Aim: Recent evidence indicates that neuroinflammation and oxidative stress play vital roles in the pathological process of major depressive disorder (MDD). Cinnamic acid (CA), a naturally occurring organic acid, has been reported to ameliorate neuroinflammation and oxidative stress for treatment of diabetes-related memory deficits. Here, we explored whether CA pretreatment ameliorated lipopolysaccharide (LPS)-induced depressive-like behaviors in mice by suppressing neuroinflammation and by improving oxidative stress status. Methods: The mice were treated with CA, vehicle, or fluoxetine as a positive control. After 14 days, LPS (1 mg/kg, i.p.) or saline was administered. The depression-like behaviors were examined by the sucrose preference test (SPT), the forced swimming test (FST), and the tail suspension test (TST). Furthermore, the levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), and brain-derived neurotrophic factor (BDNF) in the hippocampus and cortex of mice were assayed. Results: Our results demonstrated that CA pretreatment at the doses of 100 and 200 mg/kg significantly attenuated depressive-like behaviors in the TST, FST, and SPT. In addition, not only the upregulation of pro-inflammatory cytokines (IL-6 and TNF-α) but also oxidative stress parameters including SOD, GSH, and MDA in the hippocampus and cortex of mice treated with LPS were dramatically improved by CA pretreatment. Finally, CA pretreatment strikingly ameliorated the downregulation of BDNF induced by LPS in the hippocampus and cortex of mice. Conclusion: Our results indicated that CA may have therapeutic potential for MDD treatment through attenuating the LPS-induced inflammation and oxidative stress along with significant improvement of BDNF impairment.

Major depressive disorder (MDD) is the most common psychiatric disease that initiates severe problems on society and the economy as it is always associated with psychosocial functional impairment and health care costs. Numerous pieces of evidence suggest that neuroinflammation and oxidative stress are closely implicated in the pathophysiology of MDD [1‒3]. Patients with MDD exert all of the primary characteristics of inflammatory responses, including elevated pro-inflammatory cytokine levels; abnormal changes in oxidative stress parameters such as malondialdehyde (MDA), superoxide dismutase (SOD), and GST; soluble adhesion molecules; and chemokines in both peripheral blood and brain tissues [1]. In addition, a similar consequence was also observed in the hippocampus and other brain regions of the animal models treated by lipopolysaccharide (LPS), along with behavioral dysfunction as detected by the forced swimming test (FST) and tail suspension test (TST) [4]. These molecular changes could be reversed by antidepressant treatment in both clinical and preclinical studies [1]. Besides, growing evidence indicates that the brain-derived neurotrophic factor (BDNF), one well-studied representative member of the neurotrophic factor family, is closely involved in the pathophysiology of depression [5]. Moreover, that oxidative parameters production and BDNF signaling damage were mediated by the LPS-induced pro-inflammatory cytokine has been well revealed [6]. Therefore, intervention in the course of neuroinflammation as well as oxidative stress may be a beneficial strategy for MDD treatment.

Cinnamic acid (CA) is a natural organic acid found in many plants including Cinnamon (Cinnamomum cassia), a widely used flavoring material and natural spice for food around the world. According to previous studies, a variety of beneficial effects of CA have been demonstrated in animal models associated with neuroinflammation and oxidative stress [7]. For instance, the reduction in cholinergic dysfunction and the oxidative stress, such as glutathione (GSH) and SOD, by CA improves memory in diabetic mice [8]. Additionally, CA has been shown to upregulate the suppressor of cytokine signaling 3 and inhibit the expression of pro-inflammatory cytokine via the cyclic AMP response element binding pathway in both microglia and astroglia [9]. In the MPTP mouse model of PD, CA was found to activate PPARα to protect the nigrostriatal axis and improve motor behaviors [10]. Here, the present study was carried out to explore whether CA ameliorated LPS-induced depressive-like behaviors in mice by suppressing pro-inflammatory responses and improving oxidative stress status, which are associated with the change of BDNF.

