Antidepressant-Like Effect of Onion

70454 (013)

Biosci. Biotechnol. Biochem., 72, 70454-1–7, 2008

Antidepressant-Like Effect of Onion (Allium cepa L.) Powder in a Rat Behavioral Model of Depression

y Hiroyuki SAKAKIBARA,1;2 Saki YOSHINO,1 Yoshichika KAWAI,1 and Junji TERAO1;

1Departments of Food Science, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan 2Institute for Environmental Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan

Received July 17, 2007; Accepted September 20, 2007; Online Publication, January 7, 2008 [doi:10.1271/bbb.70454]

The present study evaluated the antidepressant-like St. John’s wort have been reported to disturb drug effect of the quercetin-rich vegetable, onion, by using metabolizing systems.5) Therefore, the search for regu- the rat behavioral model of depression, the forced larly eaten foods with antidepressant activity seems to swimming test (FST). Daily administration of onion be an essential approach to finding an effective powder at a dosage of 50 mg/kg of body weight/day for antidepressant treatment without side effects. 14 days significantly reduced the immobility time in FST Onion is a vegetable that is consumed regularly withoutAdvance changing the motor dysfunction, indicating View that throughout the world and contains a high amount of the daily consumption of onion exerted antidepressant- flavonoids, mainly quercetin.6) Several research groups like activity. The plasma corticosterone level was have shown that flavonoids, including quercetin, have elevated after an FST trial, and pretreatment with diverse effects on the prevention of oxidative stress- onion powder did not modulate this elevation. Although related chronic diseases such as ischemic heart disease the FST trial tended to increase the dopaminergic and diabetes.7,8) It was also recently been reported that activity in the rat hypothalamus, the administration of quercetin protected the brain from apoptotic death onion powder (50 mg/kg) suppressed the increase in the through its ability to modulate intracellular signals;9) turnover of this neurotransmitter. However, the same quercetin glycosides have also been shown to prevent prevention was also observed with a higher dosage of depression in the forced swimming test (FST), a major Proofs10–12) onion, in which no significant antidepressant effect was animal model for screening antidepressants. These apparent. The results of the present study suggest that studies imply that a daily intake of quercetin-rich foods, onion exerted antidepressant-like activity in a behav- for example onion, would be helpful for protecting ioral model that acted independently of the hypothala- against and treating depression. However, there have mic-pituitary-adrenal axis. been no studies using FST to examine the antidepres- sant-like effects of foods and foodstuffs, as far as we are Key words: onion; antidepressant-like effect; forced aware. swimming test; quercetin; hypothalamic- We evaluated in the present study the antidepressant- pituitary-adrenal axis like effect of onion as a representative quercetin-rich vegetable by using FST with rats. Additionally, the Depression has attracted strong attention as a major effect of onion on the activation of the hypothalamic- public health problem worldwide. The prevention and pituitary-adrenal axis (HPA) and the regulation of treatment of depression are urgent issues to be ad- dopaminergic and serotonergic activity in the brain dressed, as approximately 20% of the population in the were examined. US has been estimated to suffer from some depressive symptoms.1) Exposure to chronic stress is known to be Materials and Methods one of the triggers that provoke depressive illness, although its mechanism has not been elucidated.2,3) Onion powder and chemicals. Onion (Allium cepa L.) Although a wide variety of antidepressant drugs and was harvested in Japan during the summer season of antidepressant herbal medicines are available to treat 2006. Dried onion was kindly provided by Creative & depression, most of the synthetic drugs are not without Connection Co. (Tokyo, Japan) after peeling and freeze- side effects.4) In addition, some herbal medicines such as drying. The dried onion was powdered into less than

