PURPOSE:The inflammatory activation and metabolic disorders of cardiomyocytes are essential mechanisms in sepsis-related cardiac dysfunction. Kaempferitrin (Kae), a flavonoid compound, possesses various properties including anti-inflammatory and anti-glycation effects. Hence, the current study is conducted to investigate the protective effects of Kae against sepsis-induced cardiac dysfunction. METHODS:C57BL/6 J mice were treated with Kae for 2 h, followed by lipopolysaccharide (LPS) treatment. After 12 h, the echocardiographic measurements were conducted. Serum test, pathological analysis, transcriptomics, western blotting, and RT-PCR were used for exploring mechanisms. Additionally, in vitro, H9c2 and AC16 cardiomyocyte cell lines were pretreated with Kae (10 μM) for 2 h, followed by LPS stimulation (1 μg/mL). RESULTS:In vivo, pretreatment with Kae mitigates LPS-induced cardiac dysfunction. Kae suppresses the levels of IL-6, TNF-α, IL-1β, and IL-18 in the cardiac tissue of mice mediated by LPS. Additionally, serological and histological assessments demonstrate that Kae exhibits protective effects against LPS-induced cardiomyocyte injury and apoptosis. Transcriptomic analysis reveals that the nuclear factor kappa-B (NF-κB)/NLRP3 signaling pathway may be a crucial mechanism. Meanwhile, it proved that LPS significantly activates NF-κB/NLRP3 to induce cardiomyocyte pyroptosis, which is attenuated by Kae. In vitro, H9c2 and AC16 cardiomyocyte cell lines were pretreated with Kae followed by LPS stimulation, showing an inhibition of NF-κB/NLRP3 pathway, with a decreased mRNA levels of Il-6, Tnf-α, Il-1β. The NLRP3-knock out (Nlrp3 -/- ) mice have verified that Kae ameliorating LPS-induced spetic cardiomyopathy by inhibiting NLRP3. CONCLUSIONS:This study confirms that Kae alleviates LPS-induced left ventricular remodeling and cardiac dysfunction by suppressing the NF-κB/NLRP3/pyroptosis pathway.

Curcumin, a highly hydrophobic phenolic compound, has demonstrated potent anticancer activity. However, poor water solubility and a short biological half-life hinder its clinical application. We developed Curcumin-loaded Pluronic F-127 nanoparticles to enhance the bioavailability of Curcumin. It has been reported that excessive autophagy is considered to be the main mechanism of death of various cancer cells. The aim of this study is to investigate whether the Curcumin-loaded Pluronic F-127 nanoparticles exert anti-colon cancer effects by modulating autophagy and explore the specific regulatory mechanism. The proliferative, migratory and apoptotic activity of CT26 cells was assessed by CCK-8 assay, wound healing assay and flow cytometry, respectively. In addition, levels of reactive oxygen species (ROS) were examined by DCFH-DA assay in vitro. ATP levels were detected by the ELISA. The expression levels of autophagy-related proteins and apoptosis-related proteins were visualized by western blotting. Curcumin-loaded Pluronic F-127 nanoparticle inhibited the proliferation of CT26 cells and the growth of colon tumours by promoting cellular autophagy. In addition, Curcumin-loaded Pluronic F-127 nanoparticle reduced mitochondrial membrane potential and impaired mitochondrial function by increasing ROS levels, disrupting ATP biosynthesis. Then the decreased ATP/AMP ratio activated the AMPK/mTOR/ULK1 autophagy signalling pathway and induced autophagy-dependent apoptosis in CT26 cells. Intriguingly, the apoptosis and excessive autophagy induced by Curcumin-loaded Pluronic F-127 nanoparticle were reversed after pretreatment with the antioxidant N-acetyl-L-cysteine. Curcumin-loaded Pluronic F-127 nanoparticle induced autophagy-dependent apoptosis through ROS-AMPK/mTOR/ULK1 signalling in colon cancer cells. Our study offers new insights for colon cancer treatment advancement.

