Sesquiterpenoids from the Root of Panax ginseng Attenuates

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Sesquiterpenoids from the root of Panax Ginseng attenuates lipopolysaccharide-induced depressive-like behavior through the BDNF/TrkB and Sirt 1/NF-#B signaling pathways Weidong Wang, Xiaofeng Liu, Jinping Liu, Enbo Cai, Yan Zhao, Haijun Li, Lianxue Zhang, Pingya Li, and Yugang Gao J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.7b04835 • Publication Date (Web): 13 Dec 2017 Downloaded from http://pubs.acs.org on December 17, 2017

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Journal of Agricultural and Food Chemistry

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Sesquiterpenoids from the root of Panax Ginseng attenuates

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lipopolysaccharide-induced depressive-like behavior through the

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BDNF/TrkB and Sirt 1/NF-κB signaling pathways

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Weidong Wang†,#, Xiaofeng Liu‡,#, Jinping Liu§,#, Enbo Cai†, Yan Zhao†,*, Haijun Li§,

6

Lianxue Zhang†, Pingya Li§, Yugang Gao†,*

7 8

†

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130118, China

College of Chinese Medicinal Materials, Jilin Agriculture University, Changchun

10

‡

Ningxia People's Hospital, Yinchuan 750021, China

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§

Jilin University, Changchun 130021, China

12 13

* Corresponding author:

14

College of Chinese Medicinal Materials, Jilin Agriculture University, Changchun

15

130118,

16

[email protected] (Y. Zhao); [email protected] (Y.G. Gao).

Jilin,

China.

Tel/Fax:

+86

431

84533358,

17 18

#

These authors contributed equally to this work.

1

ACS Paragon Plus Environment

E-Mail

address:


19

Sesquiterpenoids from the root of Panax Ginseng attenuates

20

lipopolysaccharide-induced depressive-like behavior through the

21

BDNF/TrkB and Sirt 1/NF-κB signaling pathways

22 23

Abstract: The previous study indicated sesquiterpenoids from the root of Panax

24

ginseng (SPG) exhibited significant antidepressant-like effect, which might be

25

mediated by the modification of the dopaminergic, GABAergic and glutamatergic

26

systems. This study was to investigate SPG’s antidepressant effects and mechanisms

27

on lipopolysaccharide (LPS)-induced depression-like behavior. In the tail suspension

28

test (TST) and forced swimming test (FST), SPG (0.25 and 1 mg/kg, i.g.) and

29

fluoxetine (20 mg/kg, i.p.) effectively reduced the immobility time. SPG treatment

30

significantly reduced serum levels of IL-6 and TNF-α, and increased suppressed SOD

31

activity in hippocampus. In addition, SPG effectively up-regulated the brain-derived

32

neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB) and sirtuin type 1

33

(Sirt 1) expression in the hippocampus, down-regulated the inhibitor of kappa B-alpha

34

(IκB-α) and nuclear factor-kappa B (NF-κB) phosphorylation. These results suggested

35

that SPG exhibited antidepressant-like effect through the BDNF/TrkB and Sirt

36

1/NF-κB signaling pathways.

37 38

Keywords: sesquiterpenoids; LPS-induced depression; inflammation; neurotrophy

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INTRODUCTION

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Major depressive disorder (MDD) is a recurrent disorder of mental illness. The

42

main clinical features are low emotional depression and cognitive impairment, with

43

high prevalence, high recurrence rate, high suicide rate, high disability rate and so on.

44

1, 2

45

2020. 3 MDD has become a serious global public health problem, mainly due to the

46

lack of proper understanding of MDD, the low treatment rate, and the pain and loss of

47

depression itself to patients, families and society. Therefore, it is important to explore

48

the pathophysiological mechanisms of MDD and to find better therapeutic cureways,

49

which has become an important scientific problem in the field of neuroscience.