Materials

Trans-CA (C80857), LPS (0111: B4), and sucrose (V900116) were purchased from Sigma-Aldrich (St. Louis, MO, USA). Fluoxetine (Flu) (F131623) was provided by Aladdin (Shanghai, China). The corresponding primary antibodies including anti-BDNF (28205-1-AP, Proteintech Group Inc., Rosemont, IL, USA) and anti-β-actin (20536-1-AP, Proteintech Group Inc., Rosemont, IL, USA) were obtained from indicated manufactures. SOD (A006-2-1), GSH (A001-3-2), and MDA (A003-1-2) assay kits were obtained from Nanjing Jiancheng Bioengineering Institute (Nanjing, China). The tumor necrosis factor-α (TNF-α) (88-7324) and interleukin-6 (IL-6) (88-7064) ELISA kits were purchased from Thermo Fisher Scientific (USA).

Animal Treatment

Adult male C57BL/6J mice (22 ± 2 g), aged 8–10 weeks, were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd (Beijing, China). Mice were housed in the standard conditions of temperature (22 ± 1°C), humidity, with a 12-h light/dark cycle, and allowed access to food and water ad libitum. Animal experimental procedures were approved by the Animal Care and Use Committee of Xiamen University (No. SYXK 2018-003) and carried out in compliance with the National Institutes of Health (NIH) Guide (No. 85-23, revised 1985) for the care and use of laboratory animals.

Mice were randomly divided into 6 treatment groups (n = 12): control, LPS (vehicle, 0.5% methylcellulose, 10 mL/kg), LPS + Flu (fluoxetine 20 mg/kg, as a positive control group), and LPS + CA (50, 100, and 200 mg/kg, respectively). All mice were intragastrically administered once daily for 14 days. Mice were injected i.p. with saline or LPS (1.0 mg/kg) 30 min after the last treatment on 14th day. Then, the behavioral tests were carried out after LPS injection for 24 h. Mice were then sacrificed for various biochemical detections.

Sucrose Preference Test

All mice were separately housed for 48 h prior to the sucrose preference test and then habituated to 1% sucrose for 24 h. Water deprivation for 24 h on testing day, mice were allowed free access to 1% sucrose and water from two pre-weighed bottles. The two bottles were switched for another 12 h to avoid side preference. The fluid intakes were assessed after 24 h, and sucrose preference was defined as follows: sucrose preferences = sucrose consumption/(sucrose consumption + water consumption) × 100%.

Forced Swimming Test

The FST was carried out according to the procedure as previously described with moderate modifications [6, 11]. Mice were placed individually into a glass cylinder (35 cm height × 18 cm diameter) containing freshwater (23 ± 1°C). The immobile duration was recorded within the last 4 min during a 6-min test. Immobility was defined as the absence of active, escape-oriented behaviors, with small movements necessary to keep the head above water.

Tail Suspension Test

The TST was carried out based on the method as previously described [12]. In brief, the animals were suspended individually 40 cm above the bottom for 6 min with the help of one adhesive tape placed approximately 1 cm from the tip of the tail. The total immobile duration was assessed for the last 4 min. Immobility was considered as mice did not show any agitation and hanged passively. Any mice that climbed their tails were excluded from the data analysis.

Measurement of Oxidative Stress

Concentrations of SOD, GSH, and MDA were measured by using assay kits according to the manufacturer’s instructions, respectively. In brief, cortical and hippocampal tissues were homogenized in saline (0.9% NaCl) at a ratio of 1:9 (wt/v) on ice. Supernatant concentrations were detected after centrifugation at 3,000 rpm for 20 min at 4°C.

Measurement of TNF-α and IL-6

Concentrations of TNF-α and IL-6 were determined using ELISA kits following the manufacturer’s protocol. Briefly, cortical and hippocampal samples were homogenized in PBS (pH7.4) (wt/v, 1:9). Supernatant protein concentrations were determined after centrifugation at 12,000 rpm for 20 min at 4°C. The sample absorbance was read at 450 nm using a multifunctional plate reader (Thermo Scientific Multiskan GO, Waltham, MA, USA). A four-parameter logistic curve (log-log) was applied to calculate the sample concentrations according to the standard curve by using ELISAcalc software.

Western Blot Analysis

Briefly, total proteins were extracted from cortical and hippocampal tissues in a RIPA lysis buffer containing the protease and phosphatase inhibitor cocktail (Thermo Fisher, Waltham, MA, USA) and then centrifuged at 12,000 g for 30 min at 4°C. Samples were size-fractioned by 10% SDS-PAGE and transferred to PVDF membranes (Millipore, Billerica, MA, USA). Membranes were blocked with 5% nonfat dry milk and then immunoblotted with specific primary antibodies at 4°C overnight. Afterward, the membranes were incubated with the corresponding secondary antibodies for 1 h at room temperature. The protein signals were visualized and quantified by autoradiography (GelView 6000 Plus, China) with an enhanced chemiluminescence kit (Millipore Corporation, Billerica, MA, USA).

