Ginseng (Panax ginseng C.A. MEYER, Araliaceae), which contains protopanaxadiol-type and protopanaxatriol-type ginsenosides, has been used for inflammation, fatigue, stress, and tumor in Asian countries. Orally administered ginsenosides are metabolized to their aglycones 20(S)-protopanaxadiol (PPD) and 20(S)-protopanaxatriol (PPT) by gut microbiota. However, their anti-fatigue effects have not been studied thoroughly. Therefore, we investigated the anti-fatigue activities of PPD and PPT in mice, using the weightloaded swimming (WLS) and the rota-rod tests. Ginseng water extract (GW), ginseng saponin fraction (GWS) and ginseng polysaccharide fraction (GWP) at concentrations of 50 and 100 mg/kg and PPD and PPT at 5 and 10 mg/kg were orally administered to mice once daily for 5 d. GW, GWS, and PPT significantly increased the WLS time, however, GWP and PPD did not cause any significant change. PPT induced the most significant increase in WLS time. PPD (10 mg/kg) and PPT (5 and 10 mg/kg) inhibited the WLS-induced increase in corticosterone, lactate, lactate dehydrogenase (LDH), and creatinine levels as well as the reduction in glucose level. PPT increased the riding time in the rota-rod test, and also inhibited corticosterone, lactate, and creatinine levels. These findings suggest that the anti-fatigue effect of ginseng may be attributable to its saponins, particularly PPT, rather than to its polysaccharides. Key words Panax ginseng; 20(S)-protopanaxadiol; 20(S)-protopanaxatriol; fatigueFatigue is described as the lack of energy and motivation to initiate and sustain voluntary physical and mental activities.1) Physical fatigue is the transient inability of a muscle to maintain physical performance and is made more severe by physical stress. Mental fatigue is a transient decrease in cognitive performance. Most cases of fatigue may be attributed to lifestyle factors such as alcohol abuse and excessive physical activity, medical conditions such as multiple sclerosis and Parkinson's disease, or psychological problems such as anxiety and stress. Therefore, natural products including ginseng have been studied with the aim of developing anti-fatigue drugs to improve athletic ability, delay fatigue, and enhance the elimination of fatigue in humans. [2][3][4][5][6] Ginseng (the root of Panax ginseng C.A. MEYER, Araliaceae) has been widely used as a traditional Chinese medicine for enhancing body strength, recovering physical balance, and stimulating metabolic function in Asian countries. It contains various active constituents such as ginsenosides, polysaccharides, polyacetylenes, phenolic compounds, and peptides. 7)Of constituents, ginsenosides have been reported to show biological activities, including anti-inflammatory, anti-fatigue, anti-stress, and anti-tumor activities. [8][9][10][11][12] The ginsenosides are classified as protopanaxadiols or protopanaxatriols. Orally administered protopanaxadiol-type and protopanaxatriol-type ginsenosides are metabolized to 20(S)-protopanaxadiol (PPD) via compound K and 20(S)-protopanax...

Stress is a common and unavoidable phenomenon in human life.1,2) Exposure to stress induces glucocorticoid release via the activation of the hypothalamo-pituitary-adrenal (HPA) axis and it modulates immune cells and further modulates cytokine production.3-5) Among these cytokines, proinflammatory interleukin (IL)-6 and tumor necrosis factor (TNF)-α are up-regulated by stress and are associated with host defense systems.6) The failure to cope with stress exacerbates both psychological and immune disorders, including anxiety, depression, cardiovascular disturbances, neuronal degeneration of the central nervous system and chronic fatigue syndromes. 7,8) Ginseng (the root of Panax ginseng C.A. MEYER, Araliaceae) has been widely used as a traditional Chinese medicine for the treatment of various maladies such as inflammation, anxiety, depression, fatigue, and stress. Its representative constituents are dammarane-type ginsenosides, which are classified into protopanaxadiols, such as ginsenosides Rb1, Rb2, Rc, and Rd, and protopanaxatriols such as ginsenosides Re and Rg1.9,10) These ginsenosides have been previously reported to show various biological activities, including anti-inflammatory, 10,11) anti-allergic, 12) anxiolytic, 13) anti-stress 14) and anti-tumor activities. 16-19) These metabolites have many pharmacological activities similar to ginseng, including anti-tumor, anti-diabetic, and anti-inflammatory effects.20-22) Therefore, to understand the pharmacological effect of ginseng, understanding the biological activities of two metabolites, 20(S)-protopanaxadiol and 20(S)-protopanaxatriol, of various ginsenosides is important. Nevertheless, the pharmacological effects of the ginsenoside metabolites have not been studied thoroughly.In our preliminary study, we also found that ginseng saponin extract showed anti-stress effect in mice. Therefore, in the present study, we investigated further the anti-stress effects of ginseng saponin metabolites, 20(S)-protopanaxadiol (PPD) and 20(S)-protopanaxatriol (PPT), in immobilized mice. MATERIALS AND METHODSMaterials Bicuculline, buspirone, dexamethasone, flumazenil and WAY-100635 were purchased from Sigma (St. Louis, MO, U.S.A.). 20(S)-Protopanaxadiol (purity ≥98% by HPLC) and 20(S)-protopanaxatriol (purity ≥98% by HPLC) were purchased from Ambo Institute (Daejeon, Korea). Orally administered 20(S)-protopanaxadiol and 20(S)-protopanaxatriol were suspended in 0.5% carboxymethylcellulose (CMC) solution and intraperitoneally injected buspirone, flumazenil, bicuculline, and WAY-100635 were dissolved in sterilized saline.Animals Male ICR mice (age, 7 weeks-old; weight, 24-28 g) were purchased from Samtako Biokorea (Seoul, Korea) and acclimated for 1 week before use. All animals were maintained under a constant temperature (24±2°C) and humidity (60±10%) with an alternating 12 h light-dark cycle. They were fed standard laboratory chow (Samyang Co., Seoul, Korea) with tap water ad libitum. Each group consisted of 7 mice for all experiments. The mice were randomly divided