50

According to the WHO forecast, MDD will be the second most common disease in

Although a series of hypotheses have been proposed, such as the theory of

51

monoamine

52

hyperfunction theory, immune dysfunction theory and neurotrophic deficiency theory，

53

the exact pathophysiological mechanisms of MDD remain obscure, which is a

54

complex clinical existence, including different nervous system process.

55

current industry recognized mechanism of MDD, the monoaminergic hypothesis

56

predicts that the decrease in monoamine neurotransmitters levels in the synaptic cleft

57

is the cause of MDD.

58

antidepressants

59

noradrenaline reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors

60

(SSRIs), which can increase monoamine levels, are the most widely used drugs for

61

MDD.

8

neurotransmitters,

(TCAs),

5-7

hypothalamus-hypophysis-adrenal

axis

(HPA)

4

As the

Accordingly, the chemical drugs, including tricyclic monoamine

oxidase

inhibitors

(MAOIs),

selective

Nonetheless, 10% to 30% of MDD patients do not respond to existing 3



9

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treatments.

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neurotrophy, were introduced to understand MDD.

64

neuroinflammatory diseases, such as Parkinson's and Alzheimer's disease, have high

65

rates of comorbidity with MDD. 12-14 And peripheral inflammation, such as sepsis and

66

systemic inflammatory diseases, was also found to be associated with the

67

development

68

immunoinflammatory pathway, in particular the release of proinflammatory cytokines,

69

such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis

70

factor-alpha (TNF-α), can cause neuroendocrine and neurochemical changes leading

71

to MDD. 16-19

72

Therefore, several other mechanisms, such as inflammatory and

of

MDD.

15

Studies

have

10,11

shown

Notably, several other

that

the

activation

of

The lipopolysaccharide (LPS) immunoreactive model is a recognized 20-22

73

inflammatory-related animal model of MDD.

As the major component of the

74

outer membrance of Gramnegative bacteria, LPS can activate innate immune response

75

and secrete proinflammatory cytokines, such as IL-1β, IL-6 and TNF-α.23 These

76

cytokines affect neurotransmission and plasticity in the brain, trigger oxidative stress,

77

and inhibit neurogenesis in adults, all of which are thought to be the underlying

78

mechanisms of depression. 22, 24

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Panax ginseng, a traditional Chinese herbal medicine, is widely used in oriental

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society because of its obvious pharmacological effects on the central nervous system

81

(CNS), endocrine, immune and cardiovascular system. 25 P. ginseng can also be used

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in the food field. In the process of ginseng, a lot of waste water and waste gas would

83

be produced. Exhaust gas could be collected by condensation, which contains a large 4


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number of sesquiterpenoids. 26 Our previous study indicated that the sesquiterpenoids

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from the root of P. ginseng (SPG) exhibited significant antidepressant-like effect,

86

which was probably related to the dopaminergic, GABAergic and glutamatergic

87

systems. 27 However, the mechanism of antidepressant-like effect of SPG had not been

88

exactly described. Considering the immunomodulatory effect of P. ginseng, this study

89

was to evaluate the possible effect of SPG on LPS-induced antidepressant-like

90

behavior and discover its exact mechanism.

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MATERIALS AND METHODS

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SPG. SPG was extracted from ginseng (4 years old, Fusong, China) by ASI

93

Spe-ed SFE-2 supercritical CO2 extraction system (Allentown, PA, USA), and then

94

separated by distillation, and the sesquiterpenoids fraction were analyzed by GC-MS

95

according our previous method.

96

sesquiterpenoids compounds in SPG, accounting for 66% of the total.

27

As shown in Figure 1, there are 21 kinds of

97

Experimental Animal. Male ICR mice (18 g ~ 22 g) were purchased from

98

experimental animal Changchun ACEE Technology Co. ltd (Changchun, China). All

99

mice were adapted to the new laboratory 7 days prior to the experiment. Standard

100

laboratory conditions were temperature 23 ± 2 °C, relative humidity 50 ± 10 % and a

101

12-h light/12-h dark cycle with food and water available ad libitum for the duration of

102

the study. All experiments were conducted in accordance with the Jilin Agricultural

103

University animal laboratory guidelines, which were approved by the Jilin

104

Agricultural

105

(No.ECLA-JLAU-17016).