Statistical Analysis

Statistical analysis was performed by using GraphPad Prism (Prism 8, Graph Pad Software Inc., San Diego, CA, USA). The data were analyzed by one-way ANOVA followed by Tukey’s post hoc test and expressed as mean ± SEM. p < 0.05 was considered statistically significant.

CA Alleviated Depressive-Like Behaviors Induced by LPS in Mice

The TST and FST have been the most widely used methods to assess potential antidepressant-like activity [13]. To explore whether CA possesses antidepressant activity in depressive models induced by LPS, we investigated the behavioral effects of CA in the TST and FST. As shown in Figure 1, the differences between treatment groups were statistically significant through one-way ANOVA analysis. Post hoc analysis by the Bonferroni test showed that immobility duration in both TST and FST increased significantly in mice injected with LPS (1 mg/kg) when compared with the vehicle without injection of LPS. Flu, as a positive control, significantly decreased the immobility time in both tests as expected. Interestingly, the 14-day treatment with CA significantly reduced the immobility duration at the dosages of 100 and 200 mg/kg in the TST and FST (Fig. 1a, b). Additionally, no difference was observed in both peripheral and central activity among all groups (Fig. 1d) in the OFT, indicating that CA did not have a potential role on spontaneous locomotor activity which would result in immobile behavior during the FST and TST.

Fig. 1.

CA pretreatment alleviated the behavioral changes in mice treated with LPS. a, b Increase in immobility time in the TST (a) and FST (b) induced by LPS was significantly alleviated by CA pretreatment. c CA administration significantly improved the decrease of sucrose consumption in the SPT induced by LPS. d Pretreatment with CA did not affect the spontaneous locomotor activity of mice in OFT. Data were expressed as mean ± SEM (n= 11–16). ###p< 0.001 versus Con; *p< 0.05, **p< 0.005 versus LPS + Veh. SPT, sucrose preference test.

Fig. 1.

CA pretreatment alleviated the behavioral changes in mice treated with LPS. a, b Increase in immobility time in the TST (a) and FST (b) induced by LPS was significantly alleviated by CA pretreatment. c CA administration significantly improved the decrease of sucrose consumption in the SPT induced by LPS. d Pretreatment with CA did not affect the spontaneous locomotor activity of mice in OFT. Data were expressed as mean ± SEM (n= 11–16). ###p< 0.001 versus Con; *p< 0.05, **p< 0.005 versus LPS + Veh. SPT, sucrose preference test.

Close modal

CA Alleviated LPS-Induced Anhedonia in Mice

The change in sucrose consumption was a vital index to evaluate anhedonia in mice. As shown in Figure 1c, sucrose preference was altered notably by LPS stimulation in mice. LPS treatment strikingly reduced sucrose intake in comparison with that of the control group without LPS stimulation, whereas mice treated with CA (100 and 200 mg/kg) showed an increased sucrose consumption (Fig. 1c). In addition, the administration of Flu also blocked the decrease in sucrose preference produced by LPS.

CA Decreases LPS-Induced Elevated TNFα and IL-6 Levels in the Hippocampus and Cortex of Mice

Next, the effect of CA pretreatment on pro-inflammatory cytokines in the hippocampus and cortex was measured. The concentrations of TNFα and IL-6 were remarkably changed by LPS treatment as shown in Figure 2. However, pretreatment with CA treatment (100 and 200 mg/kg) reversed these increases in a significant manner. Additionally, similar results were observed in the group of Flu pretreatment.

Fig. 2.

Effects of CA pretreatment on oxidative parameters in mice treated with LPS. a, b Decreased levels of SOD in the hippocampus and cortex of mice induced by LPS were significantly alleviated by CA pretreatment. c, d Downregulation of GST in the hippocampus and cortex of mice induced by LPS was significantly alleviated by CA administration. e, f Pretreatment with CA remarkably blocked the upregulation of MDA in the hippocampus and cortex of mice induced by LPS. Data were expressed as mean ± SEM (n= 6–10). ##p< 0.01, ###p< 0.001 versus Con; *p< 0.05, **p< 0.005 versus LPS + Veh.

Fig. 2.