y To whom correspondence should be addressed. Fax: +81-88-633-7089; E-mail: [email protected] Abbreviations: FST, forced swimming test; HPA, hypothalamic-pituitary-adrenal; HPLC, high-performance liquid chromatography; DA, dopamine; DOPAC, 3,4-dihydroxyphenylacetic acid; 5-HT, 5-hydroxytryptamine; 5-HIAA, 5-hydroxyindoleacetic acid 70454-2 H. SAKAKIBARA et al. 150-mm particles with a mesh, and kept in a desiccator at the arena 15 h after the last treatment. Hand-operated 4 C until needed. The antidepressant drugs imipramine counters were employed to score the locomotion (hydrochloride form), dopamine (DA), 3,4-dihydroxy- (number of line crossings) and rearing frequency phenylacetic acid (DOPAC), serotonin (5-HT), 5-hy- (number of times seen standing on the hind legs) within droxyindoleacetic acid (5-HIAA), isoproterenol and 1- a 5-min period. octansulfonic acid sodium salt were purchased from Sigma-Aldrich Co. (St. Louis, MO, USA). Aprotinin Dissection and tissue collection. Another set of rats was from Wako Pure Chemicals Industries (Osaka, received onion powder at a dosage of 50 or 500 mg/kg Japan). of body weight as just described, and was then subjected to FST. After the 5-min test session, the rats were Animals. Male CD (SD) rats (4 weeks old; Charles immediately sacrificed by decapitation, and the hypo- River Japan, Yokohama, Japan) were housed in a con- thalamus region was collected. Trunk blood was col- trolled-environment room (temperature, 23 1 C; hu- lected in ethylenediaminetetraacetic acid-coated tubes, midity, 45–50%; light-dark cycle, 12 h each; lights on, 8 and aprotinin (30 KIU/ml) was quickly added. Plasma a.m.). The rats had free access to laboratory feed (MF; was obtained after centrifugation (1,600 g for 10 min), Oriental Yeast Co., Tokyo, Japan) and tap water. This and the dissected hypothalamus regions were stored at study was performed according to the guidelines for the 80 C until needed for analyses. The groups of animals care and use of laboratory animals of The University of no subjected to the FST trial were also sacrificed and Tokushima Graduate School, Institute of Health Bio- dissected. sciences. All efforts were made to minimize animal suffering and to reduce the number of animals used. Measurement of corticosterone in the plasma. The plasma corticosterone level was determined in duplicate AdvanceFST procedure with rats. FST was performed View on rats by using an EIA kit (Cayman Chemical Company, Ann according to the method of Porsolt et al.13) with some Arbor, MI, USA). modifications. Briefly, a group of 42 rats was randomly divided into six groups and treated as follows: one group Determination of neurotransmitter levels in the rat was orally administered with imipramine (15 mg/kg of hypothalamus region. Neurotransmitter levels in the body weight), four groups were orally administered with hypothalamus region were analyzed by a high-perform- onion powder dissolved in deionized water (15, 50, 150, ance liquid chromatograph (HPLC) coupled with a or 500 mg/kg of body weight), and the final group coulometric array detector, using the method of received a vehicle (deionized water). Each test solution Lakshmana and Raju15) and Vaarmann et al.16) with was prepared daily just before administration, and some modifications.Proofs Briefly, the hypothalamus (50 mg) administered once daily during the period 1–3 p.m. was mixed with 0.5 ml of ice-cold 0.12 M perchloric acid over a period of 14 d. containing 0.1% cysteine, and 0.5 nmol of isoproterenol The rats were placed in an acrylic cylinder (450 mm was then added as an internal standard. The sample 192 mm i.d.) filled with water at 25 1 C to a depth of mixture was homogenized and then centrifuged at 17 cm for 15 min (pre-test session) after 14 d of treat- 12,000 g for 15 min at 4 C. The supernatant was filtered ment. Twenty-four hours after the pre-test session, the through a 0.2-mm Millex-LG membrane filter (Millipore animals were once again exposed to the same conditions Co., Bedford, MA, USA). A portion of the filtrate (10 ml) for 5 min (test session). Between the pre-test session and was subjected to HPLC in a Capcell Pak C18 MGII main test session, a drug solution was administered column (250 mm 4:6mm I.D., Shiseido Co., Tokyo, orally three times, the first being just after the pre-test Japan) equipped with a guard column (10 mm 4:0mm session, then 5 h before the main test, and finally 1 h I.D.). The columns were maintained at 25 C. The before the main test. A rat was judged immobile if it mobile phase was acetonitrile/55 mM tartaric acid and remained floating in the water, except for small move- 45 mM sodium acetate containing 0.65 mM 1-octanesul- ments to keep its head above the water. FST was fonic acid sodium salt (10:90, v/v) at a flow rate of performed during the period 1–3 p.m. and recorded with 1.0 ml/min. The neurotransmitters and their metabolites a video camera. The tapes were evaluated by observers were detected by using a coulometric array detector who had not been informed about the kind of treatment (5600A CoulArray System, ESA, Chemsford, MA, each animal had received. USA) at +200 mV for DA, 5-HT and DOPAC, and at The effect of onion on the locomotor activity was also +550 mV for 5-HIAA. evaluated. Onion powder was administered to rats daily for one week after the FST trial, and the rats underwent Statistics. Differences were ascertained by using an an open field test according to the method of Carlini et analysis of variance (ANOVA). Multiple comparisons al.14) The rats were placed in open-field apparatus among treatments were checked with the Fisher-PLSD consisting of an arena 70 cm in diameter divided into 18 test. The results are considered significant if the pro- approximately equal areas. For the open field observa- bability of error was less than 5%. tions, each rat was individually placed at the center of Antidepressant-Like Effect of Onion Powder 70454-3 Table 1. Body Weight Gain during the Onion Administration to Rats Table 2. Locomotor Activity in the Open Field Test on Rats for 14 Days Treatment Locomotion Rearing Body weight (g) Treatment Vehicle (deionized water) 125 625 4 Day 1 Day 14 Imipramine 84 6 27 3 Onion Powder, 15 mg/kg 131 830 2 Vehicle (deionized water) 97:9 3:8 219:1 11:4 50 mg/kg 101 11 26 4 Imipramine 98:0 4:5 203:7 10:5 150 mg/kg 136 11 30 4 Onion powder, 15 mg/kg 94:3 1:5 213:1 4:7 500 mg/kg 120 628 2 50 mg/kg 95:6 5:3 215:0 12:3 150 mg/kg 97:3 2:2 217:7 10:5 The behavioral parameters were recorded for 5 min after a 21 d oral 500 mg/kg 94:6 3:3 206:8 12:3 administration of onion to rats. Locomotion: number of line crossings. Rearing: number of times seen standing on hind legs. Each value represents Each value represents the mean S.D. (n ¼ 7). the mean S.E. (n ¼ 7). P < 0:05 vs. vehicle group.

