Modulating cholesterol 25-hydroxylase: a strategy to accelerate haematoma clearance after intracerebral haemorrhage to improve outcome

Stroke is a life-threatening condition in which there is a disruption of blood supply to the brain. Haemorrhagic stroke is the deadliest type of stroke leading to a 50% chance of death, and those who survive are usually left with life-changing impairments that affect everyday living. The longer-term effects of stroke include difficulties with movement and balance, and problems with communication, remembering things, concentration, vision and swallowing as well as extreme fatigue. Currently there are no effective treatment options for haemorrhagic stroke so there is an urgent need to find new therapies to improve patient survival and quality of life. One type of haemorrhagic stroke ('intracerebral haemorrhage') occurs when a blood vessel suddenly ruptures and begins bleeding into the brain. Blood then accumulates inside the brain, leading to a rise in pressure that causes brain cells to die. Blood that is now in the brain contains various cells (including red blood cells) that start to release 'toxic factors' that can cause further damage to brain cells. It is important therefore, to try and get rid of the blood as quickly as possible, to reduce the chances of it causing any harm. Our tissues/organs contain a group of cells called 'phagocytes' whose job is to eat any harmful cells and smaller particles to try to protect our bodies from any of their harmful effects. In haemorrhagic stroke, these 'phagocytes' try to eat up the red blood cells and toxic factors. However, this job can take time and trying to find a way to help the phagocytes get rid of the blood quicker and more efficiently would help to prevent further damage to the brain. We have discovered that the amount of a protein called 'cholesterol 25-hydroxylase' (Ch25h) goes up in the phagocytes after haemorrhage, and we believe that this protein might help the phagocytes to work better to clear away the blood. In this application we will bring together a unique team of scientists who will use animal models of brain haemorrhage as well as tissue from patients who died from this condition to learn more about what Ch25h is doing in the brain. We will try to work out if Ch25h can help the phagocytes to remove blood. Normally in cells, Ch25h stimulates the production and release of other molecules including 25-hydroxycholesterol (25-HC). We will therefore give 25-HC to animals that have brain haemorrhage and test if this increases how well the blood is removed from the brain, and if it can also improve the symptoms seen in this type of stroke. By doing this work, we hope to identify a potential new way to improve outcome and reduce the negative impact of haemorrhagic stroke, a life-threatening condition with no current treatment options.

Intracerebral haemorrhage (ICH) is the deadliest type of stroke with over 50% mortality that accounts for almost 6% of all global deaths, with those who survive frequently being left with life-changing impairments. Currently there are no effective treatment options for ICH so there is an urgent need for new therapies to improve patient survival and quality of life. The haematoma and erythrocyte breakdown products are responsible for much of the morbidity and mortality associated with ICH. Efficient removal of the haematoma to prevent its damaging effects is therefore key to improving patient outcome. Resolution of the haematoma can occur through endogenous processes including phagocytosis of erythrocytes by resident and invading phagocytes (microglia and monocyte-derived macrophages (MDMs), respectively). However, endogenous clearance is usually incomplete and enhancing this is an alternative therapeutic strategy for ICH. Our preliminary data provides novel evidence that the cholesterol metabolising enzyme cholesterol 25-hydroxylase (Ch25h) can regulate phagocytosis and the efficiency of microglia/MDM-mediated haematoma clearance leading to improved outcome in a mouse model of ICH. Ch25h encodes an enzyme that catalyses the conversion of cholesterol into 25-hydroxycholesterol (25-HC). In this application we will use our complementary expertise to further our understanding of the effects of Ch25h on ICH and determine if we can improve outcome after ICH by stimulating haematoma clearance through modulation of the Ch25h pathway using 25-HC. Completion of this project will identify, for the first time, a novel role for Ch25h in microglia/MDM function and recovery after ICH and, highlight a new therapeutic avenue for improving outcome in ICH patients, an area of significant unmet medical need.