The oxygen-sensing prolyl hydroxylase domain proteins (PHDs) regulate cellular metabolism, but their role in neuronal metabolism during stroke is unknown.
Researchers report that PHD1 deficiency provides neuroprotection in a murine model of permanent brain ischemia.
This was not due to an increased collateral vessel network. Instead, PHD1−/− neurons were protected against oxygen-nutrient deprivation by reprogramming glucose metabolism.
Indeed, PHD1−/−neurons enhanced glucose flux through the oxidative pentose phosphate pathway by diverting glucose away from glycolysis. As a result, PHD1−/− neurons increased their redox buffering capacity to scavenge oxygen radicals in ischemia.
Intracerebroventricular injection of PHD1-antisense oligonucleotides reduced the cerebral infarct size and neurological deficits following stroke.
These data identify PHD1 as a regulator of neuronal metabolism and a potential therapeutic target in ischemic stroke.