Stroke is the third most common cause of death in the developed world. Stroke results from cerebral ischaemia and leads to neuro-glial cell death. Cell death is induced by a cascade of events and potently stimulates a potentially deleterious inflammatory response. The inflammation is driven by cytokine release; one of the major cytokines involved being interleukin-1. IL-1<span lang=EN-US style='font-family:Symbol'>b, which is implicated in ischaemic brain damage, is converted from its inactive form by caspase-1. In this study the IL-1 pathway in ischaemic brain damage was manipulated with the endogenous IL-1 antagonist, IL-1 receptor antagonist (IL-1ra) and with the caspase-1 inhibitor RU36384. As a preliminary step the induction of transient cerebral ischaemia with the filament technique of middle cerebral artery occlusion (tMCAo) in rats was characterised, and found to be reproducible. Administration of IL-1ra (10<span lang=EN-US style='font-family:Symbol'>mg) into the lateral cerebral ventricle (icv) at ischaemia and reperfusion resulted in a 43% reduction in total lesion volume. This effect was also obtained by administering (20<span lang=EN-US style='font-family:Symbol'>mg) at later time points out to 3h after the initiation of ischaemia (41% reduction). After independently confirming the effects of RU36384 on IL-1<span lang=EN-US style='font-family:Symbol'>b processing <i>in vitro. </i>RU36384 was administered to rats icv after tMCAo and reduced ischaemic lesion volume when compared to control in a dose dependent fashion. Administration of 5<i>, </i>10, 20 and 40<span lang=EN-US style='font-family:Symbol'>mg at ischaemia and reperfusion resulted in reductions of 37%, 46%, 65%<i> </i>and 40% respectively. This effect was sustained out to 3h after the initiation of ischaemia but lost by 6h. Administration of RU36384 did not alter cardiorespiratory variables or core body temperature when compared to control animals. These data implicate IL-1 as an important mediator of cell death after cerebral ischaemia and indicate that its therapeutic manipulation may have a role in the clinical arena.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:288275 |
| Date | January 2003 |
| Creators | Ross, Jerard |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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