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Oxidative stress mediates the pathogenesis of neurodegenerative disorders. Gartanin, a natural xanthone of mangosteen, possesses multipharmacological activities. Herein, the neuroprotection capacity of gartanin against glutamate-induced damage in HT22 cells and its possible mechanism(s) were investigated for the first time. Glutamate resulted in cell death in a dose-dependent manner and supplementation of 1-10 µM gartanin prevented the detrimental effects of glutamate on cell survival. Additional investigations on the underlying mechanisms suggested that gartanin could effectively reduce glutamate-induced intracellular ROS generation and mitochondrial depolarization. We further found that gartanin induced HO-1 expression independent of nuclear factor erythroid-derived 2-like 2 (Nrf2). Subsequent studies revealed that the inhibitory effects of gartanin on glutamate-induced apoptosis were partially blocked by small interfering RNA-mediated knockdown of HO-1. Finally, the protein expression of phosphorylation of AMP-activated protein kinase (AMPK) and its downstream signal molecules, Sirtuin activator (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), increased after gartanin treatment. Taken together, these findings suggest gartanin is a potential neuroprotective agent against glutamate-induced oxidative injury partially through increasing Nrf-2-independed HO-1 and AMPK/SIRT1/PGC-1α signaling pathways. [ABSTRACT FROM AUTHOR]

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 T3 CA protected HT22 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, T3 CA significantly induced nuclear factor erythroid 2-related factor 2 ( Nrf2) 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 T3 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 T3 CA were partially reversed by brusatol, which reduced protein level of Nrf2, or by inhibiting HO-1 with si RNA or Zn PP- IX, a specific inhibitor of HO-1. Conclusions Taken together, these results clearly demonstrate that T3 CA protects neurons against OS-induced cell death partially through Nrf2/ ARE/ HO-1 signaling pathway, which further supports that T3 CA might be a promising novel therapeutic agent for OS-associated diseases. [ABSTRACT FROM AUTHOR]