200

150 * * 100

AdvanceImmobility time (sec) 50 View

0 Vehicle IMIP 15 50 150 500 Onion powder (mg/kg)

Fig. 1. Effect of Onion Powder on the Immobility Time in FST with Rats. A test solution was administered orally once daily over a period of 14 days. IMIP indicates the antidepressant drug, imipramine (15 mg/kg of body weight). Each value represents the mean S.E. (n ¼ 7). P < 0:05 vs. vehicle group.Proofs Results and 500 mg/kg of body weight) as shown in Fig. 2. Five minutes of the FST trial caused a significant 1.6-fold FST with rats increase in the corticosterone level compared with that Onion powder (15, 50, 150, or 500 mg/kg of body of the vehicle control without the FST trial. Neither weight) or the synthetic antidepressant, imipramine (15 dosage of onion powder affected this increase in mg/kg) was orally administered to the rats once daily corticosterone level induced by the FST trial. for 14 d. There was no difference in body weight gain among all the groups after 14 d of being administered Neurotransmitter turnover in the hypothalamus re- with the onion powder (Table 1). Figure 1 shows the gion effects of onion powder on FST with rats. Daily Following the vehicle treatment, the FST trial in- treatment of the rats with onion powder (50 mg/kg) dicated a tendency toward a decrease in DA level and for 14 d significantly reduced the immobility time in an increase in the level of its metabolite (DOPAC) in FST. The decrease in immobility time of the animals the hypothalamus (Table 3). Consequently, the ratio treated with onion powder was comparable to that seen of metabolite/transmitter (DOPAC/DA) increased in animals treated with imipramine. The locomotion (Fig. 3A), although the difference was not statistically activity was significantly decreased by administering significant. The serotonergic ratio (5-HIAA/5-HT) imipramine (Table 2). In the case of onion powder showed a similar tendency after the FST trial (Fig. 3B). (50 mg/kg), the activity tended to be decreased, but not However, treating the rats with onion powder at both significantly. On the other hand, little effect on FST and dosages (50 and 500 mg/kg of body weight) prevented in the open field test was apparent after the admin- this tendency toward an increase in this ratio after the istration of 15, 150 or 500 mg/kg of onion powder. FST trial.

Plasma corticosterone level Discussion The baseline level of corticosterone in the rat plasma was not affected by administration of onion powder (50 One of the purposes of this study was to evaluate the 70454-4 H. SAKAKIBARA et al.

