- Email: [email protected]
Fucoidan exerts antidepressant-like effects in mice via regulating the stability of surface AMPARs
Biochemical and Biophysical Research Communications xxx (xxxx) xxx
Contents lists available at ScienceDirect
Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc
Fucoidan exerts antidepressant-like effects in mice via regulating the stability of surface AMPARs Mingxing Li a, *, Xuejiao Sun a, Qian Li a, Yong Li b, Can Luo a, Hailong Huang c, Jing Chen a, Chenzi Gong a, Yajie Li a, Yifeng Zheng d, Song Zhang a, Xiaolin Huang a, Hong Chen a, ** a
Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, 442000, China Department of Rehabilitation Medicine, Zhongnan Hospital, Wuhan University, Wuhan, 430071, China d Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 16 September 2019 Accepted 3 October 2019 Available online xxx
The inflammatory hypothesis is one of the most important mechanisms of depression. Fucoidan is a bioactive sulfated polysaccharide abundant in brown seaweeds with anti-inflammatory activity. However, the antidepressant effects of fucoidan on chronic stress-induced depressive-like behaviors have not been well elucidated. Here, we used two different depressive-like mouse models, lipopolysaccharide (LPS) and chronic restraint stress (CRS) models, to explore the detailed molecular mechanism underlying its antidepressant-like effects in C57BL/6J mice by combining multiple behavioral, molecular and immunofluorescence experiments. Adenovirus-mediated overexpression of caspase-1 and pharmacological inhibitors were also used to clarify the antidepressant mechanisms of fucoidan. We found that acute administration of fucoidan did not produce antidepressant effects in the tail suspension test (TST) and forced swim test (FST). Interestingly, chronic fucoidan administration not only dose-dependently reduced stress-induced depressive-like behaviors in the TST, FST, sucrose preference test (SPT), and novelty-suppressed feeding test (NSFT), but also alleviated the downregulation of brain-derived neurotrophic factor (BDNF)-dependent synaptic plasticity via inhibiting caspase-1-mediated inflammation in the hippocampus of mice. Moreover, fucoidan significantly ameliorated behavioral and synaptic plasticity abnormalities in the overexpression of caspase-1 in the hippocampus of mice. Furthermore, blocking BDNF abolished the antidepressant-like effects of fucoidan in mice. Therefore, our findings clearly indicate that fucoidan provides a potential supplementary noninvasive treatment for depression by inhibition of hippocampal inflammation. © 2019 Elsevier Inc. All rights reserved.
Keywords: Fucoidan Lipopolysaccharide Chronic restraint stress Caspase-1 BDNF AMPARs
1. Introduction Abbreviations: p.o., Per os; i.p., Intraperitoneally; TST, Tail suspension test; FST, Forced swim test; LPS, Lipopolysaccharide; CRS, Chronic restraint stress; SPT, Sucrose preference test; NSFT, Novelty-suppressed feeding test; mPFC, Medial prefrontal cortex; Hip, Hippocampus; qRT-PCR, Quantitative real-time PCR; GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; Iba1, Ionized calcium binding adapter molecule 1; IL-1b, Interleukin-1beta; IL-18, Interleukin-18; BDNF, Brain-derived neurotrophic factor; CREB, cAMP response element binding protein; AMPARs, aamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; BS3, Bis(sulfosuccinimidyl)suberate; AAV, Adeno-associated virus; GFP, Green fluorescent protein; CUS, Chronic unpredictable stress; NMDARs, N-methyl-D-aspartate receptors. * Corresponding author. Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan, 430030, China. ** Corresponding author. E-mail addresses: [email protected] (M. Li), [email protected] (H. Chen).
Major depression disorder (MDD) is a significant cause of morbidity and a major contributor to disability worldwide [1], there is an urgent need to elucidate the pathophysiological mechanisms of depression, and identify novel antidepressants with milder adverse effects and more reliable efficacy. Increasing evidence indicates a critical role of inflammation in the pathophysiology of MDD [2]. Clinical trials and meta-analysis consistently confirm elevated levels of proinflammatory cytokines, such as interleukin (IL)-1b, IL-6 and tumor necrosis factor (TNF)-a, in the serum and brain of depressed patients [3,4]. MDD patients also show increased expression of caspase-1 mRNA in periphery blood mononuclear cells [5]. It is well known that caspase-1 is an inflammatory caspase, and activation of caspase-1
https://doi.org/10.1016/j.bbrc.2019.10.043 0006-291X/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: M. Li et al., Fucoidan exerts antidepressant-like effects in mice via regulating the stability of surface AMPARs, Biochemical and Biophysical Research Communications, https://doi.org/10.1016/j.bbrc.2019.10.043
2
M. Li et al. / Biochemical and Biophysical Research Communications xxx (xxxx) xxx
mediates the maturation of IL-1b. Anti-cytokine treatment for MDD significantly improves depressive symptoms with small-tomoderate size effect [3,4]. Additionally, chronic stress increases the production of peripheral and central proinflammatory cytokines in rodents, which ultimately mediates chronic stress-induced depressive-like behaviors [2,6]. Chronic antidepressant treatment alleviates the increased levels of IL-1b, IL-6 and TNF-a in the cerebral cortex and hippocampus [7e9]. More importantly, caspase1-mediated inflammation modulates depressive-like behaviors through multiple mechanisms and can be reduced by antidepressants [6,7]. Collectively, these findings suggest that cytokine modulators may be novel drugs for depression. Fucoidan, a sulfated polysaccharide containing L-fucose and sulfate groups, is mainly found in derived from marine brown seaweeds and is now used as an ingredient in dietary supplements. Furthermore, fucoidan exerts various physiological and biological activities, including anti-inflammatory and antioxidative [10,11], suggesting its potential role for medical use. Recent study suggests that fucoidan significantly decreases the levels of IL-1b and TNF-a in LPS-stimulated BV2 microglia [12]. Additionally, fucoidan inhibits the neurodegenerative changes in b-amyloid (Ab)-induced neurotoxicity in basal forebrain neuronal cultures [13]. Interestingly, fucoidan pretreatment improves CRS-induced depression through modulating the central noradrenergic and enhancing hippocampal BDNF [14]. These findings suggest that fucoidan has potential neuroprotective and antidepressant-like effects, although the underlying regulatory mechanisms of its effects in depression remain still obscure. Here, we examined the antidepressant-like actions of fucoidan in two depressive-like mouse models, and confirmed by TST, FST, SPT and NSFT. Moreover, we assessed the expression of proinflammatory cytokines, BDNF signaling pathway and AMPARs in the mPFC and hippocampus of mice. Lastly, by using methods including AAV vector and pharmacological inhibitors, we determined the possible involvement of anti-inflammatory activity in the antidepressant-like actions of fucoidan.
2. Materials and methods 2.1. Animals Adult male C57BL/6J mice (8e10 weeks) were purchased from Beijing Vitalriver Laboratory Animal Corp. Ltd (Beijing, China). The mice were housed in standard laboratory conditions (22 ± 2 C; 12 h light/dark cycle) with free access to food and water, except when specified otherwise. All procedures were approved by the Animal Care and Use Committee of Huazhong University of Science and Technology.
2.3. Behavior tests and experimental procedures Detailed information on experimental procedures was provided in Supplementary Information. 2.4. Statistical analysis All data were presented as the mean ± SEM and analyzed using IBM PASW Statistics 18.0 (New York, USA). Comparisons among multiple groups were evaluated using one-way analysis of variance (ANOVA) or two-way ANOVA followed by Bonferroni’s post hoc multiple comparison tests where appropriate. Significance was assigned at p < 0.05. 3. Results 3.1. Fucoidan exerts antidepressant-like effects in mice We first used the classical antidepressant fluoxetine as a comparison and investigated acute antidepressant effects of fucoidan in the TST and FST, which were widely used in screening antidepressant agents. Mice received a single administration of fucoidan and fluoxetine 30 min prior to the test. There was no significant decreased immobility in the fucoidan pretreated group when compared with the control group respectively (Fig. S1). Moreover, fluoxetine produced antidepressant-like effects in the TST and FST (Fig. S1). Previous study has demonstrated that fucoidan prevents CRS-induced depression in rats [14]. Therefore, we further tested the antidepressant effects of fucoidan on the LPS model of depression (Fig. 1A). There was no significant difference in the body weight during the two weeks of treatment (Fig. 1B). Consistently, mice in LPS group displayed decreased body weight (Fig. 1C) and increased immobility in the TST (Fig. 1D) and FST (Fig. 1E) when compare to vehicle-treated control group. Interestingly, fucoidan pretreatment could dose-dependently reverse LPS-induced depressive-like behaviors (Fig. 1CeE), indicating that chronic fucoidan administration may be enough to produce significant antidepressant-like actions. The observation was further confirmed in CRS model of depression (Fig. 1F). As predicted, stressed mice exerted decreased sucrose preference (Fig. 1G), elevated latency to feed in the NSFT (Fig. 1H), increased immobility in the TST (Fig. 1I) and FST (Fig. 1J) when compared to vehicle-treated control group, verifying the effectiveness of CRS model. Moreover, repeated administration of both fucoidan and fluoxetine fully reversed CRS-induced depressive-like behaviors in mice (Fig. 1GeJ). Taken together, these results suggest that fucoidan has antidepressant-like effects in mice. 3.2. Fucoidan treatment prevents stress-induced increase of caspase-1 expression and attenuation of BDNF-CREB pathway in the hippocampus
2.2. Drugs Fucoidan, lipopolysaccharide (LPS), fluoxetine and K252a were purchased from Sigma-Aldrich (Saint Louis, USA). Crosslinker bis(sulfosuccinimidyl)suberate (BS3) was purchased from Thermo Scientific (Rockford, USA). The dosages of fucoidan (25, 50 and 100 mg/kg), fluoxetine (20 mg/kg), LPS (1.0 mg/kg) and K252a (25 mg/kg, dissolved in 0.5% DMSO) were chosen based on previous studies [14e16] and dissolved in sterile saline before use. Fucoidan was given per os (p.o.). Fluoxetine and K252a were intraperitoneally (i.p.) injected in volumes 5 ml/kg. Fucoidan, fluoxetine and K252a were administrated 30 min before LPS or daily restraint stress.
