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Mariegabrielle Zurich - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of drug-induced neurotoxicity based on metabolomics, proteomics and electrical activity measurements in complementary CNS in vitro models
Toxicology in Vitro, 2015Co-Authors: Luise Schultz, Mariegabrielle Zurich, Maxime Culot, Anaelle Da Costa, Christophe Landry, Patricia Bellwon, Theresa Kristl, Katrin Hörmann, Silke Ruzek, Stephan AicheAbstract:The present study was performed in an attempt to develop an in vitro integrated testing strategy (ITS) to evaluate drug-induced neurotoxicity. A number of endpoints were analyzed using two complementary Brain Cell Culture models and an in vitro blood-Brain barrier (BBB) model after single and repeated exposure treatments with selected drugs that covered the major biological, pharmacological and neuro-toxicological responses. Furthermore, four drugs (diazepam, cyclosporine A, chlorpromazine and amiodarone) were tested more in depth as representatives of different classes of neurotoxicants, inducing toxicity through different pathways of toxicity. The developed in vitro BBB model allowed detection of toxic effects at the level of BBB and evaluation of drug transport through the barrier for predicting free Brain concentrations of the studied drugs. The measurement of neuronal electrical activity was found to be a sensitive tool to predict the neuroactivity and neurotoxicity of drugs after acute exposure. The histotypic 3D re-aggregating Brain Cell Cultures, containing all Brain Cell types, were found to be well suited for OMICs analyses after both acute and long term treatment. The obtained data suggest that an in vitro ITS based on the information obtained from BBB studies and combined with metabolomics, proteomics and neuronal electrical activity measurements performed in stable in vitro neuronal Cell Culture systems, has high potential to improve current in vitro drug-induced neurotoxicity evaluation.
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Amiodarone biokinetics, the formation of its major oxidative metabolite and neurotoxicity after acute and repeated exposure of Brain Cell Cultures
Toxicology in Vitro, 2015Co-Authors: Giuliana Pomponio, Mariegabrielle Zurich, Luise Schultz, Dieter G. Weiss, Luca Romanelli, Alexandra Gramowski-voss, Emma Di Consiglio, Emanuela TestaiAbstract:The difficulty in mimicking nervous system complexity and Cell-Cell interactions as well as the lack of kinetics information has limited the use of in vitro neurotoxicity data. Here, we assessed the biokinetic profile as well as the neurotoxicity of Amiodarone after acute and repeated exposure in two advanced rodent Brain Cell Culture models, consisting of both neurons and glial Cells organized in 2 or 3 dimensions to mimic the Brain histiotypic structure and function. A strategy was applied to evidence the abiotic processes possibly affecting Amiodarone in vitro bioavailability, showing its ability to adsorb to the plastic devices. At clinically relevant Amiodarone concentrations, known to induce neurotoxicity in some patients during therapeutic treatment, a complete uptake was observed in both models in 24 h, after single exposure. After repeated treatments, bioaccumulation was observed, especially in the 3D Cell model, together with a greater alteration of neurotoxicity markers. After 14 days, Amiodarone major oxidative metabolite (mono-N-desethylamiodarone) was detected at limited levels, indicating the presence of active drug metabolism enzymes (i.e. cytochrome P450) in both models. The assessment of biokinetics provides useful information on the relevance of in vitro toxicity data and should be considered in the design of an Integrated Testing Strategy aimed to identify specific neurotoxic alerts, and to improve the neurotoxicity assay predictivity for human acute and repeated exposure.
