Investigating the interplay of diet and inflammation on cerebral ischaemia

Abstract

Cerebral ischaemia occurs when cerebral blood flow (CBF) is compromised and brain tissue becomes starved of oxygen and nutrients, leading to cell death and neurological deficits. Ischaemic events in the brain can be either focal or global, and are major pathological features of age-related diseases, such as stroke and dementia. Several modifiable risk factors, such as diet, can exacerbate ischaemic damage. The aim of this thesis was to investigate how different dietary states, obesity and high sugar, affect inflammation and ischaemic outcomes in murine models of global and focal ischaemia. In order to investigate global ischaemic pathology, we sought to characterise a mouse model of chronic cerebral hypoperfusion, bilateral common carotid artery occlusion (BCAS). We demonstrated a sustained reduction in CBF at 3 months in BCAS animals; however, consequent neuropathology and cognitive deficits were absent. Additionally, we measured clinically validated markers of hypoperfusion (vascular endothelial growth factor, myelin associated protein, and proteolipid protein 1), that had not previously been investigated in the context of the BCAS, but found that there was no change in tissue oxygenation. We hypothesise that the reduction in CBF was not severe enough to induce global ischaemia and subsequent neuropathology. Turning our focus to focal ischaemic pathology, we used middle cerebral artery occlusion (MCAo) to investigate how diet affects ischaemic injury. We found that stroke induced long-term changes in depressive/anxiety-like behaviours, and also altered the levels of plasma lipids and adipokines, which may have negative impacts on vascular health. Obese mice also had long-term alterations in depressive and anxiety-like behaviours after stroke, but these changes did not differ significantly from lean mice that had equivalent lesion volumes. Next, we investigated how hyperglycaemia affects stroke outcomes. We found that hyperglycaemia exacerbates ischaemic brain damage by augmenting interleukin (IL)-1β dependent post-stroke inflammation. We showed that macrophage production of IL-1β post-stroke is glycolysis dependent, and in the context of hyperglycaemic conditions, is potentiated by increased substrate availability. Furthermore, we identify pyruvate as an essential metabolite downstream of glycolysis that regulates IL-1β production, and we hypothesise that this is mediated via succinate accumulation. This thesis produces mechanistic insight into the inflammatory pathology of focal and global ischaemia. Specifically, we have shown that obese and hyperglycaemic states have distinct impacts on post-stroke outcomes, primarily by regulating inflammatory and metabolic processes in immune cells. Ultimately, gaining a better mechanistic insight into how diet-related diseases and dietary factors modulate ischaemic pathology may help identify new therapeutic targets, increase health and lifestyle education, and improve public awareness.

Date of Award	1 Aug 2020
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Stuart Allan (Supervisor), Catherine Lawrence (Supervisor), David Brough (Supervisor) & Patrick Strangward (Supervisor)