Fucoidan has been demonstrated to inhibit microglia activation and decrease inflammation-associated cytokines [10,11]. Furthermore, fucoidan significantly blocks CRS-induced decrease in BDNF mRNA expression in the hippocampus [14]. We thus investigated the antidepressant-like actions of fucoidan on mRNA levels of inflammatory genes and BDNF in different brain regions. As expected, mice in LPS group showed the augmentation of Iba1, caspase-1 and IL-1b levels and reduction of BDNF level in the mPFC (Fig. S2A) and hippocampus (Fig. 2A) as compared with vehicle-treated group. Additionally, fucoidan pretreatment significantly prevented LPSinduced increase of Iba1, caspase-1, and IL-1b in the hippocampus (Fig. 2A). However, fucoidan failed to restored LPS-induced changes
Please cite this article as: M. Li et al., Fucoidan exerts antidepressant-like effects in mice via regulating the stability of surface AMPARs, Biochemical and Biophysical Research Communications, https://doi.org/10.1016/j.bbrc.2019.10.043
M. Li et al. / Biochemical and Biophysical Research Communications xxx (xxxx) xxx
3
Fig. 1. Fucoidan exerts antidepressant-like effects in mice. (A) Schematic timeline of experimental procedures. (B) The effects of 2 weeks fucoidan administration (p.o.) on body weight. (C) Repeated administration of fucoidan for 2 weeks prevented LPS-induced body weigh decrease in mice. (D-E) Fucoidan administration dose-dependently reduced LPSinduced increase in immobility time in TST (D) and FST (E). (F) The schematic representation of the CRS procedure and treatments in mice. (G-J) Effects of fucoidan on sucrose preference test (SPT)(G), novelty-suppressed feeding test (NSFT)(H), TST (I) and FST (J) after CRS. All data are shown as means ± SEM (n ¼ 9e10 mice/group). *p < 0.05, **p < 0.01, and ***p < 0.001.
in the mPFC (Fig. S2A). Furthermore, fucoidan administration also fully restored hippocampal BDNF expression (Fig. 2A). We next used western blotting to detect the expression of caspase-1, BDNF and its downstream molecules cAMP response element binding protein (CREB). LPS significantly elevated caspase-1 p20 protein expression and downregulated BDNF and phosphorylation of CREB (pCREB) expression in the mPFC (Fig. S2B) and hippocampus (Fig. 2B) when compared to vehicle-treated group. Interestingly, fucoidan treatment in the LPS groups significantly reduced caspase1 level and increased BDNF and pCREB expression in the hippocampus (Fig. 2B). These results clearly indicate the effectiveness of fucoidan in mitigating LPS-induced inflammation in the hippocampus. Meanwhile, CRS significantly increased the expression of Iba1, caspase-1 and IL-1b and reduced the BDNF expression in the mPFC (Fig. S2C) and hippocampus (Fig. 2C) compared with the vehicletreated group. Similar to the LPS results, fucoidan only reversed these changes in the hippocampus (Fig. 2C). Moreover, fucoidan administration not only fully restored CRS-induced increase in hippocampal caspase-1 p20 expression, but also prevented the downregulation of BDNF and pCREB expression in the hippocampus of CRS group (Fig. 2D and Fig. S2D). These results indicate the neuroprotective effects of fucoidan against depression. Taken together, these results suggest that fucoidan produces antidepressant effects through inhibiting caspase-1-mediated inflammation in the hippocampus.
3.3. Fucoidan enhances the stability of surface AMPARs in the hippocampus BDNF signaling pathway plays a pivotal role in regulating glutamatergic neurotransmission, which participates in the pathophysiology of depression, we thus examine the expression of AMPARs in the mPFC and hippocampus. As shown in Fig. 3A, LPS exposure significantly decreased GluA1 and GluA2 mRNA levels in the mPFC and hippocampus as compared to vehicle-treated group. Fucoidan significantly attenuated the reduction of GluA1 and GluA2 caused by LPS in the hippocampus (Fig. 3A). The phosphorylation of the AMPARs is well known to regulate synaptic efficacy [17]. LPS significantly decreased the phosphorylation on Ser845 (pSer845) of GluA1 compared with vehicle-treated group, and these changes in the hippocampus could be blocked by pretreatment with fucoidan (Fig. 3B). Based on these results, it seems that fucoidan upregulates the expression of the AMPARs in the postsynaptic membrane of hippocampus. To test this, we performed western blotting and surface receptor cross-linking with BS3 assays. As predicted, there was a significant reduction in the surface expression of AMPARs in the hippocampus of LPS-treated mice (Fig. 3C), and these changes were reversed by fucoidan pretreatment (Fig. 3C). These results suggest that AMPARs function may contribute to the antidepressant-like effects of fucoidan. Furthermore, fucoidan treatment also fully restored the CRSinduced decrease in hippocampal GluA1 and GluA2 mRNA
Please cite this article as: M. Li et al., Fucoidan exerts antidepressant-like effects in mice via regulating the stability of surface AMPARs, Biochemical and Biophysical Research Communications, https://doi.org/10.1016/j.bbrc.2019.10.043
4
M. Li et al. / Biochemical and Biophysical Research Communications xxx (xxxx) xxx
Fig. 2. Fucoidan treatment prevents stress-induced increase of caspase-1 protein expression and attenuation of BDNF-CREB pathway in the hippocampus. (A) Fucoidan administration dose-dependently reduced LPS-induced increase of ionized calcium binding adapter molecule 1 (Iba1), caspase-1, and interlukin-1b (IL-1b) mRNA in the hippocampus. (B) Effects of fucoidan treatment on the protein levels of caspase-1, pCREB and BDNF induced by LPS in the hippocampus. (C) Fucoidan inhibited the expression of inflammatory genes and increased the expression of BDNF mRNA in the hippocampus after CRS. (D) Effects of fucoidan treatment on the expression of caspase-1, pCREB and BDNF induced by CRS in the hippocampus. All data are shown as means ± SEM (n ¼ 4 mice/group). *p < 0.05, **p < 0.01, and ***p < 0.001.
Please cite this article as: M. Li et al., Fucoidan exerts antidepressant-like effects in mice via regulating the stability of surface AMPARs, Biochemical and Biophysical Research Communications, https://doi.org/10.1016/j.bbrc.2019.10.043
M. Li et al. / Biochemical and Biophysical Research Communications xxx (xxxx) xxx
5
Fig. 3. Fucoidan enhances the stability of surface AMPARs in the hippocampus. (A) Fucoidan reversed the downregulation of GluA1 and GluA2 mRNA induced by LPS in the hippocampus of mice. (B) The downregulation of the phosphorylation on Ser845 (pSer845) of GluA1 induced by LPS in the hippocampus was alleviated by pretreatment with fucoidan. (C) Fucoidan reversed the decreased surface expression of GluA1 and GluA2 in the hippocampus induced by LPS. (D) Fucoidan prevented the decreased expression of GluA1 and GluA2 mRNA induced by CRS in the hippocampus. (E) Fucoidan reverted the decrease of pSer845 of GluA1 induced by CRS in the hippocampus. (F) Fucoidan blocked the reduction of surface expression of GluA1 and GluA2 caused by CRS. All data are shown as means ± SEM (n ¼ 4 mice/group). *p < 0.05, **p < 0.01, and ***p < 0.001.
expression (Fig. 3D). Meanwhile, mice in the CRS group displayed a significant decrease in level of GluA1 pSer845 (Fig. 3E), and this reduction in the hippocampus could be rescued by fucoidan treatment (Fig. 3E). Additionally, fucoidan could obviously restored the CRS-induced decrease in the surface expression of AMPARs in the hippocampus (Fig. 3F). Collectively, our results indicate that fucoidan could reverse stress-induced reduction in synaptic expression of AMPARs via inhibiting caspase-1-mediated inflammation in the hippocampus of mice. 3.4. Inhibition of caspase-1-mediated inflammation and upregulation of BDNF signaling pathway is necessary for the antidepressant action of fucoidan Our previous study shows that caspase-1 overexpression in the hippocampus induces depressive-like behaviors [6]. We then used a viral expression experiment to investigate the antidepressant-like effects of fucoidan (Fig. 4A). It was shown that hippocampus was successfully transfected (Fig. 4B) and displayed increased levels of caspase-1 (Fig. 4C). We also found that AAV-Casp1 injection significantly reduced the levels of BDNF-CREB pathway and GluA1 pSer845 compared with AAV-GFP treatment (Fig. 4C), which were
reversed by the administration of fucoidan (Fig. 4C). Further, AAVCasp-1 mice displayed decreased sucrose preference (Fig. 4D) and increased immobility in the TST and FST (Fig. 4E) compared with AAV-GFP mice. These behavioral changes were completely restored in fucoidan pretreatment (Fig. 4DeE). Together, these findings indicate that fucoidan induces the antidepressant-like effects through inhibiting caspase-1-mediated inflammation in the hippocampus. To determine whether BDNF played an important role in the antidepressant-like effects of fucoidan, we used a potent pharmacological inhibitor of TrkB, K252a. Mice were injected with K252a 30 min prior to fucoidan administration (Fig. S3A), and there were no changes in the TST and FST (Fig. S3B). Further, stressed mice were cotreated with fucoidan and K252a for 2 weeks, and the depressive-like behaviors were assayed (Fig. 4F). Interestingly, these combined treatments not only block the restoring effects of fucoidan on the stressed mice in the SPT (Fig. 4G), TST and FST (Fig. 4H), but also prevented the protective effects of fucoidan on the expression of BDNF-CREB pathway and GluA1 pSer845 (Fig. 4I) in the hippocampus of stressed mice. These results suggest that fucoidan requires the hippocampal BDNF-CREB pathway to exert its antidepressant-like actions in mice.
