Abstract
This study aimed to investigate the antidepressant effect and the mechanism of action of Kai-Xin-San (KXS) in fluoxetine-resistant depressive (FRD) rats. Two hundred male Wistar rats weighing 200±10 g were exposed to chronic and unpredictable mild stresses (CUMS) for 4 weeks and given fluoxetine treatment simultaneously. The rats that did not show significant improvement in behavioral indexes were chosen as the FRD model rats. These rats were randomly divided into four groups: FRD model control; oral fluoxetine and aspirin; oral KXS at a dose of 338 mg·kg–1·day–1; and oral KXS at a dose of 676 mg·kg–1·day–1. Rats continued to be exposed to CUMS and underwent treatment once a day for 3 weeks, then cytokine (COX-2, IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-10, TGF-β, and TNF-α) levels in the hippocampus and serum, and organ coefficients were measured. Both doses of KXS improved the crossing and rearing frequencies, sucrose-preference index, and body weight in FRD rats. KXS at a dose of 338 mg·kg–1·day–1reduced COX-2, IL-2, IL-6, TNF-α levels, increased IL-10 level in the hippocampus, and reduced IL-2 and TNF-α levels in serum. KXS at a dose of 676 mg·kg–1·day–1reduced TNF-α level in the hippocampus, reduced IL-2 and TNF-α levels in serum, and increased IFN-γ and IL-10 levels in the hippocampus and serum. There were no significant differences in organ-coefficients of the spleen among and between groups. The results suggested that oral administration of KXS in FRD rats was effective in improving behavior disorders by influencing various inflammatory pathways.
Kai-Xin-San; Fluoxetine-resistant depression; Chronic unpredictable mild stress; Inflammatory factor; Anti-depression
Introduction
Major depression is a common and sometimes fatal disorder that has a worldwide prevalence greater than 15%. It is estimated that major depressive disorder will be the second largest contributor to the global burden of disease by 2020. Despite considerable advances in the treatment of major depressive disorder in the past few years, treatment-resistant depression (TRD) remains a common condition that affects approximately 30% of this population (11. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163: 28–40, doi: 10.1176/appi.ajp.163.1.28.
https://doi.org/10.1176/appi.ajp.163.1.2...
). Therefore, identifying a potential drug that is effective in treating resistant depression with low toxicity is important.
Many studies have shown that increased plasma concentrations of interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α were found in major depression patients with a history of poorer response to antidepressants than in treatment-responsive patients (22. Maes M, Bosmans E, De Jongh R, Kenis G, Vandoolaeghe E, Neels H. Increased serum IL-6and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine 1997; 9: 853–858, doi: 10.1006/cyto.1997.0238.
https://doi.org/10.1006/cyto.1997.0238...
–44. O'Brien SM, Scully P, Fitzgerald P, Scott LV, Dinan TG. Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy. J Psychiatr Res 2007; 41: 326–331, doi: 10.1016/j.jpsychires.2006.05.013.
https://doi.org/10.1016/j.jpsychires.200...
). Similarly, patients with increased inflammatory activity before treatment have been reported to be less responsive to antidepressants (55. Benedetti F, Lucca A, Brambilla F, Colombo C, Smeraldi E. Interleukine-6 serum levels correlate with response to antidepressant sleep deprivation and sleep phase advance. Prog Neuropsychopharmacol Biol Psychiatry2002; 26: 1167–1170, doi: 10.1016/S0278-5846(02)00255-5.
https://doi.org/10.1016/S0278-5846(02)00...
–77. Mikova O, Yakimova R, Bosmans E, Kenis G, Maes M. Increased serum tumor necrosis factor alpha concentrations in major depression and multiple sclerosis. Eur Neuropsychopharmacol 2001; 11: 203–208, doi: 10.1016/S0924-977X(01)00081-5.
https://doi.org/10.1016/S0924-977X(01)00...
