Actions of interleukin-1 in cerebral ischaemia

Abstract

Cerebral ischaemia is characterised by an interruption in cerebral blood flow (CBF)leading to neuronal dysfunction and death. Pre-existing systemic inflammation isstrongly associated with exaggerated brain injury following cerebral ischaemia withexperimental studies showing that increased damage is mediated by interleukin (IL)-1dependent pathways. The mechanisms through which systemic inflammation worsensstroke have yet to be elucidated, therefore in this thesis we sought to further determinehow systemic inflammation affects outcome after acute cerebral ischaemia.The effects of acute pre-existing inflammation on cerebral perfusion and infarct volumeafter transient middle cerebral artery occlusion (MCAo) in rats were measured usingmagnetic resonance imaging (MRI). Systemic IL-1 caused a severe reduction in CBFand increase in infarct volume compared to vehicle. CBF changes were accompanied byupregulation of the vasoconstricting peptide endothelin (ET)-1. Blockade of ET-1receptors reversed hypoperfusion, reduced ischaemic damage and improved functionaloutcome when assessed at 48h.Streptoccocus pneumoniae is the most common infection in patients at risk of strokeand is associated with an elevated inflammatory profile. The effect of an acute S.pneumoniae challenge on stroke outcome was assessed in mice and rats followingtransient MCAo. S. pneumoniae induced a systemic IL-1 response, exacerbated braininjury and increased platelet adhesion to the endothelium. Blockade of IL-1 with IL-1receptor antagonist (IL-1Ra) and administration of glycoprotein (Gp) Ibalpha (to reduceplatelet-endothelial interactions) reversed infection-mediated exacerbation of ischaemicinjury and improved functional impairments after MCAo.Presence of chronic inflammation in the form of advanced age and obesity areassociated with poorer outcomes following ischaemic stroke. The neuroprotectiveeffects of delayed IL-1Ra on stroke outcome were assessed in aged lean and corpulentrats versus young rats at 7 days post-stroke. IL-1Ra reduced ischaemic damage, bloodbrain barrier (BBB) breakdown, improved functional outcomes and preservedneurogenesis 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 bothacute and chronic pre-existing inflammatory disorders that are risk factors for stroke.Systemic IL-1 leads to excessive ischaemic damage through effects on the endotheliumand the coagulation cascade. These results lend further support to the hypothesis thatIL-1 is a potential therapeutic target in ischaemic stroke.

Date of Award	31 Dec 2014
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Stuart Allan (Supervisor), Stephen Williams (Supervisor) & Adrian Parry-Jones (Supervisor)