Aspey, Benjamin Steven; (2000) Studies of an ischaemic stroke model (middle cerebral artery occlusion in the rat) and modifications to improve its consistency. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The work in this study has been mainly directed towards developing consistent protocols for an animal model of ischaemic stroke, suitable for novel drug combination strategies, using the intraluminal suture method of middle cerebral artery occlusion (MCAO) in the rat. Following optimisation of the measurement protocols, it was found that more consistent volumes of cerebral infarction were produced in the animal model when a silicone-coated type of intraluminal suture was used for permanent MCAO in Sprague-Dawley rats (coefficient of variation (cv) 19.9%), compared to an uncoated type (cv 66.6%). This more consistent protocol was used in a therapeutic screening study, combining 619C89, a sodium channel blocker to inhibit glutamate release, with BB-823, a platelet activating factor (PAF) antagonist to inhibit inflammatory responses. Although both agents individually reduced infarct volume, combined administration was only slightly and not significantly more effective. This may have been due to either a ceiling effect or the possibility that both agents targetted the same pathological mechanism. Both glutamate and PAF have been previously shown to induce the expression of cyclo-oxygenase (COX-2). However, molecular studies showed that although COX-2 induction was glutamate-mediated, 619C89 had no effect on the process, and the effect of BB-823 was only slight. A persistent problem with the model was the degree of residual variability, which was possibly obscuring small but significant differences. An attempt was made to improve reproducibility of the protocol further, by investigating the effect of animal strain. In the context of permanent MCAO, Fischer-344 rats had more consistent infarct volumes (cv 10%). Extending this approach to the context of temporary MCAO, Wistar rats had more consistent results (cv 9.5%). The direction of this study turned from investigating novel therapies to developing consistent protocols. Since reliable animal models are essential for preclinical studies, the present findings should significantly benefit stroke research.

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