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maturation dependent effects of chlorpyrifos and parathion and their oxygen analogs on acetylcholinesterase and neuronal and glial markers in aggregating Brain Cell Cultures
Toxicology and Applied Pharmacology, 2000Co-Authors: Florianne Monnettschudi, Mariegabrielle Zurich, Benoit Schilter, Lucio G Costa, Paul HoneggerAbstract:Abstract An in vitro model, the aggregating Brain Cell Culture of fetal rat telencephalon, has been used to study the maturation-dependent sensitivity of Brain Cells to two organophosphorus pesticides (OPs), chlorpyrifos and parathion, and to their oxon derivatives. Immature (DIV 5–15) or differentiated (DIV 25–35) Brain Cells were treated continuously for 10 days. Acetylcholinesterase (AChE) inhibitory potency for the OPs was compared to that of eserine (physostigmine), a reversible AChE inhibitor. Oxon derivatives were more potent AChE inhibitors than the parent compounds, and parathion was more potent than chlorpyrifos. No maturation-dependent differences for AChE inhibition were found for chlorpyrifos and eserine, whereas for parathion and paraoxon there was a tendency to be more effective in immature Cultures, while the opposite was true for chlorpyrifos-oxon. Toxic effects, assessed by measuring protein content as an index of general cytotoxicity, and various enzyme activities as Cell-type-specific neuronal and glial markers (ChAT and GAD, for cholinergic and GABAergic neurons, respectively, and GS and CNP, for astrocytes and oligodendrocytes, respectively) were only found at more than 70% of AChE inhibition. Immature compared to differentiated cholinergic neurons appeared to be more sensitive to OP treatments. The oxon derivates were found to be more toxic on neurons than the parent compounds, and chlorpyrifos was more toxic than parathion. Eserine was not neurotoxic. These results indicate that inhibition of AChE remains the most sensitive macromolecular target of OP exposure, since toxic effects were found at concentrations in which AChE was inhibited. Furthermore, the compound-specific reactions, the differential pattern of toxicity of OPs compared to eserine, and the higher sensitivity of immature Brain Cells suggest that the toxic effects and inhibition of AChE are unrelated.
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the naturally occurring food mycotoxin fumonisin b1 impairs myelin formation in aggregating Brain Cell Culture
Neurotoxicology, 1999Co-Authors: Florianne Monnettschudi, Mariegabrielle Zurich, O Sorg, J M Matthieu, Paul Honegger, B SchilterAbstract:The effects of subchronical applications of the mycotoxin Fumonisin B 1 (FB 1) were analyzed in vitro, using aggregating Cell Cultures of fetal rat telencephalon as a model. As Cells in the aggregates developed from an immature state to a highly differentiated state, with synapse and compact myelin formation, it was possible to study the effects of FB 1 at different developmental stages. The results showed that FB 1 did not cause Cell loss and it had no effects on neurons. However it decreased strongly the total content of myelin basic protein, the main constituent of the myelin sheath, during the myelination period (DIV 18-28). The loss of myelin was not accompanied by a loss of oligodendrocytes, the myelinating Cells. However FB 1 had effects on the maturation of oligodendrocytes, as revealed by a decrease in the expression of galactocerebroside, and on the compaction of myelin, as shown by a reduction of the expression of the myelin/oligodendrocyte glycoprotein MOG. The content of the cytoskeletal component glial fibrillary acidic protein (GFAP) was decreased in differentiated astrocytes, exclusively, while neurons were not affected by 40 μM of FB 1 applied continously for 10 days. In summary, FB1 selectively affected glial Cells. In particular, FB1 delayed oligodendrocyte development and impaired myelin formation and deposition.
James A. Radosevich - One of the best experts on this subject based on the ideXlab platform.
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Insulin-like growth factors and binding proteins in the fetal rat: alterations during maternal starvation and effects in fetal Brain Cell Culture.
Neurochemical research, 1993Co-Authors: George E. Shambaugh, James A. Radosevich, R. P. Glick, B. E. Metzger, Terry G. UntermanAbstract:Maternal malnutrition adversely affects fetal body and Brain growth during late gestation. We utilized a fetal Brain Cell Culture model to examine whether alternations in circulating factors may contribute to reduce Brain growth during maternal starvation; we then used specific immunoassay and western blotting techniques, and purified peptides to investigate the potential role that altered levels of insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) may play in impaired growth during maternal nutritional restriction.
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The impact of maternal serum on development of enolase activity in fetal rat Brain Cell Culture.
