Timing-dependent neuroprotection of dexamethasone in neonatal hypoxic-ischemic brain injury mouse model : Transcriptomic insights into synaptic signaling and calcium homeostasis

Background: Neonatal hypoxic–ischemic (HI) brain injury is a leading cause of neurodevelopmental disabilities. While dexamethasone has shown potential neuroprotective effects, its molecular mechanisms and the optimal timing of administration remain incompletely understood. Main body: In this study, we investigated the neuroprotective effects of dexamethasone pretreatment in a neonatal hypoxic–ischemic brain injury model and explored the underlying molecular mechanisms using next-generation sequencing (NGS). Neuropathological analysis demonstrated that dexamethasone pretreatment attenuated brain injury. Differentially expressed genes (DEGs) were identified based on an adjusted p-value (FDR) < 0.05 using the Benjamini–Hochberg correction. A total of 962 DEGs were identified, including 407 upregulated and 555 downregulated genes. Functional enrichment analysis revealed that upregulated genes were primarily associated with central nervous system development, synaptic signaling, and ionic homeostasis, whereas downregulated genes were mainly involved in cellular metabolic processes. Protein–protein interaction network analysis further demonstrated that DLG4, CALM1, and GRIN1 were highly interconnected within the enriched signaling pathways. Conclusion: Our findings demonstrate that dexamethasone provides time-dependent neuroprotection by stabilizing synaptic networks and modulating metabolic demand. These results highlight the critical importance of early intervention and provide a molecular framework for developing pharmacological strategies against neonatal HI injury