Article pubs.acs.org/JAFC
Cite This: J. Agric. Food Chem. 2018, 66, 265−271
Sesquiterpenoids from the Root of Panax ginseng Attenuates Lipopolysaccharide-Induced Depressive-Like Behavior through the Brain-Derived Neurotrophic Factor/Tropomyosin-Related Kinase B and Sirtuin Type 1/Nuclear Factor-κB Signaling Pathways Weidong Wang,†,‡ Xiaofeng Liu,†,§ Jinping Liu,†,∥ Enbo Cai,‡ Yan Zhao,*,‡ Haijun Li,∥ Lianxue Zhang,‡ Pingya Li,∥ and Yugang Gao*,‡ ‡
College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin 130118, People’s Republic of China Ningxia People’s Hospital, Yinchuan, Ningxia 750021, People’s Republic of China ∥ Jilin University, Changchun, Jilin 130021, People’s Republic of China §
ABSTRACT: The previous study indicated sesquiterpenoids from the root of Panax ginseng (SPG) exhibited a significant antidepressant-like effect, which might be mediated by the modification of the dopaminergic, GABAergic, and glutamatergic systems. This study was to investigate antidepressant effects and mechanisms on the lipopolysaccharide (LPS)-induced depression-like behavior of SPG. In the tail suspension test (TST) and forced swimming test (FST), SPG (0.25 and 1 mg/kg, i.g.) and fluoxetine (20 mg/kg, i.p.) effectively reduced the immobility time. SPG treatment significantly reduced serum levels of IL-6 and TNF-α and increased suppressed superoxide dismutase (SOD) activity in the hippocampus. In addition, SPG effectively upregulated the brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB), and sirtuin type 1 (Sirt 1) expression in the hippocampus and downregulated the inhibitor of κB-α (IκB-α) and nuclear factor-κB (NF-κB) phosphorylation. These results suggested that SPG exhibited an antidepressant-like effect through the BDNF/TrkB and Sirt 1/ NF-κB signaling pathways. KEYWORDS: sesquiterpenoids, LPS-induced depression, inflammation, neurotrophy
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INTRODUCTION Major depressive disorder (MDD) is a recurrent disorder of mental illness. The main clinical features are low emotional depression and cognitive impairment, with high prevalence, high recurrence rate, high suicide rate, high disability rate, etc.1,2 According to the World Health Organization (WHO) forecast, MDD will be the second most common disease in 2020.3 MDD has become a serious global public health problem, mainly as a result of the lack of proper understanding of MDD, the low treatment rate, and the pain and loss of depression itself to patients, families, and society. Therefore, it is important to explore the pathophysiological mechanisms of MDD and to find better therapeutic cureways, which has become an important scientific problem in the field of neuroscience. Although a series of hypotheses have been proposed, such as the theory of monoamine neurotransmitters, hypothalamus− pituitary−adrenal (HPA) axis hyperfunction theory, immune dysfunction theory, and neurotrophic deficiency theory, the exact pathophysiological mechanisms of MDD remain obscure, which is a complex clinical existence, including different nervous system processes.4 As the current industry-recognized mechanism of MDD, the monoaminergic hypothesis predicts that the decrease in monoamine neurotransmitter levels in the synaptic cleft is the cause of MDD.5−7 Accordingly, the chemical drugs, including tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective noradrenaline reuptake inhibitors (SNRIs), and selective serotonin © 2017 American Chemical Society
reuptake inhibitors (SSRIs), which can increase monoamine levels, are the most widely used drugs for MDD.8 Nonetheless, 10−30% of MDD patients do not respond to existing treatments.9 Therefore, several other mechanisms, such as inflammatory and neurotrophy, were introduced to understand MDD.10,11 Notably, several other neuroinflammatory diseases, such as Parkinson’s and Alzheimer’s diseases, have high rates of comorbidity with MDD.12−14 Peripheral inflammation, such as sepsis and systemic inflammatory diseases, was also found to be associated with the development of MDD.15 Studies have shown that the activation of the immunoinflammatory pathway, in particular the release of proinflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL6), and tumor necrosis factor-α (TNF-α), can cause neuroendocrine and neurochemical changes, leading to MDD.16−19 The lipopolysaccharide (LPS) immunoreactive model is a recognized inflammatory-related animal model of MDD.20−22 As the major component of the outer membrance of Gramnegative bacteria, LPS can activate innate immune response and secrete proinflammatory cytokines, such as IL-1β, IL-6, and TNF-α.23 These cytokines affect neurotransmission and plasticity in the brain, trigger oxidative stress, and inhibit Received: Revised: Accepted: Published: 265
