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Pharmacological studies on the sedative and hypnotic effect of salidroside from the Chinese medicinal plant Rhodiola sachalinensis.

Abstract

This is the preliminary study of sedative and hypnotic activity of salidroside (a major component of Rhodiola sachalinensis) in mice by using synergism with pentobarbital as an index for the hypnotic effect. Loss of the righting reflex was used to determine the start of sleep. Sleep latency and sleeping time were evaluated in this experiment. The results showed that salidroside could obviously shorten the sleep latency and prolong the sleeping time of mice produced by pentobarbital sodium (55 mg/kg, i.p.). Salidroside produces significant sedative-hypnotic effect. The dose-effect relationship is remarkable.

[c] 2006 Elsevier GmbH. All rights reserved.

Keywords: Salidroside; Sedative-hypnotic activity

Introduction

Salidroside ((4-hydroxy-phenethyl)-[beta]-D-glucopyranoside (Fig. 1), [C.sub.14][H.sub.20][O.sub.7]: 300.30) isolated from Rhodiola sachalinensis A. Bor. (Hongjingtian in Chinese) is one of the most popular traditional Chinese medicines. This herb has a reputation for stimulating the nervous system, decreasing depression, enhancing work performance, resisting anoxia, microwave radiation, eliminating fatigue, preventing high altitude sickness and improving sleep, etc. (Stancheva and Mosharrof, 1987; Ming et al., 1988). As a drug of "source of adaptation to environment" in Chinese traditional medicine, it has been used in such special posts as diver, astronaut, pilot and mountaineer to enhance the body's ability to survive in adverse environments (Ming, 1986; Xu et a I., 1998). Furthermore, its' effect on extending human life was also found. The major active constituent of this medicinal herb is salidroside (Li and Chen, 2001). The purpose of this study, therefore, was to confirm that salidroside can improve sleep and possess sedative and hypnotic action.

Materials and methods

Agents

Diazepam (DZP, 2.0 mg/kg, Sigma) was used as the standard hypnotic drug. Salidroside (purity 99%) was purchased from Tianjin jianfeng Natural Product R & D Co., Ltd. (Tianjin Jianfeng, Tianjin, China). It was dissolved in water for injection before used.

Animals

Male adult ICR mice weighing 20-22g (experimental animal center of Heilongjiang University of Chinese Medicine, Harbin, China) were used in this study. Each mouse was used only for one experiment. All animals were housed in acrylfiber cages (440 x 270 x 178 mm, 12-15 per cage) at an airconditioned, sound-attennuated room with controlled temperature (24[+ or -]2[degrees]C) and humidity (55[+ or -]15%). This room was kept on a 12:12-h light-dark cycle (lights on at 7:00 h am, 50-120 lx). The animals were allowed free access to food (standard laboratory animal food) and water except during the experiments and acclimated 7 days before they were used (Zhao et al., 2004). All animal experiments used in this study were conducted in accordance with the European Community guidelines for the use of experimental animals and approved by the Animal Care Committee of Heilongjiang University of Chinese Medicine.

[FIGURE 1 OMITTED]

Evaluation of sleep latency and sleeping time

It is suggested that the righting reflex is a useful method in assessing whether or not the animals are 'asleep' (Enginar et al., 1991; Matsumoto et al., 1996). Observers were blind to the drug treatment. Following the pentobarbital injection, index of hypnotic effect were recorded. The index were recorded as follows: Time elapsed between the administrations of pentobarbital until loss of righting reflex was recorded as the sleep latency, while the time from the loss to its recovery was considered as the sleeping time (Erden et al., 2001).

Experimental procedure

Experiment 1: effects of different dose of pentobarbital sodium on sleeping time of mice

The method of pentobarbital induced sleeping in mice is a classic pharmacological experiment on screening of sedative and hypnotic drugs. The differential dose of pentobarbital can effect experimental result significantly. Through this experiment, we can determine a best dose of pentobarbital sodium on sleeping time of mice. The experiments were carried out from 11:00 to 15:00 h in a quiet room in which the temperature was maintained at 22[+ or -]24[degrees]C. Mice were grouped of ten each. They were treated as follows: group 1, 2, 3, 4 and 5 received the pentobarbital (dose 40, 45, 50, 55, 60 mg/kg, i.p.). Sleeping time of mice were recorded.

Experiment 2: effects of drug on the sleep latency and duration of sleep in pentobarbital sodium treated mice

The experiments were carried out from 11:00 to 15:00h in a quiet room in which the temperature was maintained at 22[+ or -]24[degrees]C. Mice were grouped of ten each. They were treated as follows: Croup 1 received water for injection as the control, groups 2 received diazepam (2.0mg/kg, i.p.), 3, 4, 5, 6, 7 and 8 received the salidroside (dose 25, 50, 100, 200, 400, 800 mg/kg, i.p.). Animals were administered with pentobarbital sodium (55 mg/kg i.p.) 40min later and index of hypnotic effect were recorded. The mice were placed on a warm table during sleeping time. No animal was tested more than once (Erden et al., 1997).

Data analysis and statistics

All values obtained are represented as mean [+ or -]SEM. Data were analyzed by one-way analysis of variance (ANOVA) or two-way ANOVA followed by Student-Newman-Keuls test for multiple comparisons. Student's t-test was used to evaluate the difference between two groups at the same time. Differences with p < 0.05 were considered statistically significant.

Results

Effects of different dose of pentobarbital sodium on sleeping time of mice

In this experiment, we investigated the effect of the five differential doses of pentobarbital sodium on sleeping time in mice. We found that the coefficient of variation (CV) of the suprathreshold dose is smaller than the threshold dose significantly (Table 1). Both the sleeping time and the CV were considered, we applied the suprathreshold dose of 55 mg/kg as the experimental dose.

