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Yokukansan, a traditional Japanese herbal medicine, alleviates the emotional abnormality induced by maladaptation to stress in mice.

ABSTRACT

The aim of the present study was to examine the effect of yokukansan, a traditional Japanese herbal medicine that is composed of Atractylodis lanceae Rhizoma, Poria, Cnidii Rhizoma, Uncariae Uncis cum Ramulus, Angelicae Radix, Bupleuri Radix and Glycyrrhizae Radix, on the emotional abnormality induced by maladaptation to stress in mice. Mice were exposed to repeated restraint stress for 60 or 240 min/day for 14 days. From the 3rd day of stress exposure, mice were given yokukansan orally (p.o.) or the [5-HT.sub.1A] receptor agonist flesinoxan intraperitoneally (i.p.) immediately after the daily exposure to restraint stress. After the final exposure to restraint stress, the emotionality of mice was evaluated using an automatic hole-board apparatus. A single exposure to restraint stress for 60 min induced a decrease in head-dipping behavior in the hole-board test. This emotional stress response disappeared in mice that had been exposed to repeated restraint stress for 60 min/day for 14 days, which confirmed the development of stress adaptation. In contrast, mice that were exposed to restraint stress for 240 min/day for 14 days did not develop this stress adaptation, and still showed a decrease in head-dipping behavior. The decreased emotionality observed in stress-maladaptive mice was significantly recovered by chronic treatment with yokukansan (1000 mg/kg, p.o.) as well as flesinoxan (0.25 and 0.5mg/kg, i.p.) immediately after daily exposure to stress. These findings suggest that yokukansan may have a beneficial effect on stress adaptation and alleviate the emotional abnormality under conditions of excessive stress.

Keywords:

Yokukansan

Hole-board

Emotional behavior

Restraint stress

Stress adaptation

Mouse

Introduction

The ability to adapt to stress is an important defensive function of a living body, and impairment of this ability may contribute to some stress-related disorders. Thus, the identification of substances that have beneficial effects on the brain mechanisms that contribute to stress adaptation could help to pave the way for new therapeutic strategies for stress-related mood disorders such as anxiety and depression. A growing body of evidence suggests that the brain serotonin (5-HT) nervous system is an important component related to the etiology, expression and treatment of anxiety and depression (Nordquist and Oreland, 2010). There are now believed to be seven kinds of 5-HT receptor families, [5-HT.sub.1-7], that comprise a total of 14 structurally and pharmacologically distinct 5-HT receptor subtypes (Hoyer et al., 2002). The results of our previous studies suggested that brain 5-HT nervous systems, especially [5-HT.sub.1A] receptors, may be involved, at least in part, in the development of adaptation to stress (Tsuji et al., 2000, 2001, 2003).

Yokukansan is a traditional Japanese herbal medicine that is composed of seven kinds of dried medicinal herbs, i.e., Atractylodis lanceae Rhizoma, Poria, Cnidii Rhizoma, Uncariae Uncis cum Ramulus, Angelicae Radix, Bupleuri Radix and Glycyrrhizae Radix. Yokukansan has been approved in Japan as a remedy for neurosis, insomnia, and irritability in children. Recently, yokukansan has been reported to improve behavioral and psychological symptoms, such as anxiety, hallucinations, agitation, irritability and sleep disturbance in patients with Alzheimer's disease and other forms of dementia when used clinically (Iwasaki et al. 2005a, b; Shinno et al., 2007; Mizukami et al., 2009; Hayashi et al., 2010; Kawanabe et al., 2010; Okahara et al., 2010; Nagata et al., 2012). Interestingly, an in vitro binding study demonstrated that yokukansan has a partial agonistic effect toward [5-HT.sub.1A] receptors (Terawaki et al., 2010). If we consider our previous findings (Tsuji et al., 2000, 2001, 2003), this report led us to speculate that yokukansan may have a beneficial effect on the development of stress adaptation.