Please cite this article as: M. Li et al., Fucoidan exerts antidepressant-like effects in mice via regulating the stability of surface AMPARs, Biochemical and Biophysical Research Communications, https://doi.org/10.1016/j.bbrc.2019.10.043
6
M. Li et al. / Biochemical and Biophysical Research Communications xxx (xxxx) xxx
Fig. 4. Inhibition of caspase-1-mediated inflammation and upregulation of BDNF signaling pathway is necessary for the antidepressant action of fucoidan. (A) Schematic representation of AAV-based constructs for overexpression of caspase-1 and the timeline of experimental procedure. (B) Representative fluorescence of injection sites in the hippocampus. Scale bars, 200 mm. (C) Effects of fucoidan treatment (50 mg/kg, p.o.) on the expression of caspase-1, BDNF and the phosphorylation levels of CREB and GluA1 in the hippocampus of mice (n ¼ 4 mice/group). (D-E) Fucoidan prevented overexpression of caspase-1-induced depression in the SPT (D), TST (E) and FST (E) (n ¼ 10 mice/group). (F) Schematic timeline of procedures. (G-H) K252a pretreatment abolished the antidepressant effects of fucoidan in SPT (G), TST (H) and FST (H) after CRS (n ¼ 10 mice/group). (I) K252a blocked the restoring effects of fucoidan on BDNF expression and the phosphorylation levels of CREB and GluA1 in the hippocampus of stressed mice (n ¼ 4 mice/group). All data are shown as means ± SEM. *p < 0.05, **p < 0.01, and ***p < 0.001.
4. Discussion In this study, we demonstrated that fucoidan exerted antidepressant-like on two depressive-like mouse models. Furthermore, fucoidan showed comparable antidepressant activity to the classical antidepressant fluoxetine. We proposed that fucoidan potentially inhibited caspase-1-mediated inflammation in the hippocampus, which subsequently promoted BDNF-CREB pathway. This resulted in increased phosphorylation of Ser845 of GluA1, enhancing the stability of surface AMPARs in the hippocampus, eventually regulated depressive-like behaviors in mice. These results indicate that the antidepressant-like effects of fucoidan may be dependent on anti-inflammatory activity. Accumulating evidence indicates that inflammation is implicated in the etiology of depression [2,3]. Anti-inflammatory agents can be used as a direct treatment strategy or an adjuvant to dietary supplement. For example, chronic treatment with celecoxib attenuates chronic unpredictable stress (CUS)-induced depressivelike behaviors via reducing COX-2 enzyme in brain [18]. Several studies have demonstrated that fucoidan significantly decreases IL1b level in cerebral ischemia-reperfusion injury with a dosedependent manner [19], and ameliorates hepatic ischemia-
reperfusion injury through suppressing the activity of caspase-1 [20]. Additionally, fluoxetine attenuates neuroinflammation through the suppression of NLRP3-caspase-1-IL-1b axis activity and the enhancement of BDNF [6,15,21]. Consistent with these findings, our results showed that both LPS and CRS significantly elevated the levels of Iba1, caspase-1 and IL-1b in the mPFC and hippocampus, whereas treatment with fucoidan only inhibited activation of microglia and elevation of caspase-1-IL-1b pathway in the hippocampus. Further, fucoidan also alleviated depressive-like behaviors in AAV-caspase-1 mice. Based on the close relationship between inflammation and depression, thus it is indeed reasonable to predict that the antidepressant-like effects of fucoidan is closely with its anti-inflammatory activity. Proinflammatory cytokines affect synaptic plasticity, which is associated with anhedonia, behavioral despair and cognitive impairment [22]. For example, increased inflammation is associated with the dysfunction of glutamatergic neurotransmission in depressed patients [23]. Furthermore, LPS induces depressive-like behaviors through promoting production of proinflammatory cytokines in activated microglia and inhibiting BDNF-dependent synaptic plasticity [24]. CUS also increases hippocampal microglia activation and attenuates phosphorylation of GluA1, eventually
Please cite this article as: M. Li et al., Fucoidan exerts antidepressant-like effects in mice via regulating the stability of surface AMPARs, Biochemical and Biophysical Research Communications, https://doi.org/10.1016/j.bbrc.2019.10.043
M. Li et al. / Biochemical and Biophysical Research Communications xxx (xxxx) xxx
leading to LTP impairments and cognitive dysfunction. Chronic treatment with minocycline can reverse these changes in the hippocampus [25]. Moreover, our previous study demonstrates that increased level of caspase-1 impairs hippocampal synaptic plasticity through promoting the production of IL-1b, not IL-18 [6]. Interestingly, fucoidan prevents the production of proinflammatory cytokines in primary microglia [10,12]. In present study, we found that fucoidan not only significantly attenuated the reduced levels of the phosphorylation of GluA1, but also increased surface expression of AMPARs in the hippocampus. Although the large molecules of fucoidan is unlikely to cross blood brain barrier, systemic administration of fucoidan is effective in protecting neuronal function in different ways [10,11,13,14]. Taken together, fucoidan may enhance hippocampal glutamatergic neurotransmission through inhibiting caspase-1-IL-1b inflammation pathway. BDNF plays a critical role in synaptic plasticity, neurogenesis and other physiological processes. BDNF level is abnormally low in depressed patients than healthy controls and can be notably restored by antidepressant treatment [26]. Similarly, the level of BDNF is also downregulated in depressive animals and the reduction can be reversed by antidepressants [15,27]. BDNF levels in the mPFC and hippocampus serve as biochemical markers for monitoring the development of and therapeutic response for depression. Furthermore, increased proinflammatory cytokines reduce the level of BDNF and impairs BDNF-dependent synaptic plasticity [6]. Based on these findings, we found that the levels of BDNF-CREB pathway were markedly reduced by caspase-1-mediated inflammation in two different animal models of depression. Lee et al. reported that fucoidan restored CRS-induced the reduction of BDNF mRNA in the hippocampus of rats [14]. Our present study also demonstrated that fucoidan treatment not only reversed the levels of BDNF-CREB pathway in the hippocampus, but also restored BDNF-dependent synaptic plasticity in stressed mice. Moreover, the pharmacological effect of BDNF is regulated by the specific receptor TrkB. Thus, these effects were also completely blocked by pretreatment with K252a, suggesting that BDNF-CREB pathway was required for the antidepressant activity of fucoidan. Interestingly, fucoidan had the prophylactic effects in depressed mice, suggesting that fucoidan supplementation may prevent the onset of depression associated with inflammation. There are limited reports on the adverse effects of fucoidan. Therefore, further studies also need to investigate whether supplementation of fucoidan-rich foods could prevent relapse in depressed patients. In summary, our results indicated that the antidepressant-like effects of fucoidan was mediated, at least in part, by enhancing BDNF-CREB pathway and normalized the levels of surface AMPARs via inhibiting caspase-1-mediated inflammation in the hippocampus of depressed mice, thus provided a potential therapeutic treatment for mood disorder.
Author contributions M.X.L. and H.C. conceived and designed the project and wrote the manuscript, M.X.L., X.J.S., Q.L., C.L., H.L.H., J.C., C.Z.G., Y.J.L., Y.F.Z. and S.Z. performed the behavioral experiments. M.X.L., X.J.S., Q.L. and Y.L. performed the biochemical measurements. M.X.L., X.J.S., X.L.H. and Y.L. analyzed the data. All authors read and approved the final manuscript.
Declaration of competing interest The authors declare that there is no conflict of interest.
