Abstract
Among a series of xanthones identified from mangosteen, the fruit of Garcinia mangostana L. (Guttifereae), α- and γ-mangostins are known to be major constituents exhibiting diverse biological activities. However, the effects of γ-mangostin on oxidative neurotoxicity and impaired memory are yet to be elucidated. In the present study, the protective effect of γ-mangostin on oxidative stress-induced neuronal cell death and its underlying action mechanism(s) were investigated and compared to that of α-mangostin using primary cultured rat cortical cells. In addition, the effect of orally administered γ-mangostin on scopolamine-induced memory impairment was evaluated in mice. We found that γ-mangostin exhibited prominent protection against H2O2- or xanthine/xanthine oxidase-induced oxidative neuronal death and inhibited reactive oxygen species (ROS) generation triggered by these oxidative insults. In contrast, α-mangostin had no effects on the oxidative neuronal damage or associated ROS production. We also found that γ-mangostin, not α-mangostin, significantly inhibited H2O2-induced DNA fragmentation and activation of caspases 3 and 9, demonstrating its antiapoptotic action. In addition, only γ-mangostin was found to effectively inhibit lipid peroxidation and DPPH radical formation, while both mangostins inhibited β-secretase activity. Furthermore, we observed that the oral administration of γ-mangostin at dosages of 10 and 30 mg/kg markedly improved scopolamine-induced memory impairment in mice. Collectively, these results provide both in vitro and in vivo evidences for the neuroprotective and memory enhancing effects of γ-mangostin. Multiple mechanisms underlying this neuroprotective action were suggested in this study. Based on our findings, γ-mangostin could serve as a potentially preferable candidate over α-mangostin in combatting oxidative stress-associated neurodegenerative diseases including Alzheimer's disease.
Highlights
The generation of reactive oxygen species (ROS) including superoxide anion (⋅O2-), hydroxyl radical (⋅OH), and hydrogen peroxide is recognised as a key factor in oxidative stress to the cells [1]
The H2O2-induced ROS production was significantly inhibited by γ-mangostin at 3~10 μM concentrations (Figure 3(b) (∗, P < 0 05 vs. H2O2-treated cells without α- or γ-mangostin)), which was confirmed by fluorescence microscopy (Figure 3(c))
Α-mangostin showed no significant effects on H2O2-induced oxidative damage or ROS production at the concentrations tested in this study (Figures 3(a)–3(c))
Summary
The generation of reactive oxygen species (ROS) including superoxide anion (⋅O2-), hydroxyl radical (⋅OH), and hydrogen peroxide is recognised as a key factor in oxidative stress to the cells [1]. Oxidative stress-induced neuronal damage has been recognised as an important mechanism involved in many neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease [4, 5]. It has been suggested that an augmentation in the cellular level of ROS and free radicals produces more Aβ peptide, which in turn exerts further oxidative stress and toxic insults on neurons [8]. With the accumulative evidence for oxidative stress as an important factor in AD, antioxidants that reduce ROS and prevent oxidative stress-induced neuronal death have been intriguing potential candidates to prevent or treat AD [4, 5]. Various approaches considering heterogeneous and multifactorial characteristics of AD are attempted to explore favorable efficacy of antioxidant therapy in AD [9]
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