Experimental cell research, 1990Co-Authors: George E. Shambaugh, D. Clough, L. Munari, R. R. Koehler, James A. RadosevichAbstract:The effect of gestational age on serum-mediated changes in enolase activity was tested in a fetal rat Brain Cell Culture. After 6 days exposure to graded concentrations (10 and 20%) of nonpregnant female rat sera, enolase activity in Brain Cell Cultures increased from 2.83 ± 0.03 to 3.74 ± 0.19 μmol/min/mg protein, P < 0.01. By contrast, similar concentrations of 20-day maternal serum progressively decreased enzyme activity from 1.52 ± 0.14 to 1.19 ± 0.08 μmol/min/mg protein. The inhibitory effect was apparent at 14 days gestation and became progressively greater during late gestation to reach a maximum at 20 days. Combining equal concentrations of 20-day pregnant with either nonpregnant or adult male serum neutralized the inhibitory activity. When serum from 20-day pregnant rats was partitioned by a dialysis membrane with a 50,000 MW pore size, inhibitory activity could be similarly neutralized by male or nonpregnant female serum. When 20-day maternal serum was passed successively through filters with a greater than 300,000, 100,000, and 50,000 MW exclusion, the inhibitory activity was apparent in all fractions excluded by a molecular weight of 50,000. No inhibition was apparent in fractions that were not excluded by 50,000 MW pore size. Inhibition of enolase activity was greatest in the fraction with MW greater than 300,000. Binding of IGF II could also be demonstrated in this fraction. Binding of IGF II was evident in the fraction greater than 100,000 MW but could not be demonstrated in fractions with a lower molecular weight. The presence of mRNA for IGF II in 20-day fetal rat Brain Cell Cultures was evident when total Cellular RNA was analyzed by an RNAase protection assay. It is proposed that a high-molecular-weight component of maternal serum in late gestation can bind endogenously generated IGF II. Such binding, by depleting the necessary growth factors, could inhibit in vitro growth and development of enolase activity.
George E. Shambaugh - One of the best experts on this subject based on the ideXlab platform.
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Insulin-like growth factors and binding proteins in the fetal rat: alterations during maternal starvation and effects in fetal Brain Cell Culture.
Neurochemical research, 1993Co-Authors: George E. Shambaugh, James A. Radosevich, R. P. Glick, B. E. Metzger, Terry G. UntermanAbstract:Maternal malnutrition adversely affects fetal body and Brain growth during late gestation. We utilized a fetal Brain Cell Culture model to examine whether alternations in circulating factors may contribute to reduce Brain growth during maternal starvation; we then used specific immunoassay and western blotting techniques, and purified peptides to investigate the potential role that altered levels of insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) may play in impaired growth during maternal nutritional restriction.
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The impact of maternal serum on development of enolase activity in fetal rat Brain Cell Culture.
Experimental cell research, 1990Co-Authors: George E. Shambaugh, D. Clough, L. Munari, R. R. Koehler, James A. RadosevichAbstract:The effect of gestational age on serum-mediated changes in enolase activity was tested in a fetal rat Brain Cell Culture. After 6 days exposure to graded concentrations (10 and 20%) of nonpregnant female rat sera, enolase activity in Brain Cell Cultures increased from 2.83 ± 0.03 to 3.74 ± 0.19 μmol/min/mg protein, P < 0.01. By contrast, similar concentrations of 20-day maternal serum progressively decreased enzyme activity from 1.52 ± 0.14 to 1.19 ± 0.08 μmol/min/mg protein. The inhibitory effect was apparent at 14 days gestation and became progressively greater during late gestation to reach a maximum at 20 days. Combining equal concentrations of 20-day pregnant with either nonpregnant or adult male serum neutralized the inhibitory activity. When serum from 20-day pregnant rats was partitioned by a dialysis membrane with a 50,000 MW pore size, inhibitory activity could be similarly neutralized by male or nonpregnant female serum. When 20-day maternal serum was passed successively through filters with a greater than 300,000, 100,000, and 50,000 MW exclusion, the inhibitory activity was apparent in all fractions excluded by a molecular weight of 50,000. No inhibition was apparent in fractions that were not excluded by 50,000 MW pore size. Inhibition of enolase activity was greatest in the fraction with MW greater than 300,000. Binding of IGF II could also be demonstrated in this fraction. Binding of IGF II was evident in the fraction greater than 100,000 MW but could not be demonstrated in fractions with a lower molecular weight. The presence of mRNA for IGF II in 20-day fetal rat Brain Cell Cultures was evident when total Cellular RNA was analyzed by an RNAase protection assay. It is proposed that a high-molecular-weight component of maternal serum in late gestation can bind endogenously generated IGF II. Such binding, by depleting the necessary growth factors, could inhibit in vitro growth and development of enolase activity.
