Neuroinflammation and cognitive plasticity following experimental stroke

Langdon, Kristopher D. (2010) Neuroinflammation and cognitive plasticity following experimental stroke. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Stroke is one of the leading causes of morbidity and mortality in Canada and only relatively few individuals avail of pharmacological treatment. Consequently, most stroke patients are left with permanent disabilities. Post-stroke rehabilitation is beneficial but is often incomplete. Animal models of stroke have helped in our understanding of the mechanisms involved in the recovery of sensorimotor function but little attention has been paid to cognitive impairments, which are common following stroke. -- Importantly, patients with cognitive problems are less likely to be reintegrated into society and benefit less well from rehabilitation. Animal models of ischemia have not demonstrated the lasting cognitive impairments that are apparent in human stroke. In the second chapter of this thesis I describe a cognitive assay that detected long-term (~9 mo) alterations in learning, working and reference memory function following global ischemia. Further, I identified a sustained neuroinflammatory state confined to area CA1 at a protracted time point of 270 days post-ischemia, a time when neuroinflammation is typically thought to have subsided. -- In the third chapter I assessed the impact of increased neuroinflammation caused by systemic inflammation on ischemic outcome. Systemic inflammation 24-hours post-ischemia significantly increased neuroinflammation at 3 days post-ischemia as indicated by increases in microglia/macrophages and infiltrating neutrophils. This resulted in significant increases in functional deficits and infarct volumes assessed 30 days post-ischemia. These results confirm for the first time, that systemic inflammation at such a delayed time point, similar to what occurs in a clinical setting, has a profound impact on ischemic outcome. -- The fourth chapter attempted to develop a post-stroke intervention to enhance cognitive function. A combination of 2 hours of physical activity (wheel running) and 2 hours of cognitive activity (Hebb-Williams maze exposure) significantly improved working memory in normal rats compared with either physical or cognitive activity alone, independent of significant changes in neuronal BDNF or pCREB levels. These results are the first to suggest that cognitive training in rats, when combined with only 2 hours of wheel running, can significantly improve working memory function, a finding that may be useful in developing cognitive rehabilitation strategies following stroke in humans.

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