7
Acknowledgements This research was supported by the National Natural Science Foundation of China (81801066, 81702767) and the China Postdoctoral Science Foundation (2018M640706). Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.bbrc.2019.10.043. References [1] G.B.D. Disease, I. Injury, C. Prevalence, Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016, Lancet 390 (2017) 1211e1259, https://doi.org/10.1016/ S0140-6736(17)32154-2. [2] A.H. Miller, C.L. Raison, The role of inflammation in depression: from evolutionary imperative to modern treatment target, Nat. Rev. Immunol. 16 (2016) 22e34, https://doi.org/10.1038/nri.2015.5. [3] N. Kappelmann, G. Lewis, R. Dantzer, P.B. Jones, G.M. Khandaker, Antidepressant activity of anti-cytokine treatment: a systematic review and metaanalysis of clinical trials of chronic inflammatory conditions, Mol. Psychiatry 23 (2018) 335e343, https://doi.org/10.1038/mp.2016.167. [4] A.S. Shariq, E. Brietzke, J.D. Rosenblat, V. Barendra, Z. Pan, R.S. McIntyre, Targeting cytokines in reduction of depressive symptoms: a comprehensive review, Prog Neuropsychopharmacol Biol Psychiatry 83 (2018) 86e91, https://doi.org/10.1016/j.pnpbp.2018.01.003. [5] E. Alcocer-Gomez, M. de Miguel, N. Casas-Barquero, J. Nunez-Vasco, J.A. Sanchez-Alcazar, A. Fernandez-Rodriguez, M.D. Cordero, NLRP3 inflammasome is activated in mononuclear blood cells from patients with major depressive disorder, Brain Behav. Immun. 36 (2014) 111e117, https://doi.org/ 10.1016/j.bbi.2013.10.017. [6] M.X. Li, H.L. Zheng, Y. Luo, J.G. He, W. Wang, J. Han, L. Zhang, X. Wang, L. Ni, H.Y. Zhou, Z.L. Hu, P.F. Wu, Y. Jin, L.H. Long, H. Zhang, G. Hu, J.G. Chen, F. Wang, Gene deficiency and pharmacological inhibition of caspase-1 confers resilience to chronic social defeat stress via regulating the stability of surface AMPARs, Mol. Psychiatry 23 (2018) 556e568, https://doi.org/10.1038/ mp.2017.76. [7] Y. Pan, X.Y. Chen, Q.Y. Zhang, L.D. Kong, Microglial NLRP3 inflammasome activation mediates IL-1beta-related inflammation in prefrontal cortex of depressive rats, Brain Behav. Immun. 41 (2014) 90e100, https://doi.org/ 10.1016/j.bbi.2014.04.007. [8] J.L. Warner-Schmidt, K.E. Vanover, E.Y. Chen, J.J. Marshall, P. Greengard, Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans, Proc. Natl. Acad. Sci. U. S. A. 108 (2011) 9262e9267, https://doi.org/10.1073/pnas.1104836108. [9] R. Yirmiya, Y. Pollak, O. Barak, R. Avitsur, H. Ovadia, M. Bette, E. Weihe, J. Weidenfeld, Effects of antidepressant drugs on the behavioral and physiological responses to lipopolysaccharide (LPS) in rodents, Neuropsychopharmacology 24 (2001) 531e544, https://doi.org/10.1016/S0893133X(00)00226-8. [10] Y.Q. Cui, Y.J. Jia, T. Zhang, Q.B. Zhang, X.M. Wang, Fucoidan protects against lipopolysaccharide-induced rat neuronal damage and inhibits the production of proinflammatory mediators in primary microglia, CNS Neurosci. Ther. 18 (2012) 827e833, https://doi.org/10.1111/j.1755-5949.2012.00372.x. [11] J. Li, Q. Zhang, S. Li, W. Dai, J. Feng, L. Wu, T. Liu, K. Chen, Y. Xia, J. Lu, Y. Zhou, X. Fan, C. Guo, The natural product fucoidan ameliorates hepatic ischemiareperfusion injury in mice, Biomed. Pharmacother. 94 (2017) 687e696, https://doi.org/10.1016/j.biopha.2017.07.109. [12] H.Y. Park, M.H. Han, C. Park, C.Y. Jin, G.Y. Kim, I.W. Choi, N.D. Kim, T.J. Nam, T.K. Kwon, Y.H. Choi, Anti-inflammatory effects of fucoidan through inhibition of NF-kappaB, MAPK and Akt activation in lipopolysaccharide-induced BV2 microglia cells, Food Chem. Toxicol. 49 (2011) 1745e1752, https://doi.org/ 10.1016/j.fct.2011.04.020. [13] J.H. Jhamandas, M.B. Wie, K. Harris, D. MacTavish, S. Kar, Fucoidan inhibits cellular and neurotoxic effects of beta-amyloid (A beta) in rat cholinergic basal forebrain neurons, Eur. J. Neurosci. 21 (2005) 2649e2659, https://doi.org/ 10.1111/j.1460-9568.2005.04111.x. [14] B. Lee, I. Shim, H. Lee, D.H. Hahm, Fucoidan prevents depression-like behavior in rats exposed to repeated restraint stress, J. Nat. Med. 67 (2013) 534e544, https://doi.org/10.1007/s11418-012-0712-5. [15] Y.F. Ni, H. Wang, Q.Y. Gu, F.Y. Wang, Y.J. Wang, J.L. Wang, B. Jiang, Gemfibrozil has antidepressant effects in mice: involvement of the hippocampal brainderived neurotrophic factor system, J. Psychopharmacol. 32 (2018) 469e481, https://doi.org/10.1177/0269881118762072. [16] M.C. He, Z. Shi, N.N. Sha, N. Chen, S.Y. Peng, D.F. Liao, M.S. Wong, X.L. Dong, Y.J. Wang, T.F. Yuan, Y. Zhang, Paricalcitol alleviates lipopolysaccharideinduced depressive-like behavior by suppressing hypothalamic microglia activation and neuroinflammation, Biochem. Pharmacol. 163 (2019) 1e8,
Please cite this article as: M. Li et al., Fucoidan exerts antidepressant-like effects in mice via regulating the stability of surface AMPARs, Biochemical and Biophysical Research Communications, https://doi.org/10.1016/j.bbrc.2019.10.043
8
M. Li et al. / Biochemical and Biophysical Research Communications xxx (xxxx) xxx
https://doi.org/10.1016/j.bcp.2019.01.021. [17] R.L. Huganir, R.A. Nicoll, AMPARs and synaptic plasticity: the last 25 years, Neuron 80 (2013) 704e717, https://doi.org/10.1016/j.neuron.2013.10.025. [18] J.Y. Guo, C.Y. Li, Y.P. Ruan, M. Sun, X.L. Qi, B.S. Zhao, F. Luo, Chronic treatment with celecoxib reverses chronic unpredictable stress-induced depressive-like behavior via reducing cyclooxygenase-2 expression in rat brain, Eur. J. Pharmacol. 612 (2009) 54e60, https://doi.org/10.1016/j.ejphar.2009.03.076. [19] N. Che, Y.J. Ma, Y.H. Xin, Protective role of fucoidan in cerebral ischemiareperfusion injury through inhibition of MAPK signaling pathway, Biomol Ther 25 (2017) 272e278, https://doi.org/10.4062/biomolther.2016.098. [20] J.J. Li, Q.H. Zhang, S.N. Li, W.Q. Dai, J. Feng, L.W. Wu, T. Liu, K. Chen, Y.J. Xia, J. Lu, Y.Q. Zhou, X.M. Fan, C.Y. Guo, The natural product fucoidan ameliorates hepatic ischemia-reperfusion injury in mice, Biomed. Pharmacother. 94 (2017) 687e696, https://doi.org/10.1016/j.biopha.2017.07.109. [21] Y. Zhang, L. Liu, Y.Z. Liu, X.L. Shen, T.Y. Wu, T. Zhang, W. Wang, Y.X. Wang, C.L. Jiang, NLRP3 inflammasome mediates chronic mild stress-induced depression in mice via neuroinflammation, Int. J. Neuropsychopharmacol. 18 (2015), https://doi.org/10.1093/ijnp/pyv006. [22] S.M. Thompson, A.J. Kallaracka, M.D. Kvarta, A.M. Van Dyke, T.A. LeGates, X. Cai, An excitatory synapse hypothesis of depression, Trends Neurosci. 38 (2015) 279e294, https://doi.org/10.1016/j.tins.2015.03.003. [23] K.D. Young, W.C. Drevets, R. Dantzer, T.K. Teague, J. Bodurka, J. Savitz,
[24]
[25]
[26]
[27]
Kynurenine pathway metabolites are associated with hippocampal activity during autobiographical memory recall in patients with depression, Brain Behav. Immun. 56 (2016) 335e342, https://doi.org/10.1016/j.bbi.2016.04.007. J.C. Zhang, W. Yao, C. Dong, C. Yang, Q. Ren, M. Ma, M. Han, J. Wu, Y. Ushida, H. Suganuma, K. Hashimoto, Prophylactic effects of sulforaphane on depression-like behavior and dendritic changes in mice after inflammation, J. Nutr. Biochem. 39 (2017) 134e144, https://doi.org/10.1016/ j.jnutbio.2016.10.004. M.C. Liu, J. Li, P. Dai, F. Zhao, G. Zheng, J.F. Jing, J.Y. Wang, W.J. Luo, J.Y. Chen, Microglia activation regulates GluR1 phosphorylation in chronic unpredictable stress-induced cognitive dysfunction, Stress 18 (2015) 96e106, https:// doi.org/10.3109/10253890.2014.995085. S. Srijan, D. Ronald, S. Gerard, Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications, Biol. Psychiatry 64 (2008) 527e532. M.X. Li, Q. Li, X.J. Sun, C. Luo, Y. Li, Y.N. Wang, J. Chen, C.Z. Gong, Y.J. Li, L.P. Shi, Y.F. Zheng, R.C. Li, X.L. Huang, Q.J. Xiong, H. Chen, Increased Homer1-mGluR5 mediates chronic stress-induced depressive-like behaviors and glutamatergic dysregulation via activation of PERK-eIF2alpha, Prog Neuropsychopharmacol Biol Psychiatry 95 (2019) 109682, https://doi.org/10.1016/ j.pnpbp.2019.109682.
