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(The FASEB Journal. 2006;20:1269-1271.)
© 2006 FASEB

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

Feng Chen, Elizabeth A. Eckman and Christopher B. Eckman1

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

ABSTRACT

For millennia, ginseng and some of its components have been used to treat a wide variety of medical conditions, including age-related memory impairment. Because of its purported effects and apparently low rate of side effects, ginseng remains one of the top selling natural product remedies in the United States. Given its potential role for improving age-related memory impairments and its common use in China for the treatment of Alzheimer’s disease-like symptoms, we analyzed the effects of commercially available preparations of ginseng on the accumulation of the Alzheimer’s amyloid ß peptide (Aß) in a cell-based model system. In this model system, ginseng treatment resulted in a significant reduction in the levels of Aß in the conditioned medium. We next examined the effects of several compounds isolated from ginseng and found that certain ginsenosides lowered Aß concentration in a dose-dependent manner with ginsenoside Rg3 having an approximate IC50 of under 25 µM against Aß42. Furthermore, we found that three of these isolated components, ginsenoside Rg1, Rg3, and RE, resulted in significant reductions in the amount of Aß detected in the brains of animals after single oral doses of these agents. The results indicate that ginseng itself, or purified ginsenosides, may have similarly useful effects in human disease.—Chen, F., Eckman, E. A., Eckman, C. B. Reductions in levels of the Alzheimer’s amyloid ß peptide after oral administration of ginsenosides.


Key Words: ginseng • Rg1 • Rg3 • RE • Tg2576

ALZHEIMER’S DISEASE (AD) is the most common form of dementia in the elderly. Without a treatment that significantly delays the progression of the disease, almost 14 million Americans are likely to be affected with AD by the middle of the 21st century, presenting an enormous economic and social burden (1) . Currently, approved therapeutics for the treatment of AD provide some symptomatic relief but do not substantially alter the course of the disease. Evidence gathered over the last 20 yr has strongly implicated the abnormal accumulation of the Alzheimer’s amyloid ß peptide (Aß) as a pivotal, if not causal, factor in the disease process (2 3 4) . As such, compounds that reduce Aß accumulation continue to be developed by almost every major pharmaceutical company and throughout the biotech and academic communities.

Ginseng (C. A. Meyer) has been used in traditional Chinese medicine for thousands of years to promote general well-being and to treat a variety of disorders, especially those associated with aging (5) . Recent surveys indicate that ginseng is one of the most commonly used natural products by adults in the United States with usage rates ranging up to 30% depending on the study and on the geographical area being sampled (6 7 8) .

There are seven species of ginseng grown in Asia and North America (9) . Of these, the three most commonly used and studied are Panax ginseng (Asian ginseng), Panax quinquefolius (American ginseng), and Panax japonicus (Japanese ginseng). Many components of ginseng, including ginsenosides, polysaccharides, peptides, polyacetylenic alcohols, and fatty acids, have been shown to be biologically active (5) . Most of the pharmacological activities of ginseng that have been identified to date, however, are attributed to the ginsenosides, which are structurally similar to steroid hormones (10) .

Despite its wide use, the number of carefully controlled clinical trials examining the influence of ginseng on memory is limited and interpretation is complicated due to the different types of extracts and even different ginseng species being used in different trials. For example, a 1999 comprehensive review (11) of randomized clinical trials of ginseng for any condition (physical performance, cognitive function, immune function, diabetes, and herpes simplex type-II infection) identified only 16 trials of ginseng mono-preparations that satisfied criteria of methodological quality. At least four different placebo-controlled trials of the effects of ginseng on cognitive function in healthy volunteers reported significant positive changes compared with either baseline or control groups (12 13 14 15) . More recently, Kennedy and colleagues (16 17 18 19) reported a series of double-blind, counterbalanced, placebo-controlled trials examining the effects of a single dose of standardized ginseng extract, G115, alone or in combination with other natural products, on cognitive performance and mood in healthy young volunteers. These investigators found that the "optimal dose" of ginseng significantly improved secondary memory performance, including immediate and delayed word recall and also enhanced the speed of memory task performance, although doses lower or higher than the "optimal dose" actually reduced task speed. Further they found that ginseng treatment led to a significantly decreased latency of the P300 component of the auditory-evoked potential, as well as decreased alpha, beta, and theta waveband activity in the resting "eyes closed" EEG (20) , indicating that ginseng can affect bioelectric activity in the brain while improving measures of cognitive function.

Despite its use as a memory-enhancing agent, there is a surprising paucity of data concerning the efficacy of ginseng for memory impairment in patients with AD. One published study (21) investigated the effects of a traditional Chinese medicine (a mixture of 9 natural product extracts including ginseng) on dementia using the Mini-Mental State Examination (MMSE) and other potential markers such as the P300 component of the auditory-evoked potential, cerebral blood flow, and {alpha}-aminobutyric acid levels in CSF. Ten AD patients were treated with the mixture for 3 months. There was no placebo-controlled group. The results of this small pilot study are nonetheless provocative, with significant improvements reported in all of the measures listed above. The change in P300 may be particularly interesting, as the P300 event-related brain potential, which is believed to reflect attention and memory processing, has been shown to be altered in AD (22 23 24) .

