Progress on Mechanisms of Therapeutic Potential of Oxygen Delivery in Brain Disorders

BACKGROUND: Oxygen is both essential and potentially toxic to the brain, which consumes 20-25% of the body's resting metabolic rate despite comprising only 2% of the total body weight. The exquisite sensitivity of neural tissue to oxygen imbalance positions oxygen delivery as a critical determinant of both pathophysiology and therapeutic opportunity in brain disorders. This review synthesizes recent advances in our understanding of how oxygen sensing and delivery can be harnessed for therapeutic benefit across the spectrum of neurological conditions. SUMMARY: We examine the molecular machinery of oxygen sensing, including the canonical prolyl hydroxylase domain/hypoxia-inducible factor/von Hippel-Lindau (PHD-HIF-pVHL) pathway as well as newly identified oxygen sensors such as Jumonji C domain histone demethylases and 2-aminoethanethiol (cysteamine) dioxygenase. We then explore how perturbations in oxygen delivery contribute to neurodegenerative diseases, stroke, traumatic brain injury, and neurodevelopmental disorders. Emerging therapeutic strategies are critically evaluated, including normobaric and hyperbaric oxygen therapy, therapeutic acute intermittent hypoxia, hypoxia preconditioning, and pharmacological targeting of oxygen-sensing pathways. KEY MESSAGES: Moreover, the emerging concept of tissue-specific oxygen "set points" suggests that both hypoxia and hyperoxia can be pathological and that restoring optimal oxygenation, rather than simply maximizing oxygen delivery, may represent a more nuanced therapeutic approach. Notably, recent preclinical evidence demonstrating that hypoxia itself can reverse pathology in mitochondrial disease models challenges conventional assumptions and opens new avenues for treating brain disorders characterized by relative hyperoxia. Understanding the mechanisms by which oxygen delivery influences neuroinflammation, mitochondrial function, and neural plasticity will be essential for translating these insights into effective clinical interventions.