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

Not sure if survivors want to try reduced oxygen after the stroke.

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

Hannelore Ehrenreich MD, DVM 1 

Max Gassmann DVM 2

Luise Poustka MD 3 

Martin Burtscher MD 4 

Peter Hammermann PhD 5 

Anna‐Leena Sirén MD, PhD 6

Klaus‐Armin Nave PhD 7

 Kamilla Miskowiak PhD 8,9 

1 Clinical Neuroscience, Max Planck Institute for Multidisciplinary Sciences, Göttingen,Germany 

2 Center for Integrative Human Physiology,University of Zürich, Zürich, Switzerland 

3 Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen,Germany 

4 Faculty of Sports Science, University of Innsbruck, Innsbruck, Austria 

5 HBL Investmentpartners GmbH, München‐Frankfurt, Germany

6 Departments of Neurophysiology andNeurosurgery, University of Würzburg,Würzburg, Germany 

7 Department of Neurogenetics, Max PlanckInstitute for Multidisciplinary Sciences,Göttingen, Germany 

8 Psychiatric Centre, Copenhagen UniversityHospital, Rigshospitalet, Copenhagen,Denmark 

9 Department of Psychology, University of Copenhagen, Copenhagen, Denmark 

 Correspondence:Hannelore Ehrenreich, MD, DVM, ClinicalNeuroscience, Max Planck Institute forMultidisciplinary Sciences, City Campus,Hermann‐Rein‐Str.3, 37075 Göttingen,Germany.Email:ehrenreich@em.mpg.deandehrenreich@mpinat.mpg.deManaging Editor: Ningning WangFunding informationThis work has been supported by the MaxPlanck Society, the Max PlanckFörderstiftung, the DeutscheForschungsgemeinschaft(DFG, German Research Foundation), viaDFG‐Center for Nanoscale Microscopy &Molecular Physiology of the Brain (CNMPB)and DFG‐TRR 274/1 2020–408885537. MGacknowledges the Swiss National Science 

Abstract 

Hypoxia is increasingly recognized as an important physiologicaldriving 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 O2and 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 O2supply, 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 erythropoiet in expression in the brain likely plays a decisive role in these processes, which can be imitated by recombinant human erythropoiet in treatment. This article review presents hints of how inspiratory O2manipulations 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.