Effects of drug on the sleep latency and duration of sleep in pentobarbital treated mice

In this model, Salidroside exhibited significant sedative and hypnotic synergistic action with pentobarbital sodium in mice. The sleep latency of mice were decreased obviously (Fig. 2), and the sleeping time of mice were prolonged remarkably (Fig. 3).

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

Discussion

Pentobarbital sodium is a barbiturate that induces sleep in both rodents and humans (Koch-Weser and Greenblatt, 1974). The classic method of pentobarbital induced sleeping in mice were often used to screening sedative-hypnotic drugs. Different dose of pentobarbital sodium can effect the precision of experiment enormously, Therefore, we carried out the experiment for a best hypnotic dose of pentobarbital sodium in mice. These findings suggested that the suprathreshold dose is better than the threshold dose on the precision of experiment. At the same time, the befitting duration of sleep should be considered.

In this study, salidroside showed that not only the shortening effect on the sleep latency, but also prolonging effect on the sleeping time in mice treated with hypnotic dosage of pentobarbital sodium (55mg/kg). The results showed that salidroside could improve and enhance sleep mildly. Salidroside may modulate sleep by 5-HT system in brain (Saratikov et al., 1978), but the exact role of serotonin in the regulation of sleep is still contradictory.

In summary, salidroside can enhance sleep of mice through shortening sleep latency and prolonging sleeping time. But the mechanism of regulating sleep of salidroside is not clear, However, these may not be the exclusive mechanism for the sedative action of salidroside, since other central neuronal mechanisms such as GAB A system and the reticular activating system have not been studied. Further work is presently on going in our laboratory to study the neural mechanism of salidroside on sedative and hypnotic action.

Acknowledgments

This work was supported by a grant from the Hi-TECH Research and Development Program of China (863 Program: 2003AA2Z3523). The authors would like to thank the editor and the anonymous referees for the comments and checking the language of the manuscript.

References

Enginar, N., Eroglu, L., Ulak, G., 1991. The effect of ofloxacin on pentobarbital induced sleep in mice. Pharmacol. Biochem. Behav. 40 (1), 65-67.

Erden, B.F., Ulak, G., Yildiz, F., 1997. The effect of 7-nttro indazole on pentobatbital-induced sleep in mice. Pharmacol. Res. 36, 265 267.

Erden, B.F., Ulak, G., Yildiz, F., 2001. Antidepressant, anxiogenic, and antinociceptive properties of levofloxacin in rats and mice. Pharmacol. Biochem. Behav. 68, 435-441.

Koch-Weser, J., Greenblatt, 1974. The archaic barbiturate hypnotics. N. Engl. J. Med. 291, 790-791.

Li, H.B., Chen, F., 2001. Preparative isolation and purification of salidroside from the Chinese medicinal plant Rhodiola sachalinensis by high-speed counter-current chromatography. J. Chromatogr. A 932, 91-95.

Matsumoto, K., Ojima, K., Watanabe, H., 1996. Neurosteroidal modulation of socialisolation-induced decrease in pentobarbital sleep in mice. Brain Res. 708, 1-6.

Ming, H.Q., 1986. The synthesization and pharmacological action of the salidroside. Chin. J. Pharm. Bull. 21 (6), 373.

Ming, H.Q., Xia, G.C., Zhang, R.D., 1988. Progress in Rhodiola rosea L. Chin. Traditional Herbal Drugs 19 (5), 37-42.

Saratikov, A.S., Marina, T.F., Fisanova, L.L., 1973. The effect of Rhodiola product on the serotoninergic processes in the central nervous system. Biol. Nauki 6, 142.

Stancheva, S.L., Mosharrof, A., 1987. Effect of the extract of Rhodiola rosea L. on the content of the brain biogenic monamines. Med. Physiol. 40, 85 87.

Xu, J.F., Feng, P.S., Su, Z.G., 1998. Activity of tyrosol glucosyltransferase and improved salidroside production. J. Biotechnol. 61 (1), 69-73.

Zhao, X., Cui, X.Y., Chen, B.Q., Chu, Q.P., Yao, H.Y., Ku, B.S., Zhang, Y.H., 2004. Tetrandrine, a bisbenzylisoquinoline alkaloid from Chinese herb Radix, augmented the hypnotic effect of pentobarbital through serotonergic system. Eur. J. Pharmacol. 506, 101-105.

Tingli Li (a,*), Guanghui Xu (a), Lili Wu (b), Chunyu Sun (a)

(a) Pharmaceutical College, Heilongjiang University of Chinese Medicine, Harbin, China

(b) Department of gynaecology and obstetrics, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China

*Corresponding author. Tel.: + 86 451 82193038; fax: +86 0451 82193039.

E-mail address: litingli8888@163.com (T. Li).
Table 1. Effects of different dose of pentobarbital sodium on sleeping
time of mice

Group Dose (mg/kg) n Sleeping time (min) CV (%)

1 40 10 84.3[+ or -]28.5 33.8
2 45 10 86.4[+ or -]27.8 32.2
3 50 10 89.9[+ or -]26.6 29.6
4 55 10 130.6[+ or -]17.4 13.3
5 60 10 148.6[+ or -]28.8 19.4
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Article Details
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Author:Li, Tingli; Xu, Guanghui; Wu, Lili; Sun, Chunyu
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Geographic Code:9CHIN
Date:Sep 1, 2007
Words:1725
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