Chronic toxicity of ginsenoside Re on Sprague-Dawley rats Dan Lu, Jinping Liu, Wenjie Zhao, Pingya Li n Institute of Frontier Medical Science of Jilin University, ChangChun, Jilin 130021, China article info Article history: Received 3 May 2012 Received in revised form 29 August 2012 Accepted 5 October 2012 Available online 12 October 2012 Keywords: Ginseng Ginsenoside Re Chronic toxicity Sprague-Dawley rats Orally administration abstract Ethnopharmacological relevance: Ginseng has been widely used for hundreds of years in both China and other countries. It is well accepted that the pharmacological effects of ginseng are attributed to ginsenosides. Ginsenoside Re is one of the active ingredients in ginseng. The present study was carried out to characterize the toxicity of ginsenoside Re after repeated oral administration in Sprague-Dawley rats. Materials and methods: Rats (60 males, 60 females) were administrated ginsenoside Re orally in 0, 38, 113, or 375 mg/kg/day doses for 26 weeks (n ¼15/group each sex). Clinical signs, mortality, body weights, feed consumption, urinalysis, hematology, serum biochemistry, gross findings, organ weights and histopathology were examined at the end of the test period, as well as after the 4-week recovery period. Results: Ginsenoside Re did not induce death, adverse effects or dose-dependent changes in feed consumption, or body weight gain. Some statistically significant differences were observed in hemato- logical and biochemical parameters, as well as in body weights of rats treated with ginsenoside Re. However, there was no abnormality of any organs noted in both gross and histopathological examinations. Conclusions: Ginsenoside Re is well tolerated up to a 375 mg/kg/day oral dosage level and non-toxic in both male and female rats. & 2012 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Ginseng has been extensively used by both patients and healthy individuals in many countries to restore and enhance vital energy (Chong and Oberholzer, 1988). It is well accepted that pharmacological effects of ginseng are mostly attributed to ginsenosides, the principal components in different species of ginseng. In general, the main active ginsenosides are categorized into two groups, 20(S)-protopanaxatriol (PPT-type) and 20(S)- protopanaxadiol (PPD-type), based on the number and the posi- tion of the sugar moieties attached on the dammarane skeleton (Leung et al., 2007). It has been reported that differences in the structural conformation and presence of sugars at positions C-3 and C-6 are responsible for unique characteristics of different compounds and affected their hydrophobic properties required to functionally interact with cell membrane. For the hydrophobic properties of ginsenosides effect in the permeability of cell membrane, see Popovich and Kitts (2002). Furthermore, molecu- lar modeling and sugar moiety position also influenced the ginsenosides activity (Chen et al., 2009; Qi et al., 2010). Ginsenoside Re (Re) is one of the PPT-type ginsenosides. Several typical bioactivities of Re have been found to be anti-diabetic (Xie et al., 2005; Cho et al., 2006a,b; Zhang et al., 2008;Yang et al., 2010; Liu et al., 2012), antioxidant (Xie et al., 2006; Cho et al., 2006a, b), immuno-potentiating (Song et al., 2010; Son et al., 2010;Chan et al., 2011), neuro-protective (Ji et al., 2006; Lo ´pez et al., 2007), and angiogenic modulating activity (Leung et al., 2007; Yu et al., 2007; Li and Liu, 2008). Our previous studies indicated that Re improved learning and memory in rats by enhancing the basic synaptic transmission and promoting the magnitude of LTP of the dentate gyrus (Zhao et al., 2007). Despite of the long history of usage and widespread research on ginseng activities, the chronic effects of ginseng are not well characterized and little information on toxicity is available (Chan and Fu, 2007). Chronic toxicity studies of gingseng extract were performed, and no toxic effects were found (Popov and Goldwag, 1973; Bittles et al., 1979; Hess et al., 1982, 1983). However, the dose level used in gingseng extract toxicity studies was considered low (Chan and Fu, 2007). Recently, our groups demonstrated the chronic-toxicity of 20(S)-ginsenoside Rg3 in Beagke dogs (Liu et al., 2011). In another, subchronic toxicity study, the hepatotoxicity of ginsenoside CK was also reported (Gao et al., 2011). Both ginseno- side CK and Rg3 are PPD-type ginsenosides, and there are no reports about the chronic toxicity of PPT-type ginsenoside. In order Contents lists available at SciVerse ScienceDirect journal homepage: www.elsevier.com/locate/jep Journal of Ethnopharmacology 0378-8741/$ - see front matter & 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jep.2012.10.007 n Corresponding author. Tel./fax: þ86 431 85619803. E-mail address: lipy@jlu.edu.cns (P. Li). Journal of Ethnopharmacology 144 (2012) 656–663