Inhibition of Oxidative Neurotoxicity and Scopolamine- Induced Memory Impairment by gamma-Mangostin: In Vitro and In Vivo Evidence

Abstract

Among a series of xanthones identified from mangosteen, the fruit of Garcinia mangostana L. (Guttifereae), alpha- and gamma-mangostins are known to be major constituents exhibiting diverse biological activities. However, the effects of gamma-mangostin on oxidative neurotoxicity and impaired memory are yet to be elucidated. In the present study, the protective effect of gamma-mangostin on oxidative stress-induced neuronal cell death and its underlying action mechanism(s) were investigated and compared to that of gamma-mangostin using primary cultured rat cortical cells. In addition, the effect of orally administered gamma-mangostin on scopolamine-induced memory impairment was evaluated in mice. We found that gamma-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, alpha-mangostin had no effects on the oxidative neuronal damage or associated ROS production. We also found that gamma-mangostin, not alpha-mangostin, significantly inhibited H2O2-induced DNA fragmentation and activation of caspases 3 and 9, demonstrating its antiapoptotic action. In addition, only gamma-mangostin was found to effectively inhibit lipid peroxidation and DPPH radical formation, while both mangostins inhibited beta-secretase activity. Furthermore, we observed that the oral administration of gamma-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 gamma-mangostin. Multiple mechanisms underlying this neuroprotective action were suggested in this study. Based on our findings, gamma-mangostin could serve as a potentially preferable candidate over alpha-mangostin in combatting oxidative stress-associated neurodegenerative diseases including Alzheimer's disease.