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Antidepressant-like effect of ethanol extract from Zuojin Pill, containing two herbal drugs of Rhizoma Coptidis and Fructus Evodiae, is explained by modulating the monoaminergic neurotransmitter system in mice
Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
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Antidepressant-like effect of ethanol extract from Zuojin Pill, containing two herbal drugs of Rhizoma Coptidis and Fructus Evodiae, is explained by modulating the monoaminergic neurotransmitter system in mice Qiang-Song Wang a,b, Shi-Lan Ding a,b, Hao-Ping Mao a,b, Yuan-Lu Cui a,b,n, Xue-Jie Qi a,b,n a Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, No. 88 YuQuan Road, Nankai District, Tianjin 300193, PR China b Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, PR China
art ic l e i nf o
a b s t r a c t
Article history: Received 29 November 2012 Received in revised form 12 May 2013 Accepted 14 May 2013
Ethnopharmacological relevance: Zuojin Pill (ZJP), a traditional Chinese medicinal decoction, contains two herbal drugs: Coptis chinensis Franch. and Evodia rutaecarpa (Juss.) Benth. in the ratio of 6:1 (w/w). Previous pharmacological studies have shown that two herbs in ZJP have the antagonistic effects on catecholamine secretion in bovine adrenal medullary cells. Furthermore, the alkaloids from the two herbs in ZJP may provide a protective effect for depression in individuals with a low expressing 5-HTT allele by increasing receptor concentration in serotonergic neurons. However, antidepressant effect has not been reported before and has not been fully clarified. Aim of the study: The present study aimed to investigate the antidepressant potential of ethanol extract from ZJP and its monoaminergic mechanism in mice. Materials and methods: Seven alkaloids were determined from the ethanol extract of ZJP using High Performance Liquid Chromatography (HPLC) with the gradient mobile phase. The ethanol extract from ZJP was used to evaluate the antidepressant potential in mice. Mouse models of depression including the tail suspension test (TST) and the forced swim test (FST) were used to evaluate the effects of the ethanol extract from ZJP. A possible mechanism was explored in the tests of antagonism of reserpine-induced ptosis and hypothermia, and 5-HTP induced head twitch response in mice. The contents of monoamine neurotransmitters including norepinephrine (NE), serotonin (5-hydroxytryptamine or 5-HT) in hippocampus of mice and NE, 5-HT, dopamine (DA) in striatum of mice were determined by HPLC system with Electrochemical Detector (ECD). Results: The results showed that intragastric administration of the ethanol extract from ZJP (5, 10, 20 mg/kg) or fluoxetine (7.5 mg/kg) significantly reduced the duration of immobility in TST and FST. However, the effect was not dose-dependent. Ethanol extract from ZJP (5, 10, 20 mg/kg) also increased the accumulative number of the 5-HTP-induced head twitch response in mice. The mice were treated with the ethanol extract from ZJP (5, 10, 20 mg/kg) or fluoxetine (7.5 mg/kg), which could antagonize reserpine-induced ptosis and hypothermia, moreover, both of them could elevate the contents of NE, 5-HT in hippocampus as well as NE, 5-HT, DA in striatum significantly. Conclusion: These results indicate that the ethanol extract from ZJP produced antidepressant-like effect and the possible mechanism, at least in part, is via the central monoaminergic neurotransmitter system and 5-HT plays a major role. & 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Rhizoma coptidis Fructus evodiae Alkaloids Antidepressant Monoamine neurotransmitter Traditional chinese medicine (TCM)
1. Introduction Depression is a chronic, recurring and potentially lifethreatening disease which could affect the performance and n Corresponding authors at: Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, No. 88 YuQuan Road, Nankai District, Tianjin 300193, PR China. Tel./fax: +86 22 59596170. E-mail addresses: [email protected] (Y.-L. Cui), [email protected] (X.-J. Qi).
learning, social interactions and development of normal peer relationships, and even lead to suicidal ideations later in life. According to the report of World Health Organization, it may become the second cause of illness-induced disability by the year 2020 (WHO, 2001). It is well known that monoamine neurotransmitters such as 5-HT, NE and DA in the central nervous system play a key role in the pathophysiology of depression (Elhwuegi, 2004). The increase in extracellular 5-HT and NE levels in the brain are thought to be
0378-8741/$ - see front matter & 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jep.2013.05.011
Please cite this article as: Wang, Q.-S., et al., Antidepressant-like effect of ethanol extract from Zuojin Pill, containing two herbal drugs of Rhizoma Coptidis and Fructus Evodiae, is explained by modulating..., (2013), http://dx.doi.org/10.1016/j.jep.2013.05.011
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Q.-S. Wang et al. / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
closely related to the antidepressant effect (Kapur and Mann, 1992; Papakostas, 2006). At present, several types of classical antidepressants are primary modulators of monoamine neurotransmitters. Although many antidepressant drugs could improve depressive symptoms, 30% of depressive patients failed to respond satisfactorily to commercially available antidepressants as the undesirable side-effects of antidepressant drugs, such as bupropion, mirtazapine, venlafaxine. (Papakostas et al., 2008). Therefore, there is an urgent need for research and development of more effective antidepressant therapies without any or with less adverse effects. Nowadays, the use of traditional herbs such as traditional Chinese medicine, traditional Ayurvedic medicine and other folk medicines has provided us a prospective alternative in the treatment of depression (Singh et al., 2009; Yi et al., 2009). Zoujin Pill (ZJP), a typical Traditional Chinese Medicine (TCM) formula, consists of two herbs: the rhizomes of Coptis chinensis Franch. (Ranunculaceae, officially recognized in the Chinese Pharmacopoeia as Rhizoma Coptidis) and the dried, unripe fruit of Evodia rutaecarpa (Juss.) Benth. (Rutaceae, officially recognized in the Chinese Pharmacopoeia as Fructus Evodiae) in the ratio of 6:1 (w/w). It was first recorded in Danxi's experiential therapy, a famous ancient medical manuscript, and is listed in the Chinese Pharmacopoeia as a prescription employed in patients suffering from gastric ulcer, gastroesophageal reflux disease, gastritis, and pyloric obstruction, among other disorders (The State Pharmacopoeia Commission of PR China, 2010). Depression with psychotic and somatic symptoms has been observed in association with stress gastric ulcers. It seems that there is a marked overlap among the neuronal pathogenetic pathways involved in ulcer genesis and depression. The report showed that the antidepressants duloxetine, amitriptyline and mirtazapine were capable of exerting more potent and efficacious protective effects in various experimental gastric ulcer rat models (Ji et al., 2012). Clinical studies have shown that some peptic ulcer patients benefit from combination therapy with antidepressants, even in the absence of any type of depression (Suleyman et al., 2009). Tricyclic antidepressants are particularly useful in the treatment of endogenous depression. Some tricyclic antidepressants possess definite antimuscarinic actions, thus reducing gastric secretion (Sen et al., 2002). These laboratory data and clinical reports highlight the importance of studying the action of antidepressants, not only in depressive behavior, but also in other responses to stress (i.e., stress ulcer incidence). Our previous pharmacological studies have shown that seven alkaloids, epiberberine, jatrorrhizine, coptisine, palmatine, berberine, evodiamine, rutaecarpine in the ethanol extract of ZJP, and the quantification of seven alkaloids in the ethanol extracts of ZJP was 32.65, 13.59, 110.64, 61.20, 153.0, 1.89, 1.47 mg/g, respectively, furthermore, the results showed that the alkaloids from the ethanol extract of ZJP have the anti-inflammatory (Wang et al., 2012) and two herbs in ZJP have the antagonistic effects on catecholamine in secretion in bovine adrenal medullary cells (Zhao et al., 2010). Furthermore, the evidence showed that the combination of berberine and evodiamine (the main bioactive ingredients in the herb of Rhizoma Coptidis and Fructus Evodiae respectively) might provide a protective effect for depression in individuals with a low expressing 5-HT transporter (5-HTT) allele by increasing receptor concentration in serotonergic neurons which could have more potential as an antidepressant or foodintake inhibitor than berberine or evodiamine alone (Hu et al., 2011). The 5-HTT regulates 5-HT transmission, which in turn modulates mood, emotion and appetite (Camarena et al., 2002). The 5-HTT is also well documented as the pharmacological target of selective 5-HT reuptake inhibitors, and its expression has been reported to be down-regulated by the antidepressants fluoxetine and sertraline (Johnson et al., 2009; Zhao et al., 2009). However, the antidepressant potential and pharmacological mechanism of the ethanol extract from ZJP are not clear. The
present study aimed to explore the antidepressant-like effects of the ethanol extract from ZJP (at doses of 5, 10, 20 mg/kg) using the tail suspension and forced swim tests. We investigated the probable mechanism of antidepressant-like activity by analyzing monoamine neurotransmitters, such as 5-HT, NE and DA levels in specific brain regions of striatum and hippocampus following the ethanol extracts from ZJP treatment and performing the reserpine test in depressive mice.
