Catalpol alleviates hypoxia ischemia-induced brain damage by inhibiting ferroptosis through the PI3K/NRF2/system Xc-/GPX4 axis in neonatal rats.

Hypoxic-ischemic encephalopathy (HIE) is a brain damage caused by perinatal hypoxia and blood flow reduction. Severe HIE leads to death. Available treatments remain limited. Oxidative stress and nerve damage are major factors in brain injury caused by HIE. Catalpol, an iridoid glucoside found in the root of Rehmannia glutinosa, has antioxidant and neuroprotective effects. This study examined the neuroprotective effects of catalpol using a neonatal rat HIE model and found that catalpol might protect the brain through inhibiting neuronal ferroptosis and ameliorating oxidative stress. Behavior tests suggested that catalpol treatment improved functions of motor, learning, and memory abilities after hypoxic-ischemic injury. Catalpol treatment inhibited changes to several ferroptosis-related proteins, including p-PI3K, p-AKT, NRF2, GPX4, SLC7A11, SLC3A2, GCLC, and GSS in HIE neonatal rats. Catalpol also prevented changes to several ferroptosis-related proteins in PC12 cells after oxygen-glucose deprivation. The ferroptosis inducer erastin reversed the protective effects of catalpol both in vitro and in vivo. We concluded that catalpol protects against hypoxic-ischemic brain damage (HIBD) by inhibiting ferroptosis through the PI3K/NRF2/system Xc-/GPX4 axis.