Studies on the mechanisms involved in the selective toxicity of MPTP, MPP+, and guanethidine to the central monoamine neurons in culture.
Item
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Title
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Studies on the mechanisms involved in the selective toxicity of MPTP, MPP+, and guanethidine to the central monoamine neurons in culture.
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Identifier
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AAI8914747
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identifier
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8914747
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Creator
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Friedman, Linda K.
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Contributor
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Adviser: Eugene Sachs
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Date
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1988
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Neuroscience | Psychology, Psychobiology
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Abstract
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The recently discovered neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), can induce parkinsonism in humans, monkeys, and some rodents, by selectively destroying nigrostriatal dopamine (DA) neurons. As in Parkinson's disease, other catecholamine (CA) neurons, such as DA neurons of the ventral tegmental area (VTA) and norepinephrine (NE) neurons of the locus coeruleus (LC), are also affected by MPTP, although to a lesser extent. 1-Methyl-4-phenylpyridinium ion (MPP+), the product of MPTP oxidation by monoamine oxidase B (MAOB), appears to be the toxin responsible for neuronal degeneration.;We have used primary dissociated cultures of central CA or serotonergic (5HT) neurons and examined their response upon in vitro application of the specific neurotoxins MPTP, MPP+, and guanethidine to gain understanding of the cellular mechanisms underlying preferential cell death in neurodegenerative disorders.;8 day ventral mesencephalic or pontine cultures from rat embryos of the 14th gestational day were exposed to MPTP or MPP+ for 1 week and guanethidine for 1 or 2 weeks at concentrations ranging from 0.01-200uM. Neurotoxicity was evaluated by CA histofluorescence after preincubation with alpha-methylnorepinephrine, tyrosine hydroxylase (TH) immunocytochemistry, or tritiated monoamine uptake. The effective concentration range differed for each toxin. In DA neurons, MPTP maximal toxicity occurred between 5 and 10 uM, with a reduction in uptake values by 75-90%, and almost complete disappearance of neurons positive for CA histofluorescence and TH immunocytochemistry. Increasing the concentration of MPTP to 100-200 uM resulted in reduced toxicity, with a 20-40% reduction in DA uptake and about 50% decrease in surviving DA neurons.;The metabolite of MPTP, MPP+ was a more potent toxin for the DA neurons and the toxicity increased with increasing concentrations.;DA, NE and 5HT neurons were all affected by guanethidine after 2 weeks exposure and at high concentrations. Lower concentrations produced a greater neurotoxic effect to NE neurons. One week exposure to guanethidine resulted in a selective toxicity to NE neurons, suggesting a higher affinity of this drug for the central NE neurons. (Abstract shortened with permission of author.).
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