2. Materials and methods 2.1. Reagents The rhizomes of Coptis chinensis Franch. and the dried, unripe fruit of Evodia rutaecarpa (Juss.) Benth. were purchased from Baokang Hospital of Tianjin University of Traditional Chinese Medicine (Tianjin, China) and authenticated by Prof. Tian-Xiang Li in Tianjin University of Traditional Chinese Medicine according to the Chinese Pharmacopoeia (2010 edition). The voucher specimen (No. 018723) was deposited at herbarium of Tianjin University of Traditional Chinese Medicine. The standards of berberine (98%), palmatine (98%), evodiamine (98%), rutaecarpine (99.9%) were purchased from the Chinese National Institute for Control of Pharmaceutical and Biological Products (Beijing, China). Coptisine (98%) and epiberberine (98%) were obtained from Chengdu Musttechnology Co., Ltd. (Chengdu, China). Jatrorrhizine was purchased from Phytomarker Company (Tianjin, China). Methanol and acetonitrile were of HPLC grade and obtained from Tianjin Concord Technology Co., Ltd. (Tianjin, China). Triethylamine and phosphoric acid were of analytical grade obtained from Tianjin Chemical Reagent Company (Tianjin, China). Fluoxetine hydrochloride capsules were obtained from Eli Lilly and Company (Indianapolis, IN, USA). 5-HTP was purchased from Alfa Aesar (Ward Hill, MA, USA). 2.2. Preparation of ethanol extract from ZJP and quantitative analysis of various active compounds in the ethanol extract Preparation of ethanol extract from ZJP and quantitative analysis of various active compounds in the ethanol extract have been published in our previous paper (Wang et al., 2012). 2.3. Animals Male ICR mice (weighing 18–22 g), purchased from Beijing HuaFuKang Bio-technology Co. Ltd.( SCXK 2009-0004, Beijing, China) were housed under controlled light (12 h light/12 h dark, lights on at 07:00 a.m.). Ambient temperature and relative humidity were maintained at 247 1 1C and 5575%, respectively. The animals were allowed to acclimate to the housing facilities for 7 days before the experiments began with access to water and food ad libitum. All the experiments were carried out in a quiet room between 9:00 a.m. and 3:00 p.m. Each animal was used only once. All the animals used in this study were in accordance with NIH Guide for the Care and Use of Laboratory Animals and protocol was approved by the Animal Ethics Committee of Tianjin University of Traditional Chinese Medicine (TCM-2009-037-E07). 2.4. Drug administration and treatment The ethanol extract of ZJP was dissolved in 0.9% saline and sonicated for 45 min at room temperature. Animals were randomly divided into six groups (n ¼10 per group) for the tail suspension test (TST), forced swim test (FST) and 5-HTP-induced head-twitch test. The ethanol extract of ZJP (5, 10 and 20 mg/kg), fluoxetine (7.5 mg/kg) or 0.9% saline were given once by
Please cite this article as: Wang, Q.-S., et al., Antidepressant-like effect of ethanol extract from Zuojin Pill, containing two herbal drugs of Rhizoma Coptidis and Fructus Evodiae, is explained by modulating..., (2013), http://dx.doi.org/10.1016/j.jep.2013.05.011
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intragastric administration 1 h prior to the test. Reserpine group, as a model group, was added to the test of reserpine-induced behavioral despair. 2.5. Antidepressant activity evaluation 2.5.1. Forced swimming test (FST) The FST is credited for having good predictive validity for detecting antidepressant activity, which was described and modified slightly by Porsolt et al. (1977). Briefly, mice were forced to swim in a plexiglass cylinder (20 cm in height, 10 cm in diameter) filled with water to a depth of 15 cm maintained at 25 71 1C for 6 min. After an initial vigorous activity the animals showed period of immobility by floating in the water without struggling and making only small movements necessary to keep its head above the water. The total duration of immobility (seconds) was measured during the final 4 min interval of the test and the whole process was recorded by Digibehave system (Jiliang Software Company, Shanghai, China). Decrease in the duration of immobility during the FST was considered to be a measure of antidepressant activity (Cryan and Holmes, 2005; Gao et al., 2012). 2.5.2. Tail suspension test (TST) The TST was performed according to the method described and modified slightly by Steru et al. (1985). Mice were individually suspended 15 cm above the floor by means of an adhesive tape placed approximately 1 cm from the tip of the tail for 6 min. The duration of immobility was recorded only in the final 4 min of the test. Mice were considered to be immobile only when they hung passively and completely motionless. The immobility time of the suspended mice was recorded and analyzed by the Digibehave system. 2.5.3. Open field test (OFT) In order to investigate whether the immobility time in the FST and TST is involved in the alterations in locomotor activity, the ambulatory behavior was assessed in OFT and modified slightly by (Herrera-Ruiz et al., 2006). The open field apparatus (50 cm 50 cm 40 cm) was divided equally into 25 identical squares marked by blank lines. In brief, each mouse treated with drugs 1 h prior to the test was placed into the center of the arena and allowed to explore freely for 4 min. The number of squares crossed by mice and the number of rearings on the hind paws were recorded and evaluated by Digibehave system during a test period of the last 3 min.
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Mice were placed on a shelf (20 cm above table top) and the degree of ptosis of reserpinised mice was recorded according to the following rating scale: 0, eye open; 1, one-quarter closed; 2, half closed; 3, three-quarters closed; 4, completely closed (Sánchez-Mateo et al., 2007). The rectal temperature of each animal was measured by inserting the thermister thermometer into the rectum of mice at 2 h after the injection of reserpine.
2.5.6. Measurement of the levels of monoamines in the mice striatum and hippocampus Mice were sacrificed by decapitation without anesthesia after the measurement of rectal temperatures immediately. The bilateral hippocampi and striatum were removed from the brain after a rapid dissection of cranium. The tissues were weighed, rapidly frozen and stored at −80 1C until analysis. A certain volume of icecold 0.1 M perchloric acid (1 mg tissues with 10 μL perchloric acid) was added to each tube of corresponding brain tissue, and then homogenized for 30 s. The mixture was centrifuged at 14,000g for 20 min at 4 1C. The resultant supernatant was obtained and injected into the Agilent 1100 series HPLC system (Waldbronn, Germany) with Electrochemical Detector (ECD). Waters Symmetry C18 column (150 mm 3.9 mm, 5 μm) with a set of guard column was used. Mice cerebral monoamines concentrations were measured following the procedures described previously (Dhir and Kulkarni, 2007): the mobile phase contained 19% methanol, 3% acetonitrile and 78% phosphate buffer, where the buffer consisted of 0.1 M KH2PO4, 0.01 M octane sulfonate (OSA), 0.1 mM EDTA (pH, 3.6). The flow rate was 1.0 mL/min and the column temperature was kept at 35 1C. The monoamines were measured at a potential of +0.7 V using an Ag/AgCl reference electrode.
