Study On The Effects And Mechanisms Of Ginsenoside Re In An Alzheimer's Disease Mouse Model Through A Metabonomic Method

Objective: Alzheimer's disease(AD)is a lethal neurodegenerative disease.The pathogenesis of AD is complex,and there are presently no approved treatments that can slow its progression.It has been reported that ginsenoside Re(G-Re),an active pharmacological component of ginseng,can ameliorate the symptoms of AD,but the underlying mechanisms are not clear.In this study,we used the metabolomics technology to study the regulatory mechanism of G-Re on biomarkers in AD model mice,providing novel ideas for the early diagnosis,precise medicine and drug development of AD.Methods: An AD animal model was induced by intracerebroventricular injection of ?-amyloid in 12-week-old healthy male Kunming mice.Mice were randomly divided into four groups(eight animals in each group): control(saline-lesioned,saline-treated),AD(A?-lesioned,saline-treated),high-dose G-Re(A?-lesioned,treated with G-Re at 4 mg/kg/day),and low-dose G-Re(A?-lesioned,treated with G-Re at 1 mg/kg/day),and delivered by intragastric administration for 30 days.Cognitive function of the mice was tested using a Morris water maze,and pathological changes in the brain tissue were assessed by immunohistochemistry.Global metabolite profiling using ultra performance liquid chromatography–mass spectrometry was carried out to identify the metabolites that were differentially expressed in the plasma of mice.Results: 1.G-Re improved the learning and memory ability of AD mice.In the 5-day place navigation trial,the escape latency of the AD model group was markedly longer than that of the control group(p < 0.05),and the treatment with high doses of G-Re reduced the escape latency on the latter two training days in contrast with the AD group(p < 0.05).In the spatial exploration trial,the lengths of time spent in the target quadrant were obviously shorter and the number of crossings of the previous position of the platform were clearly lower in the AD model group than in the control group(p < 0.05),whereas a reverse trend was shown after the treatment with high doses of G-Re(p < 0.05).2.G-Re reduced A? accumulation in the brains of AD mice.By observing the cerebral cortex and hippocampi of mice,the neurons were tightly arranged with large and regular nuclei with clear nucleoli in the control group,and no A? deposition was observed.In the AD model group,in contrast,the neurons were sparsely distributed with darkly stained nuclei,and there were dark brown,compact A? deposits.In the high-dose G-Re treatment group,the abnormalities observed in the AD mice gradually improved: clear nucleoli were visible and the A? deposits were light brown and sparser.3.G-Re restored plasma metabolic alterations in AD mice.A total of 10 potential biomarkers were identified in the plasma of AD mice.The peak intensities of tryptophan,hexadecasphinganine,phytosphingosine,and various lysophosphatidylcholines were lower whereas that of phenylalanine was higher in the AD mice than in the control mice.The peak intensities of phenylalanine were reduced in the plasma of G-Re treatment group compared to the AD group(p < 0.05),while those of tryptophan,hexadecasphinganine,phytosphingosine,and the LPCs were significantly raised(p < 0.05).Conclusion: Ginsenoside Re can improve the learning and memory abilities of AD mice and reduce the deposition of A? in mice brains through the intervention of metabolic pathways related to amino acids,lecithin and sphingolipid,and thus exert the therapeutic effect on AD.