Exploiting moderate hypoxia to benefit patients with brain disease: Molecular mechanisms and translational research in progress

Hypoxia is increasingly recognized as an important physiological driving force. A specific transcriptional program, induced by a decrease in oxygen (O(2)) availability, for example, inspiratory hypoxia at high altitude, allows cells to adapt to lower O(2) and limited energy metabolism. This transcriptional program is partly controlled by and partly independent of hypoxia-inducible factors. Remarkably, this same transcriptional program is stimulated in the brain by extensive motor-cognitive exercise, leading to a relative decrease in O(2) supply, compared to the acutely augmented O(2) requirement. We have coined the term “functional hypoxia” for this important demand-responsive, relative reduction in O(2) availability. Functional hypoxia seems to be critical for enduring adaptation to higher physiological challenge that includes substantial “brain hardware upgrade,” underlying advanced performance. Hypoxia-induced erythropoietin expression in the brain likely plays a decisive role in these processes, which can be imitated by recombinant human erythropoietin treatment. This article review presents hints of how inspiratory O(2) manipulations can potentially contribute to enhanced brain function. It thereby provides the ground for exploiting moderate inspiratory plus functional hypoxia to treat individuals with brain disease. Finally, it sketches a planned multistep pilot study in healthy volunteers and first patients, about to start, aiming at improved performance upon motor-cognitive training under inspiratory hypoxia.