2.6. Statistical analysis All results were expressed as means 7SEM excluding values given in the antagonism of reserpine-induced ptosis and hypothermia test were graphed with mean 7SD. Statistically significant differences between groups was determined by One Way Analysis of Variance (ANOVA) followed by Scheffe's multiple range test. The criterion for statistical significance was P o0.01 or P o0.05.
2.5.4. 5-HTP-induced head-twitch test To explore the possible involvement of serotonergic mechanisms in the antidepressant-like effects of the ethanol extract of ZJP, the 5-HTP-induced head-twitch test was conducted. The test is a very distinctive behavior in mice and usually can not be mistaken for such behaviors as head shakes (lateral movement of the head from side to side) or head jerks (up and down jerking) (Xu et al., 2006). One hour after the drug administration, 5-HTP (180 mg/kg) was intraperitoneally administered to mice. Immediately after the injection, mice were placed into cages, and the number of head twitches was recorded during a 20 min period by a trained observer who was blind to drug treatment. 2.5.5. Antagonism of reserpine-induced ptosis and hypothermia test The procedure was performed according to the method described by (Bourin et al., 1983). In brief, mice were injected intraperitoneally with 2.0 mg/kg reserpine at 1 h later of the treatment of drugs except the vehicle-treated control group. The degree of ptosis was determined at 1 h after reserpine treatment.
Fig. 1. Effects of the ethanol extract of ZJP (5, 10 or 20 mg/kg, p.o.) or fluoxetine (7.5 mg/kg, p.o.) on the immobility time of mice in the FST. Values were given as means 7SEM (n¼10). nPo 0.05 as compared with the vehicle group.
Please cite this article as: Wang, Q.-S., et al., Antidepressant-like effect of ethanol extract from Zuojin Pill, containing two herbal drugs of Rhizoma Coptidis and Fructus Evodiae, is explained by modulating..., (2013), http://dx.doi.org/10.1016/j.jep.2013.05.011
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3. Results 3.1. Effects of the ethanol extract of ZJP on behavioral parameters As shown in Fig. 1, the ethanol extract of ZJP decreased the immobility time in the FST as compared to vehicle control group at 1 h post drug treatment in a dose range of 5, 10 mg/kg (p.o.) (P o0.05) and the difference from the vehicle control group at the dose (20 mg/kg) was not statistically significant. The ethanol extract of ZJP caused a reduction in the immobility periods with respect to vehicle-treated group in the TST at 5 and 20 mg/kg (p.o.) (P o0.05) in Fig. 2. Furthermore, the difference from the vehicle control group at the dose (10 mg/kg) was not statistically significant. Lower dose of the ethanol extract of ZJP (5 mg/kg, p.o.) was effective in both the tests. Fluoxetine, selected as the positive control, showed decrease in immobility time in both FST (P o0.05) and TST (Po 0.05). There was no significant effect on the locomotor activity (crossings and rearings) of mice in OFT when treated with the ethanol extract of ZJP (5–20 mg/kg, p.o.) as compared to vehicle control group (Table 1).
Table 1 Effects of the ethanol extract of ZJP (5, 10 or 20 mg/kg, p.o.) or fluoxetine (7.5 mg/kg, p.o.) on the crossings and rearings number of mice in the OFT. Groups
Dose (mg/kg)
Number of crossings
Number of rearings
Vehicle Fluoxetine
– 7.5 5 10 20
115.5 7 7.6 124.3 7 8.2 98.6 7 7.8 113.6 7 7.3 99.17 13.6
21.6 7 2.1 20.7 7 2.8 18.4 7 1.9 19.17 2.2 19.6 7 3.3
Ethanol extract of ZJP
Values were given as means 7 SEM (n ¼10), there was no statistical significance between groups.
3.2. Effects of the ethanol extract of ZJP on the 5-HTP-induced head-twitch response Fig. 3 illustrates the effects of the ethanol extract of ZJP on 5-HTP-induced head twitches in mice. It was observed that all test drugs exhibited potentiation of the syndrome induced by 5-HTP as compared to vehicle control group (P o0.05). The number of head twitches was increased by 105.6%, 108.9% and 77.78% for doses of 5, 10 and 20 mg/kg compared with vehicle control group, respectively. 3.3. Effects of the ethanol extract of ZJP on reserpine-induced ptosis and hypothermia in mice The effects of treatment with drugs on reserpine-induced ptosis and hypothermia were shown in Table 2. The mice treated with only reserpine at the dose of 2 mg/kg presented significant alterations of ptosis and hypothermia compared with the vehicle control group (Po0.01). Intragastric administration of the ethanol extract of ZJP (5, 10 and 20 mg/kg) could antagonize significantly the ptosis and hypothermia induced by reserpine in mice as compared with the group of reserpine (Po0.01). Fluoxetine (7.5 mg/kg) significantly antagonized all the effects induced by reserpine (P o0.05 or Po 0.01).
Fig. 3. Effects of the ethanol extract of ZJP (5, 10 or 20 mg/kg, p.o.) or fluoxetine (7.5 mg/ kg, p.o.) on 5-HTP-induced (180 mg/kg) head twitches in mice. Values were given as means7SEM (n¼ 10). nPo0.05 as compared with corresponding vehicle group.
3.4. Effects of the ethanol extract of ZJP on the concentration of monoamines in the mice striatum and hippocampus Results of the contents of neurotransmitter in mice hippocampus and striatum were shown in Fig. 4–6. The mice treated with reserpine at dose of 2.0 mg/kg significantly decreased the levels of NE and 5-HT in the hippocampus and NE, DA and 5-HT in the striatum as compared with vehicle-treated group (P o0.01). The pretreatment of the ethanol extract of ZJP (5, 10 and 20 mg/kg) could significantly elevate the levels of NE and 5-HT in the hippocampus and NE, DA and 5-HT in the striatum as compared with the reserpine group (P o0.05 or P o0.01).
4. Discussion
Fig. 2. Effects of the ethanol extract of ZJP (5, 10 or 20 mg/kg, p.o.) or fluoxetine (7.5 mg/kg, p.o.) on the immobility time of mice in the TST. Values were given as means 7 SEM (n¼ 10). nP o0.05 as compared with the vehicle group.
The antidepressant effect of herbs has been paid more and more attention because of increasing incidence of depression and predominance of traditional herbs in therapy (Wong et al., 2004; Zhou et al., 2011). Animal models of depression play an important role in the scientific screening and evaluation of antidepressants. Both FST and TST are widely used to screen pharmacological antidepressant-like activity. After an initial period of struggling, mice become immobile, resembling a state of despair and mental disorder. The state of immobility in the FST and TST claim to represent a condition similar to human depression and amenable to reversal by antidepressant drug (Renard et al., 2003). In the mice FST, not 20 mg/kg but 10 mg/kg the ethanol extract of ZJP acutely decreased immobility time. However, 20 mg/kg significantly inhibited the immobility period in TST, on
Please cite this article as: Wang, Q.-S., et al., Antidepressant-like effect of ethanol extract from Zuojin Pill, containing two herbal drugs of Rhizoma Coptidis and Fructus Evodiae, is explained by modulating..., (2013), http://dx.doi.org/10.1016/j.jep.2013.05.011
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Table 2 Antagonist effects of the ethanol extract of ZJP (5, 10 or 20 mg/kg, p.o.) or fluoxetine (7.5 mg/kg, p.o.) on the reserpine-induced ptosis and hypothermia in mice (n ¼10). Groups
Dose (mg/kg)
− 2 7.5 5 Ethanol extract 10 of ZJP 20
Vehicle Reserpine Fluoxetine
Reserpine (2.0 mg/kg)
Mean score of ptosis
Rectal temperature (1C)
− + + + +
0nn 3.6 7 0.5# 1.6 7 0.8nn 2.4 7 1.1nn 2.0 7 1.2nn
37.5 70.6nn 36.4 70.4# 36.9 70.5n 37.5 70.4nn 37.2 70.5nn
+
2.4 7 0.8nn
37.2 70.5nn
Values were given as means 7 SD (n¼ 10). n
Po 0.05 as compared with the reserpine group. Po 0.01 as compared with the reserpine group. Po 0.01 as compared with the vehicle group.
nn
#
Fig. 6. Effects of the ethanol extract of ZJP (5, 10 or 20 mg/kg, p.o.) or fluoxetine (7.5 mg/kg, p.o.) on the DA in the striatum. The values were expressed as means7 SEM (n ¼6). #Po 0.01 as compared with the vehicle group. nPo 0.05, nnPo 0.01 as compared with the reserpine group.