In this study, we have directly examined the influence of ginseng and several isolated ginsenosides on the accumulation of the Alzheimer’s Aß peptide in both cell culture models systems and in an animal model. These results, coupled with the provocative studies reported on ginseng’s ability to promote memory improvement, strongly argue for a carefully controlled clinical study to examine the influence of ginseng and, perhaps more importantly, several isolated ginsenosides on AD.

MATERIALS AND METHODS

Chemicals and reagents
Extracts of American ginseng and Chinese ginseng were purchased from HerbPharm (Williams, OR). Ginsenosides Re, Rg1, Rg3, Rb1, Rb2, panaxadiol, panaxatriol, pseudoginsenoside F11, and notoginsenoside R1 were purchased from the National Institute for the Control of Pharmaceutical and Biological Products (Beijing, China). For in vivo studies, the ginsenosides Re, Rg1, and Rg3 were first assessed for purity and structural identity using both mass spectrometry and NMR by the Mayo Clinic Chemistry Core Facility.

Cell culture and drug screening
A Chinese hamster ovary (CHO) cell line stably transfected with human ßAPP 695wt, CHO 2B7 (25 ,26) , was cultured in Ham’s F-12 medium (Life Technologies, Inc.) with 10% newborn calf serum, penicillin/streptomycin and maintained in 100 µg/mg Zeocin (Invitrogen). Confluent CHO 2B7 cells were seeded into 96-well plates and treated with the indicated concentration of each of the ginsenosides for 3 h. All wells contained identical concentrations of DMSO. After treatment, the medium was removed for Aß analysis and for assessment of LDH release and the remaining cells were analyzed by MTS (Cell Titer 96® Aqueous Non-Radioactive Cell Proliferation Assay (Promega)) for changes in cellular metabolism as we have done previously (25) .

Determination of Aß concentration
Aß40 and Aß42 were measured by sandwich ELISA essentially as described previously (25 ,27) , except that antibody pairs 2.1.3.35.86/4G8 and 33.1.1/13.1.1 were used to detect Aß42 and Aß40, respectively. Aß concentration was determined by comparing values obtained for samples with those obtained for synthetic Aß42 and Aß40 standards (Bachem). Values are means ± the SE obtained from triplicate culture wells.

In vivo compound testing
Three- to four-month-old female transgenic mice overexpressing the human APP gene containing the Swedish mutation that causes familial AD (Tg2576 line; ref 28 ) were used for testing the effects of ginsenoside Re, Rg1, and Rg3 in vivo under a protocol approved by the Mayo Foundation Institutional Animal Care and Use Committee. The compounds were initially dissolved in DMSO and then diluted to an appropriate stock concentration in 0.9% sodium chloride. All animals were dosed orally (po) by gavage (20 G needle from Braintree Scientific Corp.). The volume administered was maintained constant at 8 ml/kg of body wt (i.e., 200 µl for a typical 25 g mouse) such that the concentration of the compounds administered was 25 mg/kg of body wt for ginsenosides Re, Rg1, and Rg3 and 10mg/kg for the positive control drug LY-411575. The final concentration of DMSO in the administered dose was controlled <2.5%. Eighteen hours after compound administration, the animals were killed and their brains were removed for analysis. For Aß analysis, hemibrains were dounce homogenized in 70% formic acid at 150 mg tissue/ml formic acid solution. Homogenates were transferred to a chilled ultracentrifuge and were then spun at 100,000 g for 1 h at 4°C. Supernatants were collected and neutralized with formic acid neutralization buffer (1.0 M Tris base, 0.5 M NaH2PO4, and 0.05% NaN3; 1:20) for Aß quantitation by ELISA. Aß40 and Aß42 were assayed by ELISA similar to that described for the cell-based studies above. Four individual experiments were performed. To compare across studies, the values for an individual study were normalized using the values obtained for the control animals included in each study. Values represent the mean ± SE for the n number shown, after normalizing.

RESULTS

We have previously reported the development and validation of a high throughput assay for the detection of compounds that can influence the accumulation of Aß (25) . Using this assay, we initially examined the influence of two commonly available ginseng extracts on Aß 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 Aß (Aß42). As discussed above, ginseng contains a number of potentially bioactive compounds, several of which are available in pure form. To determine if any of these could influence Aß concentration, we analyzed their effects on the assay at 50 µM. As shown in Table 1 , panaxadiol, Rb1, and Rb2 treatment reduced Aß40 levels without significantly affecting the levels of Aß42 while panaxatriol showed no significant influence on either Aß40 or Aß42. Three particular compounds stood out from this series with respect to their ability to reduce Aß42, notably ginsenoside Re, which reduced Aß42 by 32.2 ± 3.3%; ginsenoside Rg1, which reduced Aß42 by 19.4 ± 4% with no effect on Aß40; and ginsenoside Rg3, which reduced Aß42 by 69.3 ± 1.8%.


