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Biomedical subjects

M Gerlach

Publications and source records attributed to M Gerlach.

At least 91 records · Page 5Linked to original sources
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

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

Intraoperative microdialysis and tissue-pO2 measurement in human glioma.

The amino acid glutamate is one of the major neurotoxins in the pathogenesis of neuronal death after ischemia or trauma. Microdialysis studies in both man and animal have shown elevated extracellular levels after primary lesions. Monitoring of cerebral tissue oxygenation (p(ti)O2) has been used in recent years to detect and prevent episodes of low cerebral oxygenation, e.g. after trauma or subarachnoid hemorrhage. Intraoperative monitoring of p(ti)O2 combined with microdialysis in the peritumoral edema has been chosen to study the responses of glutamate and oxygen levels during resection. In 7/9 patients p(ti)O2 was below "critical" 10 mm Hg. Elevating inspiratory oxygen concentration to 100% led to an increase of p(ti)O2 by 2.5-4 fold and a decrease of glutamate and aspartate by 50-80%. A close correlation between p(ti)O2 and microdialysis glutamate levels was not clearly shown due to frequent intraoperative manipulations.

Aspartic Acid↗
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

Nitric oxide inhibits tissue factor synthesis, expression and activity in human monocytes by prior formation of peroxynitrite.

OBJECTIVE: Nitric oxide (NO) has antithrombotic properties by regulating platelet function, whereas direct effects on plasmatic coagulation are rarely described. In sepsis and inflammation, when synthesis of NO, oxygen radicals and toxic metabolites is crucial, the expression of tissue factor (TF) on monocytes stimulated by lipopolysaccharides (LPS) induces intravascular coagulation. This study was performed to examine the influence of NO and the NO-dependent metabolite peroxynitrite on LPS-induced TF expression and activity in human monocytes. DESIGN: Experimental study. SETTING: Laboratory for cell biology. METHODS: Human peripheral blood mononuclear cells were isolated from buffy coats by gradient centrifugation. The NO-releasing compounds SIN1 and NOC18 were used under different conditions. TF antigen was assayed by flow cytometry, and its activity by a clotting assay. TF-mRNA was measured by reverse transcriptase polymerase chain reaction (RT-PCR-ELISA). MEASUREMENTS AND RESULTS: Whereas NOC18, a pure NO donor, had no effect, SIN1, releasing both NO and superoxide (O2-), reduced TF expression and activity in a dose- and time-dependent manner; superoxide dismutase (SOD) reversed the SIN1-mediated effect. Adding the O2(-)-deliberating system hypoxanthin/xanthin oxidase (which had no significant effect per se) to NOC18, or using the NO and O2- reaction product peroxynitrite resulted in a reduction of TF expression. RT-PCR-ELISA indicated upregulation of TF-mRNA by SIN1 with a peak at 500 microM; higher doses had less effect. CONCLUSION: These data demonstrate an influence of NO on LPS-induced TF expression in monocytes by prior formation of peroxynitrite; furthermore, the balance between NO and O2- seems to play a crucial role.

Dose-Response Relationship, Drug↗
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

In vitro studies of ferritin iron release and neurotoxicity.

The increase in brain iron associated with several neurodegenerative diseases may lead to an increased production of free radicals via the Fenton reaction. Intracellular iron is usually tightly regulated, being bound by ferritin in an insoluble ferrihydrite core. The neurotoxin 6-hydroxydopamine (6-OHDA) releases iron from the ferritin core by reducing it to the ferrous form. Iron release induced by 6-OHDA and structurally related compounds and two other dopaminergic neurotoxins, 1-methyl-4-phenylpyridinium iodide (MPP+) and 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), were compared, to identify the structural characteristics important for such release. 1,2,4-Trihydroxybenzene (THB) was most effective in releasing ferritin-bound iron, followed by 6-OHDA, dopamine, catechol, and hydroquinone. Resorcinol, MPP , and TaClo were ineffective. The ability to release iron was associated with a low oxidation potential. It is proposed that a low oxidation potential and an ortho-dihydroxyphenyl structure are important in the mechanism by which ferritin iron is mobilized. In the presence of ferritin, both 6-OHDA and THB strongly stimulated lipid peroxidation, an effect abolished by the addition of the iron chelator deferoxamine. These results suggest that ferritin iron release contributes to free radical-induced cell damage in vivo.

