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Reductions in levels of the Alzheimer’s amyloid ßbeta; peptide after oral administration of ginsenosides

Mayo Clinic College of Medicine, Departments of Pharmacology and Neuroscience, Jacksonville, Florida, USA

¹Correspondence: Mayo Clinic College of Medicine, Birdsall Bldg. Rm. 327, 4500 San Pablo Rd., Jacksonville, Florida 32224, USA. E-mail: Eckman{at}mayo.edu

SPECIFIC AIMS

Ginseng and several of its components have been used for millennia for the treatment of a variety of conditions, including age-related memory decline. In this manuscript, we examined whether ginseng and several compounds isolated from ginseng are capable of reducing the levels of the Alzheimer’s amyloid ßbeta; (Aßbeta;) peptide both in cell-based assays and in vivo in a mouse model.

PRINCIPAL FINDINGS

1. Ginseng and several of its isolated components result in significant reductions in Aßbeta;42 levels in cell-based assays

1.1 Initial analysis of the effects of ginseng on Aßbeta; levels in a cell-based assay
We have previously reported the development and validation of a high throughput assay for the detection of compounds that can influence the accumulation of Aßbeta;. Using this assay we initially examined the influence of two commonly available ginseng extracts on Aßbeta; levels. As shown in Table 1 , ethanol-derived extracts of both American ginseng and Chinese ginseng resulted in significant, albeit modest, reductions in the longer more pathogenic form of Aßbeta; (Aßbeta;42). Ginseng contains several potentially bioactive compounds, several of which are available in pure form. To determine if any of these could influence Aßbeta; concentration, we analyzed their effects on the assay at 50 µM. As shown in Table 1 , panaxadiol, Rb1, and Rb2 treatment reduced Aßbeta;40 levels without significantly affecting the levels of Aßbeta;42, while panaxatriol showed no significant influence on either Aßbeta;40 or Aßbeta;42. Three particular compounds stood out from this series with respect to their ability to reduce Aßbeta;42, notably ginsenoside Re, which reduced Aßbeta;42 by 32.2 ± 3.3%; ginsenoside Rg1, which reduced Aßbeta;42 by 19.4 ± 4% with no effect on Aßbeta;40; and ginsenoside Rg3, which reduced Aßbeta;42 by 69.3 ± 1.8%.

1.2 Treatment of cells with ginsenoside F11, Re, Rg1, or Rg3 results in a dose dependent decrease in Aßbeta; levels in the conditioned medium
Given the potential role of Aßbeta;42 in Alzheimer’s disease (AD) pathogenesis, we focused the remainder of our studies on those compounds that significantly influenced Aßbeta;42. Dose-response analyses of Re, Rg1, and Rg3 on Aßbeta;40 and Aßbeta;42 levels in the cell-based assays were performed. In addition, dose-response analysis of F11 was also performed given its selective, albeit modest, effects on Aßbeta;42. All four of the compounds showed a dose-responsive influence on the levels of Aßbeta;42 detected in the conditioned medium of CHO-2B7 cells (see main text). Ginsenoside Rg3 appeared the most potent in the series, with an apparent IC₅₀ of <25 µM. Treatment of the cells with 200 µM Rg3 resulted in a substantial 84.4 ± 1.468% reduction in Aßbeta;42 levels. Consistent with a selective effect on Aßbeta;42 observed in the initial screens, all four of the compounds tested showed a lower percent reduction on Aßbeta;40 than on Aßbeta;42.

