Highlights • Genetic loss of PHD1 provides substantial protection against brain ischemic injury • PHD1 loss reprograms glucose metabolism without vascular changes • Increased oxPPP flux, at the expense of glycolysis, enhances redox balance in neurons • Intracerebroventricular delivery of anti-PHD1 oligos protects against stroke
Despite (minor) improvements in stroke treatment, stroke remains the 4th leading cause of death and the most common reason of severe disability. Research led by Prof. Peter Carmeliet and Dr. Annelies Quaegebeur (VIB/KU Leuven) indicates inhibition of PHD1 offers protection against stroke, via an unexpected mechanism, raising hope for future stroke treatment.
Brain cells rely on oxygen and glucose to generate energy, necessary to function normally. In stroke, reduced blood supply threatens this energy balance, causing neurons to die. The Carmeliet lab discovered that brain cells sense and adapt to a shortage of oxygen and nutrients via PHD1.
The Peter Carmeliet lab observed that mice lacking 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 > 70% (which is an unusually large beneficial effect), but mice lacking PHD1 also performed much better in functional tests after stroke. Peter Carmeliet: “These results established for the first time that blocking PHD1 offered large protection against irreparable brain damage when blood vessels can no longer supply vital nutrients to brain cells.”
A critical problem when brain cells are deprived of oxygen is that they generate “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. The Peter Carmeliet lab focused on a completely new concept, i.e. utilizing the endogenous power of brain cells to enhance the neutralization of these toxic side-products. Inhibition of PHD1 reprograms the use of sugar in low-oxygen conditions.
Dr. Annelies Quaegebeur: “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.”
Prof. Peter Carmeliet: “Similar to genetic loss of PHD1, treating mice with a pharmacological PHD1 blocker protected mice against stroke. This raises the possibility that PHD1 inhibition might be clinically useful, but future research will be necessary to unveil the therapeutic potential in this debilitating disorder. http://www.vib.be/en/news/Pages/-VIB-researchers-discover-possible-strategy-against-stroke.aspx
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