Gartanin Protects Neurons against Glutamate-Induced Cell Death in HT22 Cells: Independence of Nrf-2 but Involvement of HO-1 and AMPK

Abstract

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.

Hypoxia modulates the antioxidant effect of hydroxytyrosol in MCF-7 breast cancer cells

“…The Nrf2 independent induction of HO-1 has been previously reported in the literature. In this sense, the natural xanthone gartanin is known to induce HO-1 independently of Nrf2 [ 47 ], and nitro-linoleic acid was described to promote HO-1 expression in Nrf2 deficient cells through cAMP, AP-1 and E-box response element interactions [ 48 ]. Moreover, in muscle atrophy, HO-1 increase was dependent on forkhead box O1 (FOXO1) but not on Nrf2 [ 49 ].…”

Mangosteen Pericarp and Its Bioactive Xanthones: Potential Therapeutic Value in Alzheimer’s Disease, Parkinson’s Disease, and Depression with Pharmacokinetic and Safety Profiles

“…MP and xanthones derived from MP have recently attracted researchers’ attention for their pharmacological actions in neurons. Firstly, MP-derived xanthones such as garcinone D or gartanin exerted neuroprotective activities and mitigated oxidative injury, possibly via Nrf-2/HO-1 and STAT3/Cyclin D1 [ 17 ], or AMPK/SIRT1/PGC-1α signaling pathways [ 18 ], respectively. In addition, the xanthone derivatives exhibited anti-inflammatory effects in the brain [ 19 , 20 ].…”

Neuroprotective effect of salidroside against central nervous system inflammation‐induced cognitive deficits: A pivotal role of sirtuin 1‐dependent Nrf‐2/HO‐1/NF‐κB pathway

“…Activation of the Nrf‐2/HO‐1 pathway inactivated NF‐κB, reduced airway inflammation, and relieved allergic asthma (Shin et al, ). Increased expression of SIRT1 and Nrf‐2/HO‐1 protected neuron against oxidative injury in HT22 cells (X. Y. Gao, Wang, et al, ). However, whether SIRT1 mediates CNS inflammation‐induced cognitive deficits via antioxidant and anti‐inflammatory damage and the underlying molecular mechanisms need to be further explored.…”