). Given these findings, researchers hypothesized that inflammation may influence the effects of antidepressants. To support this hypothesis, the chronic unpredictable mild stress (CUMS) paradigm was tested by administering lipopolysaccharide (LPS) daily before the stressor. It was found that pretreatment with LPS, mimicking inflammation, had no significant effect on depression-related behaviors but attenuated the antidepressant action of fluoxetine significantly, suggesting that inflammation might play a role in the pathophysiology of antidepressant resistance (88. Wang Y, Cui XL, Liu YF, Gao F, Wei D, Li XW, et al. LPS inhibits the effects of fluoxetine on depression-like behavior and hippocampal neurogenesis in rats. Prog Neuropsychophamacol Biol Psychiatry 2011; 35: 1831–1835, doi: 10.1016/j.pnpbp.2011.07.004.
https://doi.org/10.1016/j.pnpbp.2011.07....
).
Kai-Xin-San (KXS) (99. Dong XZ, Li ZL, Zheng XL, Mu LH, Zhang G, Liu P. A representative for emotional disease, Ding-Zhi-Xiao-Wan restores 5-HT system deficit through interfering the synthesis and transshipment in chronic mild stress-induced depressive rats. J Ethnopharmacol 2013; 150: 1053–1061, doi: 10.1016/j.jep.2013.10.018.
https://doi.org/10.1016/j.jep.2013.10.01...
) is a well-known formula that was first recorded in an ancient Chinese book: "Tai Ping Hui Min He Ji Ju Fang". KXS consists of Ginseng (Panax ginseng C.A. Meyer), hoelen (Wolf Poria cocos, Schw), polygala (Polygala tenuifolia Willd), and Acorus (Acorus tatarinowii Schott) in a ratio of 3:3:2:2. For thousands of years, it has been a renowned Chinese herbal formula for treating depression and ameliorating various learning and memory deficits, such as desolation, moodiness, and forgetfulness.
Our previous studies in mice models have indicated that KXS has antidepressant-like effects as demonstrated by the tail suspension test and forced swim test. It also significantly elevated the levels of central monoamine neurotransmitters, including 5-hydroxytryptamine, dopamine, and noradrenaline (1010. Zhou XJ, Liu M, Yan JJ, Can Y, Liu P. Antidepressant-like effect of the extracted of Kai Xin San, a traditional Chinese herbal prescription, is explained by modulation of the central monoaminergic neurotransmitter system in mouse. J Ethnophamacol 2012;139: 422–428, doi: 10.1016/j.jep.2011.11.027.
https://doi.org/10.1016/j.jep.2011.11.02...
,1111. Hu Y, Liu P, Guo DH, Rahman K, Wang DX, Chen ML, et al. Behavioral and biochemical effects of Kaixin-San, a traditional Chinese medicinal empirical formula. Drug Dev Res 2008; 69: 267–271, doi: 10.1002/ddr.20252.
https://doi.org/10.1002/ddr.20252...
). Simultaneously, KXS could ameliorate chronic fatigue syndrome by promoting proliferation of splenocytes in mice and modulate the detrimental effects of cytokines (1212. Cao Y, Hu Y, Liu P, Zhao HX, Zhu XJ, Wei YM. Effects of a Chinese traditional formula Kai Xin San (KXS) on chronic fatigue syndrome mice induced by forced wheel running. J Ethnopharmacol 2012; 139: 19–25, doi: 10.1016/j.jep.2011.08.030.
https://doi.org/10.1016/j.jep.2011.08.03...
). KXS exerts its antidepressant-like and nootropic effect in a CUMS model by modulating the hypothalamic-pituitary-adrenal axis, monoamine neurotransmitter levels, and cholinergic systems (1313. Dang H, Sun L, Liu X, Peng B, Wang Q, Jia W, et al. Preventive action of Kai Xin San aqueous extract on depressive-like symptoms and cognition deficit induced by chronic mild stress. Exp Biol Med 2009; 234: 785–793, doi: 10.3181/0812-RM-354.
https://doi.org/10.3181/0812-RM-354...
).
Based on the biological effects of KXS that have been explored previously, the current study aimed to assess its potential antidepressant action and its influence on inflammatory processes to identify potential mechanisms in fluoxetine-resistant depressive rats.
