Hypoxic preconditioning improves long-term functional outcomes after neonatal hypoxia-ischemic injury by restoring white matter integrity and brain development

Aims Neonatal hypoxia-ischemia (H/I) results in gray and white matter injury, characterized by neuronal loss, failure of neural network formation, retarded myelin formation, and abnormal accumulation of oligodendrocyte progenitor cells (OPCs). These changes lead to severe neurological deficits and mortality. Sublethal hypoxic preconditioning (HPC) can protect the developing brain against H/I. However, limited evidence is available concerning its effect on white matter injury. Methods In this study, P6 neonatal Sprague-Dawley rats were subjected to normoxic (21% O-2) or HPC (7.8% O-2) for 3 hours followed 24 hours later by H/I brain injury. Neurological deficits were assessed by gait, righting reflex, foot fault, and Morris water maze tests. Compound action potential of the corpus callosum was recorded 35 days after surgery, and the correlation between axon myelination and neurological function was determined. Results Hypoxic preconditioning significantly attenuated H/I brain injury at 7 days and remarkably improved both sensorimotor and cognitive functional performances up to 35 days after H/I. HPC-afforded improvement in long-term neurological outcomes was attributable, at least in part, to restoration of the differentiation and maturation capacity in oligodendrocyte progenitor cells, amelioration of microglia/macrophage activation and neuroinflammation, and continuation of brain development after H/I. Conclusions Hypoxic preconditioning restores white matter repair, development, and functional integrity in developing brain after H/I brain injury.