PubMed Health⌕ Search

Biomedical subjects

M Gerlach

Publications and source records attributed to M Gerlach.

At least 127 records · Page 7Linked to original sources
PubMed1993

Effects of nimodipine on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced depletions in the biogenic amine levels in mice.

In view of the calcium hypothesis the effect of nimodipine (Bay e 9736, CAS 66085-59-4) on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced depletions in dopamine and serotonin were investigated in C57-BL/6 mice. Oral treatment with nimodipine (5 mg/kg and 20 mg/kg b.i.d., respectively, for 9 days) prior to, during and following administration of MPTP appeared to attenuate MPTP-induced neurochemical changes in a dose-related manner. The results suggest that nimodipine reduces MPTP-induced damages, especially in the serotoninergic system, through its calcium antagonistic effects.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

Relevance of tumour necrosis factor-alpha and interleukin-1-alpha in the pathogenesis of hypoxia-related organ failure.

Tumour necrosis factor-alpha (TNF) and Interleukin-1-alpha (IL-1) are both cytokines which are known to be released by stimulated macrophages during septic events. Because of their influence on the function of the vascular endothelium, TNF and IL-1 contribute to the pathogenesis of hypoperfusion and organ dysfunction. The finding of elevated cytokine levels in patients with hypoxic organ failure, suggesting a relation between systemic oxygen supply and humoral mechanisms, led us to perform laboratory investigations on the relevance of TNF and IL-1 for the pathogenesis of hypoxia-related deterioration of the microcirculation. In vivo studies with anaesthetized rats demonstrated a synergism between hypoxaemia and endotoxaemia on the development of lethal organ failure. In vitro studies with human monocytes showed that a hypoxic atmosphere was not able to induce synthesis or release of TNF and IL-1, whereas re-oxygenation after hypoxia initiated a significant increase in TNF and IL-1 synthesis, probably mediated by oxygen radicals. Finally, experiments with human endothelial cells established that hypoxia is able to induce high affinity receptors for TNF in a time- and dose-dependent manner. These studies demonstrate that hypoxia influences humoral mechanisms which are known to contribute to the pathogenesis of vessel dysfunction, probably through a cytokine-dependent pathway of hypoxia-related organ dysfunction.

Animals↗
PubMed1992

Isolation and characterization of two binding proteins for advanced glycosylation end products from bovine lung which are present on the endothelial cell surface.

Nonenzymatic glycosylation of proteins, as occurs at an accelerated rate in diabetes, can lead to the formation of advanced glycosylation end products of proteins (AGEs), which can bind to endothelial cells, thereby altering cellular function in a manner which could contribute to the pathogenesis of diabetic angiopathy. In this report, we describe the isolation of two endothelial cell surface-associated proteins which mediate, at least in part, the interaction of AGEs with endothelium. Based on pilot studies demonstrating AGE binding activity with comparable characteristics in bovine endothelial cell and lung extracts, the material from lung was sequentially subjected to chromatography on hydroxylapatite, fast protein liquid chromatography Mono S, and gel filtration. Two distinct polypeptides, approximately 35 and approximately 80 kDa, were purified to homogeneity, each of which bound AGEs as demonstrated by competitive binding assays using cellular binding proteins immobilized on a plastic surface. NH2-terminal sequence analysis indicated that the approximately 35-kDa protein was novel, whereas the NH2-terminal sequence of the approximately 80-kDa protein was identical to that of lactoferrin. Immunocytologic studies using polyclonal antibody prepared to each of the purified polypeptides demonstrated the presence of immunoreactive material on the surface of bovine endothelial cells maintained under serum-free conditions. Furthermore, immunoelectron microscopic studies with antibodies to the approximately 35- and approximately 80-kDa AGE-binding proteins conjugated to different size colloidal gold particles confirmed the presence of the target antigens on the cell surface and suggested that they were closely associated. IgG purified from polyclonal antisera to either the 35- or 80-kDa AGE-binding proteins blocked the binding of 125I-AGE-albumin to the cell surface. These results indicate that endothelial cells express specific cell surface molecules which mediate AGE-endothelial interaction. These polypeptides represent a novel class of cell surface acceptor molecules for glucose-modified proteins which may promote degradation and/or transcytosis of the ligand, and modulation of cellular function.