Material and Methods
Reagents and drugs
Fluoxetine was purchased from Eli Lilly and Company (USA). Aspirin was purchased from Bayer Medicines Company (Germany). ELISA kits for TNF-α, TGF-β, IFN-γ, COX-2, IL-1β, IL-2, IL-4, IL-6, and IL-10 were purchased from R&D Company (USA). KXS was purchased from the LvYe Medicinal Material Company (China). KXS was supplied in powder form, which was derived from a mixture of the aqueous extract as described previously (1414. Mu LH, Huang ZX, Liu P, Hu Y, Gao Y. Acute and subchronic oral toxicity assessment of the herbal formula Kai-Xin-San. J Ethnopharmacol 2011; 138: 351–357, doi: 10.1016/j.jep.2011.08.033.
https://doi.org/10.1016/j.jep.2011.08.03...
).
Animals
In total, 200 male Wistar rats weighing 200±10 g were obtained from the Animal Breeding Center of the PLA General Hospital (Beijing, China). All rats were kept in a temperature- (23±2°C) and humidity-controlled (60±10%) facility on a 12-h light/dark cycle with free access to food and water. All animal experimental protocols were approved by the Animal Experimentation Ethics Committee of General Hospital of Chinese PLA. All animal handling procedures were performed in compliance with the ‘Principles of Laboratory Animal Care’ and the Chinese legislation for the use and care of laboratory animals.
Fluoxetine-resistant depression model and drug administration
Twelve rats were randomly assigned as the normal control group, housed undisturbed in 4 per cage without contact with the stressed animals. The remaining 188 rats were used to replicate the CUMS model following the established protocol (1515. Hu Y, Liu M, Liu P, Guo DH, Wei RB, Rahman K. Possible mechanism of the antidepressant effect of 3,6′-disinapoyl sucrose from Polygala tenuifolia Willd. J Pharm Pharmacol 2011; 63: 869–874, doi: 10.1111/j.2042-7158.2011.01281.x.
https://doi.org/10.1111/j.2042-7158.2011...
). Rats received 4 weeks of stress stimulations, which consisted of high-speed agitation (10 min), immobilization (2 h), tilted cage (12 h), deprivation of food or water (24 h), continuous illumination (24 h), and forced swimming in ice water (5 min). Rats were randomly assigned one stimulation daily from 3:00–5:00 pm over 4 weeks, and the stressed rats were housed in individual cages to sustain the depressive state until the end of the experiment. Among the 188 rats, 12 were randomly assigned as depression model control (CUMS group), treated with CUMS stimulations only (administered water orally, with no fluoxetine), used for screening the FRD rats; the other 176 rats were administered fluoxetine (20 mg· kg–1·day–1, orally) for 4 weeks simultaneously. After 4 weeks, behavior tests (crossing frequency, rearing times, and sucrose preference) were performed. Among the 176 rats, the rats whose behavior index had no significant improvement compared with the CUMS rats and was significantly lower than that of normal rats were chosen as the FRD model. Ultimately, 48 rats met the criteria and were randomly divided into four groups. The rats were sequentially given CUMS stress and treated with water (n=12, FRD model group), fluoxetine (20 mg·kg–1·day–1) combined with aspirin (20 mg·kg–1·day–1) (n=12, Flu+Aspirin group), KXS at 338 mg·kg–1·day–1 (n=12, KXS-338 group), and KXS at 676 mg–1·kg–1·day–1(n=12, KXS-676 group) orally at 9:00-10:00 am for 3 weeks. Twelve rats in the normal control group were continuously administered water. The time interval between fluoxetine and aspirin in the Flu+Aspirin group was 30 min.
Open-field test
The locomotor activity was assessed to detect immobility or changes in motor activity in the open-field test performed on days 0, 28, and 46 of the experiment. The open-field apparatus was a cubic open field arena measuring 80 cm in length, 80 cm in width, and 60 cm in height. The box floor was divided into 25 squares (5 squares long × 5 squares wide). Rats were placed individually into the center of the arena and allowed to explore freely for 5 min. The floor was wiped cleaned with 70% ethanol between tests. The number of square line crossings with all four paws and rearing (when the rat stood on its hind limbs) were recorded.