A series of behavioral experiments have demonstrated that repeated exposure to the same type of stress stimuli diminishes acute stress responses. For example, Kennett and co-workers reported that male rats exposed to a single restraint stress for 120 min exhibited a reduction in locomotion in an open field, but this change in behavior disappeared after repeated exposure to restraint stress for 120 min/day for 7 days (Kennett et al., 1985a,b, 1986). Similar behavioral adaptive responses to stress stimuli in rats have been confirmed by other researchers (Ohi et al., 1989; Haleem and Parveen, 1994; Haleem, 1996), which suggests that this animal model may be useful for investigating the mechanisms of stress adaptation. Furthermore, to further characterize models of stress adaptation, we examined behavioral responses in rats that were produced by either single or repeated exposure to restraint stress for 60 or 240 min. A single exposure to restraint stress reduces locomotor activity, and this stress response disappears in rats that are exposed to repeated restraint stress for 60 min/day for 7 days, which confirms the development of stress adaptation. Flowever, this adaptive response to stress stimuli was not observed in rats exposed to restraint stress for 240 min/day for 7 days. Thus, we can create stress-adaptive and -maladaptive models by repeatedly exposing rats to different degrees of restraint stress (Takeda et al., 1996; Tsuji et al., 2003).

In the present study, we tried to create a stress-maladaptive model in mice, and examined the effect of yokukansan on the emotional abnormality observed in this animal model.

Materials and methods

The present studies were conducted in accordance with the Guide for the Care and Use of Laboratory Animals as adopted by the Committee on the Care and Use of Laboratory Animals of the international University of Health and Welfare, which is accredited by the Ministry of Education, Culture, Sports, Science, and Technology, Japan.

Animals

Male ICR mice (Japan SLC Inc., Shizuoka, Japan) weighing 25-30 g were housed at a room temperature of 23 [+ or -] 1[degrees]C with a 12-h light-dark cycle (light on 7:00a.m. to 7:00p.m.). Food and water were available ad libitum. All experiments were carried out in the light phase of the cycle.

Materials

The powdered water extract of yokukansan used in the present study were manufactured according to the formulation previously reported (Mizukami et al., 2009; Terawaki et al., 2010) and supplied by Tsumura & Co. (Tokyo, Japan). Yokukansan is composed of seven dried medicinal herbs: 4.0g of Atractylodis lanceae Rhizoma, 4.0g of Poria, 3.0 g of Cnidii Rhizoma, 3.0 g of Uncariae Uncis cum Ramulus, 3.0 g of Angelicae Radix, 2.0 g of Bupleuri Radix and 1.5 g of Glycyrrhizae Radix. These herbs are registered in the Pharmacopeia of Japan ver. 16. The same active ingredients derived from the herbal medicines in extract powders were also detected in standard solutions for the herbal medicines. The developed plates were either examined by spraying with a 4-dimethylaminobenzaldehyde reagent or dilute sulfuric acid, or irradiated with ultraviolet light. Upon comparison with the standard solutions for the herbal medicines, one spot among the spots from the yokukansan extract showed the same color tone and Rf value. In addition, the amounts of active ingredients such as glycyrrhizin, saikosaponin [b.sub.2] and ferulic acid have been determined by high-performance liquid chromatography analysis and stable contents have been secured. The chromatographic conditions for glycyrrhizin were column: a stainless steel column packed with octadecylsilanized silica gel for liquid chromatography, mobile phase: a mixture of [H.sub.2]O, C[H.sub.3]CN and C[H.sub.3]COOH, column temperature: a constant temperature of about 40 C, flow rate: 1.2 ml/min, detector: an ultraviolet absorption photometer (wavelength: 254 nm). The chromatographic conditions for saikosaponin b2 were column: a stainless steel column packed with octadecylsilanized silica gel for liquid chromatography, mobile phase: a mixture of [H.sub.2]O, MeOH and C[H.sub.3]CN, column temperature: a constant temperature of about 50[degrees]C, flow rate: 1.0 ml/min, detector: an ultraviolet absorption photometer (wavelength: 254 nm). The chromatographic conditions for ferulic acid were column: a stainless steel column packed with octylsilanized silica gel for liquid chromatography, mobile phase: a mixture of [H.sub.2]O, C[H.sub.3]CN and [(HCOO).sub.2], column temperature: a constant temperature of about 25[degrees]C, flow rate: 1.2 ml/min, detector: an ultraviolet absorption photometer (wavelength: 320 nm). Manufacturing processes and quality are standardized based on the Good Manufacturing Practices defined by the Ministry of Health, Labor and Welfare of Japan. Yokukansan has been approved by the Ministry of Health, Labor and Welfare of Japan as prescriptions covered under the National Health Insurance plan. The three-dimensional high-performance liquid chromatography (3D-HPLC) profile of representative batches of yokukansan is shown in Fig. 1. The compounds shown on the chromatogram were classified on the basis of the constituent herbs of Yokukansan (Table 1) (Mizukami et al., 2009; Nagata et al., 2012). Flesinoxan, a [5-HT.sub.1A] receptor agonist, was provided by Solvay (Noord-Holland, The Netherlands). Yokukansan was dissolved in purified water and treated orally (p.o.) in a volume of 10 ml/kg. Flesinoxan was dissolved in saline and treated intraperitoneally (i.p.) in a volume of 10 ml/kg. The dosage of drugs were decided based on the previous reports (Tsuji et al., 2000,2001; Kamei et al., 2009; Kanno et al., 2009; Yamaguchi et al., 2012).