Fig. 4. Effects of the ethanol extract of ZJP (5, 10 or 20 mg/kg, p.o.) or fluoxetine (7.5 mg/kg, p.o.) on the NE and 5-HT in the hippocampus. The values were expressed as means 7SEM (n¼ 6). #Po 0.01 as compared with the vehicle group. n P o0.05, nnPo 0.01 as compared with the reserpine group.
Fig. 5. Effects of the ethanol extract of ZJP (5, 10 or 20 mg/kg, p.o.) or fluoxetine (7.5 mg/kg, p.o.) on the NE and 5-HT in the striatum. The values were expressed as means 7 SEM (n¼ 6). #Po 0.01 as compared with the vehicle group. nPo 0.05, nn P o0.01 as compared with the reserpine group.
lower dose (10 mg/kg, p.o.) there was no change as compared with vehicle-treated group. Despite the apparent conceptual similarity with the FST, behavior in the TST may have a different neurochemical basis.
Additionally, intra- and inter-strain differences in performance indicate that despite a face value similarity, the neurochemical pathways involved in mediating performance in these two widely used tests are not identical (Bai et al., 2001). However, the effect was not dosedependent. In FST and TST, false-positive results can be obtained with certain drugs, in particular psychomotor stimulants, which decrease immobility time by stimulating locomotor activity. Therefore, additional testing for locomotor activity along with FST and TST is generally advocated. However, all test drugs did not affect the locomotor activity in the OFT. Our results demonstrated that antidepressant activity of the ethanol extract of ZJP seemed not to be related to motor effects. The 5-HTP effectively increases central nervous system synthesis of 5-HT. It is the immediate precursor of 5-HT and is widely available as a dietary supplement, which is well absorbed after an oral dose (Turner and Blackwell, 2005). In the present study, pretreatment with the ethanol extract of ZJP significantly increased the number of head twitches induced by 5-HTP, suggesting that a serotoninergic mechanism may be involved in the antidepressant-like effect of the ethanol extract of ZJP. The antidepressant mechanism of the ethanol extract of ZJP was investigated on the reserpine-induced animal depression model. The ethanol extract of ZJP antagonized ptosis and hypothermia induced by reserpine that can irreversibly inhibit the vesicular uptake of monoamines, including NE, DA and 5-HT and its metabolites. The results showed that the ethanol extract of ZJP significantly increased NE and 5-HT in mice hippocampus and NE, DA and 5-HT in the striatum (apart from 5-HT in 20 mg/kg, p.o.). Furthermore, association studies suggested that depression was characterized by an over activity of the hypothalamic-pituitary–adrenal (HPA) axis that resembles the neuroendocrine response to stress (Pariante, 2003). Various evidences have implicated the involvement of the dopaminergic system in the pathophysiology of depression (Nemeroff, 2008). It was an indication that the antidepressant effect of test drug was likely to be associated with central monoaminergic neurotransmitter system, including functional stimulation of noradrenergic and serotoninergic systems as well as dopaminergic pathways. Thus, the antidepressant-like effect of the ethanol extract of ZJP may be due to the preservation of monoamine neurotransmitters. It is worth noting that the effects of ethanol extract of ZJP on the results of FST, TST and head twitches induced by 5-HTP were not dose-dependent. Firstly, it could be related to the multiple pharmacological effects from the interaction of the active ingredients in ethanol extract of ZJP. The active ingredients may influence the biogenic amines differentially depending upon the
Please cite this article as: Wang, Q.-S., et al., Antidepressant-like effect of ethanol extract from Zuojin Pill, containing two herbal drugs of Rhizoma Coptidis and Fructus Evodiae, is explained by modulating..., (2013), http://dx.doi.org/10.1016/j.jep.2013.05.011
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dose. It was reported that berberine decreased the immobility time in both the forced-swim and tail-suspension tests without dose-dependent (Kulkarni and Dhir, 2007), which suggested the possible involvement of more than one or all the biogenic amine systems in its antidepressant activity. Secondly, the intestinal absorption mechanisms of alkaloids in the ethanol extract of ZJP were different involvement of P-glycoprotein, which was another reason that there was no dose-dependent behavior in the results of FST, TST and head twitches induced by 5-HTP. The intestinal absorption of alkaloids was restricted as the involvement of Pglycoprotein in vivo. Such as berberine, the study showed that berberine possessed a biphasic effect on modulation of Pglycoprotein ATPase activity (stimulation at low concentration and inhibition at high concentration) (Najar et al., 2010). Furthermore, Jateorhizine, coptisine, palmatine, and berberine are all Pglycoprotein substrates, and they have no significant inhibitory effects on the activity of P-glycoprotein at concentrations of 1– 100 μM (Zhang et al., 2011), which may be one of the reasons for their low bioavailability. Thirdly, Pharmacokinetics and metabolism mechanism of alkaloids in the ethanol extract of ZJP could be another influencing factor on the no dose-dependent effects of ZJP treatments. The studies showed that after intravenous administration, plasma jatrorrhizine concentrations showed a biphasic decline, dose-independent clearance and half-life of terminal elimination phase, and a relatively large distribution volume. The metabolic properties of jatrorrhizine was suggested to multiple metabolic pathways (Shi et al., 2012). The further research on metabolic processes of the ethanol extract of ZJP will be developed in vivo in the future. In conclusion, the results demonstrated that the ethanol extract of ZJP could possess an antidepressant-like effect in the FST and TST, which was not due to the alteration in the locomotor activity. In addition, this work provides evidence that the antidepressantlike effect in the TST is dependent on the interaction with the serotonergic, noradrenergic and dopaminergic systems as well as the elevation of 5-HT, NA and DA levels in the mouse hippocampus and striatum, which demonstrated that the antidepressant-like effect of the ethanol extract of ZJP is mediated, at least in part, via the central monoaminergic neurotransmitter system and 5-HT plays a major role.
Conflict of interest The authors declare that there are no conflicts of interest.
Acknowledgments We gratefully acknowledge Prof. Xiu-Mei Gao and Prof. De-Qin Zhang of the Tianjin University of Traditional Chinese Medicine for their professional technical support and funding support. This work was supported by the National Natural Science Foundation of China (81173469), Program for New Century Excellent Talents in University (NCET-09-0899) and the Key Program of the Natural Science Foundation of Tianjin, China (10JCZDJC21200). References Bai, F., Li, X., Clay, M., Lindstrom, T., Skolnick, P., 2001. Intra- and interstrain differences in models of “behavioral despair”. Pharmacology Biochemistry and Behavior 70, 187–192. Bourin, M., Poncelet, M., Chermat, R., Simon, P., 1983. The value of the reserpine test in psychopharmacology. Arzneimittelforschung 33, 1173–1176. Camarena, B., Ruvinskis, E., Santiago, H., Montiel, F., Cruz, C., Gonzalez-Barranco, J., Nicolini, H., 2002. Serotonin transporter gene and obese females with impulsivity. Molecular Psychiatry 7, 829–830.
