The effect of diet on the cellular response to a small focal ischemic stroke

Fifield, Kathleen E. (2021) The effect of diet on the cellular response to a small focal ischemic stroke. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Overwhelming evidence demonstrates that diet-induced obesity increases the risk of ischemic stroke. Furthermore, obesity is associated with worse neurological outcomes following overt ischemic strokes. The majority of strokes seen clinically; however, are covert, small strokes that often evade detection. How obesity impacts the cellular response to covert strokes is unclear. Furthermore, whether obesity alters the cellular response within the infarct core or penumbra is not known. To address these issues, I developed a mouse model of diet-induced obesity by feeding mice a high fat diet (HFD) for twelve weeks. Intra-cortical injections of Endothelin-1, a vasoconstrictor was used to induce a focal ischemic stroke that is representative of covert strokes observed in the clinic. To distinguish the ischemic core from the penumbra, an intra-cardiac injection of a dextran-linked fluorochrome was given at the time of euthanasia to label perfused blood vessels. Quantification of the number of labelled blood vessels per area allowed post mortem distinction of the infarct core from the penumbra in brain sections. Using this technique the cellular responses were examined in each region following stroke. The results show that: (1) prolonged high fat diet worsens stroke outcomes following small covert strokes; (2) cellular responses within the core and penumbra are distinct with the majority of neurons dying in the core by 4 hours. Neurons in the penumbra can survive up to 72 hours post-stroke despite extensive blood brain barrier (BBB) breakdown, leukocyte infiltration and astrogliosis; (3) acute administration of docosahexanoic acid (DHA) post-stroke ameliorates BBB disruption at 24 hours post-stroke in both diet groups, but its efficacy is attenuated in high-fat diet fed mice. In summary, diet-induced obesity exacerbates covert-like stroke injuries by worsening the cellular responses in the varying levels of perfusion across the infarct, while DHA may be a viable treatment for covert strokes.

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