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|Title:||Investigation of the molecular mechanisms of aluminium and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity.|
|Presented at:||University of Leicester|
|Abstract:||This study has used cell culture to examine the molecular mechanisms of actions of two neurotoxins, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and aluminium (A1), both implicated in brain disease, with a view to identify key pathophysiological events that lead from insult to neuronal cell death. The study of oxygen radical involvement in MPTP toxicity was undertaken in three neurochemically discrete cell lines. MPTP was found to be selectively toxic for catecholaminergic neurones. Inhibition studies with selective monoamine oxidase inhibitors revealed that MPTP metabolism by both MAO-A and MAO-B is a prerequisite for neurotoxicity. The finding that MAO-A contributes equally to MPTP metabolism has not been previously reported. Levels of toxicity were decreased with co-incubation of MPTP with some antioxidants, indicating that oxygen radical generation plays an integral role in cell death. One major target identified for MPTP induced damage was found to be DNA. FACS analysis showed an increased expansion of nucleoids that is indicative of strand breakage. The cytotoxic effects of Al were initially examined using three neuronal cell lines and the cholinergic cell line was found to be the most sensitive. Al toxicity was found to be more apparent when bound to transferrin than to citrate and mediation of the effects of Al-Tf was shown to occur via the transferrin receptor. Two major functional targets were identified to be affected by Al in B50 cells. Increasing concentrations of Al caused increased compaction of chromatin that may be associated with the changes in gene expression observed with Al toxicity. Levels of specific proteins, namely ?-tubulin, amyloid precursor protein and neurone specific enolase, were observed by immunofluorescence to be increased following prolonged exposure of cells with Al. Al also affected neurotrophic activity by inhibiting the induction of proto-oncogene expression by basic fibroblast growth factor (bFGF). Preliminary studies showed that, in response to A1 toxicity, levels of bFGF mRNA were increased, suggesting an increase in autocrine activity of insulted cells. Modulation of neurotrophic activity and interaction with the nucleus may be of primary importance to the neurotoxicity of Al.|
|Rights:||Copyright © the author. All rights reserved.|
|Appears in Collections:||Theses, Dept. of Health Sciences|
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