Neuroprotective Effects of Alpha-Mangostin on MPP⁺-Induced Apoptotic Cell Death in Neuroblastoma SH-SY5Y Cells

Abstract

In vitro studies have shown that extracts from mangosteen (Garcinia mangostana Linn.) act as antioxidants and cytoprotective agents against oxidative damage. The protective effect of alpha-mangostin, the major xanthone found in the pericarp of the mangosteen, in cellular models of Parkinson's disease (PD), has not been investigated. This study aims to investigate whether alpha-mangostin could protect SH-SY5Y neuroblastoma cells from MPP+-induced apoptosis. The effects of alpha-mangostin on MPP+-induced cell death were evaluated with a cell viability assay, staining for nuclear DNA morphology, flow cytometry for apoptotic cells and reactive oxygen species (ROS) production, quantitative real-time PCR for the expression of p53, Bax, and Bcl-2, and western blot analysis for cleaved caspase-3. Concomitant treatment with alpha-mangostin attenuated the effect of MPP+ on cell viability and apoptotic cell death. Alpha-mangostin reduced ROS formation induced by MPP+. Bax/Bcl-2 expression ratio and expression of p53 were significantly lower in cells cocultured with alpha-mangostin and MPP+. The cotreated cells showed a significant decrease in activated caspase-3 compared with MPP+ treatment alone. Our data suggest that cytoprotection of alpha-mangostin against MPP+-induced apoptosis may be associated with the reduction of ROS production, modulating the balance of pro- and antiapoptotic genes, and suppression of caspase-3 activation.

The Pivotal Neuroinflammatory, Therapeutic and Neuroprotective Role of Alpha-Mangostin

“…Studies [2,81,82] have proven that depletion of mitochondrial membrane potential results in reduction in intracellular ATP, downregulation of proapoptotic Bcl-2 and upregulation of antiapoptotic Bax, secretion of cytochrome c from mitochondria into cytosol, stimulation of the caspase cascade, and augmentation of poly (ADP-ribose) polymerase (PARP) cleavage were the main events involved in the mitochondrial apoptotic pathway is triggered by α-MG. Numerous authors [83][84][85] believe that ROS is an interceder during apoptosis signaling. Furthermore, ROS are higher in cells experiencing apoptosis and antioxidants proven to safeguard neuronal cells against apoptosis triggered by a multiplicity of apoptotic mediators.…”

“…Furthermore, ROS are higher in cells experiencing apoptosis and antioxidants proven to safeguard neuronal cells against apoptosis triggered by a multiplicity of apoptotic mediators. Moreover, ROS trigger caspase-3 and caspase-3-like proteases in different cell categories including neuronal cells, resulting in nuclear compression and DNA disintegration [83,[86][87][88][89]. Nevertheless, ROS also trigger apoptosis, possibly by reducing secretion of Bcl-2, an antiapoptotic molecule [83,90,91].…”

“…Moreover, ROS trigger caspase-3 and caspase-3-like proteases in different cell categories including neuronal cells, resulting in nuclear compression and DNA disintegration [83,[86][87][88][89]. Nevertheless, ROS also trigger apoptosis, possibly by reducing secretion of Bcl-2, an antiapoptotic molecule [83,90,91]. Also, Bcl-2 and Bax may regulator the mitochondrial penetrability modification pore, which can instigate the movement of cytochrome c and some apoptosis-triggered dynamics that activate the stimulation of caspase cascade leading to apoptosis [83,90].…”

“…Nevertheless, ROS also trigger apoptosis, possibly by reducing secretion of Bcl-2, an antiapoptotic molecule [83,90,91]. Also, Bcl-2 and Bax may regulator the mitochondrial penetrability modification pore, which can instigate the movement of cytochrome c and some apoptosis-triggered dynamics that activate the stimulation of caspase cascade leading to apoptosis [83,90]. Studies [83,92] have proven that caspase-3 is associated with apoptotic activities happening in the mitochondrial-adjunct pathway, which are related to nuclear compression and DNA cleavage.…”

“…Also, Bcl-2 and Bax may regulator the mitochondrial penetrability modification pore, which can instigate the movement of cytochrome c and some apoptosis-triggered dynamics that activate the stimulation of caspase cascade leading to apoptosis [83,90]. Studies [83,92] have proven that caspase-3 is associated with apoptotic activities happening in the mitochondrial-adjunct pathway, which are related to nuclear compression and DNA cleavage. Furthermore, studies [83,93] have shown that caspase-3 also stimulates phosphatidylserine externalization from the internal to external leaflets of the plasma membrane.…”