Apparatus

The automatic hole-board apparatus (model ST-1, Muromachi Kikai Co. Ltd., Tokyo, Japan) consisted of a gray wooden box (50 cm x 50 cm x 50 cm) with four equidistant holes 3 cm in diameter in the floor. An infrared beam sensor was installed on the wall to detect the number and duration of rearing and head-dipping behaviors. The distance that mice moved on the hole-board were recorded by an overhead digital video camera; the heads of the mice were painted yellow and the digital video camera followed their center of gravity. Data from the digital video camera were collected through a custom-designed interface (DVTrack, Muromachi Kikai) as a reflection signal. Head-dipping behaviors were double-checked via an infrared beam sensor and the overhead digital video camera. Thus, only when both the head intercepted the infrared beam and the head was detected at the hole by the digital video camera was head-dipping behavior counted. All of the data were analyzed and stored in a personal computer using analytical software (Comp ACT HBS, Muromachi Kikai).

[FIGURE 1 OMITTED]

Experimental procedure

Effects of exposure to repeated restraint stress on the emotionality of mice as estimated by the hole-board test

Mice were either exposed to repeated restraint stress for 60 or 240min/day by being inserted into a syringe (50 ml) (stressed group) or left in their home cage (non-stressed group) for 1,3, 7 or 14 days. After the final exposure to restraint stress, the emotionality of mice was estimated using the automatic hole-board apparatus (Takeda et al., 1998; Tsuji et al., 2000, 2001). Namely, each mouse was placed in the center of the hole-board and allowed to freely explore the apparatus for 5 min. The exploratory behaviors of mice on the hole-board, i.e., distance moved, the number and duration of rearing, and the number and duration of head-dips, were automatically recorded. At the end of the experiments, the thymus, spleen and adrenal gland were removed, and the weights of the wet tissues were measured.

Effects of yokukansan or flesinoxan on the emotional abnormality of mice induced by exposure to repeated restraint stress

Mice were either exposed to repeated restraint stress for 240min/day (stressed group) or left in their home cage (non-stressed group) for 14 days. From the 3rd day of exposure to stress, mice were given yokukansan, flesinoxan or vehicle immediately after the daily exposure to restraint stress. After the final exposure to restraint stress, the emotionality of mice was estimated in the hole-board test, and the weights of the wet tissues of the thymus, spleen and adrenal gland were measured.

Effects of yokukansan on the emotional abnormality of mice induced by exposure to a single restraint stress

Mice were treated with yokukansan or vehicle. 60 min later, mice were either exposed to a single restraint stress (stressed group) or left in their home cage (non-stressed group) for 240 min, and the emotionality of mice was estimated in the hole-board test.

Effects of acute or chronic treatment with yokukansan on the emotionality of naive mice

Mice were treated acutely or chronically (once a day for 14 days) with yokukansan or vehicle. 60 min and 24 h after acute or chronic treatment with yokukansan, respectively, the emotionality of mice was estimated in the hole-board test.