BackgroundNephrotoxicity is the major side effect in cisplatin chemotherapy. Previously, we reported that the ginsenosides Rk3 and Rh4 reduced cisplatin toxicity on porcine renal proximal epithelial tubular cells (LLC-PK1). Here, we aimed to evaluate the protective effect of ginsenosides Rk3 and Rh4 on kidney function and elucidate their antioxidant effect using in vitro and in vivo models of cisplatin-induced acute renal failure.MethodsAn enriched mixture of ginsenosides Rk3 and Rh4 (KG-KH; 49.3% and 43.1%, respectively) was purified from sun ginseng (heat processed Panax ginseng). Cytotoxicity was induced by treatment of 20μM cisplatin to LLC-PK1 cells and rat model of acute renal failure was generated by single intraperitoneal injection of 5 mg/kg cisplatin. Protective effects were assessed by determining cell viability, reactive oxygen species generation, blood urea nitrogen, serum creatinine, antioxidant enzyme activity, and histopathological examination.ResultsThe in vitro assay demonstrated that KG-KH (50 μg/mL) significantly increased cell viability (4.6-fold), superoxide dismutase activity (2.8-fold), and glutathione reductase activity (1.5-fold), but reduced reactive oxygen species generation (56%) compared to cisplatin control cells. KG-KH (6 mg/kg, per os) also significantly inhibited renal edema (87% kidney index) and dysfunction (71.4% blood urea nitrogen, 67.4% creatinine) compared to cisplatin control rats. Of note, KG-KH significantly recovered the kidney levels of catalase (1.2-fold) and superoxide dismutase (1.5-fold).ConclusionConsidering the oxidative injury as an early trigger of cisplatin nephrotoxicity, our findings suggest that ginsenosides Rk3 and Rh4 protect the kidney from cisplatin-induced oxidative injury and help to recover renal function by restoring intrinsic antioxidant defenses.

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Eclalbasaponin II derived from Eclipta prostrata L. (Asteraceae) has been reported to have anti-fibrotic, anti-bacterial and autophagic activities, but its effect on cognitive function has not been investigated. We studied the effect of eclalbasaponin II on cholinergic blockade-induced memory impairment in mice using the passive avoidance, Y-maze, and Morris water maze tasks. Eclalbasaponin II (10 or 20 mg/kg, p.o.) significantly ameliorated the cognitive dysfunction induced by scopolamine in the passive avoidance, Y-maze, and the Morris water maze tasks. To identify the mechanism of the memory-ameliorating effect of eclalbasaponin II, acetylcholinesterase (AChE) activity assay, Western blot analysis and electrophysiology were conducted. Eclalbasaponin II inhibited the AChE activity in ex vivo study, and the administration of eclalbasaponin II and its metabolite, echinocystic acid, increased the phosphorylation levels of memory-related signaling molecules, including protein kinase B (Akt) and glycogen synthase kinase-3β (GSK-3β), in the hippocampus. Although eclalbasaponin II did not affect hippocampal long term potentiation (LTP), echinocystic acid significantly enhanced hippocampal LTP formation (30 μM). These results suggest that eclalbasaponin II ameliorates cholinergic blockade-induced cognitive impairment via AChE inhibition, LTP formation and the activation of Akt-GSK-3β signaling, and that eclalbasaponin II may be a useful to treat cognitive impairment derived from cholinergic dysfunction.