treated with 1-methyl-4-phenylpyridinium.

The ability of selegiline to protect against the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been attributed to the inhibition of the conversion of MPTP to 1-methyl-4-phenylpyridinium (MPP+), catalyzed by monoamine oxidase-B. Selegiline, however, has been found to rescue neurons in MPP(+)-treated mice after they have sustained lethal damage independently of monoamine oxidase-B inhibition. In our present study, we investigate whether selegiline can protect and/or rescue MPP(+)-injured dopaminergic neurons in co-cultures of mesencephalic and striatal cells of embryonic C57B1/6 mouse brains. Cells were exposed to selegiline (1, 10, 100 microM) in three different schemes: (i) in control cultures on the 8th day for 48 h; (ii) pretreatment: on the 8th day for 48 h, followed by administration of MPP+ (0.5 microM) on the 9th day for 24 h; (iii) delayed treatment: on the 9th day for 48 h, while MPP+ was administered on the 8th day and remained in culture during treatment with selegiline. In the delayed scheme, selegiline (1 microM) increased dopamine content, number of tyrosine hydroxylase immunoreactive cells and astrocytes in the cultures. We question whether selegiline protects cells injured by a toxic stressor via an astrocyte-mediated mechanism.

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

PubMed1996

Characteristics of fetal heart rate changes during the expulsive stage of bovine parturition in relation to fetal outcome.

OBJECTIVE: To characterize fetal heart rate (FHR) patterns of nonacidotic (N-AC) and acidotic (AC) calves during the expulsive stage of parturition. ANIMALS: 32 calves born to heifers, either unassisted or by moderate traction. PROCEDURE: Cardiotocograms (CTG) evaluated qualitatively (visual) and quantitatively by a moving window technique (width 10, shift 5 minutes) for baseline FHR, variability, and periodic alterations (accelerations and decelerations). RESULTS: Significant differences were apparent between increase in baseline FHR of N-AC and AC calves; change in FHR (delta-FHR), taking into account individual FHR, is a more discriminating parameter. The predominant reaction to uterine contraction is a decrease in FHR; variable decelerations were the most common type in both groups, and late decelerations were seen only in AC calves. Additional characteristics of variable decelerations were more frequently seen in AC calves. CONCLUSIONS: CTG parameters during expulsion can discriminate between AC and N-AC calves, but specific characteristics are not exclusively restricted to AC or N-AC calves. CLINICAL RELEVANCE: CTG recordings during bovine parturition in cattle provide information on the fetal condition and can be used in the future to study the effects of medication and manipulations to the fetus.

Acidosis↗

PubMed1995

A morphometric analysis of bipolar and multipolar TH-IR neurons treated with the neurotoxin MPP+ in co-cultures from mesencephalon and striatum of embryonic C57BL/6 mice.

Mesencephalic cultures contain two morphologically different tyrosine hydroxylase (TH)-immunoreactive (IR) neurons, fusiform bipolar, and pyramidal multipolar, which project to different anatomical structures (ventral striatum and neostriatum). The possibility of functional difference of these cells in Parkinson's disease led us study the effect of 1-methyl-4-phenylpyridinium (MPP+) on them. Survival and morphology of the two groups was studied in dissociated co-cultures from mesencephalon and striatum of embryonic C57BL/6 mice. Cells were grown at first in serum containing medium and then in serum free medium supplemented with hormones. Cultures were exposed to different concentrations of MPP+ on day 9 and 13 for 24 hr. They were fixed and stained with an anti-TH antibody. 0.1-1.0 microM MPP+ caused a dramatic reduction of the total area of TH-IR neurons. At 0.1 microM MPP+ some area was reduced, at 0.5 microM it appeared similar to controls, and decreased further at 1.0 microM. The relation of soma to total area showed that the decrease of the neuronal size was mainly due to the degeneration of the neuronal processes. The length of neuronal tree as well as the number of terminal segments were reduced dose dependently when cells were treated with the toxin. Similar results were obtained for bipolar and multipolar neurons. A significant difference in the decrease in total area was observed between the two age groups when cells were treated with MPP+, as older cells appeared to be more sensitive. When other parameters were checked no apparent difference was present.

1-Methyl-4-phenylpyridinium↗

PubMed1995

MPP+ selectively affects calcium homeostasis in mesencephalic cell cultures from embryonal C57/Bl6 mice.

1-Methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) serves as a valuable tool in animal models of Parkinson's disease. Primary cell cultures of mesencephalon from C57/Bl6 mice were used to investigate the effects of various dopaminergic neurotoxins on the intracellular calcium metabolism. MPP+ was compared to its precursor MPTP and a structural analogue paraquat (methylviologen). Direct addition of these neurotoxins (10 microM) to fura-2-labeled cells did not change intracellular calcium concentrations in the presence of 1 mM extracellular calcium. When mesencephalic neurons were exposed to the compounds for 24 hours, only MPP+ led to an increase in calcium concentration in the absence and presence of extracellular calcium (36%, p < 0.05 and 47%, p < 0.01 versus control group). Intracellular calcium concentrations in cortical cultures devoid of dopaminergic cells were not changed by the above neurotoxins. Thus MPP+ is shown to selectively increase intracellular calcium concentrations in mesencephalic cultures.