Transplantation of bone marrow mesenchymal stem cells (BMSCs) represents an encouraging strategy for the repair of spinal cord injury (SCI), however, its effectiveness on treating SCI remains controversial. Bilobalide isolated from Ginkgo biloba leaves shows significant neuroprotective effects. We examined the role and underlying mechanism of bilobalide in the efficacy of BMSC transplantation on SCI. Primary BMSCs were isolated from neonatal rats, and cell viability was assessed by MTT assay. Neuronal markers (MAP-2, NeuN, NSE and Tuj1), autophagy markers (LC3 and Beclin1), and Fragile X mental retardation protein (FMRP)/With-no-lysine kinase-1 (WNK1) signaling were measured using RT-qPCR and western blotting. The relationship of FMRP and WNK1 was estimated by RNA immunoprecipitation, while WNK1 mRNA stability was assessed with actinomycin D assay. In a SCI rat model, tissue injury was examined using HE and Nissl staining. Bilobalide treatment facilitated neural differentiation of BMSCs, as well as enhanced autophagy and inhibited WNK1 signaling. The promotive effect of bilobalide on BMSC differentiation was antagonized when overexpressing WNK1 or inhibiting autophagy. Bilobalide upregulated FMRP to promote WNK1 mRNA decay, thus reducing WNK1 expression. FMRP knockdown reversed the promoted functions of bilobalide on autophagy and neuronal differentiation in BMSCs. Additionally, compared to either monotherapy, simultaneous treatments with bilobalide and BMSCs further facilitated autophagy and neuronal differentiation, thereby enhancing the repair of SCI in rats. Bilobalide enhances autophagy activity to promote BMSC neuronal differentiation via FMRP/WNK1 axis, thus improving functional recovery following SCI, which indicates a promising therapeutic approach for SCI.

Depression is a mental and emotional disorder that has made an opening great burden to the society. Paeoniflorin showed remarkable antidepressant-like effects in multiple animal models with depressive disorders. However, the molecule of paeoniflorin on depression is less studied. This study aims to explore the effect and the molecular mechanism of paeoniflorin on depression in a chronic restraint stress (CRS) mice model. CRS model of C57BL/6 J mice was set up. Sucrose preference test (SPT), tail suspension test (TST), open field test (OFT) and forced swimming test (FST) were used to assess depression symptoms. Immunofluorescence staining, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting were implemented to detect the expression changes of the proteins involved in extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. Results showed that paeoniflorin treatment decreased the degree of depression in the CRS mice. Further analysis showed that the expression of ERK1/2 proteins was significantly downregulated, while paeoniflorin could elevate the expression of ERK1/2 proteins in CRS mice. Finally, it showed that inhibiting signaling ERK1/2 pathway could aggravate the depressive behavior when treatment with ERK-specific inhibitor U0126, while the condition could be partially relieved when treated with paeoniflorin. In conclusion, the present study demonstrated that paeoniflorin attenuated chronic stress-induced depression-like behavior in mice by affecting the ERK1/2 pathway. These findings provided the basis for the molecular mechanism of paeoniflorin on the effect of depression, which support paeoniflorin might act as an important drug in the treatment of depression.

Ethnopharmacological relevance Paeonia lactiflora is a famous Traditional Chinese medicine widely used for immunological regulation. Paeoniflorin, the main component of Paeonia lactiflora, exerts neuroprotective and antidepressant-like effects in rodents. Aim of the study: Fibroblast growth factor 2 (FGF-2) is essentially required in the central nervous system as it acts as both a neurotrophic factor and an anti-inflammatory factor participating in the regulation of proliferation, differentiation and apoptosis of neurons in the brain. However, it is unclear whether paeoniflorin could exert antidepressant effects via regulating FGF-2. Materials and methods: In the present study, the effects of paeoniflorin were evaluated in depressive mice induced by the endotoxin lipopolysaccharide (LPS) injection. Results: The results showed that paeoniflorin markedly increased sucrose preference and reduced immobility time in LPS mice, indicating antidepressant effects. Consistent with the results from molecular docking showing paeoniflorin antagonizes TLR4, NF-kappa B and NLRP3, the biochemical analysis also indicated paeoniflorin inhibited TLR4/NF-kappa B/NLRP3 signaling, decreased proinflammatory cytokine levels and microglial activation in the hippocampus of LPS induced mice. In addition, the levels of neuronal FGF-2 and the density of dendritic spine were improved by paeoniflorin. More importantly, the FGFR1 inhibitor SU5402 prevented the antidepressant effects of paeoniflorin and blocked the neuroinflammatory and neurogenic regulatory effects of paeoniflorin, indicating that FGF-2/FGFR1 activation was required for the effects of paeoniflorin. Conclusion: Taken together, the results demonstrate that paeoniflorin exhibits neuroprotective and antidepressant effects in mice, which may be mediated by activating neuronal FGF-2/FGFR1 signaling via the inhibition of microglial activation in the hippocampus.