Sucrose-preference test
The tests were performed on days 0, 28, and 46 of the experiment. Before the sucrose-preference test, rats were deprived of food and water for 24 h and then fed with two pre-weighted bottles containing 1% sucrose solution and water for 1 h. Intake was measured by weighing the bottles before and after each test. All tests were carried out in the home cage to minimize extraneous novelty and disturbance. The sucrose preference was calculated as sucrose intake/total water intake (sucrose intake+water intake). Anhedonia was defined as a reduction in sucrose preference relative to baseline levels.
Enzyme-linked immunosorbent assay
After the experiment, rats were anesthetized with an intraperitoneal injection of 10% chloral hydrate (0.35 mL/100 g body weight). Blood samples were collected, and serum was separated from aliquots of blood samples to determine the levels of serum inflammatory cytokines. The whole brain was then quickly removed with scissors, and the hippocampus was isolated, frozen in liquid nitrogen, and stored at –80°C for further biochemical analysis. The levels of cytokines (COX-2, IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-10, TGF-β, and TNF-α) in the hippocampus and serum were measured using a paired antibody quantitative ELISA kit according to the manufacturer's instructions. The plates were measured using a microtiter plate reader (Perkin-Elmer, USA). Data are reported as ng/mL.
Statistical analysis
Data are reported as means±SE. Differences between groups were analyzed by one-way ANOVA followed by Dunnett's test. Data were analyzed statistically using SPSS 17.0 software (USA). P values less than 0.05 were considered statistically significant.
Results
Fluoxetine-resistant depression model and behavior evaluation
Results of the open-field tests and sucrose-preference tests showed that before CUMS stress treatment (day 0), the number of line crossings and rearings, sucrose-preference index and body weights between groups had no significant differences. After 4 weeks, compared with normal control, the model rats, which were treated with CUMS stress and fluoxetine (day 28), showed a significant decrease in crossing frequency, rearing frequency, sucrose-preference index, and body weight (P<0.05). After 3 weeks of treatment (day 46), compared with the model control (treated with water), rats treated with CUMS stress, and fluoxetine+aspirin showed a significant increase in crossing frequency and sucrose-preference index. Both doses of KXS reverted the reduced crossing frequency, rearing frequency, sucrose-preference index and body weights in fluoxetine-resistant rats (p<0.05) (Table 1).
Cytokines in the hippocampus
ELISA experiments showed that levels of COX-2, IL-2, and TNF-α were increased significantly and levels of IL-10 were reduced in the hippocampus of fluoxetine-resistant rats, compared with normal rats (P<0.05). Fluoxetine in combination with aspirin decreased the levels of COX-2, IL-2, IL-4, and TNF-α in the hippocampus (p<0.05). KXS at a dose of 338 mg·kg–1·day–1 reduced levels of COX-2, IL-2, IL-6 and TNF-α, and increased IL-10 levels (P<0.05). KXS at a dose of 676 mg·kg–1·day–1 lowered TNF-α levels and increased IFN-γ levels in the hippocampus (p<0.05) (Figure 1).
Effects of Kai-Xin-San (KXS) on cytokines in the hippocampus in fluoxetine-resistant depression (FRD) rats exposed to chronic and unpredictable mild stress model and randomly divided into four groups: FRD model control (Model), oral fluoxetine and aspirin (Flu+Aspirin), oral KXS at a dose of 338 mg/kg, and 676 mg/kg. Data are reported as means±SD, n=12. #P<0.05, # #P<0.01 compared to untreated Normal group. *P<0.05, **P<0.01 compared to Model control group (ANOVA followed by Dunnett's test).
Cytokines in serum
Compared with normal rats, levels of IL-2 and TNF-α were increased significantly, and the levels of IL-10 were reduced in the model group (Figure 2). This is similar to the results found in the hippocampus. Fluoxetine in combination with aspirin decreased TNF-α levels and increase IL-10 levels in serum. KXS at both doses reduced levels of IL-2 and TNF-α, KXS at a dose of 676 mg·kg–1·day–1 also increased IFN-γ and IL-10 levels in serum (P<0.05).