October 23, 2017 December 11, 2017 December 13, 2017 December 13, 2017 DOI: 10.1021/acs.jafc.7b04835 J. Agric. Food Chem. 2018, 66, 265−271
Article
Journal of Agricultural and Food Chemistry
spectrometry (GC−MS) according our previous method.27 As shown in Figure 1, there are 21 kinds of sesquiterpenoid compounds in SPG, accounting for 66% of the total. Experimental Animal. Male ICR mice (18−22 g) were purchased as the experimental animal from Changchun ACEE Technology Co., Ltd. (Changchun, China). All mice were adapted to the new laboratory 7 days prior to the experiment. Standard laboratory conditions were temperature of 23 ± 2 °C, relative humidity of 50 ± 10%, and a 12 h light/12 h dark cycle with food and water available ad libitum for the duration of the study. All experiments were conducted in accordance with the Jilin Agricultural University animal laboratory guidelines, which were approved by the Committee on the Use of Animal Protection of Jilin Agricultural University (ECLA-JLAU-17016). Experimental Design. All mice were randomly divided into five groups (with 10 in each group): control group, LPS group, LPS + fluoxetine (FLU) (20 mg/kg) group, LPS + SPG (0.25 mg/kg) group, and LPS + SPG (1 mg/kg) group. The control group and LPS group were intraperitoneally (i.p.) administered 10 mL/kg normal saline (0.9% NaCl aqueous) once daily for 7 consecutive days. However, the LPS + FLU group was administered FLU (20 mg/kg, i.p.) once daily for 7 consecutive days, and the LPS + SPG group was intragastrically (i.g.) administered 0.25 or 1 mg/kg SPG once daily for 7 consecutive days. The dose of SPG was selected according to our previous study.27 All mice received a single LPS (0.5 mg/kg, i.p.) or vehicle (0.9% NaCl aqueous) 30 min after the last drug treatment on the 7th day. Behavioral evaluation [forced swimming test (FST) and tail suspension test (TST)] was performed after LPS stimulation of 24 h. The animals were allowed to rest for 1 h between each protocol. Thereafter, the whole blood was collected from the orbit, together with brain and hippocampus immediately removed. Behavioral Evaluation. FST. The FST was executed as described previously.28,29 Each mouse was forced to swim 24 h after LPS exposure in a beaker containing 20 cm water depth (diameter of 10 cm and height of 25 cm), and the water temperature remained at 24 ± 2 °C. The mouse was considered as immobile only when it stopped struggling and floated motionless on the water. The behaviors were measured in a 6 min period, and the duration of immobility within the last 4 min was recorded. TST. The TST was carried out with reference to the previous methods.30 The tail of the mouse from the end of about 1 cm was fixed at the folder, so that it hung from the ground about 50 cm on the bar. Each mouse was suspended for 6 min, and the sum of the immobility time was observed within the last 4 min. After the end of
Figure 1. Sesquiterpenoids in SPG shown as the compoud number and percentage content.
neurogenesis in adults, all of which are thought to be the underlying mechanisms of depression.22,24 Panax ginseng, a traditional Chinese herbal medicine, is widely used in oriental society because of its obvious pharmacological effects on the central nervous system (CNS) and endocrine, immune, and cardiovascular systems.25 P. ginseng can also be used in the food field. In the process of ginseng, a lot of wastewater and waste gas would be produced. Exhaust gas could be collected by condensation, which contains a large number of sesquiterpenoids.26 Our previous study indicated that the sesquiterpenoids from the root of P. ginseng (SPG) exhibited a significant antidepressant-like effect, which was probably related to the dopaminergic, GABAergic, and glutamatergic systems.27 However, the mechanism of the antidepressant-like effect of SPG had not been exactly described. Considering the immunomodulatory effect of P. ginseng, this study was to evaluate the possible effect of SPG on the LPS-induced antidepressant-like behavior and discover its exact mechanism.