To the Editor: Major depressive disorder is one of the most leading causes of disability worldwide. The molecular pathophysiology of depression is complicated and has already attracted intensive and considerable attention.[1] Nowadays, the neurotrophic hypothesis of depression suggests that brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) receptor binding activates the downstream signaling pathways to culminate in cell survival.[2] This process is essential for neurogenesis and synaptogenesis, which are involved in the effects of antidepressants.[3] In addition to its classical role in regulating neuronal growth and plasticity, BDNF is also suggested to play a crucial role in regulating systemic metabolism. Blockade of BDNF/TrkB signaling in the periphery caused down-regulation of several metabolic molecules, including AMP-activated protein kinase (AMPK), a protein kinase participating in cellular energy regulation homeostasis.[4] Several reports indicated that lipopolysaccharide (LPS), corticosterone, and chronic stress induced a decreased phosphorylation of AMPK in the brain. However, a controversial finding from another study showed that sustained AMPK activation participated in the process of depression induced by chronic corticosterone. The discrepancy suggests a need to further investigate the role of AMPK in the pathophysiology of depression. Up to now, a systematic understanding of AMPK dysfunction in the neurotrophic hypothesis of depression is lacking. In particular, how AMPK mediates BDNF/TrkB signaling pathway is not well understood. In this way, the present study was aimed to demonstrate how BDNF/TrkB signaling and AMPK interacted in depression induced by chronic stress and tried to elucidate whether BDNF/TrkB signaling exerted its function in an AMPK-dependent manner. In the present study, we used 7,8-dihydroxyflavone to activate its receptor TrkB and evaluated its effects on neurogenesis and synaptogenesis. Moreover, we applied a pharmacological intervention approach by the pretreatment of TrkB antagonist, AMPK inhibitor/activator to assess the changes in behaviors, neurogenesis, and synaptogenesis in depressive-like mice. This finding will be a crucial step toward elucidating the relationship between regulation of the BDNF/AMPK in depression. We first evaluated the effects of 7,8-dihydroxyflavone on depressive-like behaviors. Chronic stress caused a decrease in sucrose preference, a prolongation in latency to feed, and an increase in immobility time, which can be completely reversed by 7,8-dihydroxyflavone (10 mg/kg, intraperitoneally) treatment [Figure 1A–1D]. Then we assessed BDNF and AMPK signaling activity in mice. We found that BDNF expression, TrkB phosphorylation as well as AMPK phosphorylation were significantly decreased by chronic stress, while 7,8-dihydroxyflavone restored these abnormalities [Figure 1E–1G]. We next examined whether 7,8-dihydroxyflavone altered neurogenesis and synaptogenesis in the hippocampus. The results showed that doublecortin (DCX)-positive cell and dendritic spine density were inhibited by chronic stress. On the contrary, the administration of 7,8-dihydroxyflavone reversed the reductions [Figure 1H and 1I].Figure 1: 7,8-dihydroxyflavone reversed the depressive-like behaviors and promoted BDNF-TrkB-AMPK signaling in the hippocampus. 7,8-dihydroxyflavone increases the sucrose preference (A), decreases latency to feed (B) but does not affect home-cage feed consumption (C), and reduces the immobility time (D) in chronic stress mice. 7,8-dihydroxyflavone increases BDNF expression (E), TrkB phosphorylation (F), AMPK phosphorylation (G), DCX-positive cell (H), and density of dendritic spine (I) in the hippocampus. The results suggest a regulation of BDNF/TrkB signaling mediated neurogenesis independent with AMPK (J). The behavioral and biochemical data represented mean ± SEM from 3 to 12 mice/group, respectively. ∗ P < 0.05 and ∗∗ P < 0.01 vs. Control-vehicle group. † P < 0.05 and †† P < 0.01 vs. Chronic stress-vehicle group. AMPK: AMP-activated protein kinase; BDNF: Brain-derived neurotrophic factor; TrkB: Tyrosine kinase receptor B.Then mice were co-treated with 7,8-dihydroxyflavone and K252a, a selective antagonist of the TrkB for four weeks [Supplementary Figure 1, https://links.lww.com/CM9/A432]. K252a (25 μg/kg) fully abolished the antidepressant-like effects of 7,8-dihydroxyflavone. Additionally, the effects of 7,8-dihydroxyflavone on the BDNF, TrkB, and AMPK enhancement were antagonized by the pretreatment with K252a. DCX-positive cell and dendritic spine density, which were promoted by 7,8-dihydroxyflavone, were totally blocked by K252a [Supplementary Figure 2, https://links.lww.com/CM9/A432]. These results were in accordance with