Oxytocin Regulated Neuroinflammation through OTR/Mitochondria Mediated Pathway to Improve Hypoxia-Induced Brain Injury.

Neonatal hypoxic-ischemic encephalopathy, a severe consequence of birth asphyxia, remains a leading cause of newborn mortality and permanent neurological disabilities worldwide. The limited therapeutic options and incomplete understanding of its pathological mechanisms present significant challenges in clinical management. This study aimed to investigate the therapeutic effects of oxytocin on hypoxic brain injury and elucidate its underlying molecular mechanisms. Five-day-old C57BL/6 mice were subjected to hypoxia (10% oxygen) for 7 days, with or without oxytocin treatment (0.1 mg/kg, i.p., every other day). Brain sections were examined by H&E and Nissl staining, TUNEL assay, and immunofluorescence. Western blot and real-time PCR were performed to analyze protein expression and mitochondrial DNA content in cortical tissues. OT treatment attenuated hypoxia-induced brain injury, as evidenced by improved histological outcomes in H&E and Nissl staining. OT significantly reduced neuronal apoptosis shown by TUNEL staining and decreased cleaved-caspase3 expression in cortical tissues. Furthermore, OT maintained mitochondrial homeostasis by regulating fusion-fission dynamics and mtDNA content. OT also suppressed microglial activation and neuroinflammation through downregulating NF-κB signaling and NLRP3 inflammasome. These protective effects were partially reversed by the OTR antagonist Cligosiban. Our findings demonstrate that OT protects against hypoxic neonatal brain injury via OTR signaling, which maintains mitochondrial homeostasis and prevents neuronal apoptosis and neuroinflammation. This study provides experimental evidence for OT as a potential therapeutic agent in treating hypoxic brain injury.