Objective To investigate the effect of norcepharadion B (NB) extracted from Houttuynia cordata on the injury of hippocampal neurons induced by H₂O₂ and its possible mechanism. Methods Hippocampal nerve cells (HT22) in logarithmic growth phase were divided into control group, H₂O₂ group, H₂O₂+NB group, NB group and H₂O₂+NAC group. H₂O₂ group were incubated with H₂O₂ at a final concentration of 300μmol/L for 24h; the H₂O₂+NB group were treated with 100μmol/L NB and H₂O₂+NAC group with 5mmol/L NAC for 2 hours before incubation with H₂O₂ for 24h. To determine whether phosphatidylinositol-3 kinase/protein kinase B/heme oxygenase-1 (PI3K/Akt/HO-1) pathway is involved in the neuroprotection of NB, the neurons were pretreated with Ly294002, a PI3K inhibitor, for 30min before incubation with NB and H₂O₂ for 24h. Cell survival rate was detected by CCK-8 test and apoptosis by flow cytometry. Lactate dehydrogenase (LDH), superoxide dismutase (SOD), glutathione (GSH) and malondialdehydemalonic dialdehyde (MDA) were measured by biochemical kit. Western blotting was performed to detect the expression of B-celllymphoma/leukemia-2 (Bcl-2), Bcl-2 associated X protein(Bax), and phosphorylated Akt (p-Akt) and HO-1. SPSS statistics 19.0 was used for analysis. ANOVA or Tukey′s test was used for intergroup comparison.Results (1) Cell activity. Compared with control group, the survival rate of H₂O₂ group decreased significantly, LDH in the cell supernatant increased significantly, cell shrinkage, vacuole degeneration and cell reduction were observed. However, intervention with NB or NAC significantly increased cell activity, reduced LDH release, and significantly improved cell morphological damage. (2) Oxidative damage indicators. Compared with control group, MDA in H₂O₂ group increased significantly, and SOD and GSH decreased significantly; compared with H₂O₂ group, MDA leakage decreased significantly after the intervention with NB or NAC, and the SOD and GSH activities increased significantly. (3) Apoptosis. Flow cytometry showed that the apoptosis rate in the H₂O₂ group was significantly higher than that in the control group, and the apoptosis rate of H₂O₂ group was significantly lower than that in H₂O₂＋NB group and H₂O₂＋NAC group (P<0.05). Western blotting showed that compared with control group, Bcl-2 in H₂O₂ group decreased significantly, and the Bax level increased significantly; compared with H₂O₂ group, Bcl-2 in the H₂O₂+NB group or H₂O₂+NAC group increased significantly, and the Bax level decreased significantly. (4) Western blotting showed that p-Akt and HO-1 in H₂O₂ group were higher than those in control group, and p-Akt and HO-1 in the NB+H₂O₂ group were significantly higher than those in H₂O₂ group (P<0.05). There was no significant differences between control group and NB group in the indicators all above (P>0.05). In addition, the expression level of p-Akt and HO-1 in Ly294002+H₂O₂+NB group was significantly lower than that in H₂O₂₊NB group. Conclusion NB provides neuroprotection by mitigating the neural injuries induced by H₂O₂ through anti-oxidation and anti-apoptosis, whose underlying mechanism may be attributed to signaling pathway of the activation of the PI3K/Akt/HO-1.