a previous study showing that administration of 7,8-dihydroxyflavone facilitated memory performance and hippocampal functional connectivity, as well as modulated hippocampal AMPK phosphorylation in response to traumatic brain injury. Thus, AMPK activity was dependent on BDNF/TrkB activation in depressive-like animals. To further investigate whether AMPK signaling activation is required for the antidepressant-like effects of TrkB agonist, we examined the effects of Compound C, an AMPK inhibitor, in our experiment [Supplementary Figure 3, https://links.lww.com/CM9/A432]. To our surprise, sucrose preference was increased and immobility time was decreased after 7,8-dihydroxyflavone treatment, no matter whether Compound C (10 mg/kg) was pretreated or not. Subsequently, pAMPK phosphorylation was detected to be inhibited by Compound C, indicating the role of Compound C. In addition, we found that the effects of 7,8-dihydroxyflavone on BDNF and TrkB expression were not altered by Compound C. Then, the downstream signaling of AMPK was measured. Besides, AMPK, mammalian target of rapamycin (mTOR), and glycogen synthase kinase 3 beta (GSK3β)/cAMP responsive element binding (CREB) signaling pathways are also modulated by BDNF/TrkB downstream effector Akt. The canonical BDNF/TrkB/Akt/mTOR and BDNF/TrkB/Akt/GSK3β/CREB signaling pathways are required for many antidepressants. We first found that mTOR phosphorylation was activated by either 7,8-dihydroxyflavone or Compound C. Further, co-treatment with 7,8-dihydroxyflavone and Compound C still maintained the activation of mTOR. On the other hand, the results indicated the effects of 7,8-dihydroxyflavone on pGSK3β/GSK3β and pCREB/CREB levels were partly blocked by the pretreatment of Compound C, while pAkt/Akt levels remained activated. In parallel to the western results, immunofluorescence and Golgi staining indicated that AMPK inhibitor Compound C did not alter the effects of 7,8-dihydroxyflavone on DCX-positive cell and dendritic spine density [Supplementary Figure 4, https://links.lww.com/CM9/A432]. Together, these results suggested that AMPK negatively regulated mTOR signaling but positively regulated GSK3β/CREB signaling. As AMPK inhibition did not affect the antidepressant-like effects of 7,8-dihydroxyflavone, we next used AMPK activator aminoimidazole carboxamide ribonucleotide (AICAR) to further explore the role of AMPK in our study [Supplementary Figure S5, https://links.lww.com/CM9/A432]. The results showed that AICAR treatment (100 mg/kg) alone did not induce antidepressant-like effects. However, AICAR abolished the antidepressant-like effects of 7,8-dihydroxyflavone in behavioral tests. The effects of AICAR were firstly verified by the elevation of pAMPK/AMPK levels. In addition, both pGSK3β/GSK3β and pCREB/CREB levels were up-regulated after AICAR pretreatment alone. When 7,8-dihydroxyflavone was co-treated with AICAR, BDNF levels, TrkB, Akt, and mTOR phosphorylation turned to be inactivated, suggesting that sustained AMPK activation caused the inhibition of BDNF/TrkB-induced enhancement of mTOR-mediated translation. The inhibition of BDNF/TrkB signaling was confirmed by the results from immunofluorescence and Golgi staining. It can be clearly found that the effects of 7,8-dihydroxyflavone on dendritic spine density were blocked after co-treated with AICAR [Supplementary Figure 6, https://links.lww.com/CM9/A432], suggesting that hyperactivity of AMPK suppresses the BDNF/TrkB-dependent antidepressant-like effects. A previous study on depressive disorders showed that the phosphorylation of AMPK was decreased in various brain regions and animals.[5] In parallel with these observations, the present study also found that chronic stress induced a decrease in AMPK phosphorylation. However, it is controversial whether activation of AMPK plays a beneficial or deleterious role in the central nervous system. On the one hand, AMPK activators such as metformin protected against depressive-like behaviors in chronic social defeat stress-induced depression in mice. AICAR produced antidepressant-like effects in olfactory bulbectomized mice. On the other hand, phosphorylation of AMPK in the brain was increased in LPS or corticosterone-induced depression. AMPK activation decreased the expression of BDNF and AMPK inhibition increased the expression of BDNF in the hippocampus. AMPK inactivation reversed the impairments in hippocampal synaptic plasticity in mice induced by amyloid β. Therefore, it is rational to hypothesize that the activity of AMPK is conditional in response to stress and antidepressants. The present study showed that the activation of AMPK instead of inhibition of AMPK attenuated the effects of BDNF/TrkB signaling in chronic stress-induced mice. We