Effects of Kai-Xin-San (KXS) on cytokines in serum in fluoxetine-resistant depression (FRD) rats exposed to chronic and unpredictable mild stress model and randomly divided into four groups: FRD model control (Model), oral fluoxetine and aspirin (Flu+Aspirin), oral KXS at a dose of 338 mg/kg, and 676 mg/kg. Data are reported as means±SD, n=12. #P<0.05, # #P<0.01 compared to untreated Normal group. *P<0.05, **P<0.01 compared to Model group.
Spleen coefficient
Compared with that of normal rats, the spleen coefficient in fluoxetine-resistant rats was increased significantly (P<0.05), but treatment with fluoxetine in combination with aspirin or with KXS (both doses) had no significant influence on the spleen coefficient (Figure 3).
. Effects of Kai-Xin-San (KXS) on spleen coefficient in fluoxetine-resistant depression (FRD) rats exposed to chronic and unpredictable mild stress model and randomly divided into four groups: FRD model control (Model), oral fluoxetine and aspirin (Flu+Aspirin), oral KXS at a dose of 338 mg/kg, and 676 mg/kg. Data are reported as means±SD, n=12. #P<0.05 compared to untreated Normal group.
Discussion
Depression is a psychological illness with high levels of disability and mortality, and is one of the most prevalent diseases in the world. In recent years, numerous studies have demonstrated a clear relationship between inflammation and the development of depression. For example, levels of IL-2, IL-6 in peripheral blood of patients with depression were significantly increased (1616. Chung YC, Kim SR, Park JY, Chung ES, Park KW, Won SY. Fluoxetine prevents MPTP-induced loss of dopaminergic neurons by inhibiting microglial activation. Neuropharmacol 2011; 60: 963–974, doi: 10.1016/j.neuropharm.2011.01.043.
https://doi.org/10.1016/j.neuropharm.201...
), levels of IL-2, IL-6, TNF-α in patients with first-episode depression were greater than that in normal patients (1717. Musselman D, Royster EB, Wang M, Long Q, Trimble LM, Mann TK, et al. The impact of escitalopram on IL-2-induced neuroendocrine, immune, and behavioral changes in patients with malignant melanoma: preliminary findings. Neuropsychopharmacol 2013; 38: 1921–1928, doi: 10.1038/npp.2013.85.
https://doi.org/10.1038/npp.2013.85...
), and overexpression of COX was found in the hippocampus of depressive rat models (1818. Wang Y, Yang F, Liu YF, Gao F, Jiang W. Acetylsalicylic acid as an augmentation agent in fluoxetine treatment resistant depressive rats. Neurosci Lett 2011; 499: 74–79, doi: 10.1016/j.neulet.2011.05.035.
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–2020. Schulz KF, Chalmers I, Hayes RJ, Altman D. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995; 273: 408–412, doi: 10.1001/jama.1995.03520290060030.
https://doi.org/10.1001/jama.1995.035202...
). These substances can inhibit the development of nerve cells, activate the hypothalamic-pituitary-adrenal axis simultaneously, increase the secretion of glucocorticoids and promote apoptosis (2121. Einvik G, Vistnes M, Hrubos-Strom H, Randby A, Namtvedt SK, Nordhus IH, et al. Circulating cytokine concentrations are not associated with major depressive disorder in a community based cohort. Gen Hosp Psychiat 2012; 34: 262–267, doi: 10.1016/j.genhosppsych.2012.01.017.
https://doi.org/10.1016/j.genhosppsych.2...
). These findings suggest that changes in serum cytokine (such as COX, IL-2 and TNF-α) concentrations play an important role in the development and pathophysiology of depressive disorders. Depression is associated with cytokine secretion disorders, which are associated with immune activation (2222. Irwin MR, Miller AH. Depressive disorders and immunity: 20 years of progress and discovery. Brain Behav Immun 2007; 21: 374–383, doi: 10.1016/j.bbi.2007.01.010.
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,2323. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature 2008; 455: 894–902, doi: 10.1038/nature07455.