2. Oral administration of ginsenoside RE, Rg1, or Rg3 results in significant reductions in Aßbeta; levels in the brains of Tg2576 mice, a mouse model of Aßbeta; accumulation

To determine the influence of these compounds on Aßbeta; levels in vivo, we turned to an oral-dosing paradigm in the Tg2576 mouse model. Tg2576 mice, which express the familial Alzheimer’s disease-linked Swedish mutation under control of the prion promoter, accumulate Aßbeta; in an age-dependent fashion and develop plaques associated with dystrophic neurites and prominent gliosis. Although clearly not a faithful model for all aspects of AD pathogenesis, the Tg2576 model is a reasonable model for examining compounds that influence Aßbeta; concentration. Given the limitations on the amount of compound available for testing, we chose to examine the effect of 25 mg/kg of ginsenosides Rg3, Rg1, and Re on Aßbeta; concentration in the brain after a single oral dose. For comparison, we also treated a group of mice with a secretase inhibitor, LY 411575, known to reduce Aßbeta; levels in mice. As shown in Fig. 1 , a single oral dose of ginsenosides Re, Rg1, or Rg3 at 25mg/kg resulted in a significant reduction in Aßbeta;42 concentration in the brain. As in the cell culture model, Rg3 was the most effective Aßbeta;-lowering ginsenoside tested in vivo, with a 31.1 ± 5% reduction in Aßbeta;42 relative to the vehicle control. This compares favorably to the effect we observed at the same time point after treatment of the animals with 10 mg/kg of the secretase inhibitor LY411575. As expected based on the cell culture data, each of the ginsenosides lowered Aßbeta;42 concentration in the brain to a greater extent than Aßbeta;40. Similar to previously published reports, we observed the opposite with LY411575, namely a greater effect on Aßbeta;40 than on Aßbeta;42.

View larger version (11K): [in this window] [in a new window]   Figure 1. Effect of a single oral administration of various ginsenosides on Aßbeta;42 in the brains of Tg2576 mice. LY-411575 is used as a positive control. *Statistically significant: P value Re = 9.2 x 10–5; Rg1 = 0.02; Rg3 = 8.7 x 10–5; LY = 3 x 10–4.

CONCLUSIONS AND SIGNIFICANCE

The abnormal accumulation of the Alzheimer’s Aßbeta; peptide is believed to play a pivotal, if not causal, role in AD. As such, compounds capable of reducing Aßbeta; levels are actively being sought and pursued. Using a high throughput cellular based assay, we examined the effect of ginseng and several isolated ginseng compounds on Aßbeta; concentration. In this study, we report a dose-dependent effect of several ginsenosides on Aßbeta; concentration in the cell-based assays with ginsenoside Rg3 being the most potent in the series we examined with an IC₅₀ of under 25 µM with respect to Aßbeta;42 reduction. Further, studies in the Tg2576 mouse model have indicated that even a single, orally administered dose of ginsenoside Re, Rg1, or Rg3, results in a significant reduction the amount of Aßbeta; detected in the brains of these animals at 18 h postdrug administration. Importantly, these effects were observed after an administration of only 25 mg/kg of the compounds.

Although many compounds capable of reducing Aßbeta; levels are in various stages of the pharmaceutical pipeline, ginseng and its isolated components represent a unique opportunity given that these agents have already had thousands of years of human exposure with little reported toxicity. Although there have been several studies examining the effect of ginseng on behavior, memory, and neurodegeneration in rodents, and several positive studies on its influence on memory in humans, there is a remarkable paucity of studies examining the influence of this natural product or its derivatives in AD. These results, coupled with the positive results on learning and memory, strongly argue for the initiation of a carefully controlled clinical trial to determine the efficacy of ginseng, and particular the ginsenosides Rg3 and Re, in AD. It should be noted, however, that until such a trial is conducted the use of ginseng or its isolated components for the treatment of AD should be carefully considered given the potential for possible side effects and also for natural product-drug interactions that could have deleterious effects.

FOOTNOTES

To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.05-5530fje

This Article Abstract Full Text Full Text (PDF) All Versions of this Article: fj.05-5530fjev1 20/8/1269    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Chen, F. Articles by Eckman, C. B. Search for Related Content PubMed PubMed Citation Articles by Chen, F. Articles by Eckman, C. B.