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Please cite this article as: Wang, Q.-S., et al., Antidepressant-like effect of ethanol extract from Zuojin Pill, containing two herbal drugs of Rhizoma Coptidis and Fructus Evodiae, is explained by modulating..., (2013), http://dx.doi.org/10.1016/j.jep.2013.05.011
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Please cite this article as: Wang, Q.-S., et al., Antidepressant-like effect of ethanol extract from Zuojin Pill, containing two herbal drugs of Rhizoma Coptidis and Fructus Evodiae, is explained by modulating..., (2013), http://dx.doi.org/10.1016/j.jep.2013.05.011
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Antidepressant-like effect of ethanol extract from Zuojin Pill, containing two herbal drugs of Rhizoma Coptidis and Fructus Evodiae, is explained by modulating the monoaminergic neurotransmitter system in mice Qiang-Song Wang a,b, Shi-Lan Ding a,b, Hao-Ping Mao a,b, Yuan-Lu Cui a,b,n, Xue-Jie Qi a,b,n a Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, No. 88 YuQuan Road, Nankai District, Tianjin 300193, PR China b Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, PR China
art ic l e i nf o
a b s t r a c t
Article history: Received 29 November 2012 Received in revised form 12 May 2013 Accepted 14 May 2013
Ethnopharmacological relevance: Zuojin Pill (ZJP), a traditional Chinese medicinal decoction, contains two herbal drugs: Coptis chinensis Franch. and Evodia rutaecarpa (Juss.) Benth. in the ratio of 6:1 (w/w). Previous pharmacological studies have shown that two herbs in ZJP have the antagonistic effects on catecholamine secretion in bovine adrenal medullary cells. Furthermore, the alkaloids from the two herbs in ZJP may provide a protective effect for depression in individuals with a low expressing 5-HTT allele by increasing receptor concentration in serotonergic neurons. However, antidepressant effect has not been reported before and has not been fully clarified. Aim of the study: The present study aimed to investigate the antidepressant potential of ethanol extract from ZJP and its monoaminergic mechanism in mice. Materials and methods: Seven alkaloids were determined from the ethanol extract of ZJP using High Performance Liquid Chromatography (HPLC) with the gradient mobile phase. The ethanol extract from ZJP was used to evaluate the antidepressant potential in mice. Mouse models of depression including the tail suspension test (TST) and the forced swim test (FST) were used to evaluate the effects of the ethanol extract from ZJP. A possible mechanism was explored in the tests of antagonism of reserpine-induced ptosis and hypothermia, and 5-HTP induced head twitch response in mice. The contents of monoamine neurotransmitters including norepinephrine (NE), serotonin (5-hydroxytryptamine or 5-HT) in hippocampus of mice and NE, 5-HT, dopamine (DA) in striatum of mice were determined by HPLC system with Electrochemical Detector (ECD). Results: The results showed that intragastric administration of the ethanol extract from ZJP (5, 10, 20 mg/kg) or fluoxetine (7.5 mg/kg) significantly reduced the duration of immobility in TST and FST. However, the effect was not dose-dependent. Ethanol extract from ZJP (5, 10, 20 mg/kg) also increased the accumulative number of the 5-HTP-induced head twitch response in mice. The mice were treated with the ethanol extract from ZJP (5, 10, 20 mg/kg) or fluoxetine (7.5 mg/kg), which could antagonize reserpine-induced ptosis and hypothermia, moreover, both of them could elevate the contents of NE, 5-HT in hippocampus as well as NE, 5-HT, DA in striatum significantly. Conclusion: These results indicate that the ethanol extract from ZJP produced antidepressant-like effect and the possible mechanism, at least in part, is via the central monoaminergic neurotransmitter system and 5-HT plays a major role. & 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Rhizoma coptidis Fructus evodiae Alkaloids Antidepressant Monoamine neurotransmitter Traditional chinese medicine (TCM)
1. Introduction Depression is a chronic, recurring and potentially lifethreatening disease which could affect the performance and n Corresponding authors at: Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, No. 88 YuQuan Road, Nankai District, Tianjin 300193, PR China. Tel./fax: +86 22 59596170. E-mail addresses: [email protected] (Y.-L. Cui), [email protected] (X.-J. Qi).
learning, social interactions and development of normal peer relationships, and even lead to suicidal ideations later in life. According to the report of World Health Organization, it may become the second cause of illness-induced disability by the year 2020 (WHO, 2001). It is well known that monoamine neurotransmitters such as 5-HT, NE and DA in the central nervous system play a key role in the pathophysiology of depression (Elhwuegi, 2004). The increase in extracellular 5-HT and NE levels in the brain are thought to be
0378-8741/$ - see front matter & 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jep.2013.05.011
Please cite this article as: Wang, Q.-S., et al., Antidepressant-like effect of ethanol extract from Zuojin Pill, containing two herbal drugs of Rhizoma Coptidis and Fructus Evodiae, is explained by modulating..., (2013), http://dx.doi.org/10.1016/j.jep.2013.05.011
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closely related to the antidepressant effect (Kapur and Mann, 1992; Papakostas, 2006). At present, several types of classical antidepressants are primary modulators of monoamine neurotransmitters. Although many antidepressant drugs could improve depressive symptoms, 30% of depressive patients failed to respond satisfactorily to commercially available antidepressants as the undesirable side-effects of antidepressant drugs, such as bupropion, mirtazapine, venlafaxine. (Papakostas et al., 2008). Therefore, there is an urgent need for research and development of more effective antidepressant therapies without any or with less adverse effects. Nowadays, the use of traditional herbs such as traditional Chinese medicine, traditional Ayurvedic medicine and other folk medicines has provided us a prospective alternative in the treatment of depression (Singh et al., 2009; Yi et al., 2009). Zoujin Pill (ZJP), a typical Traditional Chinese Medicine (TCM) formula, consists of two herbs: the rhizomes of Coptis chinensis Franch. (Ranunculaceae, officially recognized in the Chinese Pharmacopoeia as Rhizoma Coptidis) and the dried, unripe fruit of Evodia rutaecarpa (Juss.) Benth. (Rutaceae, officially recognized in the Chinese Pharmacopoeia as Fructus Evodiae) in the ratio of 6:1 (w/w). It was first recorded in Danxi's experiential therapy, a famous ancient medical manuscript, and is listed in the Chinese Pharmacopoeia as a prescription employed in patients suffering from gastric ulcer, gastroesophageal reflux disease, gastritis, and pyloric obstruction, among other disorders (The State Pharmacopoeia Commission of PR China, 2010). Depression with psychotic and somatic symptoms has been observed in association with stress gastric ulcers. It seems that there is a marked overlap among the neuronal pathogenetic pathways involved in ulcer genesis and depression. The report showed that the antidepressants duloxetine, amitriptyline and mirtazapine were capable of exerting more potent and efficacious protective effects in various experimental gastric ulcer rat models (Ji et al., 2012). Clinical studies have shown that some peptic ulcer patients benefit from combination therapy with antidepressants, even in the absence of any type of depression (Suleyman et al., 2009). Tricyclic antidepressants are particularly useful in the treatment of endogenous depression. Some tricyclic antidepressants possess definite antimuscarinic actions, thus reducing gastric secretion (Sen et al., 2002). These laboratory data and clinical reports highlight the importance of studying the action of antidepressants, not only in depressive behavior, but also in other responses to stress (i.e., stress ulcer incidence). Our previous pharmacological studies have shown that seven alkaloids, epiberberine, jatrorrhizine, coptisine, palmatine, berberine, evodiamine, rutaecarpine in the ethanol extract of ZJP, and the quantification of seven alkaloids in the ethanol extracts of ZJP was 32.65, 13.59, 110.64, 61.20, 153.0, 1.89, 1.47 mg/g, respectively, furthermore, the results showed that the alkaloids from the ethanol extract of ZJP have the anti-inflammatory (Wang et al., 2012) and two herbs in ZJP have the antagonistic effects on catecholamine in secretion in bovine adrenal medullary cells (Zhao et al., 2010). Furthermore, the evidence showed that the combination of berberine and evodiamine (the main bioactive ingredients in the herb of Rhizoma Coptidis and Fructus Evodiae respectively) might provide a protective effect for depression in individuals with a low expressing 5-HT transporter (5-HTT) allele by increasing receptor concentration in serotonergic neurons which could have more potential as an antidepressant or foodintake inhibitor than berberine or evodiamine alone (Hu et al., 2011). The 5-HTT regulates 5-HT transmission, which in turn modulates mood, emotion and appetite (Camarena et al., 2002). The 5-HTT is also well documented as the pharmacological target of selective 5-HT reuptake inhibitors, and its expression has been reported to be down-regulated by the antidepressants fluoxetine and sertraline (Johnson et al., 2009; Zhao et al., 2009). However, the antidepressant potential and pharmacological mechanism of the ethanol extract from ZJP are not clear. The
present study aimed to explore the antidepressant-like effects of the ethanol extract from ZJP (at doses of 5, 10, 20 mg/kg) using the tail suspension and forced swim tests. We investigated the probable mechanism of antidepressant-like activity by analyzing monoamine neurotransmitters, such as 5-HT, NE and DA levels in specific brain regions of striatum and hippocampus following the ethanol extracts from ZJP treatment and performing the reserpine test in depressive mice.