Statistical analysis

The data are presented as the mean [+ or -] S.E.M. The treatment effects were compared using one-way repeated measures analysis of variance (ANOVA) followed by the Bonferroni's post hoc test. Data presented in Figs. 1 and 2 were analyzed by two-way ANOVA with the factors being treatment and time. Probability <0.05 was accepted as significant.

[FIGURE 2 OMITTED]

Results

Effects of exposure to repeated restraint stress on the emotionality of mice as estimated by the hole-board test

The effects of exposure to repeated restraint stress on the emotionality of mice as estimated by the hole-board test are shown in Figs. 2 and 3. A single exposure to restraint stress for 60 min induced significant decreases in the number and duration of head-dipping behaviors in the hole-board test (Fig. 2A and B). These emotional stress responses disappeared in mice that were exposed to the same duration of restraint stress repeatedly once a day for 14 days (Fig. 2A and B), which suggests the development of stress adaptation. Similar adaptation was also observed in the organs, e.g., an observed decrease in the thymus weight recovered under exposure to stress for 60 min/day for 14 days (Fig. 2C). About the data presented in Fig. 2A-C, two-way ANOVA indicates a significant interaction between treatment and time (Fig. 2A: [F.sub.3,101] = 4.96, p = 0.003; Fig. 2B: [F.sub.3,101] = 2.87, p = 0.040; Fig. 2C: [F.sub.3,71] = 3.16, p = 0.030).

In contrast, the mice that were exposed to restraint stress daily for 240 min/day for 14 days did not develop stress adaptation, and still showed a significant decrease in the number and duration of head-dipping behaviors (Fig. 3A and B) as well as a decrease in the tissue weight of the thymus (Fig. 3C). Additionally, a significant increase in the adrenal weight was also observed (Fig. 3E). About the data presented in Fig. 3A, two-way ANOVA indicates that head-dip count changed with treatment but they did not differ among the time (treatment factor; [F.sub.1,59] = 50.19, p< 0.001; time factor: [F.sub.2,59] = 2.23, p = 0.117; interaction: [F.sub.2,59] = 2.41, p = 0.099). Similar effects were observed in head-dip duration (Fig. 3B) (treatment factor: [F.sub.1,59] = 78.75, p< 0.001; time factor: [F.sub.2,59] = 0.60, p = 0.555; interaction: [F.sub.2,59] = 0.61, p = 0.547). On the contrary, about the data presented in Fig. 3C and E, a significant interaction between treatment and time was observed (Fig. 3C: [F.sub.2,60] = 3.32, p = 0.043; Fig. 3E: [F.sub.2,60] = 9.68, p < 0.001).

Effects of yokukansan on the abnormality of emotion and organs of mice induced by exposure to unadaptable stress

The effects of yokukansan on the abnormality of emotion and organs of mice induced by exposure to unadaptable stress are shown in Figs. 4 and 5. Repeated exposure to restraint stress for 240 min/day for 14 days induced significant decreases in the number and duration of head-dipping behaviors in the hole-board test ([F.sub.3,51] = 26.94, p < 0.001, Fig. 4A; [F.sub.3,51] = 31.18, p < 0.001, Fig. 4B), together with a decrease and increase in the weights of the thymus and adrenal gland, respectively ([F.sub.2,25] =8.59, p< 0.001, Fig. 5A; [F.sub.2,26] = 10.96, p < 0.001, Fig. 5C). Among these findings, decrease in head-dipping behavior and the increase in adrenal weight were partially but significantly inhibited by chronic treatment with yokukansan (1000 mg/kg, p.o.) immediately after the daily exposure to restraint stress (Figs. 4A, B and 5C), while the decrease in thymus weight was unaffected (Fig. 5A).

[FIGURE 3 OMITTED]

Effects of flesinoxan on the abnormality of emotion and organs of mice induced by exposure to unadaptable stress

The effects of flesinoxan on the abnormality of emotion and organs of mice induced by exposure to unadaptable stress are shown in Figs. 6 and 7. Repeated exposure to restraint stress for 240 min/day for 14 days induced significant decreases in the number and duration of head-dipping behaviors in the hole-board test ([F.sub.3,55] = 8.15, p < 0.001, Fig. 6A; [F.sub.3,55] = 8.57, p< 0.001, Fig. 6B), together with a decrease and increase in the weights of the thymus and adrenal gland, respectively ([F.sub.2,25] = 14.44, p < 0.001, Fig. 7A; [F.sub.2,25] = 5.97, p < 0.001, Fig. 1C). Similar to yokukansan, chronic treatment with flesinoxan (0.25 and/or 0.5mg/kg, i.p.) immediately after the daily exposure to restraint stress inhibited the decrease in head-dipping behavior and the increase in adrenal weight (Figs. 6A, B and 1C).

