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Exploiting moderate hypoxia to benefit patients with brain disease: Molecular mechanisms and translational research in progress
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Exploiting moderate hypoxia to benefit patients with brain disease: Molecular mechanisms and translational research in progress
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Journal Article
Exploiting moderate hypoxia to benefit patients with brain disease: Molecular mechanisms and translational research in progress
2023
Overview
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. 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. Highlights This review focuses on the brain and sketches hypoxia as a physiological driving force, inducing specific transcriptional programs. Moderate inspiratory hypoxia may improve brain function and performance. Our concept of “functional hypoxia” is introduced as a demand‐responsive mediator of “brain hardware upgrade” on extensive motor‐cognitive exercise. Hypoxia‐induced erythropoietin (EPO) expression in the brain plays a decisive role in these processes, constituting what we coined the “brain EPO circle.” The brain EPO circle underlies the adaptation to challenge, that is, enhanced brain function including cognition and accomplishment on demand: “Brain doping.” Recombinant human EPO imitates the effects of brain‐expressed EPO, explaining the strong neuroprotective and procognitive impact of this treatment. A pilot study in healthy volunteers and first patients is outlined, exploiting moderate inspiratory plus functional hypoxia in humans for improving cognition.