* 25 * * 20

15

10

Corticosterone (ng/ml) 5

0 50 500 50 500 Vehicle Vehicle Onion powder Onion powder + FST trial

Fig. 2. Effect of Onion Powder on the Plasma Corticosterone Level in Rats after the FST Trial. Onion powder (mg/kg of body weight) was administered orally once daily over a period of 14 d. The FST trial was performed for 5 min as described in the Materials and Methods section. Each value represents the mean S.E. (n ¼ 5). P < 0:05 vs. vehicle group without the FST Advancetrial. View Table 3. Effects of the Onion Powder Administration and FST Trial on Neurotransmitter Levels in the Rat Hypothalamus

+FST trial Onion powder Onion powder Vehicle (mg/kg) Vehicle (mg/kg) 50 500 50 500 DA 2:5 0:62:1 0:32:4 0:31:8 0:42:3 0:32:3 0:5 DOPAC 3:0 0:62:7 0:32:6 0:34:4 1:63:0 0:32:7 0:3 5-HT 26:7 3:028:9 2:727:0 2:719:4 3:724:0 2:822:0 2:7 5-HIAA 20:6 0:923:8 2:720:9 0:919:2 1:Proofs421:2 1:319:8 1:2 Each value is the mean S.D. expressed as nmol/g of wet tissues for 5 animals in each group. Rats were administered with the vehicle (distilled water) or onion powder (50 or 500 mg/kg of body weight/day) for 14 d, and were then subjected to measurement of the neurotransmitter levels in the hypothalamus as described in the Materials and Methods section. DA, dopamine; DOPAC, 3,4-dihydroxyphenylacetic acid; 5-HT, 5-hydroxytryptamine; 5-HIAA, 5-hydroxyindoleacetic acid. antidepressant-like effect of onion by an animal model been clarified. Psychostimulants, which exert an indis- for depression. We employed the forced swimming test criminate motor stimulating activity, have previously (FST) on rats developed by Porsolt et al.13) The been shown to have efficacy at decreasing immobility in immobility displayed by rodents when subjected to an FST, but no antidepressant activity.17) In order to unavoidable stress such as forced swimming is thought exclude a false positive result, we employed an addi- to reflect a state of despair or lowered mood, which is tional open field test to check the motor stimulating thought to reflect depressive illness in humans. Addi- activity of onion. The administration of imipramine did tionally, immobility time has been shown to be reduced not significantly stimulate the locomotion activity, but by treatment with antidepressant drugs.17) Moreover, a in fact lowered this activity (Table 2). Fifty mg/kg of significant correlation has been found between the onion powder, the dose that decreased the immobility in clinical efficacy of antidepressant drugs and their FST, also tended to lower the locomotion activity. These potency.17) However, there are few studies that have tendencies were also observed in our previous study18) used FST to examine the antidepressant-like effects of and elsewhere.11) Therefore, the reduction in immobility foods and foodstuffs. The present study has shown that time after a 14 d administration of onion powder (50 onion powder significantly reduced the immobility time mg/kg) can be attributed to an inherent antidepressant- in FST after repeated administration to rats at a dosage like effect. of 50 mg/kg of body weight for 14 d (Fig. 1). The One of the major functional ingredients in onion is other dosages we tested (15, 150 and 500 mg/kg) did flavonoids, especially quercetin glycosides.6) Several not affect the duration of immobility. Such a U-shaped studies have recently proposed an antidepressant-like activity curve has been reported for some herbal effect of such quercetin glycosides as hyperoside, medicines,10,11,18) although the reason for this has not isoquercitrin and rutin from the results of FST stud- Antidepressant-Like Effect of Onion Powder 70454-5