Effects of yokukansan on the emotional abnormality of mice induced by exposure to a single restraint stress

The effects of yokukansan on the emotional abnormality of mice induced by exposure to a single restraint stress are shown in Table 2. A single exposure to restraint stress for 240 min induced significant decreases in the number ([F.sub.2,36] = 17.08, p< 0.001) and duration ([F.sub.2,36] = 13.37, p< 0.001) of head-dipping behaviors in the hole-board test. Pre-treatment with yokukansan (1000 mg/kg, p.o.) did not affect these behavioral changes.

Effects of acute or chronic treatment with yokukansan on the emotionality of naive mice

The effects of acute or chronic treatment with yokukansan on the emotionality of naive mice are shown in Tables 3 and 4. Neither acute (Table 2) nor chronic (Table 3) treatment with yokukansan (1000 mg/kg, p.o.) affected exploratory behavior in the hole-board test.

Discussion

The hole-board test, which was first introduced by Boisser and Simon (1964), offers a simple method for measuring the response of an animal to an unfamiliar environment. In the hole-board test, a pronounced inhibition of head-dipping behavior was observed in rats that had been exposed to stress stimuli (Rodriguez Echandia et al., 1987). We also previously reported that either treatment with benzodiazepine anxiogenics or exposure to acute restraint stress produced a decrease in head-dipping behavior in mice (Takeda et al., 1998; Tsuji et al., 2000, 2001, 2003). These findings indicate that head-dipping behavior in the hole-board test is a good index for evaluating the emotionality of rodents.

The present study demonstrated that a single exposure to restraint stress for 60 min produced a decrease in the number and duration of head-dipping behaviors of mice in the hole-board test, and these acute emotional responses were recovered by exposure to repeated restraint stress for 60 min/day for 14 days. These findings are in good agreement with previous reports in rats (Kennett et al., 1985a,b, 1986; Ohi et al., 1989; Haleem and Parveen, 1994; Haleem, 1996; Takeda et al., 1996; Tsuji et al., 2003), and confirm the development of stress adaptation. However, mice that had been exposed to repeated restraint stress for 240 min/day for 14 days continued to show a decrease in head-dipping behavior in the hole-board test, together with a decrease and increase in the weights of the thymus and adrenal gland, respectively. Such an emotional maladaptation to stress stimuli and morphological abnormality in organs were also observed in our previous studies using rats (Takeda et al., 1996; Tsuji et al., 2003), which suggests an inability to adapt to stressful conditions. Thus, in the following studies, we used this stress-maladaptive model to examine whether yokukansan can have a beneficial effect on stress adaptation.

The most important finding in the present study is that the significant decreases in both the number and duration of head-dipping behaviors of stress-maladaptive mice were partially but significantly inhibited by chronic treatment with yokukansan immediately after daily exposure to stress. Recent clinical studies revealed that yokukansan improves behavioral and psychological symptoms, such as anxiety, hallucinations, agitation, irritability and sleep disturbance in patients with various forms of dementia (Iwasaki et al., 2005a, b; Shinno et al., 2007; Mizukami et al., 2009; Hayashi et al., 2010; Kawanabe et al., 2010; Okahara et al., 2010; Nagata et al., 2012). Furthermore, behavioral and pharmacological studies using experimental animals demonstrated that yokukansan was effective or reducing various problematic mental symptoms, i.e., abnormal social interactions (Kanno et al., 2009; Fujiwara et al., 2011; Takeda et al., 2012; Nishi et al., 2012), anxiety (Kamei et al., 2009; Mizoguchi et al., 2010; Yamaguchi et al., 2012) and sleep disturbance (Egashira et al., 2011). In addition to these previous reports, the present findings provide the new insight that yokukansan can alleviate the emotional abnormality induced by maladaptation to excessive stress stimuli.

