Exploring stroke: the role of infection, inflammation and other comorbidities

Learoyd, Annastazia (2017) Exploring stroke: the role of infection, inflammation and other comorbidities. PhD thesis, University of Nottingham.

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Abstract

Recovery from a stroke is affected by a wide range of factors. A multitude of comorbidities, including old age and diabetes, all increase the risk of death or disability as a result of a stroke. In addition, medical complications can affect stroke outcome. Infections are known to increase the risk of death or disability when contracted in the first week after stroke onset. However, by analysing data from a clinical trial, we have found that infections are actually detrimental for a lot longer than one week. Any infection acquired in the first 76 days after stroke increases the risk of death in comparison to patients with other post-stroke medical complications. Additionally, patients who contract infections and survive up to 90 days post-stroke have more disabilities and are more reliant on assistance compared to stroke patients who did not acquire medical complications.

Inflammation has been identified as a possible cause for the effect of infection and requires further investigation. Neuroinflammation is a firmly established response to stroke and inflammatory processes within the stroke infarct are well characterised. But inflammation in other brain regions, not directly affect by the stroke, receives less attention. Using immunohistochemistry techniques, we looked at microglia number and activation over 28 days post-stroke in nine different regions across the rodent brain, ranging from the prefrontal cortex to the substantia nigra. Microglia activation was present in all assessed brain regions at least once between 1 and 7 days post-stroke, showing that the neuroinflammatory response to a stroke is not limited to the stroke infarct, but instead encompasses the whole brain.

In light of this, it is feasible that changes in neuroinflammation will contribute to the detrimental effects of post-stroke infection. We developed an animal model of infection at a chronic time point post-stroke by administering lipopolysaccharide (LPS) intraperitoneally at 15 days post-stroke. Not only did this initiate a peripheral inflammatory response and increased in symptoms of sickness, but in stroke animals the administration of LPS increased microglia activation in the stroke-affected striatum and decreased microglia activation in the prefrontal cortex compared to controls. This supports a possible role of neuroinflammation in propagating disability after infection.

While the LPS model would be useful for investigating the role of neuroinflammation further this model does not account for other comorbidities which may also have an effect. Animal models incorporating multiple comorbidities common in stroke patients are rarely used. We aimed to develop a comorbid animal model which could be used in stroke research by administering 12 month old rats a high fat diet. Although these aged obese animals successfully underwent several procedures common in stroke research, they did not develop additional desired comorbidities such as insulin resistance, diabetes and hypertension. This limits their usefulness in stroke research.

Overall, a range of work has been completed highlighting a number of areas in stroke research. While some of the work has limited potential, the detrimental effect of infections acquired post-stroke requires further attention with research needed to investigate its mechanisms and possible therapeutics. The LPS model of chronic post-stroke infection is an ideal model for this work.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Trueman, R.
Fone, K.C.F.
Keywords: Cerebrovascular disease, Stroke, Complications, Infections, Inflammation, Neuroinflammation
Subjects: R Medicine > RC Internal medicine
W Medicine and related subjects (NLM Classification) > WL Nervous system
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID: 41365
Depositing User: Learoyd, Annastazia
Date Deposited: 17 Jul 2017 04:40
Last Modified: 19 Jul 2017 01:10
URI: http://eprints.nottingham.ac.uk/id/eprint/41365

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