Amino Acid Sequence↗
PubMed1992

The molecular pharmacology of L-deprenyl.

L-Deprenyl, the selective inhibitor of monoamine oxidase type B (MAO-B), has gained wide acceptance as a useful form of adjunct therapeutic drug in the treatment of Parkinson's disease. This review summarizes the molecular pharmacology of L-deprenyl, and the advances in our understanding of its possible mode of action in Parkinson's disease. L-Deprenyl belongs to the class of enzyme-activated irreversible inhibitors also described as 'suicide' inhibitors, because the compound acts as a substrate for the target enzyme, whose action on the compound results in irreversible inhibition. L-Deprenyl first of all forms a noncovalent complex with MAO as an initial, reversible step. The subsequent interaction of L-deprenyl with MAO leads to a reduction of the enzyme-bound flavin-adenine dinucleotide (FAD), and concomitant oxidation of the inhibitor. This oxidized inhibitor then reacts with FAD at the N-5-position in a covalent manner. The observed in vitro selectivity of L-deprenyl for MAO-B may be accounted for by differences in the affinities of the two MAO subtypes for reversible interaction with L-deprenyl, differences in the rates of reaction within the noncovalent complexes to form the irreversibly inhibited adduct, or a combination of both these factors. However, if selective inhibition is to be maintained in vivo, correct dosage schedules are critically important, since all selective MAO inhibitors described up to now lack selectivity at high doses. In experimental animals L-deprenyl is protective against the damaging effects of several neurotoxins, including the dopaminergic agents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) and the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). Beside MAO-B inhibition, which above all explains the prevention of neurotoxic action of MPTP by preventing its metabolism, L-deprenyl appears to exhibit other mechanisms of action which are independent of its action on MAO-B.

Animals↗
PubMed1991

MPTP mechanisms of neurotoxicity and their implications for Parkinson's disease.

Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) gives rise to motor deficits in humans and other primates which closely resemble those seen in patients with Parkinson's disease. These deficits are associated with a relatively selective loss of cells in the pars compacta of the substantia nigra and severe reductions in the concentrations of dopamine, noradrenaline and serotonin in the striatum. Similarly, in mice of various different strains the administration of MPTP also induces a marked loss of dopaminergic cells with severe depletion of biogenic amines, but higher doses of MPTP are required to produce these effects in mice than in primates. This review summarises advances made in understanding the biochemical events which underlie the remarkable neurotoxic action of MPTP. Major steps in the expression of neurotoxicity involve the conversion of MPTP to the toxic agent 1-methyl-4-phenylpyridinium ion (MPP+) by type B monoamine oxidase (MAO-B) in the glia, specific uptake of MPP+ into the nigro-striatal dopaminergic neurones, the intraneuronal accumulation of MPP+, and the neurotoxic action of MPP+. This is exerted mainly through the inhibition of the enzymes of the respiratory chain (Complex I), the disturbance of Ca2+ homeostasis, and possibly by the formation of free radicals. The relevance of the MPTP model to idiopathic Parkinson's disease is discussed.

Animals↗
PubMed1991

Neurochemical and behavioural features induced by chronic low dose treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the common marmoset: implications for Parkinson's disease?

Protracted long-term treatment of common marmosets with 15 doses (0.5-4.5 mg/kg, i.p.) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; total dose 25 mg/kg, given over 29 days) caused transitory changes in motor behaviour reminiscent of human Parkinson's disease. 16 days from the start of MPTP administration, all animals showed motor impairment, consisting of profound akinesia and a rigid posture, but in no case resting tremor. Biogenic amines were measured in nigrostriatal regions one month after finishing MPTP treatment. There was a profound loss of dopamine and serotonin in the substantia nigra and in the striatum; noradrenaline was only reduced in the putamen. Continuous analyses of the concentrations of biogenic amine metabolites in the CSF during this study revealed persistent dopaminergic disturbances and temporary alterations in serotoninergic and noradrenergic function.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Treatment with antioxidants does not prevent loss of dopamine in the striatum of MPTP-treated common marmosets: preliminary observations.

