Hypoxia/reoxygenation cycles, reactive oxygen species and succinate: A mechanistic framework for apnea of prematurity?

We review clinical observations and experimental data to examine the pathophysiological mechanisms by which apnea of prematurity and intermittent hypoxemia destabilizes respiratory control and might lead to neurodevelopmental disorders. Clinically, both apnea and hypoxemia are characterized by marked heterogeneity in definitions, monitoring approaches, and temporal patterns, complicating comparisons across studies. Clinical evidence suggests that cumulative hypoxemic burden, rather than apnea duration alone, is a key determinant of respiratory and neurodevelopmental morbidity in preterm neonates. Repeated hypoxemia-reoxygenation cycles enhance peripheral chemoreceptor sensitivity, narrow the CO₂ reserve, and promote respiratory instability during a critical developmental window. Animal models of intermittent hypoxia demonstrate that this sensitization is mediated by reactive oxygen species (ROS) signaling and a metabolic response involving neuronal adenosine release, activation of xanthine oxidase and NADPH oxidase ultimately converging to inhibition of mitochondrial complex I and metabolic depression during the hypoxic phase. This response is clinically evidenced by a reduction of EEG amplitude occurring during apnea. Recent data suggest that subtle changes in biochemical equilibrium within the Krebs cycle favor succinate accumulation during the hypoxic phase, which is then rapidly oxidized during reoxygenation, leading to enhanced ROS production, as demonstrated in models of ischemia-reperfusion injury and neonatal severe hypoxia. We finally provide preliminary data showing that the succinate dehydrogenase inhibitor dimethyl malonate reduces oxidative phosphorylation in brain sample of mice pups, therefore establishing an experimental framework to address the hypothesis that succinate accumulation contributes to ROS synthesis in a rodent model of apnea of prematurity.