1-Methyl-4-phenylpyridinium↗
PubMed1997

Evidence for increased oxidative stress in alcohol-dependent patients provided by quantification of in vivo salicylate hydroxylation products.

The hypothesis of increased oxidative stress in alcohol-dependent patients postulates that altered free radical metabolism is involved in the various symptoms associated with this disease, including brain atrophy, peripheral polyneuropathy, alcoholic liver fibrinogenesis, and cancer. Using an in vivo assay for quantitation of hydroxyl radical (.OH) levels in peripheral blood, we detected increased values in patients suffering from alcohol dependence when compared with non-dependent control persons. The assay used in this study involves the injection of acetylsalicylic acid, which is metabolized in vivo by direct reaction with .OH to 2,3-dihydroxybenzoic acid (DHBA). The time curve for the concentration of the reaction product (2,3-DHBA), determined by high-performance liquid chromatography, thus estimates the .OH radical level in the peripheral blood of individuals undergoing this test. For the first time, we used the intravenous application of acetylsalicylic acid to avoid artifacts arising from differences in gastrointestinal resorption, known to be disturbed in alcoholism. The areas under the 2,3-DHBA time curves differed significantly (p < 0.05) between patients and controls (0.54 +/- 0.27 vs. 0.36 +/- 0.19 microM.h). This study presents further evidence for alterations in radical metabolism in vivo in patients suffering from alcohol dependence. The assay can also be used in further studies dealing with antioxidative treatment (radical scavengers) to evaluate the effectiveness of such therapy.

Adult↗
PubMed1997

Global and extended coagulation monitoring during extracorporeal lung assist with heparin-coated systems in ARDS patients.

Heparin-coated systems for extracorporeal lung-assist (ECLA) were developed to reduce hemorrhagic risk by lowering the systemic heparinization, monitored by global tests, e.g. activated coagulation time (ACT) and activated partial thromboplastin time (APTT). Since this strategy gives no insight into procoagulant states, five ARDS patients receiving ECLA with heparin-coated systems were investivated for changes in coagulation using both global and extended tests. During ECLA onset the APTT and ACT were within or near normal ranges, platelets decreased 76.5% within 48 h, fibrinogen decreased 28.7%, thrombin-antithrombin-III complexes were elevated before ECLA (53 micrograms/L), but demonstrated an additional peak (238 micrograms/L), plasminogen-activator-inhibitor-1 increased 12-fold, and the C1-inhibitor dropped 14.1%. In conclusion, after the onset of ECLA from a previous prethrombotic state, the precoagulant, anticoagulant, fibrinolytic and complement systems were activated in a similar way to that reported for non-heparinized systems with high-dose heparin. This was however only monitored by an extended test panel which was unable to predict thromboembolic events during ECLA.

Adult↗
PubMed1996

A post mortem study on neurochemical markers of dopaminergic, GABA-ergic and glutamatergic neurons in basal ganglia-thalamocortical circuits in Parkinson syndrome.