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to common marmosets causes a profound loss of dopamine and serotonin in the striatum. Additional daily systemic treatment of monkeys with the antioxidants ascorbic acid (100 mg/kg) and alpha-tocopherol (2,350 mg/kg) prior to, during and following administration of MPTP does not prevent the loss of dopamine and serotonin in the striatum, suggesting that these antioxidants are unable to protect dopaminergic neurones against neurotoxicity of MPTP.

Animals↗
PubMed1991

(-)-Deprenyl treatment of patients with Parkinson's disease does not affect erythrocyte catechol-O-methyl transferase activity.

(-)-Deprenyl has been increasingly used in recent years as an adjuvant with levodopa and a decarboxylase inhibitor in the treatment of Parkinson's disease. The inhibition of dopa decarboxylase and monoamine oxidase B resulting from this combination suggests that there may be a counter-regulatory increase in the activity of the third main enzyme in the catabolism of levodopa, i.e. catecholamine-O-methyl transferase (COMT). The current study on 36 patients with Parkinson's disease under long-term treatment with levodopa/dopadecarboxylase inhibitor showed, however, that the erythrocyte-COMT was unaffected by additional (-)-deprenyl medication. The patients in this study received levodopa and benserazide either with (-)-deprenyl (n = 21) or without (-)-deprenyl (n = 15). When allowance was made for the different genotypes, COMTLL, COMTLH, and COMTHH, there were no differences in the enzyme activities between the two treatment groups and the untreated controls (n = 26). On the basis of these results, consideration is given to the conditions in which COMT inhibitors are likely to be of value in the treatment of Parkinson's disease.

Aged↗
PubMed1991

Active site-blocked factor IXa prevents intravascular thrombus formation in the coronary vasculature without inhibiting extravascular coagulation in a canine thrombosis model.

To assess the contribution of Factor IX/IXa, to intravascular thrombosis, a canine coronary thrombosis model was studied. Thrombus formation was initiated by applying current to a needle in the circumflex coronary artery. When 50% occlusion of the vessel developed, the current was stopped and animals received an intravenous bolus of either saline, bovine glutamyl-glycyl-arginyl-Factor IXa (IXai), a competitive inhibitor of Factor IXa assembly into the intrinsic Factor X activation complex, bovine Factor IX, or heparin. Animals receiving saline or Factor IX developed coronary occlusion due to a fibrin/platelet thrombus in 70 +/- 11 min. In contrast, infusion of IXai prevented thrombus formation completely (greater than 180 min) at doses of 460 and 300 micrograms/kg, and partially blocked thrombus formation at 150 micrograms/kg. IXai attenuated the accumulation of 125I-fibrinogen/fibrin at the site of the thrombus by approximately 67% (P less than 0.001) and resulted in approximately 26% decrease in serotonin release from platelets in coronary sinus (P less than 0.05). Hemostatic variables in animals receiving IXai, remained within normal limits. Animals given heparin in a concentration sufficient to prevent occlusive thrombosis had markedly increased bleeding, whereas heparin levels that maintained extravascular hemostasis did not prevent intracoronary thrombosis. This suggests that Factor IX/IXa can contribute to thrombus formation, and that inhibition of IXa participation in the clotting mechanism blocks intravascular thrombosis without impairing extravascular hemostasis.

Animals↗
PubMed1991

Endothelium and regulation of coagulation.

