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Behavioral and biochemical studies of total furocoumarins from seeds of Psoralea corylifolia in the chronic mild stress model of depression in mice.

Abstract

Depression is related to alterations of the monoamine oxidase (MAO), hypothalamic-pituitary-adrenal (HPA) axis, and oxidative systems, and some antidepressants achieve their therapeutic effects through alteration of following biochemical markers of depression: MAO-A and MAO-B activities, cortisol levels, superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels. The seeds of Psoralea corylifolia, otherwise known as Buguzhi, have long been used for treatments of various symptoms associated with aging in China. Furocoumarins are the most widespread secondary metabolites in this species. The present study was designed to evaluate the potential antidepressant-like activity of total furocoumarins of P. corylifolia (TFPC) in the chronic mild stress (CMS) model of depression. Mice subjected to CMS exhibited a reduction in sucrose intake. Conversely, brain MAO-A and MAO-B activities, plasma cortisol levels, and liver SOD activity and MDA levels were increased following CMS exposures. The time-course for reversal of CMS-induced deficits in sucrose consumption by TFPC was dose-dependent. Thus, the statistically significant effect of the higher dose of TFPC (50 mg/kg body wt.) was observed after 3 days of treatment, while 6 days of treatment were required in the group receiving a lower dose (30 mg/kg body wt.) of TFPC. TFPC reversed these biochemical changes. These results suggest that TFPC may possess potent and rapid antidepressant properties that are mediated via MAO, the HPA axis and oxidative systems and these antidepressant actions could make TFPC a potentially valuable drug for the treatment of depression in the elderly.

[c] 2006 Elsevier GmbH. All rights reserved.

Keywords: Psoralea corylifolia; Total furocoumarins; Depression; Chronic mild stress; Mice

Introduction

Depression is a major public health problem related to alterations of the biochemical markers and some antidepressants achieve their therapeutic effects through reversing alteration of these markers. There is an association between monoamine oxidase-A and B (MAO) activity and susceptibility to psychiatric conditions (Wouters, 1998). MAO activity balance could be a factor in determining the severity of depression (Wouters, 1998). Depression is characterized by an over activity of the hypothalamic-pituitary-adrenal (HPA) axis that resembles the neuroendocrine response to stress (Holsboer et al., 1995). Elevated cortisol levels have been the most widely used peripheral marker of stress responses and have become a well-established index of the HPA axis activation in psychophysiology research in humans (Kirschbaum and Hellhammer, 1994; van Heeringen et al., 2000). Recent clinical evidence indicates that antidepressants decrease the HPA axis response to stress (Schule et al., 2006). Tricyclic amitriptyline treatment significantly decreased saliva cortisol concentrations in hypercortisolemically depressed patients (Heuser et al., 1996), suggesting that reducing HPA axis activity in depressed subjects is of primary importance for therapeutic effects. On the other hand, psychiatric disorders are known to be associated with changes in reactive oxygen species, including antioxidant enzyme activity and lipid peroxidation. Superoxide dismutase (SOD) and malondialdehyde (MDA), a product of lipid peroxidation, are considered possible biochemical markers of mental disorder (Lukash et al., 2002). Clinical studies showed that patients with major depression had elevated SOD activity and MDA levels that were significantly reversed by antidepressant drugs (Bilici et al., 2001).

The seeds of Psoralea corylifolia L. (Leguminosae) have long been used for treatment of the symptoms of aging (Jiangsu College of New Medicine, 1977). Furocoumarins are the most widespread secondary metabolites in this species. A clinical trial by Partonen (1998) demonstrated that administration of furocoumarin psoralen inhibited hepatic melatonin metabolism to treat seasonal affective disorders in humans in Finland. Our laboratory demonstrated that the furocoumarins psoralen and isopsoralen exhibited in vitro inhibitory actions on MAO-A and MAO-B activities in rat brain mitochondria (Kong et al., 2001), thus indicating that inhibition of MAO in the CNS by furocoumarins might provide an alternative explanation. Subsequent study showed that total furocoumarins from P. corylifolia (TFPC) appeared to reduce the immobility time in the mouse forced swim test and attenuated the increases in brain MAO-A and MAO-B activities and plasma cortisol concentrations induced by swim stress (Chen et al., 2005). The aim of the current study was to examine further the behavioral and biochemical effects of TFPC treatment in the chronic mild stress (CMS) model of depression.