2. Materials and methods 2.1. Reagents The rhizomes of Coptis chinensis Franch. and the dried, unripe fruit of Evodia rutaecarpa (Juss.) Benth. were purchased from Baokang Hospital of Tianjin University of Traditional Chinese Medicine (Tianjin, China) and authenticated by Prof. Tian-Xiang Li in Tianjin University of Traditional Chinese Medicine according to the Chinese Pharmacopoeia (2010 edition). The voucher specimen (No. 018723) was deposited at herbarium of Tianjin University of Traditional Chinese Medicine. The standards of berberine (98%), palmatine (98%), evodiamine (98%), rutaecarpine (99.9%) were purchased from the Chinese National Institute for Control of Pharmaceutical and Biological Products (Beijing, China). Coptisine (98%) and epiberberine (98%) were obtained from Chengdu Musttechnology Co., Ltd. (Chengdu, China). Jatrorrhizine was purchased from Phytomarker Company (Tianjin, China). Methanol and acetonitrile were of HPLC grade and obtained from Tianjin Concord Technology Co., Ltd. (Tianjin, China). Triethylamine and phosphoric acid were of analytical grade obtained from Tianjin Chemical Reagent Company (Tianjin, China). Fluoxetine hydrochloride capsules were obtained from Eli Lilly and Company (Indianapolis, IN, USA). 5-HTP was purchased from Alfa Aesar (Ward Hill, MA, USA). 2.2. Preparation of ethanol extract from ZJP and quantitative analysis of various active compounds in the ethanol extract Preparation of ethanol extract from ZJP and quantitative analysis of various active compounds in the ethanol extract have been published in our previous paper (Wang et al., 2012). 2.3. Animals Male ICR mice (weighing 18–22 g), purchased from Beijing HuaFuKang Bio-technology Co. Ltd.( SCXK 2009-0004, Beijing, China) were housed under controlled light (12 h light/12 h dark, lights on at 07:00 a.m.). Ambient temperature and relative humidity were maintained at 247 1 1C and 5575%, respectively. The animals were allowed to acclimate to the housing facilities for 7 days before the experiments began with access to water and food ad libitum. All the experiments were carried out in a quiet room between 9:00 a.m. and 3:00 p.m. Each animal was used only once. All the animals used in this study were in accordance with NIH Guide for the Care and Use of Laboratory Animals and protocol was approved by the Animal Ethics Committee of Tianjin University of Traditional Chinese Medicine (TCM-2009-037-E07). 2.4. Drug administration and treatment The ethanol extract of ZJP was dissolved in 0.9% saline and sonicated for 45 min at room temperature. Animals were randomly divided into six groups (n ¼10 per group) for the tail suspension test (TST), forced swim test (FST) and 5-HTP-induced head-twitch test. The ethanol extract of ZJP (5, 10 and 20 mg/kg), fluoxetine (7.5 mg/kg) or 0.9% saline were given once by
Please cite this article as: Wang, Q.-S., et al., Antidepressant-like effect of ethanol extract from Zuojin Pill, containing two herbal drugs of Rhizoma Coptidis and Fructus Evodiae, is explained by modulating..., (2013), http://dx.doi.org/10.1016/j.jep.2013.05.011
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intragastric administration 1 h prior to the test. Reserpine group, as a model group, was added to the test of reserpine-induced behavioral despair. 2.5. Antidepressant activity evaluation 2.5.1. Forced swimming test (FST) The FST is credited for having good predictive validity for detecting antidepressant activity, which was described and modified slightly by Porsolt et al. (1977). Briefly, mice were forced to swim in a plexiglass cylinder (20 cm in height, 10 cm in diameter) filled with water to a depth of 15 cm maintained at 25 71 1C for 6 min. After an initial vigorous activity the animals showed period of immobility by floating in the water without struggling and making only small movements necessary to keep its head above the water. The total duration of immobility (seconds) was measured during the final 4 min interval of the test and the whole process was recorded by Digibehave system (Jiliang Software Company, Shanghai, China). Decrease in the duration of immobility during the FST was considered to be a measure of antidepressant activity (Cryan and Holmes, 2005; Gao et al., 2012). 2.5.2. Tail suspension test (TST) The TST was performed according to the method described and modified slightly by Steru et al. (1985). Mice were individually suspended 15 cm above the floor by means of an adhesive tape placed approximately 1 cm from the tip of the tail for 6 min. The duration of immobility was recorded only in the final 4 min of the test. Mice were considered to be immobile only when they hung passively and completely motionless. The immobility time of the suspended mice was recorded and analyzed by the Digibehave system. 2.5.3. Open field test (OFT) In order to investigate whether the immobility time in the FST and TST is involved in the alterations in locomotor activity, the ambulatory behavior was assessed in OFT and modified slightly by (Herrera-Ruiz et al., 2006). The open field apparatus (50 cm 50 cm 40 cm) was divided equally into 25 identical squares marked by blank lines. In brief, each mouse treated with drugs 1 h prior to the test was placed into the center of the arena and allowed to explore freely for 4 min. The number of squares crossed by mice and the number of rearings on the hind paws were recorded and evaluated by Digibehave system during a test period of the last 3 min.
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Mice were placed on a shelf (20 cm above table top) and the degree of ptosis of reserpinised mice was recorded according to the following rating scale: 0, eye open; 1, one-quarter closed; 2, half closed; 3, three-quarters closed; 4, completely closed (Sánchez-Mateo et al., 2007). The rectal temperature of each animal was measured by inserting the thermister thermometer into the rectum of mice at 2 h after the injection of reserpine.