Selye (1936, 1946), who pioneered research on the biological effects of stress stimuli, reported the uniform responses that are elicited in a mammal when its homeostasis is threatened by various types of nocuous stimuli, including enlargement of the adrenal gland and atrophy of the thymus. We obtained consistent results, in that stress-maladaptive mice showed a decrease and increase in the weights of the thymus and adrenal gland, respectively. Interestingly, in addition to emotional abnormality, the increase in adrenal weight was also partially but significantly inhibited by chronic treatment with yokukansan. Although the significance of this effect of yokukansan is not yet clear, the present findings suggest that yokukansan might be able to alleviate the endocrinological abnormality under the stressful conditions.

In contrast to chronic treatment, acute treatment with yokukansan did not alleviate the emotional abnormality of stress-maladaptive mice. Also, neither acute nor chronic treatment with yokukansan affected the emotionality of naive mice. Therefore, some neural plasticity induced by chronic treatment under stressful conditions may be involved in the alleviative effects of yokukansan found in the present study. Although the distinct mechanisms are unclear, a possible explanation is that [5-HT.sub.1A] receptors may be involved. Previous studies using stress-adaptive and -maladaptive animals have provided evidence that an increase in brain 5-HT signaling through [5-HT.sub.1A] receptors may be a key factor in the adaptation to repeated exposure to stress (Kennett et al., 1985a, b, 1986; Ohi et al., 1989; Tsuji et al., 2003). As a finding of supporting this hypothesis, the present study also showed that the decrease in emotional behavior as well as increase in adrenal weight of stress-maladaptive mice was improved by chronic treatment with [5-HT.sub.1A] receptor agonist flesinoxan. Recently, an in vitro binding study demonstrated that yokukansan had an agonistic activity to [5-HT.sub.1A] receptors (Terawaki et al., 2010). Furthermore, many researchers have reported that the ameliorative effects of yokukansan were counteracted by [5-HT.sub.1A] receptor antagonist (Kanno et al., 2009; Nishi et al., 2012; Yamaguchi et al., 2012). It is therefore possible that the alleviative effect of yokukansan might be due, at least in part, to the activation of [5-HT.sub.1A] receptors.

[FIGURE 4 OMITTED]

[FIGURE 5 OMITTED]

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In conclusion, the present findings suggest that yokukansan may have a beneficial effect on the process of stress adaptation, and alleviate the emotional abnormality under stressful situations. Although further studies on the molecular and neuronal mechanisms of the alleviative effects of yokukansan will be needed, the present findings suggest that yokukansan may be effective for the clinical treatment of mental illness that results from maladaptive coping with stressful situations such as adjustment disorder.

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http://dx.doi.org/10.1016/j.phymed.2013.08.025

ARTICLE INFO

Article history:

Received 5 June 2013

Received in revised form 19 July 2013

Accepted 22 August 2013

Conflict of interest

The authors declare that they have no conflict of interests to disclose.

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Minoru Tsuji (a, b) *, Tomoko Takeuchi (a), Kazuya Miyagawa (a), Daisuke Ishii (a), Taro Imai (a), Kotaro Takeda (a), Masaki Kitajima (b), Hiroshi Takeda (a,b)

(a) Department of Pharmacology, School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi 324-8501, Japan

(b) Advanced Education and Research Center for Kampo Medicine, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi 324-8501, Japan

* Corresponding author at: Department of Pharmacology, School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi 324-8501, Japan. Tel.: +81 287 24 3489; fax: +81 287 24 3489.

E-mail address: mtsuji@iuhw.ac.jp (M. Tsuji).
Table 1
Classification of the compounds identified in the three-dimensional
chromatogram.

