CZK, a novel alkaloid derivative from Clausena lansium, alleviates ischemic stroke injury through Nrf2-mediated antioxidant effects.

Anti-oxidant stress is a potential strategy for the treatment of ischemic stroke. Here, we found a novel free radical scavenger termed as CZK, which is derived from alkaloids contained in Clausena lansium. In this study, we first compared cytotoxicity and biological activity between CZK and its parent's compound Claulansine F. It was found that CZK had lower cytotoxicity and improved anti-oxygen-glucose deprivation/reoxygenation (OGD/R) injury than its parent's compound. Free radical scavenging test showed that CZK had a strong inhibitory effect on hydroxyl free radicals with the IC of 77.08 nM. Intravenous injection of CZK (50 mg/kg) significantly alleviated ischemia-reperfusion injury, manifested by reduced neuronal damage and decreased oxidative stress. Consistent with the findings, the activities of superoxide dismutase (SOD) and reduced glutathione (GSH) were increased. Molecular docking predicted that CZK might be combined with nuclear factor erythroid 2-related factor 2 (Nrf2) complex. Our results also confirmed that CZK upregulated the contents of Nrf2 and its target gene products Heme Oxygenase-1 (HO-1), and NAD(P)H: Quinone Oxidoreductase 1 (NQO1). In conclusion, CZK had a potential therapeutic effect for ischemic stroke by activating Nrf2-mediated antioxidant system.