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NOX4 – A novel target for stroke therapy?

The enzyme NOX4 is responsible for the death of nerve cells following a stroke in mice. It produces hydrogen peroxide – a molecule that acts destructive in the body, if its concentrations are pathologically elevated. This discovery was made by researchers Harald Schmidt from Maastricht Uuniversity, Christoph Kleinschnitz from the University of Würzburg and their co-workers as well as from the German Mouse Clinic. It has the potential for more effective therapies of strokes. When the scientists deleted the enzyme in mice or inhibited its activity with an inhibitor, the damage to the brain following a stroke in a mouse model was drastically reduced – even when the inhibitor was administered hours after the stroke.

A stroke is a life threatening event, triggered by insufficient blood flow to the brain, and the second most common cause of death worldwide. Anyone who survives it is often left with permanent damage, such as paralysis or speech disorders. To date only one therapy exists and it is only suitable for a small number of stroke patients. It involves dissolving clots in the brain to eliminate the blood circulation deficiency, but it carries the risk of brain haemorrhages. Evidently, there is an urgent need for new therapies. The hydrogen peroxide formed after a stroke offers a good place to start. However, all attempts to inhibit the effect of this aggressive molecule by scavenging it using antioxidants have failed so far. In contrast, disabling the enzyme NOX4 directly targets the root of the problem by preventing the production of hydrogen peroxide.

Disabling the gene for NOX4 has not triggered any abnormal changes in mice, as established by researchers from the German Mouse Clinic at the Helmholtz Center in Munich. This observation might prove useful for the future development of NOX4 inhibitors with minimal side-effects.

Impetus for therapy for other illnesses

It is likely that hydrogen peroxide and related molecules also play a major role in other illnesses: heart attack, cancer, and Parkinson’s and Alzheimer’s diseases. For all these complaints, antioxidative therapies have been just as unsuccessful to date as they have been for strokes. Harald Schmidt is therefore expecting the new insights to provide fresh impetus for therapy for these diseases as well.

 

Post-Stroke Inhibition of Induced NADPH Oxidase Type 4 Prevents Oxidative Stress and Neurodegeneration”, Christoph Kleinschnitz et al., PLoS Biol 8(9): e1000479. doi:10.1371/journal.pbio.1000479