Paeonol alleviates oxidative stress and brain injury in hypoxic-ischemic encephalopathy by activating the PI3K/Akt/Nrf2 signaling pathway.
Abstract
Background
Hypoxic-Ischemic Encephalopathy (HIE) is a severe neonatal neurological disorder, in which oxidative stress serves as a central mediator of brain injury. Paeonol (Pae), a phenolic compound with established anti-inflammatory and antioxidant properties, remains underexplored as a therapeutic strategy for HIE. This study investigated the neuroprotective effects of Pae against HIE-induced brain injury and explored whether its protective effects involves attenuation of oxidative stress through activation of the PI3K/Akt/Nrf2 signaling pathway.
Methods
A neonatal rat HIE model was established using the modified Rice-Vannucci method. Brain injury, oxidative stress markers, and neurological function were assessed through histological staining and behavioral testing. Network pharmacology, molecular docking, and molecular dynamics simulations were used to identify and validate potential targets. An H2O2-induced oxidative stress model in PC12 cells was employed for mechanistic validation, with PI3K and Nrf2 pharmacologically inhibited using LY294002 and ML385, respectively.
Results
Pae significantly reduced cerebral infarct volume and histopathological alterations, attenuated oxidative stress, and improved motor and cognitive performance in HIE rats. Network pharmacology identified the PI3K/Akt as a key target pathway, while molecular docking revealed a strong binding affinity between Pae and AKT1. Consistently, Pae activated the PI3K/Akt pathway, promoted Nrf2 nuclear translocation, and upregulated HO-1 expression in both in vivo and in vitro experiments; these effects were substantially reversed by LY294002 and ML385.
Conclusion
Pae ameliorates HIE-induced brain injury and neurological deficits via activation of the PI3K-Akt signaling pathway and reinforcement of Nrf2-mediated antioxidant defenses. These findings identify Pae as a preclinical neuroprotective candidate worthy of further exploration.