Endothelial cells form the luminal vascular surface and thus have a central role in the regulation of coagulation. One important way in which endothelial cells control the clotting system is by regulating the expression of binding sites for anticoagulant and procoagulant factors on the cell surface. In the quiescent state, endothelial cells maintain blood fluidity by promoting the activity of numerous anticoagulant pathways, including the protein C/protein S pathway. After activation, as can be brought about by cytokines, the balance of endothelial properties can be tipped to favor clot formation through coordinated induction of procoagulant and suppression of anticoagulant mechanisms. Tumor necrosis factor suppresses the endothelial anticoagulant cofactor thrombomodulin and induces expression of the procoagulant cofactor tissue factor. Working in concert, these changes can allow fibrin formation to proceed in an inflamed focus but maintain blood fluidity in the surrounding area of normal vasculature. Recent studies suggest that similar changes in endothelial coagulant properties can be induced by advanced glycosylation end products, proteins modified by glucose that accumulate in the vasculature at a rapid rate in diabetic subjects, indicating the potential relevance of these mechanisms in diabetic vascular disease.

Animals↗
PubMed1990

Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration.

Systemic infusion of low concentrations of tumor necrosis factor/cachectin (TNF) into mice that bear TNF-sensitive tumors leads to activation of coagulation, fibrin formation, and occlusive thrombosis exclusively within the tumor vascular bed. To identify mechanisms underlying the localization of this vascular procoagulant response, a tumor-derived polypeptide has been purified to homogeneity from supernatants of murine methylcholanthrene A-induced fibrosarcomas that induces endothelial tissue factor synthesis and expression (half-maximal response at approximately 300 pM), and augments the procoagulant response to TNF in a synergistic fashion. This tumor-derived polypeptide was identified as the murine homologue of vascular permeability factor (VPF) based on similar mobility on SDS-PAGE, an homologous NH2-terminal amino acid sequence, and recognition by a monospecific antibody to guinea pig VPF. In addition, VPF was shown to induce monocyte activation, as evidenced by expression of tissue factor. Finally, VPF was shown to induce monocyte chemotaxis across collagen membranes and endothelial cell monolayers. Taken together, these results indicate that VPF can modulate the coagulant properties of endothelium and monocytes, and can promote monocyte migration into the tumor bed. This suggests one mechanism through which tumor-derived mediators can alter properties of the vessel wall.

Amino Acid Sequence↗
PubMed1990

[Mercaptopurine and silylated mercaptopurine the treatment of experimental allergic encephalomyelitis].

The therapeutic effects of mercaptopurine (6-mercaptopurine, 6-MP) and a silylated derivative (6-trimethylsilylthio-9-trimethyl-silylpurine, S-MP) were compared on the course of T lymphocyte line mediated experimental allergic encephalomyelitis (t-EAE). This transferred EAE is a passively induced model disease in Lewis rats easy to elicit, reliably reproducible and characterized by a dose-dependent lethality. If given at different points in single injections the silicon derivative is shown to be more efficient than 6-MP (43/125 surviving animals compared to 26/129), severity of disease is attenuated and number of survivors increased. Silylation is able to improve blood-brain barrier and cellular permeability; S-MP suppresses intrathecal inflammatory cells more effectively than the original immunosuppressant.

Animals↗
PubMed1989

Autocrine tumor cell growth-inhibiting activities from human malignant melanoma.

Autocrine-secreted tumor cell growth-inhibiting activities were isolated from supernatants of a malignant melanoma cell line, HTZ 19-dM, established from a central nervous system melanoma metastasis. HTZ 19-dM was characterized by cyto- and immunocytochemistry and karyotyping; cells were propagated in defined serum-free tissue culture medium for up to 8 months. Supernatants were ultrafiltrated, dialyzed, lyophilized, and purified by Bio-Gel P-10 gel permeation chromatography, leading to three active fraction pools, MIAI [melanoma-inhibiting activity (MIA), 2 kDa), MIAII (Mr 11,500-17,000) and MIAIII (proteins at the cutoff of Bio-Gel P-10) inhibiting growth of 19-dM cells with 50% inhibitory concentrations of 0.79 microgram/ml (MIAI), 0.13 microgram/ml (MIAII), and 16.7 micrograms/ml (MIAII). MIAII could be further purified by reverse phase high pressure liquid chromatography; the main activity displayed a 50% inhibitory concentration of 0.33 microgram/ml. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis one major band (molecular weight about 14,000) and two minor bands (up to Mr 17,000) were identified. Macromolecular synthesis was inhibited in 19-dM cells up to greater than 99.5%; tumor stem cell colony formation was reduced by 99.89%; the inhibitory effect of MIAII was irreversible, nonsaturable, and partially antagonized by a serum factor (depending on purification stage). MIAII was heat stable (3 min at 100 degrees C) and trypsin labile. The effect of MIAII on allogeneic neuroectodermal tumors was also investigated; proliferation of two of three malignant melanomas and two of four glioblastomas was inhibited up to 85.2%; proliferation of a neuroblastoma cell line could be inhibited to 33.8%, whereas normal fibroblasts and low grade gliomas were not influenced in their proliferation.

