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NC3Rs: National Centre for the Replacement Refinement & Reduction of Animals in Research
Pilot study grant

Determining the source of variability within experimental stroke models

Dr Claire Gibson with two colleagues beside her on the left and right

At a glance

Completed
Award date
November 2014
Grant amount
£74,586
Principal investigator
Dr Claire Gibson

Co-investigator(s)

  • Dr Michael Kelly
Institute
University of Leicester

R

  • Reduction
  • Refinement
Read the abstract
View the grant profile on GtR

Application abstract

Efficacy of stroke interventions are tested using rodent middle cerebral artery occlusion (MCAO) models of focal brain ischemia but these have a poor record of translating into clinically effective treatments. The majority of experimental stroke studies use lesion volume as the primary outcome measure. However, variability in MCAO lesion volume is high with significant differences generally tested using parametric analyses requiring a normal data distribution. Data from my laboratory over the last ten years (and confirmed by others) shows that MCAO lesion volume data is not normally distributed and results in a bimodal distribution of small (purely striatal) and large (striato-cortical) lesions. We aim to determine (i) whether variability in MCAO lesion data is due to differences in cerebrovascular anatomy and, (ii) whether refinement of the surgical technique can improve outcome reproducibility. Rodents show a large variability in the Circle of Willis and studies have shown this to produce variability in lesion volume thus, requiring increased animal numbers to achieve statistical significance. However, traditional methods to assess the Circle of Willis anatomy are conducted post-mortem following the induction of MCAO. Firstly, we will assess, using MRI, whether the reported variability in outcome following MCAO is dependent upon the anatomy of the Circle of Willis and if so, can we develop a screening technique to identify 'suitable' mice to undergo MCAO and therefore reduce the number of animals undergoing MCAO.  In addition, we will assess whether a refinement in the surgical approach used to permit reperfusion followng MCAO can be applied in mice.  This will allow reperfusion to occur irrespective of the completeness of the Circle of Willis which is currently the main limitation in determining the effectiveness of reperfusion. This should reduce the variability in reperfusion associated experimental stroke models and reduce the number of animals used.

Impacts

Publications

  1. Trotman-Lucas M et al. (2019). Middle Cerebral Artery Occlusion Allowing Reperfusion via Common Carotid Artery Repair in Mice. Journal of Visualized Experiments 143: e58191. doi:10.3791/58191
  2. Trotman-Lucas M et al. (2017).  An alternative surgical approach reduces variability following filament induction of experimental stroke in mice. Disease Models & Mechanisms 10: 931-938. doi:10.1242/dmm.029108