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

PubMed1995

High dose selegiline augments striatal ubiquinol in mouse: an indication of decreased oxidative stress or of interference with mitochondrial respiration? A pilot study.

The effects of unspecific doses of the irreversible monoamine oxidase inhibitor selegiline on alpha-tocopherol, alpha-tocopherolquinone, ubiquinol and ubiquinone were studied in frontal cortex, hippocampus and striatum of male C57BL/6 mice 4 h and 96 h after a single or six injections of selegiline (100 mg/kg body weight, i.p.), respectively. Inhibition of monoamine oxidase was confirmed by activity measurements of its isoforms A and B in brain stem nuclei and striatum as well as by determination of striatal levels of dopamine and its major metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid. In general, levels of alpha-tocopherol were not altered and levels of alpha-tocopherolquinone were below the detection limit. However, 96 h following selegiline, levels of ubiquinols 9 and 10 were significantly increased, whereas levels of ubiquinones 9 and 10 concomitantly decreased in the striatum. Concentrations of ubiquinols and ubiquinones in frontal cortex and hippocampus were unchanged 96 h following selegiline. These data suggest that selegiline affects the striatal redox ratio of ubiquinol to ubiquinone which is important for cellular antioxidant defense and mitochondrial electron transfer.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1995

The TaClo concept: 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), a new toxin for dopaminergic neurons.

Due to its structural analogy to the neurotoxin MPTP, "TaClo" (1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline), a compound readily originating in vitro from tryptamine ("Ta") and chloral ("Clo"), is discussed as a potential natural inducer of parkinsonian-like symptoms. Its spontaneous formation in man has to be taken into account after application of the drug chloral hydrate or after exposure to the solvent trichloroethylene. This first representative of chloral-derived heterocycles could now indeed be demonstrated to be formed in vivo after application of its putative precursors to rats. In vivo analysis of the nigrostriatal dopamine metabolism, behavioural studies, and histochemical findings as well as a strong inhibition of the complex I of the mitochondrial respiratory chain revealed the neurotoxic potential of TaClo on the dopaminergic system.

Animals↗

PubMed1995

Studies of the potentially endogenous toxin TaClo (1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline) in neuronal and glial cell cultures.

1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) is the first representative of a new class of highly halogenated heterocycles. The similarity of the beta-carboline framework to the chemical structure of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) prompted us to investigate the neurotoxic potential of this compound. For this purpose, primary cell cultures of C57/B16 mouse mesencephalon containing dopaminergic neurons were used. Cells were grown for 10 days and exposed to the toxin for 24 hours. The morphological changes observed in tyrosine hydroxylase immunoreactive (TH-IR) neurons and glial cells included swollen dendrites and soma, loss of axons and dendrites. At a TaClo concentration of 100 microM, the number of TH-IR neurons was decreased by 50%. In case of astrocyte cultures, changes became evident and at concentrations between 50-100 microM, a cell loss of 50% was observed. Furthermore, uptake of dopamine (DA) was reduced by 43% at 100 microM TaClo. Simultaneously, the DA content was significantly reduced by 66% at 100 microM.

Animals↗

PubMed1995

Long-term behavioural effects of TaClo (1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline) after subchronic treatment in rats.

1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), which shows a great structural similarity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), when administered to rats lead to enhanced spontaneous locomotion when they were tested 4-9 days after subchronic injection at a daily dose of 0.2 mg/kg over a seven week period. However, 9 weeks after the end of the course of injections animals walked more slowly during 12 hours of nocturnal activity, and apomorphine-induced locomotion was decreased 12 weeks later. These results suggest that the drug may exert a progressive neurotoxic effect.

Analysis of Variance↗

PubMed1994

Selegiline enhances survival and neurite outgrowth of MPP(+)-treated dopaminergic neurons.

Selegiline was added to co-cultures of mesencephalon and neostriatum of C57BL/6 mouse embryos according to three schemes: (i) before and (ii) after cells were exposed to the toxin 1-methyl-4-phenylpyridinium (MPP+), (iii) in control cultures. In all schemes, selegiline enhanced the morphological differentiation of dopaminergic neurons and with delayed treatment, significantly increased their survival. These results indicate that selegiline exhibits trophic-like actions and can rescue MPP(+)-injured dopaminergic neurons in cultures.

1-Methyl-4-phenylpyridinium↗

PubMed1994

Iron, copper, zinc, magnesium, and calcium in postmortem brain tissue from schizophrenic patients.

The regional distribution of iron, copper, zinc, magnesium, and calcium in postmortem brain of schizophrenic patients was compared with that of matched controls. In none of the brain regions investigated (caudate nucleus, hippocampus, amygdala, cortex, corpus mamillare, gyrus cinguli, and hypothalamus) were significant differences observed between these two groups. In the total group, region-specific differences were found for iron, copper, zinc, and calcium, but not for magnesium. Gender differences were observed only for zinc. There was no correlation between a neuroleptic-free period before death and the content of any of the metals investigated, except for a positive correlation between copper in the hippocampus and a neuroleptic-free period. The results of the present study suggest that there are no profound differences in the content of iron, copper, zinc, magnesium, and calcium in postmortem brains between controls and schizophrenic patients.

Adult↗