Influence of anti-inflammatory interventions in the Kainic acid model of hippocampal excitotoxicity
Citation:Lorna C. Gleeson, 'Influence of anti-inflammatory interventions in the Kainic acid model of hippocampal excitotoxicity', [thesis], Trinity College (Dublin, Ireland). School of Pharmacy & Pharmaceutical Sciences, 2010, pp 306
Gleeson TCD THESIS 8906 Influence of.pdf (PDF) 190.1Mb
Excitotoxicity is implicated as a mechanism of neuronal cell death in a range of neurodegenerative disorders. Such toxicity can be induced experimentally by systemic administration of the glutamate kainate receptor agonist, kainic acid (KA). Specifically, KA induces seizures, inflammation, apoptosis and neuronal cell loss in the hippocampus, following systemic administration to rats. All changes are evident within 24 hours of KA administration and over this period, the model is representative of acute neurodegeneration. The aims of the work described in this thesis were to (i) characterise the inflammatory and apoptotic changes which occur in tandem with cell loss in a time course fashion, (ii) to determine if the inflammatory changes underlie KA-induced apoptosis and cell loss and (iii) to determine if modulation of central noradrenaline (NA) could influence KA-induced neurodegeneration, (i) Animals receiving KA showed seizures and related stereotyped behaviours within 3 hours. Expression of IL-1β, TNF-α and IFN-γ were increased in the hippocampus 4, 12 and 24 hours following KA administration. This was accompanied by an increase in expression of the microglial activation marker CD11b, the apoptotic marker caspase 3 and a reduction in cresyl violet staining of viable hippocampal neurons, 24 hours post challenge, (ii) To determine if KA- induced cell loss may be driven by the induction of inflammatory markers in the hippocampus, animals were pre-treated with the anti-inflammatory glucocorticoid, dexamethasone. Pre-treatment with dexamethasone, 1 hour prior to KA administration significantly attenuated the excitotoxin-induced increase in IFN-γ, CD11b and caspase 3 expression, but failed to influence KA-induced seizures or increased DNA fragmentation and hippocampal neuronal cell loss. Thus whilst the inflammatory related changes may contribute to apoptosis, the data suggest that microglial activation and IFN-γ expression do not account for KA-induced neuronal loss.
Author: Gleeson, Lorna C.
Publisher:Trinity College (Dublin, Ireland). School of Pharmacy & Pharmaceutical Sciences
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Type of material:thesis
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