Mechanisms of interleukin-1 action in neuronal injury

The blood supply to the brain provides essential oxygen and nutrients to support brain function. During stroke, haemorrhage (bleeding), head injury and certain types of dementia, the blood supply to the brain may be partially reduced or blocked, with fatal consequences for the patient. Our work focuses on understanding what happens in the brain and the rest of the body when the blood supply is reduced, in order to develop safer and more effective treatments for stroke. We have discovered that, in animal brains, a molecule normally associated with inflammation and infection (called interleukin-1 or IL-1 for short) increases when the blood supply is blocked. IL-1 can then kill brain cells, most importantly the nerve cells (neurones), which are essential for the brain to work properly. Our work in animals has already led to the testing of a drug that blocks the effects of IL-1 in stroke patients. However, to develop successful treatments for stroke and other conditions, we need to better understand how IL-1 kills brain cells either directly or by releasing killer molecules from other brain cells. We will test our discoveries in relevant animal models of disease and are well placed to take these findings into patients. This work may lead to new ways of blocking IL-1 and possible new treatments for stroke and related diseases.

Cerebral ischaemia is one of the leading causes of death and disability worldwide. It occurs in stroke, sub-arachnoid and intra-cerebral haemorrhage, brain trauma, surgery and tumours, birth asphyxia and vascular dementia. Despite its devastating consequences there are few, if any, effective treatments, and a history of hundreds of failed trials. These failures may be for a number of reasons, including the choice of targets, animal models (which fail to replicate human pathology), and poor recognition that cerebral ischaemia is heavily dependent on processes occurring within the vasculature. The programme addresses these concerns and builds on our record of discovery in cerebral ischaemia. We have demonstrated the importance of central nervous system inflammation and the contribution of the pro-inflammatory cytokine interleukin-1 (IL-1) to experimental brain injury, and conducted a Phase II trial of IL-1 receptor antagonist in acute stroke.
Our overall objective is to fully elucidate the mechanisms of IL-1 action in neuronal injury and to optimise new targets for the treatment of cerebral ischaemia. More specifically, within this programme of work we will:
I. Identify how IL-1 acts on astrocytes and endothelial cells to cause neuronal injury
II. Determine how IL-1 modifies neuronal susceptibility to injury
III. Translate findings to identify and validate new targets and interventions in CI
The proposed studies will use a combination of molecular, cellular and in vivo approaches, to not only identify the downstream mediators of IL-1 action, but also the interplay between the multiple cellular effects of IL-1 that we have identified to date. All in vitro findings will be validated in vivo in animal models of ischaemic brain injury. We will then take forward identified interventions, which show significant neuroprotection, for further validation as potential treatments.
This programme of translational research will relate closely to our ongoing clinical studies. We have extensive published and preliminary data supporting our hypotheses, established techniques and very experienced research staff.