Please cite this article as: M. Li et al., Fucoidan exerts antidepressant-like effects in mice via regulating the stability of surface AMPARs, Biochemical and Biophysical Research Communications, https://doi.org/10.1016/j.bbrc.2019.10.043
Contents lists available at ScienceDirect
Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc
Fucoidan exerts antidepressant-like effects in mice via regulating the stability of surface AMPARs Mingxing Li a, *, Xuejiao Sun a, Qian Li a, Yong Li b, Can Luo a, Hailong Huang c, Jing Chen a, Chenzi Gong a, Yajie Li a, Yifeng Zheng d, Song Zhang a, Xiaolin Huang a, Hong Chen a, ** a
Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, 442000, China Department of Rehabilitation Medicine, Zhongnan Hospital, Wuhan University, Wuhan, 430071, China d Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 16 September 2019 Accepted 3 October 2019 Available online xxx
The inflammatory hypothesis is one of the most important mechanisms of depression. Fucoidan is a bioactive sulfated polysaccharide abundant in brown seaweeds with anti-inflammatory activity. However, the antidepressant effects of fucoidan on chronic stress-induced depressive-like behaviors have not been well elucidated. Here, we used two different depressive-like mouse models, lipopolysaccharide (LPS) and chronic restraint stress (CRS) models, to explore the detailed molecular mechanism underlying its antidepressant-like effects in C57BL/6J mice by combining multiple behavioral, molecular and immunofluorescence experiments. Adenovirus-mediated overexpression of caspase-1 and pharmacological inhibitors were also used to clarify the antidepressant mechanisms of fucoidan. We found that acute administration of fucoidan did not produce antidepressant effects in the tail suspension test (TST) and forced swim test (FST). Interestingly, chronic fucoidan administration not only dose-dependently reduced stress-induced depressive-like behaviors in the TST, FST, sucrose preference test (SPT), and novelty-suppressed feeding test (NSFT), but also alleviated the downregulation of brain-derived neurotrophic factor (BDNF)-dependent synaptic plasticity via inhibiting caspase-1-mediated inflammation in the hippocampus of mice. Moreover, fucoidan significantly ameliorated behavioral and synaptic plasticity abnormalities in the overexpression of caspase-1 in the hippocampus of mice. Furthermore, blocking BDNF abolished the antidepressant-like effects of fucoidan in mice. Therefore, our findings clearly indicate that fucoidan provides a potential supplementary noninvasive treatment for depression by inhibition of hippocampal inflammation. © 2019 Elsevier Inc. All rights reserved.
Keywords: Fucoidan Lipopolysaccharide Chronic restraint stress Caspase-1 BDNF AMPARs
1. Introduction Abbreviations: p.o., Per os; i.p., Intraperitoneally; TST, Tail suspension test; FST, Forced swim test; LPS, Lipopolysaccharide; CRS, Chronic restraint stress; SPT, Sucrose preference test; NSFT, Novelty-suppressed feeding test; mPFC, Medial prefrontal cortex; Hip, Hippocampus; qRT-PCR, Quantitative real-time PCR; GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; Iba1, Ionized calcium binding adapter molecule 1; IL-1b, Interleukin-1beta; IL-18, Interleukin-18; BDNF, Brain-derived neurotrophic factor; CREB, cAMP response element binding protein; AMPARs, aamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; BS3, Bis(sulfosuccinimidyl)suberate; AAV, Adeno-associated virus; GFP, Green fluorescent protein; CUS, Chronic unpredictable stress; NMDARs, N-methyl-D-aspartate receptors. * Corresponding author. Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan, 430030, China. ** Corresponding author. E-mail addresses: [email protected] (M. Li), [email protected] (H. Chen).
Major depression disorder (MDD) is a significant cause of morbidity and a major contributor to disability worldwide [1], there is an urgent need to elucidate the pathophysiological mechanisms of depression, and identify novel antidepressants with milder adverse effects and more reliable efficacy. Increasing evidence indicates a critical role of inflammation in the pathophysiology of MDD [2]. Clinical trials and meta-analysis consistently confirm elevated levels of proinflammatory cytokines, such as interleukin (IL)-1b, IL-6 and tumor necrosis factor (TNF)-a, in the serum and brain of depressed patients [3,4]. MDD patients also show increased expression of caspase-1 mRNA in periphery blood mononuclear cells [5]. It is well known that caspase-1 is an inflammatory caspase, and activation of caspase-1
https://doi.org/10.1016/j.bbrc.2019.10.043 0006-291X/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: M. Li et al., Fucoidan exerts antidepressant-like effects in mice via regulating the stability of surface AMPARs, Biochemical and Biophysical Research Communications, https://doi.org/10.1016/j.bbrc.2019.10.043
2
M. Li et al. / Biochemical and Biophysical Research Communications xxx (xxxx) xxx
mediates the maturation of IL-1b. Anti-cytokine treatment for MDD significantly improves depressive symptoms with small-tomoderate size effect [3,4]. Additionally, chronic stress increases the production of peripheral and central proinflammatory cytokines in rodents, which ultimately mediates chronic stress-induced depressive-like behaviors [2,6]. Chronic antidepressant treatment alleviates the increased levels of IL-1b, IL-6 and TNF-a in the cerebral cortex and hippocampus [7e9]. More importantly, caspase1-mediated inflammation modulates depressive-like behaviors through multiple mechanisms and can be reduced by antidepressants [6,7]. Collectively, these findings suggest that cytokine modulators may be novel drugs for depression. Fucoidan, a sulfated polysaccharide containing L-fucose and sulfate groups, is mainly found in derived from marine brown seaweeds and is now used as an ingredient in dietary supplements. Furthermore, fucoidan exerts various physiological and biological activities, including anti-inflammatory and antioxidative [10,11], suggesting its potential role for medical use. Recent study suggests that fucoidan significantly decreases the levels of IL-1b and TNF-a in LPS-stimulated BV2 microglia [12]. Additionally, fucoidan inhibits the neurodegenerative changes in b-amyloid (Ab)-induced neurotoxicity in basal forebrain neuronal cultures [13]. Interestingly, fucoidan pretreatment improves CRS-induced depression through modulating the central noradrenergic and enhancing hippocampal BDNF [14]. These findings suggest that fucoidan has potential neuroprotective and antidepressant-like effects, although the underlying regulatory mechanisms of its effects in depression remain still obscure. Here, we examined the antidepressant-like actions of fucoidan in two depressive-like mouse models, and confirmed by TST, FST, SPT and NSFT. Moreover, we assessed the expression of proinflammatory cytokines, BDNF signaling pathway and AMPARs in the mPFC and hippocampus of mice. Lastly, by using methods including AAV vector and pharmacological inhibitors, we determined the possible involvement of anti-inflammatory activity in the antidepressant-like actions of fucoidan.
2. Materials and methods 2.1. Animals Adult male C57BL/6J mice (8e10 weeks) were purchased from Beijing Vitalriver Laboratory Animal Corp. Ltd (Beijing, China). The mice were housed in standard laboratory conditions (22 ± 2 C; 12 h light/dark cycle) with free access to food and water, except when specified otherwise. All procedures were approved by the Animal Care and Use Committee of Huazhong University of Science and Technology.
2.3. Behavior tests and experimental procedures Detailed information on experimental procedures was provided in Supplementary Information. 2.4. Statistical analysis All data were presented as the mean ± SEM and analyzed using IBM PASW Statistics 18.0 (New York, USA). Comparisons among multiple groups were evaluated using one-way analysis of variance (ANOVA) or two-way ANOVA followed by Bonferroni’s post hoc multiple comparison tests where appropriate. Significance was assigned at p < 0.05. 3. Results 3.1. Fucoidan exerts antidepressant-like effects in mice We first used the classical antidepressant fluoxetine as a comparison and investigated acute antidepressant effects of fucoidan in the TST and FST, which were widely used in screening antidepressant agents. Mice received a single administration of fucoidan and fluoxetine 30 min prior to the test. There was no significant decreased immobility in the fucoidan pretreated group when compared with the control group respectively (Fig. S1). Moreover, fluoxetine produced antidepressant-like effects in the TST and FST (Fig. S1). Previous study has demonstrated that fucoidan prevents CRS-induced depression in rats [14]. Therefore, we further tested the antidepressant effects of fucoidan on the LPS model of depression (Fig. 1A). There was no significant difference in the body weight during the two weeks of treatment (Fig. 1B). Consistently, mice in LPS group displayed decreased body weight (Fig. 1C) and increased immobility in the TST (Fig. 1D) and FST (Fig. 1E) when compare to vehicle-treated control group. Interestingly, fucoidan pretreatment could dose-dependently reverse LPS-induced depressive-like behaviors (Fig. 1CeE), indicating that chronic fucoidan administration may be enough to produce significant antidepressant-like actions. The observation was further confirmed in CRS model of depression (Fig. 1F). As predicted, stressed mice exerted decreased sucrose preference (Fig. 1G), elevated latency to feed in the NSFT (Fig. 1H), increased immobility in the TST (Fig. 1I) and FST (Fig. 1J) when compared to vehicle-treated control group, verifying the effectiveness of CRS model. Moreover, repeated administration of both fucoidan and fluoxetine fully reversed CRS-induced depressive-like behaviors in mice (Fig. 1GeJ). Taken together, these results suggest that fucoidan has antidepressant-like effects in mice. 3.2. Fucoidan treatment prevents stress-induced increase of caspase-1 expression and attenuation of BDNF-CREB pathway in the hippocampus
2.2. Drugs Fucoidan, lipopolysaccharide (LPS), fluoxetine and K252a were purchased from Sigma-Aldrich (Saint Louis, USA). Crosslinker bis(sulfosuccinimidyl)suberate (BS3) was purchased from Thermo Scientific (Rockford, USA). The dosages of fucoidan (25, 50 and 100 mg/kg), fluoxetine (20 mg/kg), LPS (1.0 mg/kg) and K252a (25 mg/kg, dissolved in 0.5% DMSO) were chosen based on previous studies [14e16] and dissolved in sterile saline before use. Fucoidan was given per os (p.o.). Fluoxetine and K252a were intraperitoneally (i.p.) injected in volumes 5 ml/kg. Fucoidan, fluoxetine and K252a were administrated 30 min before LPS or daily restraint stress.