A to the antidepressant-like effect of onion. In addition, the U-shaped activity obtained from the onion dosage is 2.5 likely to have been caused by quercetin itself. This study investigated the antidepressant mechanism 2 for onion in an FST trial. FST has been reported to 1.5 induce such physiological effects as activation of the 1 HPA axis and an increase in the plasma corticosterone 23,24) DOPAC/DA level. Pretreating rats with the antidepressant drug, 0.5 desipramine, which significantly reduced immobility in 0 FST, has attenuated the FST-associated elevation of the Vehicle 50 500 Vehicle 50 500 blood corticosterone level.24) Our result also demon- Onion powder Onion powder + FST trial strates that a 5-minute FST trial was associated with an B elevation of plasma corticosterone (Fig. 2). On the other hand, pretreating rats with the active dosage of onion 1.2 powder did not reduce this elevation. This result indicates that the antidepressant mechanism for onion 0.8 did not involve preventing the activation of the HPA axis. Hill et al. have suggested that the duration of 0.4 immobility in FST was increased by administering 5-HIAA/5-HT corticosterone to rats.25) In addition, some antidepres- 0 sants have protected pheochromocytoma (PC-12) cells 26) Vehicle 50 500 Vehicle 50 500 from the lesions induced by corticosterone. It is AdvanceOnion powder Onion View powder therefore possible that the mechanism underlying the + FST trial antidepressant-like effect of onion involved regulating Fig. 3. Effect of Onion Powder on the Dopaminergic and Serotoner- the unbeneficial effects of corticosterone. gic Activities in the Rat Hypothalamus after the FST Trial. Neurotransmitter levels in the brain have been re- A, DOPAC/DA ratio. B, 5-HIAA/5-HT ratio. Onion powder was ported to be essential factors mediating the reduction of administered orally once daily over a period of 14 d. The FST trial immobility in FST.17) In addition, the ratios of metab- was performed for 5 min as described in the Materials and Methods section. DA, dopamine; DOPAC, 3,4-dihydroxyphenylacetic acid; olites to the original transmitters are thought to reflect 5-HT, 5-hydroxytryptamine; 5-HIAA, 5-hydroxyindoleacetic acid. intraneuronal catabolism as a consequence of the intra- Each value represents the mean S.D (n ¼ 5). cellular action of monoamine oxidase (MAO). We also analyzed the metabolite/transmitterProofs ratio (DOPAC/DA and 5-HIAA/5-HT) in order to obtain some index for ies.10–12) For example, a daily administration of hypero- the catabolic rate of neurotransmitters. The FST trial side (quercetin-3-galactoside) to rats at a dosage of 0.6– indicated a tendency toward an increase in the DOPAC/ 1.3 mg/kg/day for 12 d indicated the typical antidepres- DA and 5-HIAA/5-HT ratios (Fig. 3), as previously sant-like effect in FST; however, less than 0.3 and more reported by Drossopoulou et al.,27) indicating that the than 2.61 mg/kg exerted little effect.10) In this study, dopaminergic and serotonergic activities were increased the administration of 50 mg/kg of onion powder resulted in the hypothalamus region following the FST trial. On in a positive effect, although 15, 150 and 500 mg/kg the other hand, the administration of onion powder (50 administration were negative. Onion has been reported mg/kg of body weight) prevented this increase in the to contain around 180 mmol of quercetin glycosides per DOPAC/DA and 5-HIAA/5-HT ratios after the FST 100 g fresh weight.6) Therefore, 50 mg of onion powder trial. The quercetin glycosides present in onion may can be calculated to contain around 0.4 mg of quercetin possess an ability to prevent transmitter turnover by glycosides as the equivalent of quercetin-40-glucoside, acting as an inhibitor of MAO, as quercetin has been which is one of the major quercetin glycosides present in reported to be a selective inhibitor of MAO,28) resulting onion. Additionally, quercetin glycosides are mostly in the prevention of transmitter turnover. Nevertheless, hydrolyzed into their aglycons by mucosal and bacterial this phenomenon was also observed at a dosage of 500 enzymes in the intestines, and are then converted to mg of onion powder/kg of body weight, without any conjugated metabolites during the absorption proc- decrease in the immobility time in FST. Further study is ess.19,20) This conversion during absorption may indicate required to clarify the contribution of the MAO-inhibit- that the active metabolites responsible for the antide- ing activity toward the antidepressant-like effect of pressant-like effect of quercetin glycosides are the onion. conjugated forms rather than the glycosides them- In conclusion, the results of the present study clearly selves.21) Moreover, quercetin metabolites have recently demonstrate that onion powder exerted an antidepres- been found in the brain tissues of rodents after their oral sant-like effect in an animal model of depression. We administration.22) These facts strongly suggest that the suggest that quercetin glycosides were among its active quercetin glycosides in onion at least partly contributed compounds, indicating that quercetin-rich vegetables 70454-6 H. SAKAKIBARA et al. would be promising as antidepressants from daily foods. 1613–1620 (2003). The antidepressant-like effects of onion powder were 10) Butterweck, V., Jurgenliemk, G., Nahrstedt, A., and found to be distinct from any prevention of the Winterhoff, H., Flavonoids from Hypericum perforatum activation of the HPA axis. Recent research has reported show antidepressant activity in the forced swimming that FST trials markedly enhanced the phosphorylation test. Planta Med., 66, 3–6 (2000). 11) Butterweck, V., Nishibe, S., Sasaki, T., and Uchida, M., of mitogen-activated protein kinases and c-AMP re- 29) Antidepressant effects of Apocynum venetum leaves in a sponse element-binding protein in the brain. It is forced swimming test. Biol. Pharm. Bull., 24, 848–851 likely that the activation of these signal transduction (2001). pathways in the brain was involved in the mechanism 12) Noldner, M., and Schotz, K., Rutin is essential for the underlying the antidepressant effect of onion. 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