MRI Visualization of Melatonin‐Promoted Oligodendrogenesis and Its Neuroprotective Effects in Preterm White Matter Injury Rat Model

ABSTRACT Preterm white matter injury (PWMI) is a serious neurologic condition that threatens neonatal survival and severely impairs the cognitive and motor development of affected children. Melatonin (Mel), a neuroendocrine hormone with anti‐inflammatory and antioxidant properties, has shown neuroprotective potential in neonatal brain injury, although the mechanisms underlying its effects in PWMI remain incompletely understood. In this study, we established a neonatal rat model of PWMI and combined multimodal magnetic resonance imaging (MRI) with histological analyses to investigate the effects of Mel on oligodendrocyte precursor cells (OPCs) proliferation, differentiation, and subsequent white matter development. We discovered that Mel administration increased cerebral oxygenation and blood flow, thereby altering the cerebral metabolic microenvironment and mitigating white matter damage caused by hypoxic–ischemic injury. Moreover, Mel promoted the proliferation of OPCs and exerted neuroprotective effects by activating the protein kinase B (AKT)/glycogen synthase kinase 3 beta (GSK‐3β)/β‐catenin signaling pathway. In addition, Mel treatment facilitated neural fiber formation in distant white matter regions of PWMI models, ultimately alleviating cognitive and motor impairments in affected rats. Collectively, these findings suggest that Mel facilitates oligodendrogenesis and white matter repair after PWMI, at least in part through modulation of the AKT/GSK‐3β/β‐catenin pathway. Multimodal MRI can provide a useful noninvasive approach for monitoring treatment‐related changes in white matter injury and development, supporting further investigation of Mel as a potential therapeutic strategy for PWMI.