Effects of CA pretreatment on oxidative parameters in mice treated with LPS. a, b Decreased levels of SOD in the hippocampus and cortex of mice induced by LPS were significantly alleviated by CA pretreatment. c, d Downregulation of GST in the hippocampus and cortex of mice induced by LPS was significantly alleviated by CA administration. e, f Pretreatment with CA remarkably blocked the upregulation of MDA in the hippocampus and cortex of mice induced by LPS. Data were expressed as mean ± SEM (n= 6–10). ##p< 0.01, ###p< 0.001 versus Con; *p< 0.05, **p< 0.005 versus LPS + Veh.

Close modal

CA Suppressed LPS-Induced Oxidative Response in the Brain of Mice

As shown in Figure 3, LPS administration had prominently effects on the oxidative stress parameters including SOD, MDA, and GSH in both the cortex and hippocampus. However, the downregulation of SOD and GSH and the upregulation of MDA induced by LPS were reversed by CA treatment (100 and 200 mg/kg) as well as Flu. These results indicated that CA was capable of attenuating oxidative stress in mice induced by LPS.

Fig. 3.

Pretreatment with CA ameliorated the upregulation of pro-inflammatory factors induced by LPS in the hippocampus and cortex of mice. a, b LPS-induced increase in the TNF-α level in the hippocampus and cortex of mice was remarkably alleviated by CA administration. c, d CA administration dramatically blocked the LPS-induced upregulation of IL-6 in the hippocampus and cortex of mice. Data were expressed as mean ± SEM (n= 6–7). ###p< 0.001 versus Con; *p< 0.05, **p< 0.005 versus LPS + Veh.

Fig. 3.

Pretreatment with CA ameliorated the upregulation of pro-inflammatory factors induced by LPS in the hippocampus and cortex of mice. a, b LPS-induced increase in the TNF-α level in the hippocampus and cortex of mice was remarkably alleviated by CA administration. c, d CA administration dramatically blocked the LPS-induced upregulation of IL-6 in the hippocampus and cortex of mice. Data were expressed as mean ± SEM (n= 6–7). ###p< 0.001 versus Con; *p< 0.05, **p< 0.005 versus LPS + Veh.

Close modal

CA Blocked the Downregulation of BDNF in the Hippocampus and Cortex of Mice Treated by LPS

It has been reported that pro-inflammatory cytokines and oxidative stress could impair BDNF expression that ultimately led to neurotoxic effects [6, 14]. Therefore, we detected the expression of BDNF in the hippocampus and cortex of LPS-induced mice. As expected, LPS administration drastically downregulated the BDNF levels in both brain regions. This downregulation was strikingly blocked by Flu treatment (Fig. 4). In addition, as shown in Figure 4, CA significantly reversed LPS effects on BDNF in a dose-dependent manner in both the hippocampus and cortex of mice treated.

Fig. 4.

Pretreatment with CA ameliorated the downregulation of BDNF induced by LPS in the hippocampus and cortex of mice. a Representative immunoblots and quantitative analysis of BDNF in the hippocampus. b Representative immunoblots and quantitative analysis of BDNF in the cortex. Data were expressed as mean ± SEM (n= 6–7). ##p< 0.01, ###p< 0.001 versus Con; *p< 0.05, **p< 0.005 versus LPS + Veh.

Fig. 4.

Pretreatment with CA ameliorated the downregulation of BDNF induced by LPS in the hippocampus and cortex of mice. a Representative immunoblots and quantitative analysis of BDNF in the hippocampus. b Representative immunoblots and quantitative analysis of BDNF in the cortex. Data were expressed as mean ± SEM (n= 6–7). ##p< 0.01, ###p< 0.001 versus Con; *p< 0.05, **p< 0.005 versus LPS + Veh.

Close modal

It was experimentally identified that CA owned several pharmacological effects, such as alleviating inflammation and oxidative stress and promoting memory and motor behaviors [7‒10, 15, 16]. In the present study, we revealed that CA has antidepressant-like effects in mice treated with LPS in the FST and TST (Fig. 1), two well-known animal models that have gained widespread acceptance for detecting antidepressant activities [4, 17]. Moreover, the decreased immobility during the TST and FST after CA treatment was not associated with the alteration of the spontaneous locomotor activity (Fig. 1d), indicating that CA may have potential treatment for depression. In addition, the observation that CA treatment blocked the reduction of sucrose preference in LPS-induced mice further supported this hypothesis (Fig. 1c).

