Better awareness and improved treatment have both contributed to a reduction in the number of people dying from stroke, leading to an increase in the number of stroke survivors. Unfortunately, however, many survivors are left with life-limiting disabilities.
In this project, Dr Barry McColl and his colleagues explored the development of a new treatment that could boost brain repair in stroke survivors and improve recovery. Building on pilot data showing that administration of a protein that acts on certain types of immune cells enhances short-term recovery of forelimb function in mice, this project assessed the effects of this protein in the longer term, to gain a fuller understanding of how it works and how it might be used in the future to help human stroke survivors.
A stroke is caused by sudden interruption of the blood supply to the brain. This starves the brain tissue of oxygen and glucose, causing brain cells to die. Rapid emergency treatment can limit the damage, saving lives and reducing the long-term harm.
However, around half of the 1.3 million stroke survivors in the UK are left with life-limiting disabilities. The nature and severity of the disability will vary depending on the extent of the damage and the exact area of the brain affected, but may include limb weakness, impaired mobility, and problems with speech, balance and co-ordination. All these conditions impact on the survivor's ability to resume a normal, independent life.
In addition to the huge personal impact on the lives of survivors, the impact on society is enormous. The economic burden of stroke in the UK encompasses health and social care costs, informal care, productivity losses and benefit payments. Two-thirds of working age survivors are unable to return to work.
Improving stroke recovery is therefore a key goal.
Existing treatments for stroke work by unblocking the damaged artery; this needs to be done very quickly after stroke happens in order to limit the damage. There is no treatment currently approved to treat stroke patients beyond this initial emergency treatment – to help heal the damaged brain.
We know from previous research that the area of brain tissue around the stroke damage, and connected regions, can adapt and reorganise to boost recovery or make-up for lost function. This remarkable ability of the brain to 'rewire' itself is known as 'plasticity'. It helps to explain how, with the help of rehabilitation, people can recover functions that were initially lost. Finding a treatment that can enhance plasticity in stroke patients would facilitate a faster, more complete recovery.
This project built on the relatively new understanding of the importance of the immune response in brain recovery and repair. Previous research has shown that other cell types, including some types of immune cells called macrophages, can help the nerve cells by creating the right conditions for repair to take place. Dr McColl and his colleagues therefore explored whether further boosting the helpful functions of macrophages, including specialised macrophages called microglia that live in the brain, could enhance plasticity and improve recovery.
Dr McColl and his team had previously made a modified version of a naturally occurring protein in the body, called CSF1-Fc, which controls various functions of macrophages. In this project the team tested the effects of CSF1-Fc using an experimental type of stroke in mice that mimics a blood clot forming in an artery as happens in humans, assessing various key indicators to understand any effects of the CSF-Fc.
The results showed that CSF1-Fc treatment caused a change in the blood immune cell count, confirming that the intended immune cells were being targeted. Treatment with CSF1-Fc also accelerated recovery of forelimb function, with most mice showing function similar to pre-stroke levels by one week. Furthermore, brain scanning showed that CSF1-Fc did not change the amount of early brain damage or brain swelling after stroke, which is important as increased brain swelling might have been a risk of this approach. Finally, the team found that CSF1-Fc also did not change the number of macrophages accumulating around the damaged brain area but that it did change the amount of a protein produced by the macrophages that is linked to repair of tissues, and some additional analysis of brain scans suggested that the nerve wiring of the brain that connects different brain regions may also be altered by CSF1-Fc treatment.
The effects of stroke are devastating and rob people of their ability to live a productive, independent life.
This project showed several positive effects of CSF1-Fc treatment, including enhanced functional recovery and an increase in the amount of protein linked to brain tissue repair. The team now need to conduct further trials in different stroke models and across multiple laboratories, before being able to progress to human studies. However, their findings support the general idea that targeting immune cells like macrophages can support recovery of function after stroke, and this project is therefore a crucial step in the development of a potential new treatment to boost brain repair in stroke survivors and enhance recovery of function.
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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