title: Tenuifolin, a saponin derived from Radix Polygalae, exhibits sleep-enhancing effects in mice.
abstract: BACKGROUND
  Radix Polygalae, the dried root of Polygala tenuifolia, has been extensively used as a traditional Chinese medicine for promoting intelligence and tranquilization. Polygalasaponins extracted from the root of P. tenuifolia possess evident anxiolytic and sedative-hypnotic activities. Previous studies have reported that tenuifolin was a major constituent of polygalasaponins.
  
  
  OBJECTIVE
  The currently study aims to investigate the hypnotic effect and possible mechanism of tenuifolin in freely moving mice.
  
  
  METHODS
  The hypnotic effects of tenuifolin (20, 40 and 80mg/kg, p.o.) were assessed by electroencephalographic (EEG) and electromyographic (EMG) analysis. Double-staining immunohistochemistry test was performed to evaluate the neuronal activity of sleep-wake regulating brain areas. High performance liquid chromatograph- electrochemical detection (HPLC-ECD) and ultrafast liquid chromatography-mass spectrometry (UFLC-MS) were used for the detection of neurotransmitters. Locomotor activity was measured by Open-field Test.
  
  
  RESULTS
  Tenuifolin at doses of 40 and 80mg/kg (p.o.) significantly prolonged the total sleep time by increasing the amount of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, associated with the significant increase in the bouts of episodes respectively. After administration of tenuifolin, the cortical EEG power spectral densities during NREM and REM sleep were similar to that of natural sleep (vehicle) and thus compatible with physiological sleep. Double-immunohistochemistry staining test showed that tenuifolin increased the c-Fos positive ratios of GABAergic NREM sleep-promoting neurons in ventrolateral preoptic area (VLPO), cholinergic REM sleep-promoting neurons in laterodorsal tegmental area (LDT) and pontomesencephalic tegmental area (PPT) and decreased the c-Fos positive ratios in wake-promoting neurons (locus coeruleus (LC) and perifornical area (Pef)). Neurotransmitter detections revealed that tenuifolin significantly reduced the noradrenaline (NA) levels in LC, VLPO, PPT and LDT, elevated the GABA levels in VLPO, LC and Pef and increased the acetylcholine (Ach) levels in LDT and PPT. In addition, tenuifolin did not cause any change to locomotor activity.
  
  
  CONCLUSIONS
  Taken together, these results provide the first experimental evidence of the significant sleep-enhancing effect of tenuifolin in mice. This effect appears to be mediated, at least in part, by the activation of GABAergic systems and/or by the inhibition of noradrenergic systems. Moreover, this study adds new scientific evidence and highlights the therapeutic potential of the medicinal plant P. tenuifolia in the development of phytomedicines with hypnotic properties.
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Su-Ying
authors.initials: SY
authors.lastname: Cui
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Tu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Yue-Mei
authors.initials: YM
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Ma
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Xiang-Yu
authors.initials: XY
authors.lastname: Cui
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Yuan-Li
authors.initials: YL
authors.lastname: Huang
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Jin-Zhi
authors.initials: JZ
authors.lastname: Song
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yu
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Zhao-Fu
authors.initials: ZF
authors.lastname: Sheng
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Zi-Jun
authors.initials: ZJ
authors.lastname: Wang
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Xu
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ye
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China. Electronic address: zhyh@hsc.pku.edu.cn.
authors.forename: Yong-He
authors.initials: YH
authors.lastname: Zhang
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D004569:Electroencephalography; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D008813:Mice, Inbred ICR; D018377:Neurotransmitter Agents / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D018517:Plant Roots; D031801:Polygala / Q000737:chemistry*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012503:Saponins / Q000494:pharmacology*; D012890:Sleep / Q000187:drug effects*; D012895:Sleep, REM / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D045786:Diterpenes, Kaurane; D006993:Hypnotics and Sedatives; D018377:Neurotransmitter Agents; D010936:Plant Extracts; D016760:Proto-Oncogene Proteins c-fos; D012503:Saponins; C532370:tenuifolin diterpene; D005680:gamma-Aminobutyric Acid; D000109:Acetylcholine
keywords: EEG; GABA; Hypnotic; Noradrenaline; Polygala tenuifolia; Tenuifolin