Fucoidan has been demonstrated to inhibit microglia activation and decrease inflammation-associated cytokines [10,11]. Furthermore, fucoidan significantly blocks CRS-induced decrease in BDNF mRNA expression in the hippocampus [14]. We thus investigated the antidepressant-like actions of fucoidan on mRNA levels of inflammatory genes and BDNF in different brain regions. As expected, mice in LPS group showed the augmentation of Iba1, caspase-1 and IL-1b levels and reduction of BDNF level in the mPFC (Fig. S2A) and hippocampus (Fig. 2A) as compared with vehicle-treated group. Additionally, fucoidan pretreatment significantly prevented LPSinduced increase of Iba1, caspase-1, and IL-1b in the hippocampus (Fig. 2A). However, fucoidan failed to restored LPS-induced changes
Please cite this article as: M. Li et al., Fucoidan exerts antidepressant-like effects in mice via regulating the stability of surface AMPARs, Biochemical and Biophysical Research Communications, https://doi.org/10.1016/j.bbrc.2019.10.043
M. Li et al. / Biochemical and Biophysical Research Communications xxx (xxxx) xxx
3
Fig. 1. Fucoidan exerts antidepressant-like effects in mice. (A) Schematic timeline of experimental procedures. (B) The effects of 2 weeks fucoidan administration (p.o.) on body weight. (C) Repeated administration of fucoidan for 2 weeks prevented LPS-induced body weigh decrease in mice. (D-E) Fucoidan administration dose-dependently reduced LPSinduced increase in immobility time in TST (D) and FST (E). (F) The schematic representation of the CRS procedure and treatments in mice. (G-J) Effects of fucoidan on sucrose preference test (SPT)(G), novelty-suppressed feeding test (NSFT)(H), TST (I) and FST (J) after CRS. All data are shown as means ± SEM (n ¼ 9e10 mice/group). *p < 0.05, **p < 0.01, and ***p < 0.001.
in the mPFC (Fig. S2A). Furthermore, fucoidan administration also fully restored hippocampal BDNF expression (Fig. 2A). We next used western blotting to detect the expression of caspase-1, BDNF and its downstream molecules cAMP response element binding protein (CREB). LPS significantly elevated caspase-1 p20 protein expression and downregulated BDNF and phosphorylation of CREB (pCREB) expression in the mPFC (Fig. S2B) and hippocampus (Fig. 2B) when compared to vehicle-treated group. Interestingly, fucoidan treatment in the LPS groups significantly reduced caspase1 level and increased BDNF and pCREB expression in the hippocampus (Fig. 2B). These results clearly indicate the effectiveness of fucoidan in mitigating LPS-induced inflammation in the hippocampus. Meanwhile, CRS significantly increased the expression of Iba1, caspase-1 and IL-1b and reduced the BDNF expression in the mPFC (Fig. S2C) and hippocampus (Fig. 2C) compared with the vehicletreated group. Similar to the LPS results, fucoidan only reversed these changes in the hippocampus (Fig. 2C). Moreover, fucoidan administration not only fully restored CRS-induced increase in hippocampal caspase-1 p20 expression, but also prevented the downregulation of BDNF and pCREB expression in the hippocampus of CRS group (Fig. 2D and Fig. S2D). These results indicate the neuroprotective effects of fucoidan against depression. Taken together, these results suggest that fucoidan produces antidepressant effects through inhibiting caspase-1-mediated inflammation in the hippocampus.
3.3. Fucoidan enhances the stability of surface AMPARs in the hippocampus BDNF signaling pathway plays a pivotal role in regulating glutamatergic neurotransmission, which participates in the pathophysiology of depression, we thus examine the expression of AMPARs in the mPFC and hippocampus. As shown in Fig. 3A, LPS exposure significantly decreased GluA1 and GluA2 mRNA levels in the mPFC and hippocampus as compared to vehicle-treated group. Fucoidan significantly attenuated the reduction of GluA1 and GluA2 caused by LPS in the hippocampus (Fig. 3A). The phosphorylation of the AMPARs is well known to regulate synaptic efficacy [17]. LPS significantly decreased the phosphorylation on Ser845 (pSer845) of GluA1 compared with vehicle-treated group, and these changes in the hippocampus could be blocked by pretreatment with fucoidan (Fig. 3B). Based on these results, it seems that fucoidan upregulates the expression of the AMPARs in the postsynaptic membrane of hippocampus. To test this, we performed western blotting and surface receptor cross-linking with BS3 assays. As predicted, there was a significant reduction in the surface expression of AMPARs in the hippocampus of LPS-treated mice (Fig. 3C), and these changes were reversed by fucoidan pretreatment (Fig. 3C). These results suggest that AMPARs function may contribute to the antidepressant-like effects of fucoidan. Furthermore, fucoidan treatment also fully restored the CRSinduced decrease in hippocampal GluA1 and GluA2 mRNA
Please cite this article as: M. Li et al., Fucoidan exerts antidepressant-like effects in mice via regulating the stability of surface AMPARs, Biochemical and Biophysical Research Communications, https://doi.org/10.1016/j.bbrc.2019.10.043
4
M. Li et al. / Biochemical and Biophysical Research Communications xxx (xxxx) xxx
Fig. 2. Fucoidan treatment prevents stress-induced increase of caspase-1 protein expression and attenuation of BDNF-CREB pathway in the hippocampus. (A) Fucoidan administration dose-dependently reduced LPS-induced increase of ionized calcium binding adapter molecule 1 (Iba1), caspase-1, and interlukin-1b (IL-1b) mRNA in the hippocampus. (B) Effects of fucoidan treatment on the protein levels of caspase-1, pCREB and BDNF induced by LPS in the hippocampus. (C) Fucoidan inhibited the expression of inflammatory genes and increased the expression of BDNF mRNA in the hippocampus after CRS. (D) Effects of fucoidan treatment on the expression of caspase-1, pCREB and BDNF induced by CRS in the hippocampus. All data are shown as means ± SEM (n ¼ 4 mice/group). *p < 0.05, **p < 0.01, and ***p < 0.001.
Please cite this article as: M. Li et al., Fucoidan exerts antidepressant-like effects in mice via regulating the stability of surface AMPARs, Biochemical and Biophysical Research Communications, https://doi.org/10.1016/j.bbrc.2019.10.043
M. Li et al. / Biochemical and Biophysical Research Communications xxx (xxxx) xxx
5
Fig. 3. Fucoidan enhances the stability of surface AMPARs in the hippocampus. (A) Fucoidan reversed the downregulation of GluA1 and GluA2 mRNA induced by LPS in the hippocampus of mice. (B) The downregulation of the phosphorylation on Ser845 (pSer845) of GluA1 induced by LPS in the hippocampus was alleviated by pretreatment with fucoidan. (C) Fucoidan reversed the decreased surface expression of GluA1 and GluA2 in the hippocampus induced by LPS. (D) Fucoidan prevented the decreased expression of GluA1 and GluA2 mRNA induced by CRS in the hippocampus. (E) Fucoidan reverted the decrease of pSer845 of GluA1 induced by CRS in the hippocampus. (F) Fucoidan blocked the reduction of surface expression of GluA1 and GluA2 caused by CRS. All data are shown as means ± SEM (n ¼ 4 mice/group). *p < 0.05, **p < 0.01, and ***p < 0.001.
expression (Fig. 3D). Meanwhile, mice in the CRS group displayed a significant decrease in level of GluA1 pSer845 (Fig. 3E), and this reduction in the hippocampus could be rescued by fucoidan treatment (Fig. 3E). Additionally, fucoidan could obviously restored the CRS-induced decrease in the surface expression of AMPARs in the hippocampus (Fig. 3F). Collectively, our results indicate that fucoidan could reverse stress-induced reduction in synaptic expression of AMPARs via inhibiting caspase-1-mediated inflammation in the hippocampus of mice. 3.4. Inhibition of caspase-1-mediated inflammation and upregulation of BDNF signaling pathway is necessary for the antidepressant action of fucoidan Our previous study shows that caspase-1 overexpression in the hippocampus induces depressive-like behaviors [6]. We then used a viral expression experiment to investigate the antidepressant-like effects of fucoidan (Fig. 4A). It was shown that hippocampus was successfully transfected (Fig. 4B) and displayed increased levels of caspase-1 (Fig. 4C). We also found that AAV-Casp1 injection significantly reduced the levels of BDNF-CREB pathway and GluA1 pSer845 compared with AAV-GFP treatment (Fig. 4C), which were
reversed by the administration of fucoidan (Fig. 4C). Further, AAVCasp-1 mice displayed decreased sucrose preference (Fig. 4D) and increased immobility in the TST and FST (Fig. 4E) compared with AAV-GFP mice. These behavioral changes were completely restored in fucoidan pretreatment (Fig. 4DeE). Together, these findings indicate that fucoidan induces the antidepressant-like effects through inhibiting caspase-1-mediated inflammation in the hippocampus. To determine whether BDNF played an important role in the antidepressant-like effects of fucoidan, we used a potent pharmacological inhibitor of TrkB, K252a. Mice were injected with K252a 30 min prior to fucoidan administration (Fig. S3A), and there were no changes in the TST and FST (Fig. S3B). Further, stressed mice were cotreated with fucoidan and K252a for 2 weeks, and the depressive-like behaviors were assayed (Fig. 4F). Interestingly, these combined treatments not only block the restoring effects of fucoidan on the stressed mice in the SPT (Fig. 4G), TST and FST (Fig. 4H), but also prevented the protective effects of fucoidan on the expression of BDNF-CREB pathway and GluA1 pSer845 (Fig. 4I) in the hippocampus of stressed mice. These results suggest that fucoidan requires the hippocampal BDNF-CREB pathway to exert its antidepressant-like actions in mice.
