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Title: Hyperglycaemia in acute ischaemic stroke : brain imaging studies in a rodent model of stroke
Author: Roy, Lisa
ISNI:       0000 0004 5920 1405
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2015
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Hyperglycaemia on admission is a frequent finding in acute ischaemic stroke patients. This post-stroke hyperglycaemia (PSH) is associated with a poor clinical outcome independent of age and stroke severity. Evidence from clinical stroke studies indicates that hyperglycaemia is associated with a worse outcome in non-diabetic compared to diabetic stroke patients, but the mechanisms underlying this association are poorly understood. Previous in-house studies reported that hyperglycaemia, at clinically-relevant blood glucose levels, exacerbated the evolution of early ischaemic damage in a non-diabetic rat stroke model, indicating that the detrimental effects of hyperglycaemia occur early following the onset of focal cerebral ischaemia. In ischaemic stroke the severity and duration of ischaemia are the major determinants of acute brain damage and therefore a potential mechanism by which hyperglycaemia exacerbates ischaemic damage could be through an influence on tissue perfusion. The studies in this thesis aimed to test the hypothesis that hyperglycaemia exacerbates early ischemic damage by increasing the severity of the cerebral blood flow (CBF) deficit. Initial studies were performed to optimise a rodent model with clinically relevant blood glucose levels before and after focal cerebral ischaemia induced by permanent middle cerebral artery occlusion (MCAO). This animal model was then used in subsequent studies to assess the effect of hyperglycaemia on the CBF deficit after MCAO. The CBF deficit was assessed using two different methods: 99mTc-HMPAO blood flow autoradiography and MRI perfusion imaging. Each method offered its own advantages, for example, 99mTc-HMPAO autoradiography produces blood flow images with high spatial resolution enabling detailed semi-quantitative region of interest analysis and MRI perfusion imaging allowed repeated, quantitative CBF measurements at multiple time points after stroke. In addition, the use of MRI enabled concurrent diffusion weighted images to be acquired in order to assess the evolution of acute ischaemic damage and final T2 defined infarct volume. The results demonstrate that hyperglycaemia exacerbates acute ischaemic damage induced by MCAO but not the perfusion deficit as measured by both 99mTc-HMPAO autoradiography and MRI. These findings suggest that the primary mechanism of hyperglycaemia-associated ischaemic damage is not mediated by an increase in the severity of ischaemia. Alternatively, the harmful effects of hyperglycaemia may be predominantly mediated in the brain parenchyma. However Western blot analysis of ischaemic brain tissue showed that glucose treatment resulted in only minor changes in the levels of the calpain substrates MAP2 and αII-spectrin. Thus, the predominant mechanism exacerbated by hyperglycaemia does not appear to be calpain-mediated proteolysis, raising the possibility that hyperglycaemia affects many different mechanisms simultaneously.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC Internal medicine