Functional models of the circuitry of the basal ganglia have recently been proposed to account for the vast spectrum of motor disorders associated with the loss of anatomical or neurochemical integrity within the basal ganglia. On the basis of these hypothetical models, hypokinetic disorders such as Parkinson's disease, are thought to be associated with excessive tonic and phasic inhibition of the output from the basal ganglia to the thalamus. In the present study we have attempted to determine the validity of the proposed model by measuring neurochemical markers of inhibitory and excitatory neurotransmission in post mortem human brain tissue. We have determined the concentrations of the excitatory neurotransmitters aspartate/glutamate and of the inhibitory neurotransmitter GABA in 18 relevant regions of the thalamocortical circuits of the basal ganglia of patients who had manifested Parkinsonian symptoms, and compared them with controls of individuals who had died without any history of neurological or psychiatric disorders and had no neuropathological abnormalities. Additionally, the receptor subtype for the excitatory amino acid N-methyl-D-aspartate (NMDA) was studied in the same brain tissue in which neurotransmitter concentrations had been analysed as neurochemical markers of post-synaptic excitatory neurotransmission. In patients who had manifested Parkinsonian symptoms, glutamate and aspartate levels were found to be unchanged in all examined brain regions. In contrast, the binding of [3H]MK-801, which identifies the NMDA receptor, was reduced in the head (-42%) and body (-38%) of the caudate nucleus. In parkinsonian patients, GABA levels were diminished by 36% in the centromedial thalamus, compared to control values. These results do not confirm the changes in neurotransmitter concentrations predicted according to the model, although we cannot rule out that the predicted changes might have been observed if the Parkinsonian group had been further subdivided into groups diagnosed on the basis of the patients' clinical picture (akinetic-rigid, tremor-dominant, equivalent type) and compared with the control group.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in non-human primates is antagonized by pretreatment with nimodipine at the nigral, but not at the striatal level.

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to induce parkinsonism in man and non-human primates. Hypotheses concerning the mechanism of action of MPTP have been related to the pathogenesis of nigral cell death in Parkinson's disease. For instance, alterations of calcium influxes have been reported to be implicated in both MPTP-induced parkinsonism and Parkinson's disease. Recently, we reported that nimodipine, a blocker of L-type calcium channels, prevents dopaminergic MPTP-induced neurotoxicity in C57B1/6 black mice. The present study extended these rodent findings to the non-human primate model of Parkinson's disease and assessed the effects of nimodipine, continuously applied by pellet for 18 days, on behavioural, biochemical and histological parameters, following systemic application of MPTP in common marmosets (Callithrix jacchus). The experimental design involved five groups of common marmosets and a total of 24 animals. Monkeys assigned to group I (n = 4) received subcutaneously implanted vehicle pellets 7 days prior to subcutaneous saline injections (control). Monkeys of group II (n = 4) were treated with nimodipine pellets (80 mg) and saline injections. Marmosets in group III (n = 8) were treated with vehicle pellets and received 4 times MPTP (MPTP-HCl, 2 mg/kg body weight subcutaneously, separated by an interval of 24 h for a total of 4 days). Monkeys in group IV (n = 4) and V (n = 4) were treated as group-III animals except for the implantation of nimodipine pellets (80 mg and 120 mg, respectively) 7 days prior to toxin exposure. In common marmosets MPTP induced severe parkinsonian symptoms, a pronounced dopamine depletion in the caudate-putamen (more than 99% of control) and a loss of tyrosine hydroxylase immunoreactive cells in the substantia nigra (50% percent of control) 7 days after MPTP-administration. Pretreatment with nimodipine (120 mg pellets) did neither attenuate the behavioural impairments in MPTP-treated animals nor antagonize the striatal neurotoxin-induced dopamine depletion, but almost completely prevented (in a dose-dependent manner) the MPTP-induced decrease of nigral tyrosine hydroxylase immunoreactive cells. These data suggest that application of nimodipine, during the observation period of 7 days, protects against MPTP-induced neurotoxicity in common marmosets at the cellular nigral level, but not at the synaptic striatal level, implicating differential mechanisms of actions of MPTP-induced neurotoxicity at the nigral versus the striatal level.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

New horizons in molecular mechanisms underlying Parkinson's disease and in our understanding of the neuroprotective effects of selegiline.

