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.
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?.
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?.