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  		Table 1. Influence of various preparations of ginseng and several isolated ginsenosides (at 50 µM) on Aß42 accumulation in conditioned medium of CHO 2B7 cells after 3 h of treatment

Given the potential role of Aß42 in AD pathogenesis, we focused the remainder of our studies on those compounds that significantly influenced this longer, more pathogenic form of the peptide. Dose-response analyses of Re, Rg1, and Rg3 on Aß40 and Aß42 levels in the cell-based assays were performed. In addition, dose-response analysis of F11 was performed given its selective, albeit modest, effects on Aß42. As shown in Fig. 1 , all four of the compounds showed a dose-responsive influence on the levels of Aß42 detected in the conditioned medium of CHO-2B7 cells. Ginsenoside Rg3 appears the most potent in the series, with an apparent IC50 of <25 µM. Treatment of the cells with 200 µM Rg3 resulted in a dramatic 84.4 ± 1.468% reduction in Aß42 levels. Figure 2 shows the influence of the compounds on Aß40 levels. Consistent with a selective effect on Aß42 observed in the initial screens, all four of the compounds showed a lower percent reduction on Aß40 than on Aß42.


Figure 1
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  		Figure 1. Alterations in Aß42 accumulation in conditioned medium of CHO 2B7 cells after treatment with various ginsenosides. Cells were conditioned for 3 h, and media were removed and subjected to Aß42 analysis by sandwich ELISA. Data are percent changes in Aß42 relative to cells treated with vehicle alone. Data points are mean ± SE of triplicate culture wells. **P < 0.01; *P < 0.05, one-way ANOVA with Dunnett’s multiple comparison test.


Figure 2
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  		Figure 2. Alterations in Aß40 accumulation in the conditioned medium of CHO 2B7 cells after treatment with various ginsenosides. Cells were conditioned for 3 h, and media were removed and subjected to Aß40 analysis by sandwich ELISA. Data are percent changes in Aß40 relative to cells treated with vehicle alone. Data points are mean ± SE of triplicate culture wells. *P < 0.05, one-way ANOVA with Dunnett’s multiple comparison test.

To determine the influence of these compounds on Aß 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 Aß in an age-dependent fashion and develop plaques associated with dystrophic neurites and prominent gliosis (28 , 29) . Although clearly not a faithful model for all aspects of AD pathogenesis, the Tg2576 model is a reasonable model for examining compounds that influence Aß concentration (30 , 31) . Given 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 Aß concentration in the brain after a single oral dose. For comparison, we also treated a group of mice with a {gamma} secretase inhibitor, LY 411575, known to reduce Aß levels in mice (32 33 34) . As shown in Fig. 3 , a single oral dose of ginsenosides Re, Rg1, or Rg3 at 25mg/kg resulted in a significant reduction in Aß42 concentration in the brain. As in the cell culture model, Rg3 was the most effective Aß-lowering ginsenoside tested in vivo, with a 31.1 ± 5% reduction in Aß42 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 {gamma} secretase inhibitor LY411575. As expected based on the cell culture data, each of the ginsenosides lowered Aß42 concentration in the brain to a greater extent than Aß40 (compare Fig. 3 and Fig. 4 ). Similar to previously published reports, we observed the opposite with LY411575, namely a greater effect on Aß40 than on Aß42 (34) . Studies on the influence of other aspects of APP processing, although not part of the current study, would be interesting given the potential roles for secreted APP (sAPP) on neurite outgrowth, neuroprotection, and memory (35 36 37 38) .


Figure 3
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  		Figure 3. Effect of a single oral administration of various ginsenosides on Aß42 in 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. Absolute values for Aß vary between different mouse strains and depend on extraction conditions, assay system employed, and standards used. As such, cross-comparison of absolute values is difficult between laboratories. In this series of experiments, mean value obtained, after normalization, was 6.7 ± .25 pmol/g for Aß42 for control animals.


Figure 4
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  		Figure 4. Effect of a single oral administration of various ginsenosides on Aß40 levels in brains of Tg2576 mice. LY-411575 is used as a positive control. *Statistically significant: P value Re = 1.9 x 10–5; Rg1 = 0.0085; Rg3 = 0.00052; LY = 2.5 x 10–10. Absolute values for Aß vary between different mouse strains and depend on extraction conditions, assay system employed and standards used. As such, cross-comparison of absolute values is difficult between laboratories. In this series of experiments, mean value obtained, after normalization, was 16.7 ± .37 pmol/g for Aß40 for control animals.

DISCUSSION

The abnormal accumulation of the Alzheimer’s Aß peptide is believed to play a pivotal, if not causal, role in AD. As such, compounds capable of reducing Aß 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 Aß concentration. In this manuscript, we report a dose-dependent effect of several ginsenosides on Aß concentration in the cell-based assays with ginsenoside Rg3 being the most potent in the series we examined with an IC50 of under 25µM with respect to Aß42 reduction. Furthermore, 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 Aß 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 Aß 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 (39) . Although there have been several studies examining the effect of ginseng on behavior, memory, and neurodegeneration in rodents (40 41 42 43 44 45 46 47) and several positive studies on its influence on memory in humans (see Introduction), 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 in 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 (48 , 49) that could have deleterious effects.

Received for publication December 7, 2005. Accepted for publication February 2, 2006.

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