Proteins are commonly viewed as the workhorses in our bodies, performing critical functions within our cells and organs. Some proteins control the activity of genes; among these are the oxygen-sensing prolyl hydroxylase domain proteins (PHDs), which regulate cellular metabolism. A new study has identified PHD1 as a potential target for the treatment of cerebral infarction, more commonly referred to as ischemic stroke.

Ischemic stroke occurs when an artery to the brain, which carries fresh blood from the heart and lungs, becomes blocked. Blood supplies oxygen and glucose to the brain cells, so when an ischemic stroke occurs, these individual oxygen and nutrient-deprived neurons cannot metabolize and soon all function pauses. Meanwhile, the oxygen-deprived cells generate toxic side-products, known as oxygen radicals, which begin to kill brain cells.

Naturally, then, immediate medical treatment is crucial for anyone suffering an ischemic stroke, which all too commonly results in severe disability or even death. Yet, current stroke treatments target the consequences instead of the cause of oxygen radicals. A team of scientists from VIB, a research institute in Belgium, and University of Leuven, decided to focus their research on using the innate power of brain cells to neutralize the lethal side-products of stroke.

Power Within the Neuron

Working with mice, Dr. Peter Carmeliet and his colleagues observed how brain cells sense and adapt to a shortage of oxygen and nutrients via the oxygen-sensor PHD1. Next, the researchers genetically engineered a group of mice to lack PHD1 and induced a stroke in these rodents by obstructing a main blood vessel to the brain. Surprisingly, these mice demonstrated natural protections against stroke.

The genetically-engineered mice lacking in PHD1 not only had a substantially reduced infarct size — by more than 70 percent — but these rodents also performed much better in functional tests after the induced stroke. Examining the process more closely, the team discovered that the inhibition of PHD1 forced neurons to reprogram their use of sugar in the low-oxygen environment.

"By reprogramming glucose utilization, neurons lacking PHD1 have an improved capacity to detoxify damaging oxygen radicals, protecting the brain against stroke," Dr. Annelies Quaegebeur, first author of the study, said in a statement.

While more research is needed, the team is hoping to develop PHD1 as a therapeutic target for stroke. So far, their efforts appear rosy. According to Carmeliet, treating a group of mice with a pharmacological PHD1 blocker protected them against stroke in a similar manner as the genetically-engineered lack of PHD1.

Source: Quaegebeur A, Segura I, Schmieder R, et al. Deletion or Inhibition of the Oxygen Sensor PHD1 Protects against Ischemic Stroke via Reprogramming of Neuronal Metabolism. Cell Metabolism. 2016.