Subarachnoid haemorrhage as a valid model for stroke

Lead Research Organisation: University of Manchester
Department Name: Life Sciences

Abstract

The devastating effects of a stroke are caused most commonly by a blood clot which blocks a blood vessel that supplies the brain. Blood flow is essential for normal brain function and stopping the blood supply, even for a few minutes, can cause damage and death of brain cells and the patient. We know a great deal about what happens to the brain during a stroke, but it has been very difficult to develop new treatments that are effective for patients. This is partly because stroke patients are not easy to study. We believe that we can get important information about stroke and related brain diseases, and perhaps develop new treatments, by studying a related condition called subarachnoid haemorrhage.

In subarachnoid haemorrhage a blood vessel in the brain bursts rather than clots (as in stroke). We know that subarachnoid haemorrhage probably damages brain cells in a similar way to stroke, and now want to determine if the brain bleeding condition can be used to study stroke and to develop new drugs. We will do this by studying established animal models of stroke and subarachnoid haemorrhage, and patients with stroke and subarachnoid haemorrhage. Our research will involve imaging the brain and studying molecules in the blood, which we know are related to whether the patients will do well or not so well. We wish to test whether similar changes in the levels of these molecules occur in the blood of the animal models and patients, and also if stroke patients show changes similar to subarachnoid haemorrhage patients. We will also monitor how much brain damage occurs in both the animals and patients to see whether it is related to any changes in the molecules in the blood. If we see similar changes between animals and patients then this shows that subarachnoid haemorrhage patients can be used to study stroke and to test new treatments.

Technical Summary

Stroke results from a critical reduction in brain blood supply (cerebral ischaemia, CI), and is a leading cause of death and disability. This has been an area of intense research activity, yet the outcomes have been disappointing, and we have very limited effective treatments. The reasons for these failures are manifold, including the relevance of animal models and the difficulties of conducting research in stroke patients. Stroke patients often arrive many hours after the stroke, we can rarely access their brains ethically and their aetiology is diverse. By contrast, subarachnoid haemorrhage (SAH) patients are hospitalised quickly and have ongoing CI during their hospital stay. One-third of SAH patients suffer delayed CI which is detected promptly, allowing early studies of relevance to acute stroke. Many SAH patients also have external ventricular drains and brain microdialysis probes, allowing monitoring of events within the central nervous system. We have used this to effect in studying the pharmacokinetics of a potential treatment for stroke (interleukin-1 receptor antagonist, IL-RA) in SAH patients. Thus SAH patients may represent a valid group to study CI and its consequences, and for ?proof-of-principle? studies of new interventions.

We will test the hypothesis that SAH is a valid model in which to study the mechanisms of CI and to test new treatments for stroke, SAH and other conditions of CI.

Inflammation is now recognised as a key mediator of CI. Therefore inflammatory responses to SAH and stroke will be the principle parameter assessed in established animal models and patients. We will also measure the progression of brain injury using brain imaging.

To test our hypothesis we will:
1) Compare these parameters in animal models of SAH and SAH patients.
2) In animal models of SAH and stroke, we will compare systemic and central inflammatory responses and brain injury, as well as effects of IL-1RA, which is neuroprotective in experimental stroke.
3) Compare the progression of neuronal injury and circulating levels of inflammatory mediators in SAH and stroke patients.

If there is a strong correlation between inflammatory events and the progression of neuronal injury in SAH and stroke (albeit perhaps of different temporal patterns), this will allow us to undertake pharmacokinetic, pharmacodynamic and ?proof-of-principle? studies in SAH. It may then prove more useful to perform Phase III efficacy studies in SAH patients than in stroke patients, where so many treatments have failed, thus overcoming the translational ?bottleneck?.
 
Description EU COST action
Amount € 500,000 (EUR)
Organisation Spanish National Research Council (CSIC) 
Sector Public
Country European Union (EU)
Start 09/2013 
End 08/2015
 
Description Local Stroke Research Network Annual Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Stroke patients, carers and health professionals attended the meeting, where a poster was presented of our research.

Very useful feedback on the work from stroke patients.
Year(s) Of Engagement Activity 2010
 
Description UK Stroke Assembly 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact An annual event that enables stroke survivors and their families to express their opinions and hopes in a UK-wide forum. This was held in 2013 at Nottingham University. Around 200 people attended and participated in discussions around our research

Not yet known
Year(s) Of Engagement Activity 2013
URL http://www.strokeassembly.org.uk/content/brains-fire
 
Description World Stroke Day 2011 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Poster Presentation
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Over 100 people attended the World Stroke Day Event in Wigan. We ran a series of table-top activities and poster boards to explain our research.

N/A
Year(s) Of Engagement Activity 2011
 
Description World Stroke Day 2012 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact 160 people (patients, carers, health care professionals) attended a World Stroke Day event organised by the Northwest Local Stroke Research Network at Wigan Stadium. We ran a series of table-top activities alongside posters to engage the attendees with our research. Grant holders, postdocs and students were all involved.

Not known at this time
Year(s) Of Engagement Activity 2012