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Title: Actions of interleukin-1 in cerebral ischaemia
Author: Murray, Katie
ISNI:       0000 0004 5993 7965
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2014
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Cerebral ischaemia is characterised by an interruption in cerebral blood flow (CBF) leading to neuronal dysfunction and death. Pre-existing systemic inflammation is strongly associated with exaggerated brain injury following cerebral ischaemia with experimental studies showing that increased damage is mediated by interleukin (IL)-1 dependent pathways. The mechanisms through which systemic inflammation worsens stroke have yet to be elucidated, therefore in this thesis we sought to further determine how systemic inflammation affects outcome after acute cerebral ischaemia. The effects of acute pre-existing inflammation on cerebral perfusion and infarct volume after transient middle cerebral artery occlusion (MCAo) in rats were measured using magnetic resonance imaging (MRI). Systemic IL-1 caused a severe reduction in CBF and increase in infarct volume compared to vehicle. CBF changes were accompanied by upregulation of the vasoconstricting peptide endothelin (ET)-1. Blockade of ET-1 receptors reversed hypoperfusion, reduced ischaemic damage and improved functional outcome when assessed at 48h. Streptoccocus pneumoniae is the most common infection in patients at risk of stroke and is associated with an elevated inflammatory profile. The effect of an acute S. pneumoniae challenge on stroke outcome was assessed in mice and rats following transient MCAo. S. pneumoniae induced a systemic IL-1 response, exacerbated brain injury and increased platelet adhesion to the endothelium. Blockade of IL-1 with IL-1 receptor antagonist (IL-1Ra) and administration of glycoprotein (Gp) Ibα (to reduce platelet-endothelial interactions) reversed infection-mediated exacerbation of ischaemic injury and improved functional impairments after MCAo. Presence of chronic inflammation in the form of advanced age and obesity are associated with poorer outcomes following ischaemic stroke. The neuroprotective effects of delayed IL-1Ra on stroke outcome were assessed in aged lean and corpulent rats versus young rats at 7 days post-stroke. IL-1Ra reduced ischaemic damage, blood brain barrier (BBB) breakdown, improved functional outcomes and preserved neurogenesis in young and aged co-morbid rats at 24 hours and 7 days. Overall, these findings suggest systemic IL-1 is a common point of convergence in both acute and chronic pre-existing inflammatory disorders that are risk factors for stroke. Systemic IL-1 leads to excessive ischaemic damage through effects on the endothelium and the coagulation cascade. These results lend further support to the hypothesis that IL-1 is a potential therapeutic target in ischaemic stroke.
Supervisor: Allan, Stuart Sponsor: Neuroscience Research Institute
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: interleukin-1 ; cerebral ischaemia