## 4 Discussion  
The neuroprotective effect of ginsengides against AD have been reported before [38; 39; 40; 41; 42]. Our study reported for the first time that ginseng Rh1 significantly attenuates A\(\beta\) oligomers-induced oxidative stress and cell death in SH-SYSY cells. In addition, we further demonstrated that ginsengide Rh1 protects against A\(\beta\) oligomers-induced cell death by activating the PI3K/Akt/GSK-3 pathway. ROS overproduction is associated with various chronic and degenerative diseases, particularly cancers and neurodegenerative diseases [43]. Various neurodegenerative disorders such as Parkinson's disease, Huntington's disease, and AD may result from biochemical alterations in molecular components due to oxidative stress [44]. The ox  
Figure 5: Ginsensoside Rh1 attenuated neuronal cell death by A\(\beta\)-induced apoptosis in SH-SYSY cells. (**a**) Phospho-Akt (Ser473), (**b**) Phospho-GSK-3B (Ser9), and (**c**) Phospho-p38 MAPK (Thr180/Tyr182). All data are presented as the mean \(\pm\) SE, and the experiments were performed at least three times. ### \(p\) < 0.001 vs. Control (Con), * \(p\) < 0.01, ** \(p\) < 0.05, and *** \(p\) < 0.001 vs. A\(\beta\) oligomers (A\(\beta\)). Figure 6: Ginsensoside Rh1 attenuated A\(\beta\) oligomers-induced neuronal loss, and LY294002 eliminated the protective effects of ginsengide Rh1 in SH-SYSY cells. A\(\beta\) oligomers (4 uM) were added to SH-SYSY cells with LY294002 (10 uM) and ginsengide Rh1 for 24 h. After incubation, cell viability was measured using a CCK-8 assay. All data are presented as the mean \(\pm\) SE, and the experiments were performed at least three times. ### \(p\) < 0.001 vs. Control (Con), *** \(p\) < 0.001 vs. A\(\beta\) oligomers, and $  
idative imbalance that leads to neuronal damage may play a central role in AD, and A\(\beta\) oligomers and their assemblies could instigate neuronal damage by chemically generating ROS [45,46]. The mitochondrial respiratory chain is a significant site of ROS production in cells, and mitochondrial dysfunction is an essential factor involved in the pathogenesis of AD [47]. Therefore, targeting ROS could be a therapeutic approach in treating various neurodegenerative diseases. Ginsenoside Rg1, one of the main constituents of _Panax ginseng_, was found to be metabolized to 20 (S)- protopanaxatriol via ginseng Rh1 and F1 by gut microbiota [48]. Ginsenoside Rh1 is known to exhibit potent anti-aging, anti-inflammatory, antioxidant, immunomododulatory, and positive effects on the nervous system [49]. Also, Rh1 was found to inhibit hydrogen peroxide-induced ROS generation and subsequent cell death in rat primary astrocytes [50]. Moreover, ginseng Rh1 strongly inhibited lipopolysaccharidestandardized intracellular ROS production in RAW 264.7 cells and suppressed NO and ROS in interferon-gamma-stimulated BV2 microglial cells [51,52]. In addition to that, treatment with ginseng Rh1 significantly improved learning and memory ability by promoting cell survival in a mouse model [53]. Additionally, in our study, we found that ginseng Rh1 was able to down-regulate the A\(\beta\) oligomers-induced oxidative stress. The PI3K/Akt signaling pathway plays critical regulatory roles in neuroprotection and apoptosis by mediating ROS production [54]. Also, activation of MAPK is known to produce neuroinflammation-stimulatory responses, as well as cause neuronal cell death [15]. Moreover, recently reported studies indicated the role of GSK-3 and MAPK in hyperphosphorylation of tau, leading to neuronal loss [16,17]. Previous studies have reported that A\(\beta\) oligomers can induce apoptosis in various cell types [55,56]. Therefore, we investigated the PI3K/Akt signaling pathways together with studying GSK-3\(\beta\) and MAPK signaling.