Luise Schultz - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of drug-induced neurotoxicity based on metabolomics, proteomics and electrical activity measurements in complementary CNS in vitro models
Toxicology in Vitro, 2015Co-Authors: Luise Schultz, Mariegabrielle Zurich, Maxime Culot, Anaelle Da Costa, Christophe Landry, Patricia Bellwon, Theresa Kristl, Katrin Hörmann, Silke Ruzek, Stephan AicheAbstract:The present study was performed in an attempt to develop an in vitro integrated testing strategy (ITS) to evaluate drug-induced neurotoxicity. A number of endpoints were analyzed using two complementary Brain Cell Culture models and an in vitro blood-Brain barrier (BBB) model after single and repeated exposure treatments with selected drugs that covered the major biological, pharmacological and neuro-toxicological responses. Furthermore, four drugs (diazepam, cyclosporine A, chlorpromazine and amiodarone) were tested more in depth as representatives of different classes of neurotoxicants, inducing toxicity through different pathways of toxicity. The developed in vitro BBB model allowed detection of toxic effects at the level of BBB and evaluation of drug transport through the barrier for predicting free Brain concentrations of the studied drugs. The measurement of neuronal electrical activity was found to be a sensitive tool to predict the neuroactivity and neurotoxicity of drugs after acute exposure. The histotypic 3D re-aggregating Brain Cell Cultures, containing all Brain Cell types, were found to be well suited for OMICs analyses after both acute and long term treatment. The obtained data suggest that an in vitro ITS based on the information obtained from BBB studies and combined with metabolomics, proteomics and neuronal electrical activity measurements performed in stable in vitro neuronal Cell Culture systems, has high potential to improve current in vitro drug-induced neurotoxicity evaluation.
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Amiodarone biokinetics, the formation of its major oxidative metabolite and neurotoxicity after acute and repeated exposure of Brain Cell Cultures
Toxicology in Vitro, 2015Co-Authors: Giuliana Pomponio, Mariegabrielle Zurich, Luise Schultz, Dieter G. Weiss, Luca Romanelli, Alexandra Gramowski-voss, Emma Di Consiglio, Emanuela TestaiAbstract:The difficulty in mimicking nervous system complexity and Cell-Cell interactions as well as the lack of kinetics information has limited the use of in vitro neurotoxicity data. Here, we assessed the biokinetic profile as well as the neurotoxicity of Amiodarone after acute and repeated exposure in two advanced rodent Brain Cell Culture models, consisting of both neurons and glial Cells organized in 2 or 3 dimensions to mimic the Brain histiotypic structure and function. A strategy was applied to evidence the abiotic processes possibly affecting Amiodarone in vitro bioavailability, showing its ability to adsorb to the plastic devices. At clinically relevant Amiodarone concentrations, known to induce neurotoxicity in some patients during therapeutic treatment, a complete uptake was observed in both models in 24 h, after single exposure. After repeated treatments, bioaccumulation was observed, especially in the 3D Cell model, together with a greater alteration of neurotoxicity markers. After 14 days, Amiodarone major oxidative metabolite (mono-N-desethylamiodarone) was detected at limited levels, indicating the presence of active drug metabolism enzymes (i.e. cytochrome P450) in both models. The assessment of biokinetics provides useful information on the relevance of in vitro toxicity data and should be considered in the design of an Integrated Testing Strategy aimed to identify specific neurotoxic alerts, and to improve the neurotoxicity assay predictivity for human acute and repeated exposure.
Roderic H Fabian - One of the best experts on this subject based on the ideXlab platform.
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neuronal toxicity by macrophages in mixed Brain Cell Culture is augmented by antineuronal igg and dependent upon nitric oxide synthesis
Journal of Neuroimmunology, 1993Co-Authors: Roderic H FabianAbstract:Abstract We used mixed Brain Cell Cultures derived from dissociated neonatal rat cerebella to study interactions between mononuclear phagocytes and Brain Cells under various conditions. We found that activated macrophages were capable of selectively killing neurons, leaving other Cells undisturbed. Moreover, this activity was dependent upon nitric oxide production and, to a weaker extent, upon the NMDA receptor but not upon tumor necrosis factor. Macrophage-mediated neuronolysis was augmented by one of two anti-neuronal antibodies studied.