2.5.6. Measurement of the levels of monoamines in the mice striatum and hippocampus Mice were sacrificed by decapitation without anesthesia after the measurement of rectal temperatures immediately. The bilateral hippocampi and striatum were removed from the brain after a rapid dissection of cranium. The tissues were weighed, rapidly frozen and stored at −80 1C until analysis. A certain volume of icecold 0.1 M perchloric acid (1 mg tissues with 10 μL perchloric acid) was added to each tube of corresponding brain tissue, and then homogenized for 30 s. The mixture was centrifuged at 14,000g for 20 min at 4 1C. The resultant supernatant was obtained and injected into the Agilent 1100 series HPLC system (Waldbronn, Germany) with Electrochemical Detector (ECD). Waters Symmetry C18 column (150 mm 3.9 mm, 5 μm) with a set of guard column was used. Mice cerebral monoamines concentrations were measured following the procedures described previously (Dhir and Kulkarni, 2007): the mobile phase contained 19% methanol, 3% acetonitrile and 78% phosphate buffer, where the buffer consisted of 0.1 M KH2PO4, 0.01 M octane sulfonate (OSA), 0.1 mM EDTA (pH, 3.6). The flow rate was 1.0 mL/min and the column temperature was kept at 35 1C. The monoamines were measured at a potential of +0.7 V using an Ag/AgCl reference electrode.
2.6. Statistical analysis All results were expressed as means 7SEM excluding values given in the antagonism of reserpine-induced ptosis and hypothermia test were graphed with mean 7SD. Statistically significant differences between groups was determined by One Way Analysis of Variance (ANOVA) followed by Scheffe's multiple range test. The criterion for statistical significance was P o0.01 or P o0.05.
2.5.4. 5-HTP-induced head-twitch test To explore the possible involvement of serotonergic mechanisms in the antidepressant-like effects of the ethanol extract of ZJP, the 5-HTP-induced head-twitch test was conducted. The test is a very distinctive behavior in mice and usually can not be mistaken for such behaviors as head shakes (lateral movement of the head from side to side) or head jerks (up and down jerking) (Xu et al., 2006). One hour after the drug administration, 5-HTP (180 mg/kg) was intraperitoneally administered to mice. Immediately after the injection, mice were placed into cages, and the number of head twitches was recorded during a 20 min period by a trained observer who was blind to drug treatment. 2.5.5. Antagonism of reserpine-induced ptosis and hypothermia test The procedure was performed according to the method described by (Bourin et al., 1983). In brief, mice were injected intraperitoneally with 2.0 mg/kg reserpine at 1 h later of the treatment of drugs except the vehicle-treated control group. The degree of ptosis was determined at 1 h after reserpine treatment.
Fig. 1. Effects of the ethanol extract of ZJP (5, 10 or 20 mg/kg, p.o.) or fluoxetine (7.5 mg/kg, p.o.) on the immobility time of mice in the FST. Values were given as means 7SEM (n¼10). nPo 0.05 as compared with the vehicle group.
Please cite this article as: Wang, Q.-S., et al., Antidepressant-like effect of ethanol extract from Zuojin Pill, containing two herbal drugs of Rhizoma Coptidis and Fructus Evodiae, is explained by modulating..., (2013), http://dx.doi.org/10.1016/j.jep.2013.05.011
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3. Results 3.1. Effects of the ethanol extract of ZJP on behavioral parameters As shown in Fig. 1, the ethanol extract of ZJP decreased the immobility time in the FST as compared to vehicle control group at 1 h post drug treatment in a dose range of 5, 10 mg/kg (p.o.) (P o0.05) and the difference from the vehicle control group at the dose (20 mg/kg) was not statistically significant. The ethanol extract of ZJP caused a reduction in the immobility periods with respect to vehicle-treated group in the TST at 5 and 20 mg/kg (p.o.) (P o0.05) in Fig. 2. Furthermore, the difference from the vehicle control group at the dose (10 mg/kg) was not statistically significant. Lower dose of the ethanol extract of ZJP (5 mg/kg, p.o.) was effective in both the tests. Fluoxetine, selected as the positive control, showed decrease in immobility time in both FST (P o0.05) and TST (Po 0.05). There was no significant effect on the locomotor activity (crossings and rearings) of mice in OFT when treated with the ethanol extract of ZJP (5–20 mg/kg, p.o.) as compared to vehicle control group (Table 1).
Table 1 Effects of the ethanol extract of ZJP (5, 10 or 20 mg/kg, p.o.) or fluoxetine (7.5 mg/kg, p.o.) on the crossings and rearings number of mice in the OFT. Groups
Dose (mg/kg)
Number of crossings
Number of rearings
Vehicle Fluoxetine
– 7.5 5 10 20
115.5 7 7.6 124.3 7 8.2 98.6 7 7.8 113.6 7 7.3 99.17 13.6
21.6 7 2.1 20.7 7 2.8 18.4 7 1.9 19.17 2.2 19.6 7 3.3
Ethanol extract of ZJP
Values were given as means 7 SEM (n ¼10), there was no statistical significance between groups.
3.2. Effects of the ethanol extract of ZJP on the 5-HTP-induced head-twitch response Fig. 3 illustrates the effects of the ethanol extract of ZJP on 5-HTP-induced head twitches in mice. It was observed that all test drugs exhibited potentiation of the syndrome induced by 5-HTP as compared to vehicle control group (P o0.05). The number of head twitches was increased by 105.6%, 108.9% and 77.78% for doses of 5, 10 and 20 mg/kg compared with vehicle control group, respectively. 3.3. Effects of the ethanol extract of ZJP on reserpine-induced ptosis and hypothermia in mice The effects of treatment with drugs on reserpine-induced ptosis and hypothermia were shown in Table 2. The mice treated with only reserpine at the dose of 2 mg/kg presented significant alterations of ptosis and hypothermia compared with the vehicle control group (Po0.01). Intragastric administration of the ethanol extract of ZJP (5, 10 and 20 mg/kg) could antagonize significantly the ptosis and hypothermia induced by reserpine in mice as compared with the group of reserpine (Po0.01). Fluoxetine (7.5 mg/kg) significantly antagonized all the effects induced by reserpine (P o0.05 or Po 0.01).
Fig. 3. Effects of the ethanol extract of ZJP (5, 10 or 20 mg/kg, p.o.) or fluoxetine (7.5 mg/ kg, p.o.) on 5-HTP-induced (180 mg/kg) head twitches in mice. Values were given as means7SEM (n¼ 10). nPo0.05 as compared with corresponding vehicle group.
3.4. Effects of the ethanol extract of ZJP on the concentration of monoamines in the mice striatum and hippocampus Results of the contents of neurotransmitter in mice hippocampus and striatum were shown in Fig. 4–6. The mice treated with reserpine at dose of 2.0 mg/kg significantly decreased the levels of NE and 5-HT in the hippocampus and NE, DA and 5-HT in the striatum as compared with vehicle-treated group (P o0.01). The pretreatment of the ethanol extract of ZJP (5, 10 and 20 mg/kg) could significantly elevate the levels of NE and 5-HT in the hippocampus and NE, DA and 5-HT in the striatum as compared with the reserpine group (P o0.05 or P o0.01).
4. Discussion
Fig. 2. Effects of the ethanol extract of ZJP (5, 10 or 20 mg/kg, p.o.) or fluoxetine (7.5 mg/kg, p.o.) on the immobility time of mice in the TST. Values were given as means 7 SEM (n¼ 10). nP o0.05 as compared with the vehicle group.