found that this phenomenon was associated with the regulation of mTOR signaling. In detail, the AMPK inhibitor reversed the reduction of mTOR phosphorylation, while the AMPK activator maintained the reduction of mTOR phosphorylation in the hippocampus after chronic stress, which was consistent with the change of neurogenesis and synaptogenesis. Temporary restoration of AMPK activation is beneficial for homeostasis of energy metabolism and antidepressant-like effects. However, sustained hyperactivity of AMPK exhibits its detrimental impacts on neurons, which is due to the inhibited mTOR activity according to the results of the present study. Overall, to our knowledge, this study, for the first time, suggests that BDNF/TrkB signaling induces antidepressant-like effects in an AMPK-independent manner in chronic stress. More importantly, the results demonstrate that sustained AMPK activation impairs BDNF/TrkB signaling activity via inhibiting mTOR, which directly inhibits protein synthesis and leads to the deficiency in neurogenesis and synaptogenesis [Figure 1J]. Our study also suggests that although AMPK is a putative target for depression therapy as its core regulatory role in energy metabolism, we should be cautious when activating AMPK in patients until we are more fully aware of the complex molecular functions involved in depression and antidepressants. Acknowledgement The authors would like to thank the Instrumental Analysis Center of Huaqiao University for the help of confocal testing. Funding This work was supported by grants from the Education Department of Fujian Province [No. 2019-WJ-38] and Xiamen Municipal Health Commission [No. 2019-WJ-38]; Huaqiao University [No. ZQN-PY218]. Conflicts of interest None.

It has been reported that liquiritin produced an antidepressant-like effect in rodents. However, little information is known regarding its antidepressant activity with the regulation of fibroblast growth factor 2 (FGF-2), a protein maintaining development and maturation of the nervous central system. Therefore, the aim of the present study was to investigate the underlying FGF-2 modulation involved in the antidepressant-like effects of liquiritin. In the present study, mice were orally administrated with liquiritin for 7 days prior to LPS injection. The depressive-like behaviors, levels of FGF-2, number of Iba1 positive cells, expression of proinflammatory cytokines and density of dendritic spines were evaluated. The results showed that liquiritin significantly ameliorated the depressive-like behaviors in mice response to LPS injection. Liquiritin reversed the reduction of FGF-2 levels in the hippocampus of LPS induced mice. In addition, the microglial activation caused by LPS was attenuated by liquiritin, in accordance with downregulation in mRNA levels of proinflammatory cytokines. Moreover, liquiritin also increased the density of dendritic spines in the hippocampus, which was suppressed by LPS. In conclusion, our findings demonstrated that liquiritin exerted the antidepressant-like effects in LPS-induced depression through FGF-2 enhancement by inhibiting neuroinflammation and maintaining synaptogenesis.

ObjectiveBerberine, a cationic alkaloid first isolated in 1917, has been approved by the China Drug Administration for decades. Accumulating evidence demonstrated its antidepressant-like activities in vivo. Our previous study has shown that chronic stress leads to the upregulation of miR-34a in the hippocampus of mice. This study aims to evaluate the underlying miR-34a mediated mechanism of berberine in chronic stress-induced depression in mice.MethodsIn the present study, mice were administered with berberine during chronic stress. Levels of miR-34a, dendritic density, mitochondrial morphology, and neurogenesis were assessed in the hippocampus. Subsequently, miR-34a agomir was used as a pharmacological intervention for the investigation of berberine.ResultsThe results showed that berberine reversed the decrease in sucrose preference and the increase in latency to feed without altering total food consumption. Furthermore, chronic stress-induced overexpression of miR-34a decreased synaptotagmin-1 and Bcl-2 levels, thereby impairing spinal morphology, mitochondria and neurogenesis. Berberine inhibited miR-34a expression, in turn restored synaptotagmin-1 and Bcl-2 levels, and thus improved spinal morphology, mitochondria and neurogenesis in the hippocampus. However, the improvements induced by berberine were totally blocked by the pretreatment of miR-34a agomir, which caused the elevation of miR-34a levels in the hippocampus.ConclusionThis finding demonstrated that miR-34a downregulation was involved in the antidepressant-like effects of berberine in mice exposed to chronic stress.