Cumulative evidence supports the important role of inflammation in MDD. The primary features of an inflammatory response, including elevated levels of pro-inflammatory cytokines such as IL-6 and TNF-α and their receptors in both peripheral blood and cerebrospinal fluid, were all observed in patients with MDD. Indeed, administration of inflammatory cytokines such as TNFα or their inducers such as LPS to those healthy individuals and rodent animals causes symptoms of depression. In this study, our results revealed that pro-inflammatory cytokine levels increased significantly in both hippocampus and cortex in mice induced by LPS, which could be alleviated by CA treatment (Fig. 2). However, more work should be done to explore how exactly CA decreases the levels of pro-inflammatory cytokines.

Besides inflammation induced by LPS administration, oxidative stress has emerged as a major pathogenic cause of MDD. Oxidative stress is attributed to the imbalance between reactive oxygen species production and antioxidative defenses [1, 3]. Thus, reversion of the injurious imbalance would be advantageous to treat the patients with MDD [1, 3]. In this study, we found that the levels of antioxidant stress including SOD and GSH decreased, while the oxidative stress marker MDA increased in the hippocampus and cortex of mice treated with LPS as compared to that of the vehicle-treated group (Fig. 3). These results further confirmed that dramatic alterations in the profile of several parameters indicating the condition of oxidative stress, including SOD, GSH, and MDA, occurred after LPS administration. In addition, pretreatment with CA significantly improved the decrease in SOD and GSH levels, while the MDA level was significantly alleviated in both hippocampus and cortex (Fig. 3), indicating that CA may be beneficial for MDD treatment as its potential in attenuating oxidative stress. But, the exact mechanism of how CA affects oxidative stress remains largely unknown.

It has been well evaluated that impairment of BDNF signaling occurred during the pathophysiology of MMD mediated by pro-inflammatory cytokines (such as IL-6 and TNFα) and oxidative stress (such as MDA, GST, and SOD) [18]. Numerous studies have suggested that the serum BDNF levels in patients with MDD were lower than those of healthy individuals [19‒23]. Furthermore, postmortem studies have also revealed similar changes in various brain regions of MDD patients [21]. Similar results were also observed in the brain of different types of depressive animal models such as social defeat, chronic unpredictable moderate stress, social isolation [24‒26], and genetic animal models [14, 27] of MDD. These molecular changes could be reversed by antidepressant treatment in both clinical and preclinical studies [5]. Besides, both mRNA and protein levels in the hippocampus and cortex could be downregulated significantly by the administration of pro-inflammatory cytokines or of the cytokine-inducing LPS. In our study, LPS administration elicited a remarkable decrease in BDNF expression in the brains of mice. These results were in line with previous studies [26, 28, 29], which confirmed the connection among the pro-inflammatory cytokines, oxidative stress, and BDNF signaling. However, the exact mechanism of how CA affects the BDNF signaling is still unknown. Consequently, more studies are demanded to clarify this issue in order to provide unequivocal proof for causality.

In summary, we confirmed that CA has antidepressant activity in mice induced by LPS, which were attributed to the attenuation of LPS-induced inflammation and oxidative stress along with significant improvement of the BDNF impairment. Our results elucidate the potential benefit of CA as a promising therapeutic option for MDD.

We would like to acknowledge the help received from those who provided helpful comments on this paper.

Animal experimental procedures were approved by the Animal Care and Use Committee of Xiamen University (No. 20180613-1) and carried out in compliance with the NIH Guide (No. 85-23, revised 1985) for the care and use of laboratory animals.

The authors have no conflicts of interest to declare.

This study was supported by the Medical and Health Guidance Program of Xiamen (No. 3502Z20214ZD1257, No. 3502Z20209225, and No. 3502Z20209228), the Fundamental Research Funds for the Central Universities (No. 20720180042), the Health Science Research Personnel Training Program of Fujian Province (No. 2018-CXB-30), and the Outstanding Youth Cultivation Plan of Fujian Province (MJK [2018] No.47).

Y.L.C. and C.L.S. designed the experiments and drafted the manuscript. Z.R.G., C.X.L., L.L.L., Y.L.Y., and P.L. performed the study, and Z.Y. (Yu Zhou), Z.Y. (Yun Zhao), and L.F. performed the statistical analysis. J.X. revised the manuscript. All the authors have read and approved the final manuscript.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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