Nodakenin attenuates cerebral ischemia-reperfusion injury by modulating the PI3K/AKT/NF-κB signaling pathway.

OBJECTIVE

The research aimed to explore the protective effect of Nodakenin against cerebral ischemia-reperfusion (I/R) injury and its underlying mechanism, with a particular focus on the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor kappa B (NF-κB) signaling axis, neuroinflammation, oxidative stress and ferroptosis.

METHODS

The function of Nodakenin was investigated in a rat middle cerebral artery occlusion and reperfusion (MCAO/R) model and a PC12 cell oxygen-glucose deprivation and reoxygenation (OGD/R) model. Infarct size was evaluated by 2,3,5-triphenyltetrazolium chloride (TTC) staining, brain edema was quantified using the wet-dry weight method, and histological changes were examined by hematoxylin and eosin (HE) staining. Biochemical assays and Western blotting was detected by malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6), along with PI3K/AKT-NF-κB pathway activity.

RESULTS

Nodakenin treatment reduced infarct volume, histological damage and brain edema in cerebral I/R models. Nodakenin treatment suppressed proinflammatory cytokines, decreased MDA, restored SOD activity and attenuated ferroptosis-related alterations including Fe2+ accumulation and downregulation of GPX4 and FTH1. Consistent effects were observed in PC12 cells subjected to OGD/R. Mechanistically, Nodakenin activated the PI3K/AKT signaling pathway but suppressed NF-κB activation. These protective effects were abolished by PI3K inhibitor LY294002.

CONCLUSION

Nodakenin exerted neuroprotective effects against cerebral I/R injury by regulating the PI3K/AKT/NF-κB pathway to reduce neuroinflammation, oxidative stress and ferroptosis. These findings identify Nodakenin as a promising candidate for limiting secondary injury after ischemic stroke.