University's

Committee

on

the

use

5


of

animal

protection


106

Experimental Design. All mice were randomly divided into five groups (with

107

10 in each group): Control group, LPS group, LPS + FLU (20 mg/kg) group, LPS +

108

SPG (0.25 mg/kg) group and LPS + SPG (1 mg/kg) group. The control group and LPS

109

group was intraperitoneally (i.p.) administered 10 ml/kg normal saline (0.9 % NaCl aq)

110

once daily for 7 consecutive days. However, LPS + FLU group was administered FLU

111

(20 mg/kg, i.p.) once daily for 7 consecutive days; and LPS + SPG groups were

112

intragastrically (i.g.) administered 0.25 mg/kg or 1 mg/kg SPG once daily for 7

113

consecutive days, respectively. The dose of SPG was selected according to our

114

previous study.27 All mice received a single LPS (0.5 mg/kg, i.p.) or vehicle (0.9 %

115

NaCl aq) 30 min after the last drug treatment on 7th day. Behavioral evaluation (the

116

FST and TST) was performed after LPS stimulation of 24 h. The animals were

117

allowed to rest for 1 h between each protocol. Thereafter, the whole blood was

118

collected from the orbit; together with brain and hippocampus immediately removed.

119

Behavioral evaluation.

120

Forced Swimming Test (FST). The FST was executed as described previously.

121

28-29

122

containing 20 cm water depth (diameter 10 cm, height 25 cm), and the water

123

temperature remained at 24 ± 2 °C. The mouse was considered as immobile only

124

when it stopped struggling and floated motionless on the water. The behaviors were

125

measured in a 6 min period, and the duration of immobility within the last 4 min was

126

recorded.

127

Each mouse was forced to swim 24 hours after LPS exposure in a beaker

Tail Suspension Test (TST). The TST was carried out with reference to the 6


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previous methods.30 The tail of the mouse from the end of about 1 cm was fixed at the

129

folder, so that hanging from the ground about 50 cm on the bar. Each mouse was

130

suspended for 6 min, and the sum of the immobility time was observed within the last

131

4 min. After the end of the experiment, the mice were quickly removed from the stent

132

and returned to the cage.

133

Enzyme-Linked Immunosorbent Assay (ELISA). The blood samples were

134

centrifuged at 10000 rpm for 10 min at 4 °C to obtain the serum. The serum levels of

135

IL-6 and TNF-α were assessed using commercially available ELISA kits from R&D

136

Systems, Ltd. (Minneapolis, MN, USA) according to manufacturer’s instructions. The

137

optical density (OD) of each well was quantified at 450 nm with a microplate reader.

138

Determination of Super Oxide Dismutase (SOD) Level. Mouse hippocampus

139

samples were homogenized in 0.9 % normal saline (w:v 1:9) and then centrifuged at

140

10000 rpm for 10 min at 4 °C. The SOD activity was determined by using test kit

141

purchased from Nanjing Jiancheng Bioengineering Institute (Nanjing, China).

142

Western Blotting Analysis. The hippocampus tissue was washed and lysed with

143

buffer. The protein concentration was determined using the BCA Protein Kit

144

(Beyotime, Nanjing, China). The protein extract was decomposed on 10 %

145

SDS-polyacrylamide gel electrophoresis and then transferred to a transferred

146

polyvinylidene fluoride (PVDF) membrane. The membranes were sequentially

147

incubated with primary and secondary antibodies and enhanced chemiluminescence

148

(ECL) solutions, followed by autoradiography. Analyze the intensity of the blot using

149

Image Pro plus 6.0. 7



150

Statistical Analysis. All figures were performed using Graph pad prism software

151

version 4.00. Data were expressed as mean ± S.D. One way ANOVA was used for

152

statistical analysis of data, followed by Tukey’s post-hoc multiple comparison test.

153

Statistical significance was defined as p < 0.05.