Constituent of       Compounds
TJ-54

Atractylodis        4E,6E,12E-Tetradecatriene-8,10-diyne-1,3,14-triol,
  lanceae Rhizoma   12-isovaleroyl-2E,8E,10E-triene-4,6-diyne-1,14-
                    diol 14-isovaleroyl-2E,8E,10E-triene-4,6-diyne-
                    1,12-diol, atractylodin

Cnidii Rhizoma      Ferulic acid, ligustilide

Uncariae Uncis      Geissoschizine methyl erther, hirsuteine, hirsutine
  cum Ramulus

Angelicae Radix     Xanthotoxin, ligustilide

Bupleuri Radix      Saikosaponin b1, saikosaponin b2

Glycyrrhizae        Formononetin, formononetin-7-O-glucoside
  Radix             Liquiritigenin, liquiritin, liquiritin apioside,
                    glycyrrhizin, glycyroside, isoliquiritin apioside,
                    isoliquiritin, isoliquiritigenin, glycycoumarin

Table 2
Effect of yokukansan on the emotional abnormality of mice induced by
exposure to a single restraint stress.

Group                  Moving distance (cm)    Rearing
                                               Counts

Vehicle + non-stress   2015.0 [+ or -] 99.5    29.2 [+ or -] 1.6
Vehicle + stress       1978.1 [+ or -] 134.4   29.8 [+ or -] 1.7
Yokukansan + stress    1788.4 [+ or -] 105.4   25.3 [+ or -] 2.9

Group                  Rearing             Head-dips
                       Duration (s)        Counts

Vehicle + non-stress   30.2 [+ or -] 1.6   25.2 [+ or -] 1.5
Vehicle + stress       29.5 [+ or -] 2.2   13.7 [+ or -] 1.8 **
Yokukansan + stress    24.9 [+ or -] 4.1   11.2 [+ or -] 2.1 **

Group                  Head-dips
                       Duration (s)

Vehicle + non-stress   12.0 [+ or -] 1.2
Vehicle + stress        5.3 [+ or -] 0.9 **
Yokukansan + stress     4.4 [+ or -] 1.2 **

Mice were treated with yokukansan (1000 mg/kg, p.o.) or vehicle. 60
min later, mice were either exposed to a single restraint stress or
left in their home cage for 240 min, and the exploratory behaviors
of mice on the hole-board were measured for 5 min. The data represent
the mean with S.E.M. of 13-14 mice.

** P<0.01 vs. vehicle plus non-stressed group.

Table 3
Effect of acute treatment with yokukansan on the emotionality of
naive mice.

Group        Moving distance (cm)    Rearing
                                     Counts

Vehicle      2457.3 [+ or -] 125.4   34.6 [+ or -] 2.1
Yokukansan   2382.7 [+ or -] 89.1    33.1 [+ or -] 2.2

Group        Rearing             Head-dips
             Duration (s)        Counts

Vehicle      31.2 [+ or -] 2.0   30.3 [+ or -] 2.0
Yokukansan   32.5 [+ or -] 2.8   31.0 [+ or -] 2.3

Group        Head-dips
             Duration (s)

Vehicle      15.5 [+ or -] 1.6
Yokukansan   17.9 [+ or -] 1.4

Mice were treated with yokukansan (1000mg/kg, p.o.) or vehicle.
60 min later, the exploratory behaviors of mice on the hole-board
were measured for 5min. The data represent the mean with S.E.M.
of 16-17 mice.

Table 4
Effect of chronic treatment with yokukansan on the emotionality of
naive mice.

Group        Moving distance (cm)   Rearing
                                    Counts

Vehicle      2174.5 [+ or -] 88.4   23.1 [+ or -] 3.3
Yokukansan   2273.8 [+ or -] 76.5   22.2 [+ or -] 2.0

Group        Rearing             Head-dips
             Duration (sec)      Counts

Vehicle      18.6 [+ or -] 3.6   35.0 [+ or -] 2.6
Yokukansan   14.3 [+ or -] 1.4   36.6 [+ or -] 3.1

Group        Head-dips
             Duration (sec)

Vehicle      15.3 [+ or -] 1.9
Yokukansan   16.3 [+ or -] 2.1

Mice were chronically treated with yokukansan (1000 mg/kg, p.o.) or
vehicle once a day for 14 days. 24h after the final treatment,
exploratory behaviors of mice on the hole-board were measured for
5 min. The data represent the mean with S.E.M. of 9-10 mice.
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Author:Tsuji, Minoru; Takeuchi, Tomoko; Miyagawa, Kazuya; Ishii, Daisuke; Imai, Taro; Takeda, Kotaro; Kitaj
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Date:Feb 15, 2014
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