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 (O₂) availability, for example, inspiratory hypoxia at high altitude, allows cells to adapt to lower O₂ 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 O₂ supply, compared to the acutely augmented O₂ requirement. We have coined the term "functional hypoxia" for this important demand-responsive, relative reduction in O₂ 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 O₂ 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.