Please cite this article as: M. Li et al., Fucoidan exerts antidepressant-like effects in mice via regulating the stability of surface AMPARs, Biochemical and Biophysical Research Communications, https://doi.org/10.1016/j.bbrc.2019.10.043
6
M. Li et al. / Biochemical and Biophysical Research Communications xxx (xxxx) xxx
Fig. 4. Inhibition of caspase-1-mediated inflammation and upregulation of BDNF signaling pathway is necessary for the antidepressant action of fucoidan. (A) Schematic representation of AAV-based constructs for overexpression of caspase-1 and the timeline of experimental procedure. (B) Representative fluorescence of injection sites in the hippocampus. Scale bars, 200 mm. (C) Effects of fucoidan treatment (50 mg/kg, p.o.) on the expression of caspase-1, BDNF and the phosphorylation levels of CREB and GluA1 in the hippocampus of mice (n ¼ 4 mice/group). (D-E) Fucoidan prevented overexpression of caspase-1-induced depression in the SPT (D), TST (E) and FST (E) (n ¼ 10 mice/group). (F) Schematic timeline of procedures. (G-H) K252a pretreatment abolished the antidepressant effects of fucoidan in SPT (G), TST (H) and FST (H) after CRS (n ¼ 10 mice/group). (I) K252a blocked the restoring effects of fucoidan on BDNF expression and the phosphorylation levels of CREB and GluA1 in the hippocampus of stressed mice (n ¼ 4 mice/group). All data are shown as means ± SEM. *p < 0.05, **p < 0.01, and ***p < 0.001.
4. Discussion In this study, we demonstrated that fucoidan exerted antidepressant-like on two depressive-like mouse models. Furthermore, fucoidan showed comparable antidepressant activity to the classical antidepressant fluoxetine. We proposed that fucoidan potentially inhibited caspase-1-mediated inflammation in the hippocampus, which subsequently promoted BDNF-CREB pathway. This resulted in increased phosphorylation of Ser845 of GluA1, enhancing the stability of surface AMPARs in the hippocampus, eventually regulated depressive-like behaviors in mice. These results indicate that the antidepressant-like effects of fucoidan may be dependent on anti-inflammatory activity. Accumulating evidence indicates that inflammation is implicated in the etiology of depression [2,3]. Anti-inflammatory agents can be used as a direct treatment strategy or an adjuvant to dietary supplement. For example, chronic treatment with celecoxib attenuates chronic unpredictable stress (CUS)-induced depressivelike behaviors via reducing COX-2 enzyme in brain [18]. Several studies have demonstrated that fucoidan significantly decreases IL1b level in cerebral ischemia-reperfusion injury with a dosedependent manner [19], and ameliorates hepatic ischemia-
reperfusion injury through suppressing the activity of caspase-1 [20]. Additionally, fluoxetine attenuates neuroinflammation through the suppression of NLRP3-caspase-1-IL-1b axis activity and the enhancement of BDNF [6,15,21]. Consistent with these findings, our results showed that both LPS and CRS significantly elevated the levels of Iba1, caspase-1 and IL-1b in the mPFC and hippocampus, whereas treatment with fucoidan only inhibited activation of microglia and elevation of caspase-1-IL-1b pathway in the hippocampus. Further, fucoidan also alleviated depressive-like behaviors in AAV-caspase-1 mice. Based on the close relationship between inflammation and depression, thus it is indeed reasonable to predict that the antidepressant-like effects of fucoidan is closely with its anti-inflammatory activity. Proinflammatory cytokines affect synaptic plasticity, which is associated with anhedonia, behavioral despair and cognitive impairment [22]. For example, increased inflammation is associated with the dysfunction of glutamatergic neurotransmission in depressed patients [23]. Furthermore, LPS induces depressive-like behaviors through promoting production of proinflammatory cytokines in activated microglia and inhibiting BDNF-dependent synaptic plasticity [24]. CUS also increases hippocampal microglia activation and attenuates phosphorylation of GluA1, eventually
Please cite this article as: M. Li et al., Fucoidan exerts antidepressant-like effects in mice via regulating the stability of surface AMPARs, Biochemical and Biophysical Research Communications, https://doi.org/10.1016/j.bbrc.2019.10.043
M. Li et al. / Biochemical and Biophysical Research Communications xxx (xxxx) xxx
leading to LTP impairments and cognitive dysfunction. Chronic treatment with minocycline can reverse these changes in the hippocampus [25]. Moreover, our previous study demonstrates that increased level of caspase-1 impairs hippocampal synaptic plasticity through promoting the production of IL-1b, not IL-18 [6]. Interestingly, fucoidan prevents the production of proinflammatory cytokines in primary microglia [10,12]. In present study, we found that fucoidan not only significantly attenuated the reduced levels of the phosphorylation of GluA1, but also increased surface expression of AMPARs in the hippocampus. Although the large molecules of fucoidan is unlikely to cross blood brain barrier, systemic administration of fucoidan is effective in protecting neuronal function in different ways [10,11,13,14]. Taken together, fucoidan may enhance hippocampal glutamatergic neurotransmission through inhibiting caspase-1-IL-1b inflammation pathway. BDNF plays a critical role in synaptic plasticity, neurogenesis and other physiological processes. BDNF level is abnormally low in depressed patients than healthy controls and can be notably restored by antidepressant treatment [26]. Similarly, the level of BDNF is also downregulated in depressive animals and the reduction can be reversed by antidepressants [15,27]. BDNF levels in the mPFC and hippocampus serve as biochemical markers for monitoring the development of and therapeutic response for depression. Furthermore, increased proinflammatory cytokines reduce the level of BDNF and impairs BDNF-dependent synaptic plasticity [6]. Based on these findings, we found that the levels of BDNF-CREB pathway were markedly reduced by caspase-1-mediated inflammation in two different animal models of depression. Lee et al. reported that fucoidan restored CRS-induced the reduction of BDNF mRNA in the hippocampus of rats [14]. Our present study also demonstrated that fucoidan treatment not only reversed the levels of BDNF-CREB pathway in the hippocampus, but also restored BDNF-dependent synaptic plasticity in stressed mice. Moreover, the pharmacological effect of BDNF is regulated by the specific receptor TrkB. Thus, these effects were also completely blocked by pretreatment with K252a, suggesting that BDNF-CREB pathway was required for the antidepressant activity of fucoidan. Interestingly, fucoidan had the prophylactic effects in depressed mice, suggesting that fucoidan supplementation may prevent the onset of depression associated with inflammation. There are limited reports on the adverse effects of fucoidan. Therefore, further studies also need to investigate whether supplementation of fucoidan-rich foods could prevent relapse in depressed patients. In summary, our results indicated that the antidepressant-like effects of fucoidan was mediated, at least in part, by enhancing BDNF-CREB pathway and normalized the levels of surface AMPARs via inhibiting caspase-1-mediated inflammation in the hippocampus of depressed mice, thus provided a potential therapeutic treatment for mood disorder.
Author contributions M.X.L. and H.C. conceived and designed the project and wrote the manuscript, M.X.L., X.J.S., Q.L., C.L., H.L.H., J.C., C.Z.G., Y.J.L., Y.F.Z. and S.Z. performed the behavioral experiments. M.X.L., X.J.S., Q.L. and Y.L. performed the biochemical measurements. M.X.L., X.J.S., X.L.H. and Y.L. analyzed the data. All authors read and approved the final manuscript.
Declaration of competing interest The authors declare that there is no conflict of interest.