The antidepressant effect of herbs has been paid more and more attention because of increasing incidence of depression and predominance of traditional herbs in therapy (Wong et al., 2004; Zhou et al., 2011). Animal models of depression play an important role in the scientific screening and evaluation of antidepressants. Both FST and TST are widely used to screen pharmacological antidepressant-like activity. After an initial period of struggling, mice become immobile, resembling a state of despair and mental disorder. The state of immobility in the FST and TST claim to represent a condition similar to human depression and amenable to reversal by antidepressant drug (Renard et al., 2003). In the mice FST, not 20 mg/kg but 10 mg/kg the ethanol extract of ZJP acutely decreased immobility time. However, 20 mg/kg significantly inhibited the immobility period in TST, on
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Table 2 Antagonist effects of the ethanol extract of ZJP (5, 10 or 20 mg/kg, p.o.) or fluoxetine (7.5 mg/kg, p.o.) on the reserpine-induced ptosis and hypothermia in mice (n ¼10). Groups
Dose (mg/kg)
− 2 7.5 5 Ethanol extract 10 of ZJP 20
Vehicle Reserpine Fluoxetine
Reserpine (2.0 mg/kg)
Mean score of ptosis
Rectal temperature (1C)
− + + + +
0nn 3.6 7 0.5# 1.6 7 0.8nn 2.4 7 1.1nn 2.0 7 1.2nn
37.5 70.6nn 36.4 70.4# 36.9 70.5n 37.5 70.4nn 37.2 70.5nn
+
2.4 7 0.8nn
37.2 70.5nn
Values were given as means 7 SD (n¼ 10). n
Po 0.05 as compared with the reserpine group. Po 0.01 as compared with the reserpine group. Po 0.01 as compared with the vehicle group.
nn
#
Fig. 6. Effects of the ethanol extract of ZJP (5, 10 or 20 mg/kg, p.o.) or fluoxetine (7.5 mg/kg, p.o.) on the DA in the striatum. The values were expressed as means7 SEM (n ¼6). #Po 0.01 as compared with the vehicle group. nPo 0.05, nnPo 0.01 as compared with the reserpine group.
Fig. 4. Effects of the ethanol extract of ZJP (5, 10 or 20 mg/kg, p.o.) or fluoxetine (7.5 mg/kg, p.o.) on the NE and 5-HT in the hippocampus. The values were expressed as means 7SEM (n¼ 6). #Po 0.01 as compared with the vehicle group. n P o0.05, nnPo 0.01 as compared with the reserpine group.
Fig. 5. Effects of the ethanol extract of ZJP (5, 10 or 20 mg/kg, p.o.) or fluoxetine (7.5 mg/kg, p.o.) on the NE and 5-HT in the striatum. The values were expressed as means 7 SEM (n¼ 6). #Po 0.01 as compared with the vehicle group. nPo 0.05, nn P o0.01 as compared with the reserpine group.
lower dose (10 mg/kg, p.o.) there was no change as compared with vehicle-treated group. Despite the apparent conceptual similarity with the FST, behavior in the TST may have a different neurochemical basis.
Additionally, intra- and inter-strain differences in performance indicate that despite a face value similarity, the neurochemical pathways involved in mediating performance in these two widely used tests are not identical (Bai et al., 2001). However, the effect was not dosedependent. In FST and TST, false-positive results can be obtained with certain drugs, in particular psychomotor stimulants, which decrease immobility time by stimulating locomotor activity. Therefore, additional testing for locomotor activity along with FST and TST is generally advocated. However, all test drugs did not affect the locomotor activity in the OFT. Our results demonstrated that antidepressant activity of the ethanol extract of ZJP seemed not to be related to motor effects. The 5-HTP effectively increases central nervous system synthesis of 5-HT. It is the immediate precursor of 5-HT and is widely available as a dietary supplement, which is well absorbed after an oral dose (Turner and Blackwell, 2005). In the present study, pretreatment with the ethanol extract of ZJP significantly increased the number of head twitches induced by 5-HTP, suggesting that a serotoninergic mechanism may be involved in the antidepressant-like effect of the ethanol extract of ZJP. The antidepressant mechanism of the ethanol extract of ZJP was investigated on the reserpine-induced animal depression model. The ethanol extract of ZJP antagonized ptosis and hypothermia induced by reserpine that can irreversibly inhibit the vesicular uptake of monoamines, including NE, DA and 5-HT and its metabolites. The results showed that the ethanol extract of ZJP significantly increased NE and 5-HT in mice hippocampus and NE, DA and 5-HT in the striatum (apart from 5-HT in 20 mg/kg, p.o.). Furthermore, association studies suggested that depression was characterized by an over activity of the hypothalamic-pituitary–adrenal (HPA) axis that resembles the neuroendocrine response to stress (Pariante, 2003). Various evidences have implicated the involvement of the dopaminergic system in the pathophysiology of depression (Nemeroff, 2008). It was an indication that the antidepressant effect of test drug was likely to be associated with central monoaminergic neurotransmitter system, including functional stimulation of noradrenergic and serotoninergic systems as well as dopaminergic pathways. Thus, the antidepressant-like effect of the ethanol extract of ZJP may be due to the preservation of monoamine neurotransmitters. It is worth noting that the effects of ethanol extract of ZJP on the results of FST, TST and head twitches induced by 5-HTP were not dose-dependent. Firstly, it could be related to the multiple pharmacological effects from the interaction of the active ingredients in ethanol extract of ZJP. The active ingredients may influence the biogenic amines differentially depending upon the
Please cite this article as: Wang, Q.-S., et al., Antidepressant-like effect of ethanol extract from Zuojin Pill, containing two herbal drugs of Rhizoma Coptidis and Fructus Evodiae, is explained by modulating..., (2013), http://dx.doi.org/10.1016/j.jep.2013.05.011
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dose. It was reported that berberine decreased the immobility time in both the forced-swim and tail-suspension tests without dose-dependent (Kulkarni and Dhir, 2007), which suggested the possible involvement of more than one or all the biogenic amine systems in its antidepressant activity. Secondly, the intestinal absorption mechanisms of alkaloids in the ethanol extract of ZJP were different involvement of P-glycoprotein, which was another reason that there was no dose-dependent behavior in the results of FST, TST and head twitches induced by 5-HTP. The intestinal absorption of alkaloids was restricted as the involvement of Pglycoprotein in vivo. Such as berberine, the study showed that berberine possessed a biphasic effect on modulation of Pglycoprotein ATPase activity (stimulation at low concentration and inhibition at high concentration) (Najar et al., 2010). Furthermore, Jateorhizine, coptisine, palmatine, and berberine are all Pglycoprotein substrates, and they have no significant inhibitory effects on the activity of P-glycoprotein at concentrations of 1– 100 μM (Zhang et al., 2011), which may be one of the reasons for their low bioavailability. Thirdly, Pharmacokinetics and metabolism mechanism of alkaloids in the ethanol extract of ZJP could be another influencing factor on the no dose-dependent effects of ZJP treatments. The studies showed that after intravenous administration, plasma jatrorrhizine concentrations showed a biphasic decline, dose-independent clearance and half-life of terminal elimination phase, and a relatively large distribution volume. The metabolic properties of jatrorrhizine was suggested to multiple metabolic pathways (Shi et al., 2012). The further research on metabolic processes of the ethanol extract of ZJP will be developed in vivo in the future. In conclusion, the results demonstrated that the ethanol extract of ZJP could possess an antidepressant-like effect in the FST and TST, which was not due to the alteration in the locomotor activity. In addition, this work provides evidence that the antidepressantlike effect in the TST is dependent on the interaction with the serotonergic, noradrenergic and dopaminergic systems as well as the elevation of 5-HT, NA and DA levels in the mouse hippocampus and striatum, which demonstrated that the antidepressant-like effect of the ethanol extract of ZJP is mediated, at least in part, via the central monoaminergic neurotransmitter system and 5-HT plays a major role.
Conflict of interest The authors declare that there are no conflicts of interest.
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Please cite this article as: Wang, Q.-S., et al., Antidepressant-like effect of ethanol extract from Zuojin Pill, containing two herbal drugs of Rhizoma Coptidis and Fructus Evodiae, is explained by modulating..., (2013), http://dx.doi.org/10.1016/j.jep.2013.05.011