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MATERIALS AND METHODS
SPG. SPG was extracted from ginseng (4 years old, Fusong, China) by the ASI Spe-ed SFE-2 supercritical CO2 extraction system (Allentown, PA, U.S.A.), and then separated by distillation, and the sesquiterpenoid fractions were analyzed by gas chromatography−mass
Figure 2. Effects of SPG on the immobility time in the (A) TST and (B) FST in mice. TST and FST were performed 24 h after LPS administration. Values were the mean ± SD with 10 mice in each group. Data were analyzed by one-way ANOVA, followed by Tukey’s post-hoc test. (#) p < 0.05 and (##) p < 0.01 compared to the control group. (∗) p < 0.05 and (∗∗) p < 0.01 compared to the LPS group. 266
DOI: 10.1021/acs.jafc.7b04835 J. Agric. Food Chem. 2018, 66, 265−271
Article
Journal of Agricultural and Food Chemistry
Figure 3. Effects of SPG on the levels of neuroinflammation cytokines in serum, including (A) TNF-α and (B) IL-6. Neuroinflammation cytokines were mensurated 24 h after LPS administration. Values were the mean ± SD with 10 mice in each group. Data were analyzed by one-way ANOVA, followed by Tukey’s post-hoc test. (#) p < 0.05 and (##) p < 0.01 compared to the control group. (∗) p < 0.05 and (∗∗) p < 0.01 compared to the LPS group. the experiment, the mice were quickly removed from the stent and returned to the cage. Enzyme-Linked Immunosorbent Assay (ELISA). The blood samples were centrifuged at 10 000 rpm for 10 min at 4 °C to obtain the serum. The serum levels of IL-6 and TNF-α were assessed using commercially available ELISA kits from R&D Systems, Ltd. (Minneapolis, MN, U.S.A.) according to the instructions of the manufacturer. The optical density (OD) of each well was quantified at 450 nm with a microplate reader. Determination of the Superoxide Dismutase (SOD) Level. Mouse hippocampus samples were homogenized in 0.9% normal saline (1:9, w/v) and then centrifuged at 10 000 rpm for 10 min at 4 °C. The SOD activity was determined using a test kit purchased from the Nanjing Jiancheng Bioengineering Institute (Nanjing, China). Western Blotting Analysis. The hippocampus tissue was washed and lysed with buffer. The protein concentration was determined using the BCA Protein Kit (Beyotime, Nanjing, China). The protein extract was decomposed on 10% sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS−PAGE) and then transferred to a transferred polyvinylidene fluoride (PVDF) membrane. The membranes were sequentially incubated with primary and secondary antibodies and enhanced chemiluminescence (ECL) solutions, followed by autoradiography. The intensity of the blot was analyzed using Image Pro Plus 6.0. Statistical Analysis. All figures were performed using GraphPad Prism, version 4.00. Data were expressed as the mean ± standard deviation (SD). One-way analysis of variance (ANOVA) was used for statistical analysis of data, followed by Tukey’s post-hoc multiple comparison test. Statistical significance was defined as p < 0.05.
Effects of SPG on the Immobility Time in the TST. The immobility time of the mouse in the TST reflects the state of depression in the animal. As shown in Figure 2B, LPS significantly induced depression in mice; however, the FLU (20 mg/kg, i.p.) and SPG (0.25 and 1 mg/kg, i.g.) treatments could significantly decrease the immobility time of the mice exposed to the TST compared to LPS treatment alone. Effects of SPG on the Serum Proinflammatory Cytokine Levels. Inflammation is considered to be the underlying pathophysiological mechanism of neuropsychiatric disorders, including depression. As shown in Figure 3, in comparison to the control group, the levels of TNF-α and IL-6 in the LPS group increased significantly. In contrast, administration of FLU (20 mg/kg, i.p.) and SPG (0.25 and 1 mg/kg, i.g.) significantly reduced the serum TNF-α and IL-6 levels compared to the LPS treatment.