Puerarin, a well-studied isoflavone isolated from Pueraria lobata, produces an antidepressant-like effect. Fibroblast growth factor-2 (FGF-2) is essentially required in the central nervous system as it acts as both a neurotrophic or anti-inflammatory regulator for the proliferation, differentiation and apoptosis of neurons. There is evidence that FGF-2 holds great promise for therapeutic intervention for depression. However, nothing was known about the involvement of FGF-2 in the antidepressant-like effect of puerarin. In the present study, the underlying mechanism of puerarin was evaluated in chronic stress induced depressive-like mice. The results indicated that puerarin treatment was effective to attenuate anhedonia and despair behaviors caused by chronic stress, as the sucrose preference and the immobility time were improved by puerarin. In addition, the results demonstrated that puerarin increased the expression of FGF-2 in the hippocampus. On the contrary, SU5402, an FGFR1 inhibitor, infusion into the brain could not only block the antidepressant-like effect of puerarin, but also abolish the effect of puerarin on hippocampal neurogenesis enhancement and neuroinflammation inhibition. Taken together, these findings provide new insights into the mechanism that the antidepressant-like actions of puerarin require FGF-2/FGFR signaling for the regulation of neurogenesis and neuroinflammation.

Cisplatin, a commonly used chemotherapy drug, can increase the survival rate of cancer patients. However, it often causes various side effects, including neuronal deficit-induced cognitive impairment. Considering that curcumin is effective in neuronal protection, the action of curcumin on cognitive improvement was evaluated in cisplatin-treated C57BL/6 mice in the present study. Our results first showed that curcumin restored impaired cognitive behaviors. Consistent with this, neurogenesis and synaptogenesis were improved by curcumin. In addition, cisplatin-induced dysfunction of apoptosis-related proteins was partly reversed by curcumin. Moreover, cisplatin-induced autophagy was enhanced by curcumin. Our results also indicated that cisplatin induced autophagy through the endoplasmic reticulum (ER) stress-mediated ATF4-Akt-mTOR signaling pathway. Curcumin activated AMPK-JNK signaling, which mediated both mTOR inhibition and Bcl-2 upregulation and in turn enhanced autophagy and suppressed apoptosis, respectively. In contrast, pretreatment with the autophagy inhibitor 3-methyladenine (3-MA) completely abolished the effects of curcumin on cognitive improvement and improved neurogenesis, synaptogenesis and autophagy. Our results show that cognitive improvement induced by curcumin during chemotherapy is mediated by the enhancement of hippocampal autophagy.

Gypenosides, a saponins extract isolated from the Gynostemma pentaphyllum plant, produces neuroprotective effects in the brain. Our previous studies have shown that hippocampal glucocorticoid receptor (GR)-brain-derived neurotrophic factor (BDNF)-TrkB signaling was involved in the antidepressant-like effects of gypenosides. It remains unknown whether gypenosides could alleviate neuroinflammation in depressive-like animals. The aim of the present study was to address this issue in chronic unpredictable mild stress (CUMS). Gypenosides was administrated for four weeks, followed by sucrose preference test and tail suspension test, which were performed to evaluate the effects of gypenosides. The results showed that gypenosides reversed both the decreased sucrose preference and increased immobility time in CUMS mice. In addition, gypenosides also attenuated the increase of pro-inflammatory cytokine levels in the hippocampus of CUMS animals. Furthermore, the activation of NF-κB, as well as its upstream mediators IKKα and IKKβ were inhibited by gypenosides. Last but not the least, CUMS promoted the activation of microglia, while gypenosides suppressed it according to the reduced number of iba1 positive cells. In conclusion, this study demonstrates that gypenosides exhibits the antidepressant-like effects in mice, which may be mediated by the inhibition of microglia and NF-κB signaling in the hippocampus.