Effects Of Ginsenoside Rg2 On Alzheimer's Disease And Its Mechanism

Alzheimer's disease?AD?is another major disease that threatens human health,after cardiovascular disease,cerebrovascular disease,and tumors.At present,there is no ideal drug that can completely treat AD.Therefore,the development of new drugs for AD treatment has garnered attention.Natural products have the advantage of multiple targets,low toxicity,and wide sources.Screening anti-AD drugs from natural products has become a research hotspot.The treatment of AD by ginseng has become popular in recent years.Ginsenoside is the main active ingredient in ginseng and has anti-tumor,anti-oxidation and protective effects on the nervous system.The objective of this research is to select the active constituents from ginsenosides that confer the anti-AD properties and investigate their mechanism of action.Our experimental strategies and key findings are summarized as follows:1.Ginsenoside Rg2 attenuates A?_25-35-induced neurotoxicity in PC12 cells.A cell culture model of AD was established by using A?_25-35-induced PC12 cells.Monomeric compounds with potential anti-AD properties were initially screened using the MTT assay.Spectrophotometry and fluorescent spectrophotometry were used to detect lactate dehydrogenase?LDH?release,intracellular Ca²⁺concentration,ROS concentration,and caspase-3 activity of PC12 cells.Flow cytometry was used to detect the apoptosis of PC12 cells.The mechanism by which these compounds protect from AD was investigated at the cellular level using the aforementioned indicators.The results showed that ginsenoside Rg2 pretreatment attenuated the following phenotypes:i)A?_25-35-induced cell death,ii)increased release of LDH,iii)increase in Ca²⁺concentration,iv)levels of ROS,and v)increased caspase-3 activity.2.Ginsenoside Rg2 protects PC12 cells from A?_25-35-induced neurotoxicity by enhancing the PI3K/Akt signaling pathwayWestern blotting was performed to detect the levels of Bcl-2,Bax,caspase-3,p-AKT,and AKT.The results showed that ginsenoside Rg2 increased the Bcl-2/Bax ratio.Ginsenoside Rg2 further attenuated the A?_25-35-induced cleavage of caspase-3.It was also found to significantly enhance the phosphorylation of Akt in PC12 cells.Additionally,LY294002 completely abolished the protective effects of ginsenoside Rg2 against A?_25-35-induced neuronal cell apoptosis.These findings unambiguously indicate that the protective effect of ginsenoside Rg2 against A?_25-35-induced apoptosis in PC12 cells is mediated by the PI3K/Akt signaling pathway.3.Ginsenoside Rg2 confers protective effects on hippocampal neurons in a rat model for ADAD model could be set up successfully in rats by injecting A?25-35 into the hippocampus.Morphological and ethological tests were conducted on the model organisms to investigate the mechanism by which ginsenoside Rg2 protects from AD.Upon conducting the Morris water maze test,we found that the escape latency of the rats in the model group was prolonged,the number of platform crossings,the residence time of the effective area,and the ratio of distance from the platform to the total distance decreased significantly when compared to control rats.Compared to the model group,the escape latency of rats was shortened and the number of passages through the platform,the residence time of the effective area,and the distance between the platform and the total distance were significantly increased,in each dose group of ginsenoside Rg2.Therefore,we conclude that ginsenoside Rg2 can improve spatial learning and memory in AD rats.HE and Nissl staining results showed that the hippocampal neurons of rats in the model group were damaged and the number of cells was significantly reduced.Ginsenoside Rg2 can improve the abnormal cell structure in the hippocampus of AD rats and maintain the number of neurons,thus protecting the hippocampal neurons induced by A?_25-35.4.Mechanisms of ginsenoside Rg2 protects rats from A?25-35-induced neurotoxicityWestern blot was used to detect the expression of Bcl-2,Bax,caspase-3,p-AKT,and AKT.High-performance liquid chromatography tandem mass spectrometry was used to study the contents of the monoamine neurotransmitter.The results showed that ginsenoside Rg2 increased the Bcl-2/Bax ratio.Moreover,ginsenoside Rg2 attenuated the cleavage of caspase-3 induced by A?25-35.Ginsenoside Rg2 significantly enhanced the phosphorylation of Akt in PC12 cells.Ginsenoside Rg2 against A?_25-35-induced apoptosis-related protein change.The levels of DA,5-HT,and 5-HIVV in rat brain were significantly decreased in the model group compared with the control group,while the ginsenoside Rg2 group had higher levels of DA and 5-HT than did the model group.The ginsenoside Rg2 group,however,showed no change in the levels of 5-HIVV.This study demonstrates that ginsenoside Rg2 confers protective effects against A?_25–35-induced cell apoptosis both in vitro and in vivo.These protective effects are mediated by the PI3K/Akt pathway.Ginsenoside Rg2 further increases the levels of monoamine neurotransmitters in rat brain to improve the learning ability and memory.These findings,along with similar studies conducted on the mechanism of AD onset in other model systems may provide new tools to cure AD by using natural products.