Cutting edge

June 29, 2001

If doctors could understand the link between strokes and brain damage, they might be in a position to develop a treatment

Imagine waking up one morning unable to move major parts of your body. This nightmare is a reality for the many thousands of people who suffer a stroke each year. Almost a third will recover, a third will die and the rest will be severely disabled. There is no effective treatment for sufferers.

The devastating effects of stroke result from parts of the brain being deprived of blood carrying vital oxygen and nutrients, most commonly caused by a blocked artery. Similar damage is caused by a reduced blood supply after a brain haemorrhage, following a head injury, in some patients with heart, circulatory or respiratory disease, or occasionally during major surgery and in babies suffering birth asphyxia.

We want urgently to understand how strokes lead to brain damage and to develop treatment. Research over the past decade has revealed much about what causes a stroke and what happens in the brain when the blood supply is reduced. Nerve cells (neurones) can survive for only a few minutes without oxygen, so damage occurs rapidly. But beyond this "core" of destruction, much larger areas of neurones might die hours later, seemingly "killed" by a barrage of toxic chemicals released from dying neighbours. The key might be to find these "killer molecules" and stop them.

About ten years ago, when we began to tackle the problem, we decided that we might benefit from looking at injuries in other organs. At the time, this approach was unusual because the brain was believed to be very different from the rest of the body. Injury, infection and inflammation in other organs elicit an array of responses designed to combat the condition, but that can often get out of control and cause more problems. At the heart of this are a group of proteins known as cytokines, which influence inflammation, immune responses, cell injury and repair. The first cytokine to be discovered - interleukin-1, or IL-1 - was originally described as an "endogenous pyrogen", a molecule that causes fever by acting in the brain. We know that IL-1 causes other disease symptoms when it acts in the brain, such as loss of appetite, lethargy and sleepiness.

Normally, IL-1 is barely detectable but is produced rapidly after the brain suffers an injury, infection or a stroke. This suggests that it could be involved in brain damage, though it does not tell us how. To find out, we had to try to block IL-1 actions and look at the effect. Designing and testing drugs to block such proteins is a challenging task. However, with IL-1, nature has given us a helping hand. Most cells produce a natural blocker, known as IL-1ra, that prevents all actions of IL-1. We have shown in experimental studies that this blocker dramatically reduces brain injury caused by stroke. These results are very promising, but many exciting laboratory studies have not translated into treatments. Clinical trials in stroke have often failed because of the treatment's side-effects. But none has been reported for IL-1ra, a naturally occurring protein, in normal sufferers or in patients with other diseases. We have obtained funding from the National Lottery as a joint grant from Research into Ageing, and trials of IL-1ra in stroke have begun.

The wait for the results, which will take well over a year, is agonising. No one knows which patient has had IL-1ra or placebo. But if this protein is safe, larger trials may follow and perhaps provide hope and help for the tens of thousands of people who each year suffer the nightmare of stroke.

Nancy Rothwell is Medical Research Council professor in the school of biological sciences at Manchester University.

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