| Summary: | In this thesis, focal cerebral ischaemia was induced in three animal models in an attempt to investigate the contribution of the inflammatory response. The rat monofilament model of middle cerebral artery (MCA) occlusion, considered by some to be a pro-inflammatory model, was set up for the first time in Edinburgh and validated as suitable model for further investigation. Permanent and transient models were established to allow the evaluation of possible reperfusion injury. Both monofilament models were compared with the endothelin-1 model already established and routinely in use in the laboratory. Analysis of the volume of damage and distribution of the lesion revealed no differences between the three models. However this observation did not in itself rule out the possibility of different pathophysiological mechanisms in the three models that ultimately resulted in apparently similar sized lesions. FK506, a potent neuroprotectant widely used experimentally, exhibited different neuroprotective efficacies. In all models, FK506 significantly reduced the overall volume of both damage and oedema. The majority of the neuroprotection was observed in the cortex although striatal protection was seen in the transient rat monofilament model. The neuroprotection observed in the transient monofilament model was approximately twice that seen in the permanent model and similar to that in the endothelin-1 model suggesting distinct pathways that lead to cell death. Data for FK506 administration in the mouse monofilament model demonstrated neuroprotection for the first time in this species was included as an interesting comparison with the rat data. In summary, the re-introduction of blood to ischaemic tissue appears to alter the response of the individual cells although this does not change their ultimate fate. In instances where reperfusion is established, the tissue appears to be more amenable to neuroprotection by RK506. It is suggested that this is associated with the blockade of inflammatory mechanisms.
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