Materials and methods

Plant material and preparation

Total furocoumarins were isolated from the seeds of P. corylifolia as described previously (Deng, 2001). Airdried seeds of P. corylifolia (3 kg) were powdered, defatted with hexane at room temperature, and then soaked in 75% EtOH in water for a period of 3 days. The filtrate was concentrated in vacuo to an aqueous ethanol extract (280.66 g). The extract was re-dissolved in 95% EtOH at 60 [degrees]C in a water-bath, and kept undisturbed until a mixture of furocoumarins were separated out (22.66 g). For the analysis of TFPC, the Agilent 1100 sense HPLC system equipped with a Shimaduz, CLC-ODS analytical column (6 x 150 mm, 5 [micro]m) and a photodiode array detector was set up. The entire analysis was performed at 25 [degrees]C. The mobile phase was a mixture of methanol and water (55:45) at a flow rate of 1.0 ml/min. The detection wavelength was set at 246 nm. The main furocoumarins psoralen (retention time 9.05 min) and isopsoralen (retention time 10.25 min) were identified by HPLC using pure psoralen and isopsoralen as the two standards. Psoralen and isopsoralen (batch nos. 110739-200309 and 110738-200410) were purchased from the National Institute for the Control of Pharmaceutical and Biological Products of China (Beijing, China). The contents of psoralen and isopsoralen in the mixture were 52.47 and 44.75% (see Fig. 1). This furocoumarin mixture was used for evaluation of anti-antidepressant actions.

Animals

Male ICR mice, weighing 28-30 g each at the start of the experiment, were used. Animals were housed singly in polycarbonate cages for a minimum of one week prior to the start of the experiment and maintained on a 12-h light-dark cycle under controlled temperatures (18-22 [degrees]C). Except as described below, food and water were available ad libitum. The animals were cared in accordance with the principles and guidelines of the Guide for the Care and Use of Laboratory Animals, China Council on Animal Care. All animal procedures were approved by the Nanjing University Animal Welfare Committee.

Chronic mild stress procedure

At the start of the experiment, the animals were first trained to consume a 2% sucrose solution. Sucrose consumption and body weight were monitored throughout the experiment. After a one-week period of adaptation, sucrose solution intake baseline tests were performed (two tests per 6 days) over a period of 18 days for all subjects. These tests involved a 3-h period of food and water deprivation, followed by the offering of a sucrose solution for 1 h. Intake was determined by weighing the bottles containing sucrose solution at the beginning and at the end of each test. After this phase (18 days), one group was housed under normal conditions (normal mice) and the other group (stressed mice) was subjected throughout the experiment to chronic mild stress. The stress scheme was slightly modified from that previously used for rats by Willner et al. (1992) and for mice by Monleon et al. (1995), and consisted of the following: three 5-h periods of food and water deprivation, immediately prior to sucrose tests, one additional 16-h period of water deprivation, and two periods of continuous overnight illumination; two periods (7 and 17 h) of 45 degrees cage tile, one 17-h period in a soiled cage (100 ml water in sawdust bedding), two periods (3 and 5 h) of intermittent sound (a tone of 30 dB and 10 kc/s), and three periods (7, 9 and 17 h) of low intensity stroboscopic illumination (150 flashes/min). These stressors were scheduled throughout the 6 days, in a manner similar to that described previously, for 48 days. The normal mice were housed under identical conditions in a separate room, and had no contact with the stressed animals. They were deprived of food and water for 3 h before each sucrose intake test.