154

RESULTS

155

Effect of SPG on Behavioral Assessments.

156

Effects of SPG on the immobility time in the FST. The floating and immobility of

157

animals in the FST was widely used to assess the depressive state of mice. After 24 h

158

of intraperitoneal injection of LPS, mice were tested for immobility time in the FST.

159

Figure 2A showed the effect of SPG on immobility time. Compared with the control

160

group, the mice in LPS group showed a significantly longer immobility time in the

161

FST, which suggested that LPS (0.5 mg/kg, i.p.) could induce depressive-like effect in

162

mice. However, the FLU (20 mg/kg, i.p.) and SPG (0.25 and 1 mg/kg, i.g.) treatments

163

could significantly reverse the immobility time increasement induced by the LPS

164

treatment.

165

Effects of SPG on the immobility time in the TST. The immobility time of the

166

mouse in the TST reflects the state of depression in the animal. As shown in Figure

167

2B, LPS significantly induced depression in mice; however, the FLU (20 mg/kg, i.p.)

168

and SPG (0.25 and 1 mg/kg, i.g.) treatments could significantly decrease the

169

immobility time of the mice exposed to the TST compared with LPS treatment alone.

170

Effects of SPG on the Serum Proinflammatory Cytokine Levels.

171

Inflammation is considered to be the underlying pathophysiological mechanism of 8


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neuropsychiatric disorders, including depression. As shown in Figure 3, compared

173

with the control group, the levels of TNF-α and IL-6 in the LPS group increased

174

significantly. In contrast, administration of FLU (20 mg/kg, i.p.) and SPG (0.25 and 1

175

mg/kg, i.g.) significantly reduced the serum TNF-α and IL-6 levels compared to the

176

LPS treatment.

177

Effects of SPG on the SOD Activity in the Hippocampus. Figure 4 displayed

178

that the SOD activity in the LPS group decreased significantly compared with the

179

control group. However, FLU (20 mg/kg, i.p.) and SPG (0.25 and 1 mg/kg, i.g.)

180

significantly elevated the SOD level in the hippocampus compared to LPS.

181

Effects of SPG on some Proteins Expressions in Hippocampus. We examined

182

the expression of brain-derived neurotrophic factor (BDNF), tropomyosin-related

183

kinase B (TrkB), Sirtuin type 1 (Sirt 1), inhibitor of kappa B-alpha (IκB-α) and

184

nuclear factor-kappa B (NF-κB) in hippocampus. As shown in Figure 5, in this study,

185

we found that LPS significantly down-regulated the BDNF, TrkB and Sirt 1

186

expression, and IκB-α and NF-κB phosphorylation was significantly up-regulated

187

compared to the control. In contrast, FLU (20 mg/kg, i.p.) and SPG (0.25 and 1 mg/kg,

188

i.g.) significantly reversed the changes of the BNDF, TrkB, Sirt 1, IκB-α and NF-κB

189

levels in hippocampus induced by LPS.

190

DISCUSSION

191

Our

previous

studies

demonstrated

that

SPG

exhibited

significant

192

antidepressant-like effect mediated by the modification of the dopaminergic,

193

GABAergic and glutamatergic systems,27 but its underlying mechanism of the 9



194

antidepressant-like effect was not clear. A large number of studies indicated that

195

neuroprotective effects of candidate drugs on depression can be attributed to their

196

effective effects of inflammation and oxidative stress; and LPS can effectively induce

197

the mice depression model which can be used to screen the antidepressant drugs and

198

study the mechanism of action.

199

antidepressant activity of SPG and discover its exact mechanism in a mice depression

200

model induced by LPS. In this study, the results further indicated that SPG could

201

significantly improve depressive symptoms induced by LPS.

