Stroke is a leading cause of death and disability, with limited treatment options.
Inflammation in the brain after stroke has been shown to be important in the death of brain cells. Drugs are available that can reduce this inflammation, but more information is needed about how to use these drugs to counter the effects of stroke.
In this project, Professor Allan and colleagues will use their well-established mouse models of stroke to test the effects of these drugs to build evidence for their optimal use.
Following rigorous assessment as part of our competitive grant round, this project was recommended for its strong potential to advance knowledge in this area of great clinical importance, moving towards rapid patient benefit.
Stroke is caused by sudden interruption of the blood supply to the brain, due to a clot or bleed. This starves the brain tissue of oxygen and glucose, causing brain cells to die. It is a leading cause of death and disability.
Treatment options for stroke are very limited. For stroke caused by a clot (ischaemic stroke), a drug called tPA can be given. This breaks down the clot, restoring blood flow to the brain. Or the clot can be physically removed. While these treatments can enable recovery, they are not suitable for everyone and at present are only received by one in 10 patients.
For a stroke caused by a bleed (haemorrhagic stroke), no treatment has yet been shown to improve outcomes.
We need to find new treatments that can be given to a greater number of stroke patients, including those with both clots and bleeds.
Professor Allan and others have shown that there is inflammation in the brain after stroke, and that this inflammation is important in the death of brain cells. It is possible, therefore, that drugs that reduce inflammation could limit brain damage after stroke, representing a possible new treatment option.
Professor Allan and team have investigated this using a drug called anakinra, which works by halting the action of a chemical called interleukin-1 (IL-1), which we know can cause inflammation. Anakinra reduces the amount of brain damage in animals with experimental stroke, leading to better recovery of the animals. It is already used in the treatment of other diseases in humans and has been tested in small numbers of stroke patients, with both clots and bleeds. These human trials confirmed that anakinra can reduce inflammation. However, evidence from one trial suggested that anakinra and tPA might not work well when given together. Testing in animals, the team discovered potential negative interactions between the two drugs, reducing beneficial effects.
In this project, they set out to address two key research questions: firstly whether it is better to give anakinra before rather than after the tPA is injected; and secondly, whether another anti-inflammatory drug (isunakinra) works better than anakinra in reducing brain damage after stroke, and does not have the same problems when given with tPA.
To address these questions, they will use well-established mouse models of stroke. They can mimic the effects of stroke and test the effects of different treatments by using established measures of brain damage.
This project has high potential for patient benefit. Anakinra and isunakinra are both approved for clinical use and can be rapidly repurposed for use in the treatment of stroke and other acute brain injuries. This work will add crucial evidence about how they can best be used to treat the effects of stroke and minimise brain damage.
This work could help people like Andy, who was given just a 5% chance of survival when he suffered a massive stroke during minor surgery and has fought long and hard to overcome the effects of the damage to his brain.
Stuart Allan is Professor of Neuroscience at the University of Manchester. He has worked on brain injury for over 25 years and is recognised internationally for his work. With colleagues in Manchester, he has led research that demonstrated the importance of inflammation in stroke and that blocking the actions of IL-1could be a novel treatment approach. This has led to clinical trials of the IL-1 inhibitor drug anakinra.
He is working with colleague Craig Smith, Professor of Stroke Medicine at the University of Manchester and stroke consultant in the Manchester Centre for Clinical Neurosciences. Professor Smith is internationally recognised for his research on inflammation and stroke, and brings critical clinical insight to this project. He led the phase 2 clinical trials of anakinra in ischaemic stroke, on which this project is largely based.
Acquired brain and spinal cord injury (including stroke) is one of our current research priorities, reflecting the large unmet need in this area. Our aim is to fund research to advance understanding of how to promote repair of the brain and spinal cord following injury.
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