[FIGURE 1 OMITTED]

Drug administration

After 48 days of continuous exposure to the CMS sequence of the above-described, mildly stressful situations, when sucrose consumption was reduced significantly in stressed animals to levels not significantly different among them, the four subgroups of stressed animals were assigned randomly to one of the following treatments: (1) vehicle control, saline solution, 10 ml/kg body wt.; (2) TFPC, 30 mg/kg body wt.; (3) TFPC, 50 mg/kg body wt.; (4) amitriptyline, 10 mg/kg body wt. All drugs were administered orally once daily for 21 days.

Blood collection and biochemical assays

24 h after the last test of sucrose intake, between 10:00 and 11:00 a.m., all animals were decapitated quickly to obtain venous blood. Plasma was separated by centrifugation at 3000 rpm and stored at -20 [degrees]C until the assay of cortisol concentrations. Brain tissues were removed rapidly on the ice-plate. The tissues were washed with cold saline, blotted dry and stored at -80 [degrees]C until assay.

MAO assay

Mouse brain mitochondrial fractions were prepared following the procedure described previously (Schurr and Livne, 1976). MAO activity was assessed spectrophotometrically as described previously (Yu et al., 2002; Chen et al., 2005).

Cortisol assay

Plasma cortisol was assayed using a radioimmunoassay method following the manufacturer's instructions.

SOD and MDA assay

Mouse liver mitochondrial fraction suspended in 9 vol. of cold 0.9% NaCl, was mingled at 4 [degrees]C for 20 min. The mixture was centrifuged at 4000 rpm for 5 min at 4 [degrees]C, and then re-centrifuged at 15,000 rpm for 20 min at 4 [degrees]C. The supernatant was used for SOD and MAD assays. SOD activity was measured spectrophotometrically using the method of pyrogallol autoxidation (Wheeler et al., 1990). MDA content was measured as described previously (Yagi, 1994).

Statistical analysis

All data were expressed as mean [+ or -] s.e.m., and analyzed using one-way analysis of variance (ANOVA). A value of p < 0.05 was considered to be statistically significant in all cases. The calculation of p-values was performed using the Bonferroni alpha correction to avoid false positive results.

Results

TFPC increased sucrose intake in stressed mice

As shown in Table 1, as compared with normal animals, CMS caused a decrease in 2% sucrose intake and, until the beginning of drug treatment, sucrose intakes in normal and stressed animals were significantly different. In the vehicle-treated stressed animals, such significant reduction remained the same in subsequent days.

In stressed mice, after 3 days of treatment with TFPC at 50 mg/kg body wt., sucrose intake was significantly increased, and elevated consumptions continued for 9 days. Similar results were observed with 30 mg/kg body wt. TFPC treatment. However, 12 days after the beginning of the treatment, only TFPC at 50 mg/kg body wt. showed a tendency to increase sucrose intake compared with stressed control. These effects did not last in any significant way until the CMS was over. Sucrose preference was affected only by 6 days of treatment with amitriptyline at 10 mg/kg body wt.

TFPC reversed the elevated MAO-A and MAO-B activities induced by stress

CMS-treated animals showed significant increases of MAO-A and MAO-B cerebral activities compared to the normal control (Table 2). Oral administration of TFPC at the two doses significantly inhibited MAO-A and MAO-B activities. Amitriptyline at 10 mg/kg body wt. also depressed enzyme activities. TFPC and amitriptyline were more potent for MAO-B than MAO-A. TFPC at 50 mg/kg body wt. reduced MAO-A activity to lower than normal values. TFPC at 50 mg/kg body wt. and amitriptyline were capable of reversing MAO-B activity to values below respective normal values.

TFPC reversed the increased plasma cortisol levels induced by stress

Plasma cortisol levels increased significantly in the CMS-treated mice as compared to the normal mice (Table 2). TFPC treatment decreased the enhanced levels of plasma cortisol significantly. TFPC treatment at 50 mg/kg body wt. normalized the raised levels. However, amitriptyline administration to CMS-treated animals did not cause any significant alteration of the plasma cortisol levels.

