Developing tools for functional assessment of a milder model of stroke

Stroke is the third leading cause of death and the leading cause of disability. However, the overwhelming failure to identify a treatment has highlighted two issues that contribute to a lack of translation of preclinical stroke research: lack of long-term functional studies and co-morbidities in our stroke models. This studentship will address both these issues, whilst reducing and refining rodent use, by enabling greater use of a moderate model in rats and mice, rather than the most commonly used severe model (the intraluminal filament middle cerebral artery occlusion (MCAO) model). This model results in damage to sub-cortical areas of the brain with variable cortical damage; the resulting adverse effects are typically ‘severe’.

However, the distal MCAO model (dMCAO) produces damage only in cortical regions. It can be within the ‘moderate’ severity limit, is more reproducible, and has a lower mortality rate than the filament model. Unfortunately, it is not commonly used. The reason often quoted for this, is the lack of stable behavioural deficits observed. Therefore, evaluating the effect of a treatment on a disability measure is not always possible with this model.

We will develop a battery of behavioural tests, sensitive enough to detect deficits in the dMCAO model. Through the dissemination of our findings and protocols, we will promote the use of this less severe model in experimental stroke research. This should result both in a reduction in suffering and the number of animals that would be required for future studies. We further hypothesize that the advantages of the dMCAO will make it easier to incorporate co-morbidities because it is less severe. As modelling stroke in co-morbid animals is necessary for valid translational studies, more journals and regulators are pushing to see studies performed in aged or co-morbid animals. Our aim is to significantly increase the translational relevance of the model, whilst refining techniques and reducing animal use.