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). Drugs that can inhibit proinflammatory cytokines may produce antidepressant effects (2424. Amini H, Aghayan S, Jalili SA, Akhondzadeh S, Yahyazadeh O, Pakravan-Nejad M. Comparison of mirtazapine and fluoxetine in the treatment of major depressive disorder: a double-blind, randomized trial. J Clin Pharm Ther 2005; 30: 133–138, doi: 10.1111/j.1365-2710.2004.00585.x.
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–2626. Versiani M, Moreno R, Ramakers-van Moorsel CJA, Schutte AJ. Comparative Efficacy Antidepressants Study Group. Comparison of the effects of mirtazapine and fluoxetine in severely depressed patients. CNS Drugs 2005; 19: 137–146, doi: 10.2165/00023210-200519020-00004.
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).
Furthermore, many studies have found that TRD is also accompanied by inflammatory dysregulation. Antidepressant-induced remission of depressive symptoms has also been associated with significant decreases in pro-inflammatory cytokine levels (2727. Leo R. Di Lorenzo G, Tesauro M, Razzini C, Forleo GB, Chiricolo G, et al. Association between enhanced soluble CD40 ligand and proinflammatory and prothrombotic states in major depressive disorder: pilot observations on the effects of selective serotonin reuptake inhibitor therapy. J Clin Psychiatry 2006; 67: 1760–1766, doi: 10.4088/JCP.v67n1114.
https://doi.org/10.4088/JCP.v67n1114...
,2828. Pizzi C, Mancini S, Angeloni L, Fontana F, Manzoli L, Costa GM. Effects of selective serotonin reuptake inhibitor therapy on endothelial function and inflammatory markers in patients with coronary heart disease. Clin PharmacolTher2009; 86: 527-532.). Major depressive patients with a history of non-response to antidepressants were found to have increased plasma concentration of IL-1, IL-6 and acute phase reactants compared with treatment-responsive patients (2929. Maes M, Bosmans E, De Jongh R, Kenis G, Vandoolaeghe E, Neels H. Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine 1997;9: 853–858, doi: 10.1006/cyto.1997.0238.
https://doi.org/10.1006/cyto.1997.0238...
,3030. Sluzewska A, Sobieska M, Rybakowski JK. Changes in acute-phase proteins during lithium potentiation of antidepressants in refractory depression, Neuropsychobiology 1997;35:123-127.). Similarly, patients with increased inflammatory cytokines before treatment have been reported to be less responsive to antidepressant treatment (3131. Benedetti F, Lucca A, Brambilla F, Colombo C, Smeraldi E. Interleukine-6 serum levels correlate with response to antidepressant sleep deprivation and sleep phase advance. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 1167–1170, doi: 10.1016/S0278-5846(02)00255-5.
https://doi.org/10.1016/S0278-5846(02)00...
,3232. Lanquillon S, Krieg JC, Bening-Abu-Shach U, Vedder H. Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology 2000; 22: 370–379, doi: 10.1016/S0893-133X(99)00134-7.
https://doi.org/10.1016/S0893-133X(99)00...
). Aspirin is a non-selective COX inhibitor with a broad spectrum of pharmacological effects at multiple locations. Existing research shows that aspirin has antidepressant properties and accelerates antidepressant effects in preclinical models (3333. Brunello N, Alboni S, Capone G, Benatti C, Blom JM, Tascedda F, et al. Acetylsalicylic acid accelerates the antidepressant effect of fluoxetine in the chronic escape deficit model of depression. Int Clin Psychopharmacol 2006; 21: 219–225, doi: 10.1097/00004850-200607000-00004.
https://doi.org/10.1097/00004850-2006070...
). Clinically, aspirin has been suggested to shorten the onset of action of selective reuptake inhibitors and to increase remission rates when added to fluoxetine in an open-label study of depressed patients previously non-responsive to fluoxetine alone (3434. Mendlewicz J, Kriwin P, Oswald P, Souery D, Alboni S, Brunello N. Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int Clin Psychopharmacol 2006; 21: 227–231, doi: 10.1097/00004850-200607000-00005.
https://doi.org/10.1097/00004850-2006070...
). Therefore, it is essential to find effective treatments for TRD.