TFPC reversed the increased liver SOD activity and MDA levels induced by stress

The levels of liver SOD and MDA were elevated significantly in CMS-treated mice as compared to the normal animals (Table 2). TFPC treatment reduced MDA, but without any significant impact on SOD activity. It was worth noting that the MDA levels were decreased to below normal after TFPC treatment. Similar results were obtained for amitriptyline administration.

Discussion

The CMS model of depression in animal is accepted as a valuable method for predicting the potential antidepressant action of compounds in humans. The present data agreed with the report of Monleon et al. (1995), in which stressors significantly reduced sucrose intake. TFPC treatment showed a rapid onset of action, and the full effect was apparent after 3-9 days of the treatment. Clinical knowledge holds that antidepressants have a delayed onset of efficacy (Quitkin et al., 1996). This has encouraged the development of new therapeutic approaches that preserve the overall safe therapeutic action of existing treatments, as well as accelerate their onset of action. Our study may constitute at least behavioral evidence for an early onset of action for TFPC. This is the first study that confirms the antidepressant activity of TFPC in the CMS mice. A recent study demonstrated that TFPC treatment reduced immobility in the forced swim test in mice (Chen et al., 2005). These behavioral data may confirm previous clinical reports of the therapeutic activity of furocoumarin psoralen in affective disorders (Partonen, 1998).

Abnormalities in brain MAO activity have been implicated in the pathogenesis of psychiatric diseases (Wouters, 1998). These clinical observations were consistent with our experimental findings that the CMS-treated mice exhibit elevated MAO activity in brain. Alterations of MAO activity in this CMS model of depression have not yet been demonstrated. TFPC significantly inhibited MAO-A and MAO-B activities. Psoralen and isopsoralen were reported to elicit in vitro inhibitory actions on MAO-A and MAO-B activities (Kong et al., 2001). These findings suggest that the potential antidepressant activity of TFPC might result from inhibition of both MAO-A and MAO-B.

Dysregulation of the HPA axis system plays an important role in the pathophysiology of depression. Normalization of axis hyperactivity precedes the response to pharmacotherapy. In the present study, CMS produced an increase in plasma cortisol levels. It is possible that increases in the HPA axis activation induced by CMS may be mediated by increased cortisol. TFPC significantly decreased plasma cortisol levels in CMS-treated animals, which was consistent with our previous results showing that TFPC attenuated the increases in cortisol concentration induced by forced swim (Chen et al., 2005), suggesting that modulation of the HPA axis by TFPC played an important role in the regulation of behavior in animal models of depression. TFPC seems to be an effective therapeutic option to treat the HPA axis dysfunction in depressive disorders. It was noted that MAO is likewise responsive to the abnormal HPA axis status in depressed patients. MAO activity and cortisol levels have been considered as predictors of favorable clinical response to antidepressant treatment (Poirier et al., 1987; van Heeringen et al., 2000). Ours is the first study to investigate the temporal relationship between changes in cortisol concentration and MAO activity in the CMS model of depression.

Alteration in oxidative systems is believed to participate in the pathogenesis of neuropsychiatric disorders, and drugs which regulate system function often have antidepressant properties (Abdalla et al., 1986; Bilici et al., 2001; Li et al., 2003). In the present study, CMS induced increases in SOD activity and MDA levels. More importantly, significant reductions in MDA levels were observed following 21-day treatment with TFPC.

