Gypenosides reverses depressive behavior via inhibiting hippocampal neuroinflammation
Graphical abstract
Introduction
Depression is a common and serious medical illness that has a negative impact on both physical and mental health. The factors that contribute to the onset of depression are very complex. Due to the medical restrictions, we currently have no way of knowing the specific pathophysiology of depression. Until now, the widely accepted viewpoints hold that the typical cause of depression is associated with genetic factors, immunology, neuroendocrine, neurochemistry as well as social and environmental factors.
According to the latest research, the endothelial and dendritic cells around the neuronal membrane will be activated to generate immune substances such as cytokines or chemokines after the tissue is damaged, and then the immune substances induce the immune cells to enter the nervous system and induce neuroinflammation [1]. From the brains of patients who had suicide due to depression, the researchers found that the number of carbon monoxide synthetase in microglia was significantly increased [2]. This phenomenon was found in macrophages and astrocytes [2]. Studies have also shown that the loss of balance between pro-inflammatory cytokines and anti-inflammatory factors leads to depression. Generally, the pro-inflammatory cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) are increased in the serum or plasma of patients with depression [3]. The meta analysis shows that the pro-inflammatory factors in patients with depression are positively related to the degree of depression [4]. According to current clinical evidence, both pro-inflammatory cytokines and microglia are increased in the brain [5,6], suggesting that neuroinflammation plays an important role in the pathophysiology of depression.
Gypenosides, a saponin extract isolated from Gynostemma pentaphyllum includes approximate 140 types of gypenosides [[7], [8], [9]]. These compounds have been reported to possess antitumor [10], antioxidant [11], neuroprotective [12,13] and anti-inflammatory activities [14,15]. Nowadays, gypenosides is approved for use as a traditional Chinese OTC in clinics by the Central Drug Administration of China. Previous study showed that gypenosides protected dopaminergic neurons in primary culture against MPP(+)-induced oxidative injury [16], which provided the possibility of gypenosides for treatment of mental disorders. Recently, our previous studies demonstrated that gypenosides produced an antidepressant-like effect in mice exposed to chronic unpredictable mild stress (CUMS) or long-term corticosterone injection, which was mediated via miR-124-glucocorticoid receptor (GR)-brain-derived neurotrophic factor (BDNF)-TrkB signaling [17,18]. Considering that neuroinflammation might be involved in the pathophysiology of depression, the present study investigated whether neuroinflammation inhibition was involved in the antidepressant-like effects of gypenosides in chronic unpredictable mild stress mice.
Section snippets
Animals
Male C57/BL mice (24 ± 2 g; 8 weeks old) were purchased from Shanghai Slac Animal Center, PR China. Animals were housed five per cage (320 × 180 × 160 mm) under a normal 12 h/12 h light to dark schedule with lights on at 07:00 a.m. Animals were allowed to adjust to the housing conditions before experiments began. Ambient temperature and relative humidity were maintained at 22 ± 2 °C and at 55 ± 5%, respectively. During the entire experiment, animals had access to food and water unless otherwise
The effects of gypenosides on behaviors in mice
As shown in the Fig. 1A, CUMS induced a significant decrease in the sucrose preference [P < 0.01]. Gypenosides treatment significantly increased the sucrose preference in the CUMS group [P < 0.01]. Additionally, gypenosides didn't significantly alter the sucrose preference in the Control group.
As shown in the Fig. 1B, CUMS significantly increased the immobility time [P < 0.05] in the tail suspension test. The post-hoc test revealed that 4-week treatment with gypenosides significantly decreased
Discussion
In the present study, our results not only exhibited that gypenosides possessed the antidepressant-like action in CUMS mice, but also underlined the effects of gypenosides on neuroinflammation during the treatment. Our results clearly demonstrated that gypenosides reversed the depressive-like behaviors by inhibiting neuroinflammation in the hippocampus. To be more specific, gypenosides reversed the abnormalities as follows: (1) CUMS induced a significant decrease in sucrose preference and a
Conflict of interest
The Authors declares that there is no conflict of interest.
Acknowledgements
Funding for this study was provided by the Promotion Program for Young and Middle-aged Teacher in Science and Technology Research of Huaqiao University (ZQN-PY218) and the Outstanding Youth Scientific Research Training Program in Colleges and Universities of Fujian Province (JA14015). Also, we would like to thank Dr. Shi-Bin Wang, who kindly assisted with the experimental design, and thank Instrumental Analysis Center of HQU for the help of confocal testing.
References (46)
- et al.
Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides
Brain Behav. Immun.
(2014) - et al.
A meta-analysis of cytokines in major depression
Biol. Psychiatry
(2010) - et al.
Gypenosides protect primary cultures of rat cortical cells against oxidative neurotoxicity
Brain Res.
(2006) - et al.
Gypenosides protects dopaminergic neurons in primary culture against MPP(+)-induced oxidative injury
Brain Res. Bull.
(2010) - et al.
Icariin exerts an antidepressant effect in an unpredictable chronic mild stress model of depression in rats and is associated with the regulation of hippocampal neuroinflammation
Neuroscience
(2015) - et al.
Microglial NLRP3 inflammasome activation mediates IL-1beta-related inflammation in prefrontal cortex of depressive rats
Brain Behav. Immun.
(2014) - et al.
Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity
Cell
(1996) - et al.
Anti-neuroinflammatory effect of aurantiamide acetate from the marine fungus Aspergillus sp. SF-5921: inhibition of NF-kappaB and MAPK pathways in lipopolysaccharide-induced mouse BV2 microglial cells
Int. Immunopharmacol.
(2014) - et al.
Anaphylatoxin C5a induces inflammation and reduces insulin sensitivity by activating TLR4/NF-kB/PI3K signaling pathway in 3T3-L1 adipocytes
Biomed. Pharmacother.
(2018) - et al.
Deoxysappanone B, a homoisoflavone from the Chinese medicinal plant Caesalpinia sappan L., protects neurons from microglia-mediated inflammatory injuries via inhibition of IkappaB kinase (IKK)-NF-kappaB and p38/ERK MAPK pathways
Eur. J. Pharmacol.
(2015)
Ammoxetine attenuates diabetic neuropathic pain through inhibiting microglial activation and neuroinflammation in the spinal cord
J. Neuroinflamm.
Venenum Bufonis induces rat neuroinflammation by activiating NF-kappaB pathway and attenuation of BDNF
J. Ethnopharmacol.
Thymelaea lythroides extract attenuates microglial activation and depressive-like behavior in LPS-induced inflammation in adult male rats
Biomed. Pharmacother.
Dynamic changes in hippocampal microglia contribute to depressive-like behavior induced by early social isolation
Neuropharmacology
Prior chronic stress induces persistent polyI:C-induced allodynia and depressive-like behavior in rats: possible involvement of glucocorticoids and microglia
Physiol. Behav.
Inflammatory and neurodegenerative pathways in depression: a new avenue for antidepressant development?
Curr. Med. Chem.
Serum inflammatory cytokines and depression in coronary artery disease
Iran. Red Crescent Med. J.
Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression
Mol. Psychiatry
Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission?
J. Neuroinflamm.
Five new Ocotillone-type saponins from Gynostemma pentaphyllum
J. Nat. Prod.
Nine new dammarane saponins from Gynostemma pentaphyllum
Chem. Biodivers.
Three dammarane-type saponins from Gynostemma pentaphyllum
Planta Med.
Gypenosides induce apoptosis in human hepatoma Huh-7 cells through a calcium/reactive oxygen species-dependent mitochondrial pathway
Planta Med.
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