Effect of Tacrine‐3‐caffeic Acid, A Novel Multifunctional Anti‐Alzheimer's Dimer, Against Oxidative‐Stress‐Induced Cell Death in HT 22 Hippocampal Neurons: Involvement of Nrf2/ HO ‐1 Pathway

摘要

Summary Aims Oxidative stress ( OS ) plays an important role in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease ( AD ). This study was designed to uncover the cellular and biochemical mechanisms underlying the neuroprotective effects of tacrine‐3‐caffeic acid (T3 CA ), a novel promising multifunctional anti‐Alzheimer's dimer, against OS ‐induced neuronal death. Methods and Results T 3 CA protected HT 22 cells against high‐concentration‐glutamate‐induced cell death in time‐ and concentration‐dependent manners and potently attenuated glutamate‐induced intracellular reactive oxygen species ( ROS ) production as well as mitochondrial membrane‐potential (ΔΨ) disruption. Besides, T 3 CA significantly induced nuclear factor erythroid 2‐related factor 2 ( N rf2) nuclear translocation and increased its transcriptional activity, which were demonstrated by Western blotting, immunofluorescence, and antioxidant response element ( ARE )‐luciferase reporter gene assay. Further studies showed that T 3 CA potently up‐regulated heme oxygenase‐1 ( HO ‐1), an endogenous antioxidative enzyme and a downstream effector of Nrf2, at both mRNA and protein levels. The neuroprotective effects of T 3 CA were partially reversed by brusatol, which reduced protein level of Nrf2, or by inhibiting HO ‐1 with si RNA or Z n PP ‐ IX , a specific inhibitor of HO ‐1. Conclusions Taken together, these results clearly demonstrate that T 3 CA protects neurons against OS ‐induced cell death partially through Nrf2/ ARE / HO ‐1 signaling pathway, which further supports that T 3 CA might be a promising novel therapeutic agent for OS ‐associated diseases.