Depression in the elderly is currently a prominent health care problem, due mainly to the progressive aging of the population in many countries (Gareri et al., 2000). Most studies have reported no change or a decrease of MAO-A, along with an increase of MAO-B in the aging brain. Dysregulation of the HPA axis is more common in elderly depression than in that of younger cohorts, resulting in elevated cortisol levels (Tiemeier, 2003). MDA levels increase significantly with aging; thus enhancement of MDA levels may also reflect the safe properties of antidepressants which successfully treat psychiatric and neurological disorders in the elderly. Amitriptyline was once used in the elderly for its sedative effect. It affected HPA axis regulation in hypercortisolemic elderly depression (Heuser et al., 1996), but was not the main drug used for the elderly because of severe side-effects and a higher rate of failure in that population (Gareri et al., 2000). Accordingly, it has been suggested that antidepressants with MAO inhibition and HPA axis and oxidative system regulation may prove more useful in geriatric depression. The seeds of P. corylifolia, otherwise known as Buguzhi, have long been used in traditional Chinese medicine and as food additives (Jiangsu College of New Medicine, 1977; Chino et al., 2002). It is worth noting that clinical and experimental studies demonstrated that the therapeutic system containing psoralen showed no specific target organ toxicity, reproductive toxicity, or carcinogenicity (Ciaravi et al., 2001). Given the relative safe, antidepressant effect, normalizing key indicators of depression, TFPC from P. corylifolia might be particularly suitable for treatment of the elderly. Further preclinical and clinical studies seem warranted to assess in more detail possible antidepressant effects of TFPC, and their therapeutic role in the treatment of elderly depression.

Numerous reports have demonstrated the potency of estrogens to modulate brain function and their implications in depression (Cyr et al., 2000; Stewart et al., 2004). An early study provided strong evidence of a strict relationship between estrogen receptor and MAO-A activity in human cells of neural origin, thus supporting the hypothesis of an antidepressant effect of estrogens exerted via inhibition of the monoamine oxidative pathway (Ma et al., 1995). In addition, estrogens may modulate the activity of the HPA axis. Recently clinical study suggested that the HPA axis activity in mood disorders might be directly modulated by estrogens via estrogen receptors (Bao et al., 2005). It was found that 70% EtOH extracts of P. corylifolia possessed estrogen activity (Zhang et al., 2005). It is possible that P. corylifolia with estrogen activity in animals might be involved in modulating brain neurochemical and HPA axis systems. Further investigations to elucidate the mechanism of antidepressant action are highly desirable.

Taken together, the findings in the current study show that TFPC displays a behavioral profile consistent with an antidepressant-like action. When tested in the CMS model of depression, TFPC improved sucrose intake reduction of stressed animals in dose- and time-dependent relations. In addition, elevated MAO and SOD activity, cortisol and MDA levels induced by CMS were observed. These findings support the idea that the effect of CMS on changes in the biochemical markers of depression might be related to MAO, the HPA axis and oxidative systems. TFPC blocked brain MAO-A and MAO-B activities and reversed increased plasma cortisol levels, as well as SOD activity and MDA levels. These pharmacological actions could make TFPC a potentially valuable drug for the treatment of elderly depression.

Acknowledgements

The work was co-financed by grants from NSFC (nos. 30371755 and 90409009) and JSNSF (BK 2003070) to Ling-dong Kong.

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Y. Chen (a), H.-D. Wang (b), X. Xia (a), H.-F. Kung (c), Y. Pan (a), L.-D. Kong (a,*)

(a) State Key Laboratory of Pharmaceutical Biotechnology, Institute of Functional Biomolecules, Nanjing University, Nanjing 210093, People's Republic of China

(b) Brain Hospital affiliated to Nanjing Medical University, Nanjing 210029, People's Republic of China

(c) Center for Emerging Infectious Diseases, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N. T. Hong Kong, People's Republic of China

*Corresponding author. Tel./fax: +86 25 83594691.

E-mail address: kongld@nju.edu.cn (L.-D. Kong).
Table 1. Effects of TFPC and amitriptyline on sucrose intakes in mice
exposed to CMS

 Sucrose intake (g)
 Dose (mg/kg body wt.)
Group 0 3

Normal mice 1.78[+ or -]0.25 1.77[+ or -]0.24
CMS-treated mice
Control 0.96[+ or -]0.12 (##) 1.02[+ or -]0.16 (##)
TFPC 30 0.92[+ or -]0.21 (##) 1.33[+ or -]0.24
TFPC 50 0.99[+ or -]0.14 (##) 1.66[+ or -]0.11*
Amitriptyline 10 1.03[+ or -]0.16 (##) 1.23[+ or -]0.29

