Paeoniflorin mitigates hyperoxia-induced cognitive deficits in neonatal mice by modulating p38/JNK signaling to reduce oxidative stress and neuroinflammation.

Hyperoxia is a common environmental condition associated with oxygen therapy in neonatal intensive care units. This may lead to developmental damage to the hippocampus and long-term impairments in learning and memory. Despite the fact that paeoniflorin (PF) is well-known for its anti-inflammatory and antioxidant qualities, there is still a dearth of systematic research on its ability to improve long-term cognitive deficits after neonatal hyperoxic brain injury, particularly with regard to its role in modulating the p38/JNK MAPK signaling pathway. In this study, the effects of PF on hippocampal injury and cognitive deficits were evaluated in a neonatal mouse hyperoxia exposure model, and its mechanism of action was investigated. Neonatal mice were exposed to hyperoxia (85% oxygen for 7 days) and concurrently received PF administration for 7 days.Compared to the Hyp group, PF significantly reduced oxidative stress in the hippocampus, inhibited microglial activation and the upregulation of inflammatory factors, and alleviated histological damage. In behavioral assessments, PF significantly improved spatial learning and memory deficits, as reflected by the Morris water maze, and increased recognition preference in the novel object recognition task. Further molecular analyses showed that PF significantly inhibited the phosphorylation and activation of p38 and JNK, suggesting that it may exert a neuroprotective effect by modulating the p38/JNK-related inflammation-oxidative stress pathway. These results support PF as a potential therapeutic candidate for hyperoxia-related neurodevelopmental injury and provide experimental evidence for mechanistic research and drug development targeting perinatal oxygen therapy-related brain injury.