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RESULTS Effect of SPG on Behavioral Assessments. Effects of SPG on the Immobility Time in the FST. The floating and immobility of animals in the FST were widely used to assess the depressive state of mice. After 24 h of intraperitoneal injection of LPS, mice were tested for immobility time in the FST. Figure 2A showed the effect of SPG on the immobility time. In comparison to the control group, the mice in the LPS group showed a significantly longer immobility time in the FST, which suggested that LPS (0.5 mg/kg, i.p.) could induce a depressive-like effect in mice. However, the FLU (20 mg/kg, i.p.) and SPG (0.25 and 1 mg/kg, i.g.) treatments could significantly reverse the immobility time increasement induced by the LPS treatment.
Figure 4. Effects of SPG on the level of SOD in the hippocampus. All tests were mensurated 24 h after LPS administration. Values were the mean ± SD with 10 mice in each group. Data were analyzed by oneway ANOVA, followed by Tukey’s post-hoc test. (#) p < 0.05 and (##) p < 0.01 compared to the control group. (∗) p < 0.05 and (∗∗) p < 0.01 compared to the LPS group. 267
DOI: 10.1021/acs.jafc.7b04835 J. Agric. Food Chem. 2018, 66, 265−271
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Figure 5. Effects of SPG on the protein expression of (A) BDNF, (B) TrkB, (C) Sirt 1, (D) p-NF-κB, and (E) IκB-α. The protein expression was examined by western blotting analysis in hippocampus tissues: (I) control group, (II) LPS group, (III) LPS + FLU (20 mg/kg), (IV) LPS + SPG (0.25 mg/kg), and (V) LPS + SPG (1 mg/kg). All tests were mensurated 24 h after LPS administration. Values were the mean ± SD with 10 mice in each group. (#) p < 0.05 and (##) p < 0.01 compared to the control group. (∗) p < 0.05 and (∗∗) p < 0.01 compared to the LPS group.
Effects of SPG on the SOD Activity in the Hippocampus. Figure 4 displayed that the SOD activity in the LPS group decreased significantly compared to the control group. However, FLU (20 mg/kg, i.p.) and SPG (0.25 and 1 mg/kg, i.g.) significantly elevated the SOD level in the hippocampus compared to LPS. Effects of SPG on Some Protein Expressions in the Hippocampus. We examined the expression of brain-derived
neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB), sirtuin type 1 (Sirt 1), inhibitor of κB-α (IκB-α), and nuclear factor-κB (NF-κB) in the hippocampus. As shown in Figure 5, in this study, we found that LPS significantly downregulated the BDNF, TrkB, and Sirt 1 expressions and IκB-α and NF-κB phosphorylations were significantly upregulated in comparison to the control. In contrast, FLU (20 mg/ kg, i.p.) and SPG (0.25 and 1 mg/kg, i.g.) significantly reversed 268
DOI: 10.1021/acs.jafc.7b04835 J. Agric. Food Chem. 2018, 66, 265−271
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Journal of Agricultural and Food Chemistry
SPG treatment upregulated the expression of BDNF and TrkB, and the antidepressant effect of SPG might be related to the activation of BDNF. In conclusion, oral administration of SPG appeared to exert significant antidepressant-like effects via significant alteration of animal behavior, hippocampus inflammation, oxidative stress, and neurotrophy in LPS-induced depression in mice. In addition, the antidepressant-like effect of SPG might be attributed to neurotrophy and anti-inflammatory defenses through the BDNF/TrkB and Sirt 1/NF-κB signaling pathways. On the basis of the above, we believed that SPG might be potential materials for drug and food development against depression. Further investigations using other behavioral paradigms, such as learned helplessness, chronic unpredictable stress (CUS), and social defeat stress models, will be explored in our future scientific studies.
the changes of the BNDF, TrkB, Sirt 1, IκB-α, and NF-κB levels in the hippocampus induced by LPS.
