An international team of researchers has come up with a novel way of treating strokes by blocking the activity of an enzyme responsible for much of the damage caused to brain cells in the period following a stroke. The findings represent a major step forward in the search for new treatments for ischemic stroke, which is the second leading cause of death worldwide. EU support for the study, published in the journal PLoS (Public Library of Science) Biology, came from the EUMODIC ('The European mouse disease clinic: a distributed phenotyping resource for studying human disease') project, which is funded to the tune of EUR 12 million under the 'Life sciences, genomics and biotechnology for health' Thematic area of the Sixth Framework Programme (FP6). Earlier work on stroke treatments focused on oxidative stress, which is caused by 'reactive oxygen species' (ROS); however, treating patients with antioxidants has failed in clinical trials. In this latest study, the scientists from Australia, Germany, the Netherlands and the UK took a different approach, by preventing the production of ROS in the first place. They discovered that much of the damage caused in the aftermath of a stroke can be attributed to an enzyme called NOX4, which produces hydrogen peroxide (H2O2), a chemical commonly used in bleaching products. The team genetically engineered mice lacking the gene that produces NOX4; when these mice suffered a stroke, their brains experienced less damage than mice with working versions of the NOX4 gene. Most notably, the mice lacking the NOX4 gene scored better on tests to evaluate their neurological and motor functions and coordination. The effects of deleting the NOX4 gene were the same for male and female mice and for young and old animals - an important issue when one considers that stroke is primarily a disease of the elderly and gender has an influence on outcomes. Having ascertained the role of NOX4 in stroke damage, the team set out to test ways of exploiting this knowledge for treatment purposes. Fortunately, there is already a drug, called VAS2870, designed to block the activity of NOX4. The team discovered that treating mice with VAS2870 has the same effect as deleting the NOX4 gene, thus reducing brain damage and improving neurological function, even when administered hours after a stroke. Furthermore, blocking the action of NOX4 in this way did not appear to cause problems in other parts of the body where NOX4 is normally active such as the blood vessels that serve the kidneys and heart. 'NOX4 thus represents a most promising new therapeutic target for reducing oxidative stress in general, and brain injury due to stroke in particular,' the researchers conclude. Ischemic stroke occurs when the blood supply to the brain is disrupted, either because of a drop in blood pressure or because of a blockage in blood vessels. If the blood supply to the brain is not restored rapidly, the affected brain tissues can die, resulting in serious mental and physical problems and, in the worst cases, death. The elderly are at the greatest risk of stroke, and as populations age the incidence of this serious medical condition is likely to rise. Today, there is just one approved drug to treat strokes. However, it is far from perfect. 'It involves dissolving clots in the brain to eliminate the blood circulation deficiency, but it carries the risk of brain haemorrhages,' explains the lead author of the paper, Christoph Kleinschnitz of the University of Würzburg in Germany. In fact, the drug's effectiveness is described as 'moderate', and it can only be used in around 10% of patients. The other 90% are excluded because of contraindications. Attempts to develop additional drugs to treat strokes have so far met with failure; although many proved effective in animals, they did not work in humans. 'As a result, many pharmaceutical companies have withdrawn from drug discovery in this area,' the researchers note. Pharmacologist Professor Harald Schmidt of Maastricht University in the Netherlands led the research. He believes that the strategy of stopping oxidative stress at its source could be applied to other major health problems. He says: 'Inhibiting now the source of hydrogen peroxide or oxygen radicals may represent the long-sought solution to treating also heart attacks, heart failure, cancer, and other forms of nerve cell degeneration such as in Parkinson's or Alzheimer's disease.'
Australia, Germany, Netherlands