Loss of PHD1 Produces Greater Resistance to Stroke Damage

An interesting study on the mechanisms of cell death in stroke came out today. The damage caused by a stroke is the result of cellular reactions to first loss and then restoration of blood flow and thus oxygen supply. Many of these reactions are, strictly speaking, unnecessary and actually directly harmful. Thus tinkering with the regulating mechanisms of these processes may produce benefits by increasing resistance to cell death due to ischemic injuries like stroke. The specific approach taken by researchers here has uncovered an unusually large effect. They propose their findings as a basis for stroke treatment after the fact, but in this new era of cheap genetic engineering, one has to wonder whether a permanent genetic alteration to human patients prior to old age is feasible in this case:

Scientists have identified the oxygen sensor PHD1, also known as EGLN2, as a potential target for the treatment of brain infarction (ischemic stroke). Of all organs in our body, the brain is unique because it needs the highest levels of oxygen and glucose to function and to survive. The simple reason herefore is that brain cells absolutely rely on oxygen and glucose to generate energy, necessary to function normally. In stroke, reduced blood supply therefore threatens this energy balance, causing neurons to die.

Researchers discovered that brain cells sense and adapt to a shortage of oxygen and nutrients via PHD1. They observed that mice lacking the oxygen sensor PHD1 were protected against stroke induced by an obstruction of a main blood vessel supplying oxygen and glucose to the brain. Not only was their infarct size reduced by more than 70% (which is an unusually large beneficial effect), but mice lacking PHD1 also performed much better in functional tests after stroke.

A critical problem when brain cells are deprived of oxygen is that they generate damaging side-products, "oxygen radicals", which kill brain cells. Most previous stroke treatments are unsucessful, because they are based on the principle to target the consequences rather than the cause of these oxygen radicals. Researchers focused on a completely new concept, i.e. utilizing the endogenous power of brain cells to enhance the neutralization of these toxic side-products. The researchers now discovered that inhibition of the oxygen sensor PHD1 protects brain cells against these toxic side-products by reprogramming the use of sugar in low-oxygen conditions. "By reprogramming glucose utilization, neurons lacking PHD1 have an improved capacity to detoxify damaging oxygen radicals, protecting the brain against stroke. This is a paradigm-shifting concept in the field of stroke protection."

Link: http://www.vib.be/en/news/Pages/-VIB-researchers-discover-possible-strategy-against-stroke.aspx