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Compromised Reperfusion: The key mechanism underlying detrimental effects of age and obesity in stroke?


Project Description


Stroke is a devastating condition yet, despite much research, thrombolysis with tissue plasminogen activator (tPA) remains the only available treatment. tPA can produce dramatic effects in patient recovery through reperfusion of blood to previously ischaemic regions but, for a variety of reasons, is likely applicable to <20% patients. Thus new treatments are needed for stroke. There has however been a failure in translating successful preclinical research to effective treatments.

We and others believe a major reason for this is that the majority of previous experimental studies in stroke have failed to adequately consider the various factors associated with stroke in the clinical population. These factors include age, diabetes, hypertension, obesity, infection and atherosclerosis, all of which are associated with worse outcome when present in experimental models. Reasons why these co-morbid factors worsen outcome are not clear, though considerable evidence exists to suggest a primary target may be the cerebrovasculature. Compromised perfusion of the brain is the hallmark of stroke and restoration with tPA is known to be beneficial. We believe therefore that co-morbid factors might affect cerebral haemodynamics and reperfusion, which will result in increased damage and worse outcome in the longer term. To determine this we will use 2-dimensional optical imaging spectroscopy to assess the impact of age and obesity, clinically relevant risk factors, on the early (0-12h) cerebral haemodynamic response after experimental stroke in mice. In

addition we will establish whether age and obesity also affect cerebral haemodynamics in the longer term (28 days) and how this relates to neuronal activity and behaviour. We believe this project advance our understanding of the importance of co-morbidity in modifying the response to cerebral ischaemia, and that this will confirm the need to consider such comorbidities in developing any future new treatments for stroke.

Funding Notes

This project has a Band 3 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.


References

Berwick J, Johnston D, Jones M, Martindale J, Redgrave P, McLoughlin N, Schiessl I & Mayhew JE., (2005), “Neurovascular coupling investigated with 2-dimensional optical imaging spectroscopy in rat whisker barrel cortex.”, Eur J Neurosci 22:1655-66.

McColl BW, Rose N, Robson FH, Rothwell NJ & Lawrence CB (2010) Increased brain microvascular MMP-9 and incidence of haemorrhagic transformation in obese mice after experimental stroke. J Cereb Blood Flow Metab 30:267-72.

Murray KN, Buggey HF, Denes A & Allan SM (2013) Systemic immune activation shapes stroke outcome. Mol Cell Neurosci 53:14-25.

Pradillo JM, Denes A, Greenhalgh AD, Boutin H, Drake C, McColl BW, Barton E, Proctor SD, Russell JC, Rothwell NJ & Allan SM (2012) Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inflammation in comorbid rats. J Cereb Blood Flow Metab 32:1810-9.

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