There have been many claims that the selective monoamine oxidase type B (MAO-B) inhibitor selegiline may have distinct properties in slowing the progression of Parkinson's disease (PD). Degeneration of nigro-striatal dopaminergic neurons is the primary histopathological feature of PD. Although many different hypotheses have been advanced, the cause of chronic nigral cell death and the underlying mechanisms remain elusive as yet. Therefore, there is no clear knowledge regarding an understanding of the reported effects of selegiline on the progression of PD. However, there is a considerable body of indirect evidence that oxidative stress may play a role in the pathogenesis of this illness. Oxidative stress refers to cytotoxic consequences of hydrogen peroxide and oxygen-derived free radicals such as the hydroxyl radical (.OH), the superoxide anion (.O2), and nitric oxide (NO), which are generated as byproducts of normal and aberrant metabolic processes that utilize molecular oxygen. On the other hand, an increasing body of experimental data has implicated excitotoxicity as a mechanism of cell death in both acute and chronic neurological disease. One of the receptor which is particularly involved in the toxic effects of excitatory amino acids is the NMDA (N-methyl-D-aspartate) receptor. Excessive stimulation of this type of receptor by glutamic acid or NMDA agonists leads to a massive influx of calcium ions into the neuron followed by activation of a variety of calcium-dependent enzymes, impaired mitochondrial function, and the generation of free radicals. This article will consider the concept that excitotoxicity is linked with the generation of free radicals. In view of this idea it will be further discussed how selegiline might exert its neuroprotective effects via indirect actions on the polyamine binding site of the NMDA receptor. Under treatment with the MAO-B inhibitor selegiline, the degradation of putrescine via MAO, a key factor in regulating the polyamine metabolism, might be diminished in the Parkinsonian brain, which in turn would suppress the polyamine synthesis. Hence, the reported neuroprotective effect of selegiline might also receive a contribution from the diminished potentiation of the NMDA receptor by the polyamine binding site. On the other hand, since N1-acetylated spermine and spermidine are also good substrates of MAO-B, it is likely that these compounds will be present in the brain in increased concentrations. It therefore seems possible that they will exert a neuroprotective effect via an antagonistic modulation of the polyamine binding site of the NMDA receptor.

Binding Sites↗
PubMed1996

Early institution of bromocriptine in Parkinson's disease inhibits the emergence of levodopa-associated motor side effects. Long-term results of the PRADO study.

Long-term levodopa treatment in Parkinson's disease is typically associated with "motor side effects" consisting in dyskinesias and/or fluctuations in motility referred to as the on-off phenomena. The main objective of this prospective, randomized, multi-centre study was to determine to what extent the development of such complications could be prevented by partial substitution of levodopa monotherapy (L-DOPA/benserazide) by bromocriptine in patients with early symptoms of the disease. The basic trial population included 674 newly diagnosed Parkinsonian patients that were randomly allocated to monotherapy with levodopa or a combination therapy based upon a nearly 40% replacement of levodopa by bromocriptine. The two target regimens had to be consistently maintained for 42 months. Parkinsonian symptoms were assessed by means of the Webster rating scale, the Hoehn and Yahr scale, and the Zung Self-Rating Depression scale. Motor side effects and adverse events were recorded at each regular clinic visit. Neurological symptoms improved and stabilized in a similar manner during treatment with both regimens throughout the study period. Motor side effects were observed in more patients on levodopa alone than on combination therapy (28.8 vs 20%; p = 0.008). According to Kaplan-Meier estimates the cumulative probability of experiencing motor side effects was 0.43 on monotherapy, compared to 0.28 on combination therapy, which was equal to a one third reduction of risk (p = 0.025). In regard to motor side effects, the degree of substitution of levodopa proved relevant: patients with > 50% substitution by bromocriptine exhibited half the risk observed in those with < 30% (p = 0.045). The overall burden of motor side effects, as reflected by a sum score based upon the relevance, the severity and the extent of motor dysfunction, was also significantly less on combination therapy (p = 0.046). In conclusion, partial substitution of levodopa by bromocriptine (> 30%) as first-line treatment of Parkinson's disease proves active in the prophylaxis of levodopa associated motor side effects. Early combination therapy therefore extends the period of optimal disease control.

Aged↗