 Sucrose intake (g)
 Dose (mg/kg body wt.)
Group 6 9

Normal mice 1.74[+ or -]0.24 1.61[+ or -]0.27
CMS-treated mice
Control 0.92[+ or -]0.17 (##) 1.07[+ or -]0.17 (#)
TFPC 1.81[+ or -]0.27** 1.80[+ or -]0.19**
TFPC 2.23[+ or -]0.33** (#) 1.99[+ or -]0.13** (#)
Amitriptyline 1.83[+ or -]0.26* 1.28[+ or -]0.22

 Sucrose intake (g)
 Dose (mg/kg body wt.)
Group 12 15

Normal mice 1.71[+ or -]0.15 1.76[+ or -]0.17
CMS-treated mice
Control 1.10[+ or -]0.19 (#) 1.00[+ or -]0.11 (#)
TFPC 1.16[+ or -]0.22 1.04[+ or -]0.21
TFPC 1.37[+ or -]0.10 1.41[+ or -]0.13
Amitriptyline 1.32[+ or -]0.27 1.07[+ or -]0.18

 Sucrose intake (g)
 Dose (mg/kg body wt.)
Group 18 21 days

Normal mice 1.67[+ or -]0.26 1.85[+ or -]0.24
CMS-treated mice
Control 0.86[+ or -]0.11 (##) 0.87[+ or -]0.08 (##)
TFPC 0.87[+ or -]0.21 1.15[+ or -]0.21
TFPC 1.17[+ or -]0.22 1.36[+ or -]0.19
Amitriptyline 1.47[+ or -]0.21 1.13[+ or -]0.38

Statistical significance: (#) p < 0.05, (##) p < 0.01 vs. normal mice,
*p < 0.05, **p < 0.01 vs. CMS-treated control mice (n = 8).

Table 2. Effects of TFPC and amitriptyline on plasma cortisol levels,
liver SOD activity, liver MDA content and brain MAO-A and MAO-B
activities in mice exposed to CMS (Mean [+ or -] s.e.m.)

 Dose
 (mg/kg Cortisol content SOD activity
Group body wt.) (ng/ml) (U/mg protein)

Normal mice 1.54[+ or -]0.43 17.61[+ or -]0.42
CMS-treated
 mice
Control 2.70[+ or -]0.21 (##) 19.45[+ or -]0.46 (#)
TFPC 30 1.91[+ or -]0.34* 18.44[+ or -]0.34
TFPC 50 1.27[+ or -]0.39** 18.47[+ or -]0.15
Amitriptyline 10 2.46[+ or -]0.56 18.02[+ or -]0.44

 MAO activity
 MDA content (nmol/mg (U/g protein)
Group protein) A

Normal mice 0.281[+ or -]0.023 56.41[+ or -]4.62
CMS-treated
 mice
Control 0.326[+ or -]0.031 (#) 78.75[+ or -]4.92 (##)
TFPC 0.268[+ or -]0.032* 67.23[+ or -]5.72
TFPC 0.256[+ or -]0.026** 41.59[+ or -]3.25** (#)
Amitriptyline 0.294[+ or -]0.028* 65.27[+ or -]3.56

 MAO activity
 (U/g protein) MAO inhibition (%)
Group B A B

Normal mice 52.50[+ or -]6.72 -- --
CMS-treated
 mice
Control 99.67[+ or -]10.66 (##) -- --
TFPC 52.34[+ or -]7.50* 14.63 47.49
TFPC 36.07[+ or -]3.13** (#) 47.18 63.81
Amitriptyline 34.61[+ or -]3.36*** (#) 17.12 65.28

Statistical significance: (#) p < 0.05, (##) p < 0.01 vs. normal mice,
*p < 0.05, **p < 0.01, ***p < 0.001 vs. CMS-treated control mice
(n = 8).
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Author:Chen, Y.; Wang, H.-D.; Xia, X.; Kung, H.-F.; Pan, Y.; Kong, L.-D.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Geographic Code:9CHIN
Date:Aug 1, 2007
Words:4747
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