Biological Factors↗
PubMed1988

Pharmacokinetic studies with sustained-release formulations of levodopa in healthy volunteers.

On the basis of the results of a large number of studies of the correlation between plasma levodopa levels and the occurrence of mobility disorders, it was concluded that side-effects such as dyskinesia, end-of-dose, peak-dose and on-off phenomena, which occur especially during levodopa long-term treatment of Parkinson patients, may be caused by fluctuations in the plasma levodopa levels. Some preliminary trials using sustained-release formulations were not up to expectations. Still, we studied the question of whether it might not be possible after all to obtain sustained plasma levodopa levels over prolonged periods of time with levodopa sustained-release (S. R.) formulations, without causing a high initial peak. For this purpose, we compared the pharmacokinetics of six different levodopa S. R. formulations with a standard preparation in two randomized cross-over trials in healthy male volunteers. Although the levodopa S. R. formulations prolonged the time to peak blood levels in all cases, a plateau that was constant over a longer period of time could not be obtained. However, none of the S. R. preparations studied gave rise to a high initial peak of the plasma levodopa concentration. The levodopa concentrations had again returned to endogenous levels within no more than 8 hours of administration of all six levodopa S. R. formulations.

Adult↗
PubMed1988

4,4-Diphenylpiperidine derivates and their sila analogues. A comparative study of their interaction with neural receptor biding sites and synaptosomal monoamine uptake.

The potential anti-Parkinson drugs 1-R-4,4-diphenylpiperidines and 1-R-4,4-diphenyl-4-sila-piperidines (R = H, CH3, i-propyl and t-butyl) were evaluated for their neuroreceptor affinity with respect to their structure-activity relationship. In these compounds substitution of the central carbon at position 4 by a silicon leads to more lipophilic substances. While the binding of these compounds to dopamine, serotonin and gamma-aminobutyric acid/benzodiazepine receptors is relatively non-specific, the binding to the mu- and delta-subtypes of opiate receptors and to the 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine receptor binding site show probably pharmacologically relevant effects. In almost all cases the sila-compounds have a slightly higher receptor affinity than the corresponding carbon-compounds. The studies on the uptake sites for the biogenic amines noradrenaline, dopamine and serotonin, on the other hand, reveal some considerable differences between the carbon- and silicon-containing analogues. The 4,4-diphenyl-4-sila-piperidine has much stronger uptake inhibiting properties for noradrenaline and serotonin than the corresponding carbon compound.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1983

The interactions of 1-alkyl-4,4-diphenylpiperidines with opiate receptors.

1-Alkyl-4,4-diphenylpiperidines inhibit the binding of mu- and delta-opiate receptor agonists to crude synaptosomal membranes of rat brain. Opiate receptor affinity is dependent on the nature of the 1-alkyl substitution. In displacing [3H]etorphine, [3H]dihydromorphine and [3H][D-Ala2,D-Leu5] enkephalin, the 1-methyl-derivative was most effective (IC50 [3H]etorphine = 9 microM, IC50 [3H]dihydromorphine = 0.71 microM, IC50 [3H][D-Ala2,D-Leu5]enkephalin = 2.1 microM). 1-t-Butyl-4,4-diphenylpiperidine and its 1-isopropyl analogue, used as antiparkinsonism drugs, exhibit distinctly lower inhibiting concentration values (50% inhibition, IC50 values).

Animals↗