Traditional Chinese medicine in the treatment of depression is the focus of current research. It was documented that KXS could cure symptoms including desolation, moodiness, and forgetfulness, which are similar to symptoms of depression, such as depressed mood, anxiety, and impairment in learning and memory (1313. Dang H, Sun L, Liu X, Peng B, Wang Q, Jia W, et al. Preventive action of Kai Xin San aqueous extract on depressive-like symptoms and cognition deficit induced by chronic mild stress. Exp Biol Med 2009; 234: 785–793, doi: 10.3181/0812-RM-354.
https://doi.org/10.3181/0812-RM-354...
). As the principal herb of KXS, ginseng has been demonstrated to improve learning and memory in animals (1010. Zhou XJ, Liu M, Yan JJ, Can Y, Liu P. Antidepressant-like effect of the extracted of Kai Xin San, a traditional Chinese herbal prescription, is explained by modulation of the central monoaminergic neurotransmitter system in mouse. J Ethnophamacol 2012;139: 422–428, doi: 10.1016/j.jep.2011.11.027.
https://doi.org/10.1016/j.jep.2011.11.02...
). 3,6′-Disinapoyl sucrose is an active oligosaccharide ester found in Polygala tenuifolia Willd, exhibits notable antidepressant effects in pharmacological depression models, and alleviates stress-induced behavioral abnormalities (1515. Hu Y, Liu M, Liu P, Guo DH, Wei RB, Rahman K. Possible mechanism of the antidepressant effect of 3,6′-disinapoyl sucrose from Polygala tenuifolia Willd. J Pharm Pharmacol 2011; 63: 869–874, doi: 10.1111/j.2042-7158.2011.01281.x.
https://doi.org/10.1111/j.2042-7158.2011...
,3535. Hu Y, Liao HB, Guo DH, Liu P, Wang YY, Rahman K. Antidepressant-like effects of 3,6′-disinapoyl sucrose on hippocampal neuronal plasticity and neurotrophic signal pathway in chronically mild stressed rats. Neurochem Int 2010; 56: 461–465, doi: 10.1016/j.neuint.2009.12.004.
https://doi.org/10.1016/j.neuint.2009.12...
).
CUMS model is accepted as a valuable method for inducing experimental depression in rats. At least 20–30% of depressive rats do not respond to fluoxetine treatment (3636. Bergstrom A, Jayatissa MN, Thykjaer T, Wiborg O. Molecular pathways associated with stress resilience and drug resistance in the chronic mild stress rat model of depression: a gene expression study. J Mol Neurosci 2007; 33: 201–215, doi: 10.1007/s12031-007-0065-9.
https://doi.org/10.1007/s12031-007-0065-...
). Aspirin can assist the treatment of depression through its anti-inflammatory effects, which led us to verify if KXS also played a role in regulating inflammatory pathways. Therefore, we studied the effect of KXS on cytokines in the hippocampus and serum of TRD rats.
The effects of KXS on the immune system of TRD rats are concentration-dependent and maximum inhibition of inflammatory factors and promotion of anti-inflammatory cytokines can be obtained by adjusting the dosage of KXS to optimize its antidepressant activity. These results suggest that administration of KXS for fluoxetine-resistant depression in rats was effective in improving depression by influencing the inflammatory processes.
Acknowledgments
This work was supported by grants from the National Natural Science Foundation (Nos. 81302909, 81373996, and 81573876).
References
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» https://doi.org/10.1176/appi.ajp.163.1.28 -
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» https://doi.org/10.1006/cyto.1997.0238 -
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» https://doi.org/10.1159/000119332 -
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» https://doi.org/10.1016/j.jpsychires.2006.05.013 -
5Benedetti F, Lucca A, Brambilla F, Colombo C, Smeraldi E. Interleukine-6 serum levels correlate with response to antidepressant sleep deprivation and sleep phase advance. Prog Neuropsychopharmacol Biol Psychiatry2002; 26: 1167–1170, doi: 10.1016/S0278-5846(02)00255-5.
» https://doi.org/10.1016/S0278-5846(02)00255-5 -
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Publication Dates
-
Publication in this collection
2017
History
-
Received
31 Dec 2016 -
Accepted
27 June 2017