7
Acknowledgements This research was supported by the National Natural Science Foundation of China (81801066, 81702767) and the China Postdoctoral Science Foundation (2018M640706). Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.bbrc.2019.10.043. References [1] G.B.D. Disease, I. Injury, C. Prevalence, Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016, Lancet 390 (2017) 1211e1259, https://doi.org/10.1016/ S0140-6736(17)32154-2. [2] A.H. Miller, C.L. Raison, The role of inflammation in depression: from evolutionary imperative to modern treatment target, Nat. Rev. Immunol. 16 (2016) 22e34, https://doi.org/10.1038/nri.2015.5. [3] N. Kappelmann, G. Lewis, R. Dantzer, P.B. Jones, G.M. Khandaker, Antidepressant activity of anti-cytokine treatment: a systematic review and metaanalysis of clinical trials of chronic inflammatory conditions, Mol. Psychiatry 23 (2018) 335e343, https://doi.org/10.1038/mp.2016.167. [4] A.S. Shariq, E. Brietzke, J.D. Rosenblat, V. Barendra, Z. Pan, R.S. McIntyre, Targeting cytokines in reduction of depressive symptoms: a comprehensive review, Prog Neuropsychopharmacol Biol Psychiatry 83 (2018) 86e91, https://doi.org/10.1016/j.pnpbp.2018.01.003. [5] E. Alcocer-Gomez, M. de Miguel, N. Casas-Barquero, J. Nunez-Vasco, J.A. Sanchez-Alcazar, A. Fernandez-Rodriguez, M.D. Cordero, NLRP3 inflammasome is activated in mononuclear blood cells from patients with major depressive disorder, Brain Behav. Immun. 36 (2014) 111e117, https://doi.org/ 10.1016/j.bbi.2013.10.017. [6] M.X. Li, H.L. Zheng, Y. Luo, J.G. He, W. Wang, J. Han, L. Zhang, X. Wang, L. Ni, H.Y. Zhou, Z.L. Hu, P.F. Wu, Y. Jin, L.H. Long, H. Zhang, G. Hu, J.G. Chen, F. Wang, Gene deficiency and pharmacological inhibition of caspase-1 confers resilience to chronic social defeat stress via regulating the stability of surface AMPARs, Mol. Psychiatry 23 (2018) 556e568, https://doi.org/10.1038/ mp.2017.76. [7] Y. Pan, X.Y. Chen, Q.Y. Zhang, L.D. Kong, Microglial NLRP3 inflammasome activation mediates IL-1beta-related inflammation in prefrontal cortex of depressive rats, Brain Behav. Immun. 41 (2014) 90e100, https://doi.org/ 10.1016/j.bbi.2014.04.007. [8] J.L. Warner-Schmidt, K.E. Vanover, E.Y. Chen, J.J. Marshall, P. Greengard, Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans, Proc. Natl. Acad. Sci. U. S. A. 108 (2011) 9262e9267, https://doi.org/10.1073/pnas.1104836108. [9] R. Yirmiya, Y. Pollak, O. Barak, R. Avitsur, H. Ovadia, M. Bette, E. Weihe, J. Weidenfeld, Effects of antidepressant drugs on the behavioral and physiological responses to lipopolysaccharide (LPS) in rodents, Neuropsychopharmacology 24 (2001) 531e544, https://doi.org/10.1016/S0893133X(00)00226-8. [10] Y.Q. Cui, Y.J. Jia, T. Zhang, Q.B. Zhang, X.M. Wang, Fucoidan protects against lipopolysaccharide-induced rat neuronal damage and inhibits the production of proinflammatory mediators in primary microglia, CNS Neurosci. Ther. 18 (2012) 827e833, https://doi.org/10.1111/j.1755-5949.2012.00372.x. [11] J. Li, Q. Zhang, S. Li, W. Dai, J. Feng, L. Wu, T. Liu, K. Chen, Y. Xia, J. Lu, Y. Zhou, X. Fan, C. Guo, The natural product fucoidan ameliorates hepatic ischemiareperfusion injury in mice, Biomed. Pharmacother. 94 (2017) 687e696, https://doi.org/10.1016/j.biopha.2017.07.109. [12] H.Y. Park, M.H. Han, C. Park, C.Y. Jin, G.Y. Kim, I.W. Choi, N.D. Kim, T.J. Nam, T.K. Kwon, Y.H. Choi, Anti-inflammatory effects of fucoidan through inhibition of NF-kappaB, MAPK and Akt activation in lipopolysaccharide-induced BV2 microglia cells, Food Chem. Toxicol. 49 (2011) 1745e1752, https://doi.org/ 10.1016/j.fct.2011.04.020. [13] J.H. Jhamandas, M.B. Wie, K. Harris, D. MacTavish, S. Kar, Fucoidan inhibits cellular and neurotoxic effects of beta-amyloid (A beta) in rat cholinergic basal forebrain neurons, Eur. J. Neurosci. 21 (2005) 2649e2659, https://doi.org/ 10.1111/j.1460-9568.2005.04111.x. [14] B. Lee, I. Shim, H. Lee, D.H. Hahm, Fucoidan prevents depression-like behavior in rats exposed to repeated restraint stress, J. Nat. Med. 67 (2013) 534e544, https://doi.org/10.1007/s11418-012-0712-5. [15] Y.F. Ni, H. Wang, Q.Y. Gu, F.Y. Wang, Y.J. Wang, J.L. Wang, B. Jiang, Gemfibrozil has antidepressant effects in mice: involvement of the hippocampal brainderived neurotrophic factor system, J. Psychopharmacol. 32 (2018) 469e481, https://doi.org/10.1177/0269881118762072. [16] M.C. He, Z. Shi, N.N. Sha, N. Chen, S.Y. Peng, D.F. Liao, M.S. Wong, X.L. Dong, Y.J. Wang, T.F. Yuan, Y. Zhang, Paricalcitol alleviates lipopolysaccharideinduced depressive-like behavior by suppressing hypothalamic microglia activation and neuroinflammation, Biochem. Pharmacol. 163 (2019) 1e8,
Please cite this article as: M. Li et al., Fucoidan exerts antidepressant-like effects in mice via regulating the stability of surface AMPARs, Biochemical and Biophysical Research Communications, https://doi.org/10.1016/j.bbrc.2019.10.043
8
M. Li et al. / Biochemical and Biophysical Research Communications xxx (xxxx) xxx
https://doi.org/10.1016/j.bcp.2019.01.021. [17] R.L. Huganir, R.A. Nicoll, AMPARs and synaptic plasticity: the last 25 years, Neuron 80 (2013) 704e717, https://doi.org/10.1016/j.neuron.2013.10.025. [18] J.Y. Guo, C.Y. Li, Y.P. Ruan, M. Sun, X.L. Qi, B.S. Zhao, F. Luo, Chronic treatment with celecoxib reverses chronic unpredictable stress-induced depressive-like behavior via reducing cyclooxygenase-2 expression in rat brain, Eur. J. Pharmacol. 612 (2009) 54e60, https://doi.org/10.1016/j.ejphar.2009.03.076. [19] N. Che, Y.J. Ma, Y.H. Xin, Protective role of fucoidan in cerebral ischemiareperfusion injury through inhibition of MAPK signaling pathway, Biomol Ther 25 (2017) 272e278, https://doi.org/10.4062/biomolther.2016.098. [20] J.J. Li, Q.H. Zhang, S.N. Li, W.Q. Dai, J. Feng, L.W. Wu, T. Liu, K. Chen, Y.J. Xia, J. Lu, Y.Q. Zhou, X.M. Fan, C.Y. Guo, The natural product fucoidan ameliorates hepatic ischemia-reperfusion injury in mice, Biomed. Pharmacother. 94 (2017) 687e696, https://doi.org/10.1016/j.biopha.2017.07.109. [21] Y. Zhang, L. Liu, Y.Z. Liu, X.L. Shen, T.Y. Wu, T. Zhang, W. Wang, Y.X. Wang, C.L. Jiang, NLRP3 inflammasome mediates chronic mild stress-induced depression in mice via neuroinflammation, Int. J. Neuropsychopharmacol. 18 (2015), https://doi.org/10.1093/ijnp/pyv006. [22] S.M. Thompson, A.J. Kallaracka, M.D. Kvarta, A.M. Van Dyke, T.A. LeGates, X. Cai, An excitatory synapse hypothesis of depression, Trends Neurosci. 38 (2015) 279e294, https://doi.org/10.1016/j.tins.2015.03.003. [23] K.D. Young, W.C. Drevets, R. Dantzer, T.K. Teague, J. Bodurka, J. Savitz,
[24]
[25]
[26]
[27]
Kynurenine pathway metabolites are associated with hippocampal activity during autobiographical memory recall in patients with depression, Brain Behav. Immun. 56 (2016) 335e342, https://doi.org/10.1016/j.bbi.2016.04.007. J.C. Zhang, W. Yao, C. Dong, C. Yang, Q. Ren, M. Ma, M. Han, J. Wu, Y. Ushida, H. Suganuma, K. Hashimoto, Prophylactic effects of sulforaphane on depression-like behavior and dendritic changes in mice after inflammation, J. Nutr. Biochem. 39 (2017) 134e144, https://doi.org/10.1016/ j.jnutbio.2016.10.004. M.C. Liu, J. Li, P. Dai, F. Zhao, G. Zheng, J.F. Jing, J.Y. Wang, W.J. Luo, J.Y. Chen, Microglia activation regulates GluR1 phosphorylation in chronic unpredictable stress-induced cognitive dysfunction, Stress 18 (2015) 96e106, https:// doi.org/10.3109/10253890.2014.995085. S. Srijan, D. Ronald, S. Gerard, Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications, Biol. Psychiatry 64 (2008) 527e532. M.X. Li, Q. Li, X.J. Sun, C. Luo, Y. Li, Y.N. Wang, J. Chen, C.Z. Gong, Y.J. Li, L.P. Shi, Y.F. Zheng, R.C. Li, X.L. Huang, Q.J. Xiong, H. Chen, Increased Homer1-mGluR5 mediates chronic stress-induced depressive-like behaviors and glutamatergic dysregulation via activation of PERK-eIF2alpha, Prog Neuropsychopharmacol Biol Psychiatry 95 (2019) 109682, https://doi.org/10.1016/ j.pnpbp.2019.109682.
Please cite this article as: M. Li et al., Fucoidan exerts antidepressant-like effects in mice via regulating the stability of surface AMPARs, Biochemical and Biophysical Research Communications, https://doi.org/10.1016/j.bbrc.2019.10.043