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DISCUSSION Our previous studies demonstrated that SPG exhibited a significant antidepressant-like effect mediated by the modification of the dopaminergic, GABAergic, and glutamatergic systems,27 but its underlying mechanism of the antidepressantlike effect was not clear. A large number of studies indicated that neuroprotective effects of candidate drugs on depression can be attributed to their effective effects of inflammation and oxidative stress, and LPS can effectively induce the mice depression model, which can be used to screen the antidepressant drugs and study the mechanism of action.31 Therefore, this study was carried out to verify the antidepressant activity of SPG and discover its exact mechanism in a mice depression model induced by LPS. In this study, the results further indicated that SPG could significantly improve depressive symptoms induced by LPS. MDD is often accompanied by the activation of the immune system, with increased secretion of cytokines; in contrast, cytokines could also cause changes in individual mood and behavior, with a recent study showing that proinflammatory cytokines were associated with the etiology of depression.32 In this study, the results suggested that SPG treatment significantly reduced levels of IL-6 and TNF-α, which showed that SPG could alleviate LPS-induced inflammation of depression. In addition, there was growing evidence that the level of oxidative stress was also associated with the development of depression.33,34 The previous study also demonstrates that, with the decrease of antioxidants (SOD) in the animals with depression, the level of oxidative stress was positively correlated with the severity of depression,35 and the level of SOD was suppressed in the depression model.36,37 In this study, LPS-challenged mice exhibited suppressed SOD activity, while SPG treatment attenuated these alterations. It is well-known that Sirt 1/NF-κB is involved in the regulation of the proinflammatory cytokines.38−40 In the event of inflammation, the inhibitor of NF-κB-α and IκB-α was phosphorylated at the serine residues and then was rapidly degraded. The NF-κBp65 subunit was exposed, leading to phosphorylation and translocation of NF-κB to the nucleus subsequently.41 Released NF-κB binds to the corresponding inflammation-related genes, leading to the production of IL-6, IL-1β, and TNF-α.42 In this study, western blot analysis showed that SPG treatment inhibited LPS-induced activation of NF-κBp65 and IκB-α phosphorylation. Meanwhile, Sirt 1 can improve the NF-κB-induced inflammatory responses.40 Sirt 1 is able to inhibit NF-κB transcriptional activity by direct binding to the NF-κBp65 subunit, resulting in its deacetylation at lysine 310.43,44 In our study, the result of western blot analysis showed that SPG treatment could activate Sirt 1 expression. The antidepressant effect of SPG might be related to the alleviation of hippocampus inflammation. Moreover, there was plenty of evidence that BDNF was the most abundant neurotrophic factor in the brain and played an important role in the pathogenesis of depression.45 BDNF exerts its neuroprotective function through its specific highaffinity receptor TrkB. BDNF binding would result in the phosphorylation of TrkB, which then activates downstream molecules and triggers signaling events.38 In addition, BDNF interacts with TrkB receptors while activating downstream cascades in the pathogenesis of depression.24 In this study,
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AUTHOR INFORMATION
Corresponding Authors
*Telephone/Fax: +86-431-84533358. E-mail: zhaoyan@jlau. edu.cn. *Telephone/Fax: +86-431-84533358. E-mail: gaoyugang_
[email protected]. ORCID
Weidong Wang: 0000-0003-4628-3555 Author Contributions
† Weidong Wang, Xiaofeng Liu, and Jinping Liu contributed equally to this work.
Funding
This study was supported by the National Key R&D Program (Grant 2016YFC0500303), the Special Fund for Agroscientific Research in the Public Interest (Grant 201303111), and the Jilin Province Science and Technology Development Program (Grants 20160307005YY and 20150307012YY). Notes
The authors declare no competing financial interest.
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