The Peter Carmeliet lab 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.
Peter Carmeliet (VIB/KU Leuven): “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”.
Reprogramming of glucose metabolism – a first in class mechanism
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. 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. 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.
Dr. Annelies Quaegebeur (VIB/KU Leuven): “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.”
Translational potential of PHD1 inhibition for stroke
While further study is necessary, this research identifies PHD1 as a potential therapeutic target for stroke. Prof. Peter Carmeliet (VIB/KU Leuven): “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.
Quaegebeur et al., Deletion or Inhibition of the Oxygen Sensor PHD1 Protects against Ischemic Stroke via Reprogramming of Neuronal Metabolism, Cell Metabolism (2016)
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