31

Therefore, this study was carried out to verify the

202

MDD is often accompanied by the activation of the immune system, increased

203

secretion of cytokines; in contrast, cytokines could also cause changes in individual

204

mood and behavior; recent studies have also shown that proinflammatory cytokines

205

were associated with the etiology of depression.32 In this study, the results suggested

206

that SPG treatment significantly reduced levels of IL-6 and TNF-α, which showed

207

that SPG could alleviate LPS-induced inflammation of depression. In addition, there

208

was growing evidence that the level of oxidative stress was also associated with the

209

development of depression. 33-34 The previous study also demonstrates that with the

210

decrease of antioxidants (SOD) in the animals with depression, the level of oxidative

211

stress was positively correlated with the severity of depression; 35 and the level of

212

SOD was suppressed in the depression model. 36-37 In this study, LPS-challenged mice

213

exhibited suppressed SOD activity, while SPG treatment attenuated these alterations.

214 215

It is well known that the Sirt 1/NF-κB is involved in the regulation of the proinflammatory cytokines

38-40

. In the event of inflammation, the inhibitor of 10


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NF-κB-α and IκB-α was phosphorylated at the serine residues and then was rapidly

217

degraded. And the NF-κBp65 subunit was exposed, leading to phosphorylation and

218

translocation of NF-κB to the nucleus subsequently.41 The released NF-κB binds to

219

the corresponding inflammation-related genes, leading to the production of IL-6,

220

IL-1β and TNF-α. 42 In this study, western blot analysis showed that SPG treatment

221

inhibited LPS-induced activation of NF-κBp65 and IκB-α phosphorylation.

222

Meanwhile, Sirt 1 can improve the NF-κB-induced inflammatory responses. 40 Sirt 1 is

223

able to inhibit NF-κB transcriptional activity by direct binding to NF-κBp65 subunit

224

and resulting in its deacetylation at lysine 310. 43-44 In our study, the result of western

225

blot analysis showed that SPG treatment could activate Sirt 1 expression. The

226

antidepressant effect of SPG might be related to the alleviation of hippocampus

227

inflammation.

228

Moreover, there was plenty of evidence that BDNF was the most abundant

229

neurotrophic factor in the brain and played an important role in the pathogenesis of

230

depression.45 BDNF exerts its neuroprotective function through its specific high

231

affinity receptor TrkB. BDNF binding would result in the phosphorylation of TrkB,

232

which then activates downstream molecules and triggers signaling events.38 In

233

addition, BDNF interacts with TrkB receptors while activating downstream cascades

234

in the pathogenesis of depression.24 In this study, SPG treatment up-regulated the

235

expression of BDNF and TrkB, and the antidepressant effect of SPG might be related

236

to the activation of BDNF.

237

In conclusion, oral administration of SPG appeared to exert significant 11



238

antidepressant-like effects via significantly alterations of animal behaviors,

239

hippocampus inflammation, oxidative stress and neurotrophy in LPS induced

240

depression mice. In addition, the antidepressant-like effect of SPG might be attributed

241

to neurotrophy and anti-inflammatory defenses through the BDNF/TrkB and Sirt

242

1/NF-κB signaling pathways. Based on above, we believed that SPG might be

243

potential materials for drug and food development against depression. Further

244

investigations using other behavioral paradigms such as learned helplessness, chronic

245

unpredictable stress (CUS) and social defeat stress models will be explored in our

246

future scientific studies.

247

FUNDING SOURCES

248

This study was supported by the National key R&D program (grant No.

249

2016YFC0500303), the Special Fund for Agro-scientific Research in the Public

250

Interest (grant No. 201303111), and Jilin Province Science and Technology

251

Development Program (grant No. 20160307005YY, 20150307012YY).

252

CONFLICT OF INTEREST

253

The authors declare no conflicts of interest in the present work.

254

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FIGURE CAPTIONS

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Figure 1. The sesquiterpenoids in SPG shown as “Compoud No., Percentage

391

content”.

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Figure 2. Effects of SPG on the immobility time in the TST (A) and FST (B) in mice.

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mean ± S.D. with 10 mice in each group. Data were analyzed by one way ANOVAs,

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followed by Tukey’s post-hoc test. Compared with control group: #p

Sesquiterpenoids from the Root of Panax ginseng Attenuates

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